WO2003004498A1 - Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes - Google Patents

Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes Download PDF

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Publication number
WO2003004498A1
WO2003004498A1 PCT/US2002/021349 US0221349W WO03004498A1 WO 2003004498 A1 WO2003004498 A1 WO 2003004498A1 US 0221349 W US0221349 W US 0221349W WO 03004498 A1 WO03004498 A1 WO 03004498A1
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WIPO (PCT)
Prior art keywords
compound
treatment
group
patient
effective amount
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PCT/US2002/021349
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French (fr)
Inventor
Scott D. Edmondson
Michael H. Fisher
Dooseop Kim
Malcolm Maccoss
Emma R. Parmee
Ann E. Weber
Jinyou Xu
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Merck & Co., Inc.
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Priority to UA2004020837A priority Critical patent/UA74912C2/en
Priority to US10/481,353 priority patent/US7125873B2/en
Priority to AU2002320303A priority patent/AU2002320303B2/en
Priority to MEP-2008-667A priority patent/ME00439B/en
Priority to HU0401104A priority patent/HU225695B1/en
Priority to DE200712000056 priority patent/DE122007000056I1/en
Priority to IL15910902A priority patent/IL159109A0/en
Priority to CA002450740A priority patent/CA2450740C/en
Priority to DE122008000046C priority patent/DE122008000046I1/en
Priority to MXPA04000018A priority patent/MXPA04000018A/en
Priority to DE60210093T priority patent/DE60210093T2/en
Priority to BRPI0210866A priority patent/BRPI0210866B8/en
Priority to NZ529833A priority patent/NZ529833A/en
Priority to PL367279A priority patent/PL196278B6/en
Priority to JP2003510665A priority patent/JP3762407B2/en
Priority to SI200230301T priority patent/SI1412357T1/en
Priority to KR1020047000166A priority patent/KR100606871B1/en
Priority to EP02749813A priority patent/EP1412357B1/en
Priority to EA200400153A priority patent/EA006845B1/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Publication of WO2003004498A1 publication Critical patent/WO2003004498A1/en
Priority to IL159109A priority patent/IL159109A/en
Priority to IS7062A priority patent/IS2218B/en
Priority to HR20031098A priority patent/HRP20031098B1/en
Priority to NO20040021A priority patent/NO321999B1/en
Priority to HK05101300A priority patent/HK1068882A1/en
Priority to US11/500,252 priority patent/US20060270679A1/en
Priority to IL178307A priority patent/IL178307A/en
Priority to IS8617A priority patent/IS2964B/en
Priority to NL300287C priority patent/NL300287I2/en
Priority to CY200700019C priority patent/CY2007019I1/en
Priority to FR07C0041C priority patent/FR07C0041I2/en
Priority to LU91360C priority patent/LUC91360I2/fr
Priority to NO2007010C priority patent/NO2007010I2/en
Priority to LTPA2007006C priority patent/LTC1412357I2/en
Priority to BE2007C047C priority patent/BE2007C047I2/fr
Priority to NL300357C priority patent/NL300357I2/en
Priority to LU91470C priority patent/LU91470I2/en
Priority to FR08C0033C priority patent/FR08C0033I2/en
Priority to NO2008013C priority patent/NO2008013I2/en
Priority to CY200800014C priority patent/CY2008014I1/en
Priority to US12/694,758 priority patent/US8168637B2/en
Priority to US13/086,563 priority patent/US8440668B2/en
Priority to NO2020007C priority patent/NO2020007I1/en

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Definitions

  • Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature 0 morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral 5 vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • type 1 diabetes or insulin-dependent diabetes mellitus (DDDM)
  • type 2 diabetes or noninsulin dependent diabetes mellitus (NTDDM)
  • NTDDM noninsulin dependent diabetes mellitus
  • Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin 0 activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • sulfonylureas e.g. tolbutamide and glipizide
  • meglitinide which stimulate the pancreatic ⁇ -cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues.
  • sulfonylureas or meglitinide sulfonylureas or meglitinide
  • the biguanides increase insulin sensitivity resulting in some correction of hyperglycemia.
  • the two biguanides, phenfor in and metformin can induce lactic acidosis and nausea/diarrhea.
  • Metformin has fewer side effects than phenformin and is often prescribed for the treatment of Type 2 diabetes.
  • the glitazones i.e. 5-benzylthiazolidine-2,4-diones
  • glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype.
  • PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones.
  • Newer PPAR agonists that are being tested for treatment of Type TJ diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have occurred with some of the glitazones, such as troglitazone.
  • alpha-glucosidase inhibitors e.g. acarbose
  • PTP-1B protein tyrosine phosphatase-lB
  • DP-IV dipeptidyl peptidase-IV
  • DPP-IV dipeptidyl peptidase-IV
  • drugs that may be useful in the treatment of diabetes, and particularly type 2 diabetes. See for example WO 97/40832, WO 98/19998, U.S. Patent No. 5,939,560, Bioorg. Med. Chem. Lett., 6(10), 1163-1166 (1996); and Bioorg. Med. Chem. Lett., 6(22), 2745-2748 (1996).
  • DP-IV inhibitors in the treatment of type 2 diabetes is based on the fact that DP-TV in vivo readily inactivates glucagon like peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP).
  • GLP-1 and GIP are incretins and are produced when food is consumed. The incretins stimulate production of insulin. Inhibition of DP-TV leads to decreased inactivation of the incretins, and this in turn results in increased effectiveness of the incretins in stimulating production of insulin by the pancreas. DP-TV inhibition therefore results in an increased level of serum insulin.
  • DP-TV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycemia). Inhibition of DP-TV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of insulin secretagogues.
  • DP-IV inhibitors also have other therapeutic utilities, as discussed herein. DP-IV inhibitors have not been studied extensively to date, especially for utilities other than diabetes. New compounds are needed so that improved DP-TV inhibitors can be found for the treatment of diabetes and potentially other diseases and conditions.
  • the present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes.
  • DP-IV inhibitors compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme
  • the invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
  • the present invention is directed to compounds of the formula I:
  • Ar is phenyl which is unsubstituted or substituted with 1-5 of R3, wherein R3 is independently selected from the group consisting of:
  • Ci_6alkyl which is linear or branched and is unsubstituted or substituted with 1-5 halogens
  • X is selected from the group consisting of:
  • Rl and R are independently selected from the group consisting of: (1) hydrogen,
  • C ⁇ _ ⁇ oalkyl which is linear or branched and which is unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO 2 R 4 , SO 2 R 4 , CO2H, and CO2Ci_6alkyl, wherein the CO2Ci_6 l yl is linear or branched,
  • phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 4 , OR 4 , NHSO 2 R 4 , SO 2 R 4 , CO 2 H, and CO 2 C ⁇ _6alkyl, wherein the CO 2 Ci-6alkyl is linear or branched, and (6) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, Ci_6alkyl, and OC ⁇ _6alkyl, wherein the Cj. ⁇ alkyl and OC ⁇ _6alkyl are linear or branched and optionally substituted with 1-5 halogens;
  • R 4 is C ⁇ _6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO 2 H, and CO C ⁇ _6alkyl, wherein the CO 2 C ⁇ _6alkyl is linear or branched;
  • Ar is phenyl which is unsubstituted or substituted with 1-5 substitutents which are independently selected from the group consisting of:
  • Ar is selected from the group consisting of:
  • R* is selected from the group consisting of:
  • Ci_6alkyl which is linear or branched and which is unsubstituted or substituted with phenyl or 1-5 fluoro.
  • R is selected from the group consisting of:
  • R* is selected from the group consisting of:
  • R is hydrogen or CF3.
  • R2 is selected from:
  • Ci_6alkyl which is linear or branched and which is unsubstituted or substituted with 1-5 fluoro
  • phenyl which is unsubstituted or substituted with 1-3 substituents independently selected from fluoro, OCH3, and
  • R2 is selected from the
  • R2 is CF3 or
  • R3 is F, Br or CF3.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the compounds of the instant invention have one asymmetric center at the beta carbon atom. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.
  • Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
  • Formula I shows the structure of the class of compounds without preferred stereochemistry.
  • Formula la shows the preferred sterochemistry at the carbon atom that is attached to the amine group of the beta amino acid from which these compounds are prepared.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylene- diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • Ci_8alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that C ⁇ _8a ⁇ kyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
  • Co as in Coalkyl is defined to identify the presence of a direct covalent bond.
  • a group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
  • the term "heterocycle” as used herein is intended to include 5- or 6-membered ring systems which are within the following listing: benzimidazolyl, benzodioxanyl, benzofuranyl, benzopyrazolyl, benzothiadiazolyl, benzotriazolyl, benzothiophenyl, benzoxadiazolyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazin
  • Specific compounds within the present invention include a compound which selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
  • the subject compounds are useful in a method of inhibiting the dipeptidyl peptidase-IV enzyme in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the compounds disclosed herein as inhibitors of dipeptidyl peptidase-IV enzyme activity.
  • primates such as humans
  • a variety of other mammals can be treated according to the method of the present invention.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the present invention is further directed to a method for the manufacture of a medicament for inhibiting dipeptidyl peptidase-IV enzyme activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom inhibition of dipeptidyl peptidase- IV enzyme activity is desired.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Such term in relation to pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administration of and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • a typical reaction contains approximately 50 pM enzyme, 50 ⁇ M Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1 mg/ml BS A) in a total reaction volume of 100 ⁇ l.
  • Liberation of AMC is monitored continuously in a 96-well plate fluorometer using an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Under these conditions, approximately 0.8 ⁇ M AMC is produced in 30 minutes at 25 degrees C.
  • the enzyme used in these studies was soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculo virus expression system (Bac-To-Bac, Gibco BRL).
  • the kinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found to be in accord with literature values for the native enzyme.
  • solutions of inhibitor in DMSO were added to reactions containing enzyme and substrate (final DMSO concentration is 1%). All experiments were conducted at room temperature using the standard reaction conditions described above.
  • dissociation constants (Kj) reaction rates were fit by nonlinear regression to the Michaelis-Menton equation for competitive inhibition. The errors in reproducing the dissociation constants are typically less than two-fold.
  • the compounds of the following examples had activity in inhibiting the dipeptidyl peptidase-IV enzyme in the aforementioned assays, generally with an IC50 of less than about 1 ⁇ M.
  • Dipeptidyl peptidase-IV enzyme is a cell surface protein that has been implicated in a wide range of biological functions. It has a broad tissue distribution (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, lymphoid and myeloid cells, serum), and distinct tissue and cell-type expression levels. DP-TV is identical to the T cell activation marker CD26, and it can cleave a number of immunoregulatory, endocrine, and neurological peptides in vitro. This has suggested a potential role for this peptidase in a variety of disease processes in humans or other species.
  • the subject compounds are useful in a method for the prevention or treatment of the following diseases, disorders and conditions.
  • Type TJ Diabetes and Related Disorders It is well established that the incretins GLP-1 and GTP are rapidly inactivated in vivo by DP-TV. Studies with DP-TV ⁇ -deficient mice and preliminary clinical trials indicate that DP-TV inhibition increases the steady state concentrations of GLP-1 and GTP, resulting in improved glucose tolerance. By analogy to GLP-1 and GIP, it is likely that other glucagon family peptides involved in glucose regulation are also inactivated by DP-TV (eg. PACAP, glucagon). Inactivation of these peptides by DP-TV may also play a role in glucose homeostasis.
  • DP-TV eg. PACAP, glucagon
  • the DP-IV inhibitors of the present invention therefore have utility in the treatment of type II diabetes and in the treatment and prevention of the numerous conditions that often accompany Type II diabetes, including metabolic syndrome X, reactive hypoglycemia, and diabetic dyslipidemia. Obesity, discussed below, is another condition that is often found with Type TJ diabetes that may respond to treatment with the compounds of this invention.
  • the following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component.
  • DP-TV inhibitors may be useful for the treatment of obesity. This is based on the observed inhibitory effects on food intake and gastric emptying of GLP-1 and GLP-2. Exogenous administration of GLP-1 in humans significantly decreases food intake and slows gastric emptying (Am. J. Physiol. 277, R910-R916 (1999)). ICV administration of GLP-1 in rats and mice also has profound effects on food intake (Nature Medicine 2, 1254-1258 (1996)). This inhibition of feeding is not observed in GLP-IR ⁇ mice, indicating that these effects are mediated through brain GLP-1 receptors. By analogy to GLP-1, it is likely that GLP-2 is also regulated by DP-TV. ICV administration of GLP-2 also inhibits food intake, analogous to the effects observed with GLP-1 (Nature Medicine 6, 802-807 (2000)).
  • DP-IV inhibition may be useful for the treatment of growth hormone deficiency, based on the hypothesis that growth-hormone releasing factor (GRF), a peptide that stimulates release of growth hormone from the anterior pituitary, is cleaved by the DP-IV enzyme in vivo (WO 00/56297).
  • GRF growth-hormone releasing factor
  • GRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitro to generate the inactive product GRF[3-44] (BBA 1122, 147-153 (1992)); (2) GRF is rapidly degraded in plasma to GRF[3-44]; this is prevented by the DP-TV inhibitor diprotin A; and (3) GRF[3-44] is found in the plasma of a human GRF transgenic pig (J. Clin. Invest. 83, 1533-1540 (1989)).
  • DP-TV inhibitors may be useful for the same spectrum of indications which have been considered for growth hormone secretagogues.
  • GLP-2 glucagon-like peptide-2
  • DP-IV inhibitors for the treatment of intestinal injury
  • GLP-2 glucagon-like peptide-2
  • DP-TV a likely endogenous substrate for DP-TV
  • Regulatory Peptides 90, 27-32 (2000) may exhibit trophic effects on the intestinal epithelium.
  • Administration of GLP-2 results in increased small bowel mass in rodents and attenuates intestinal injury in rodent models of colitis and enteritis.
  • DP-IV inhibition may be useful for modulation of the immune response, based upon studies implicating the DP-TV enzyme in T cell activation and in chemokine processing, and efficacy of DP-TV inhibitors in in vivo models of disease.
  • DP-TV has been shown to be identical to CD26, a cell surface marker for activated immune cells.
  • the expression of CD26 is regulated by the differentiation and activation status of immune cells. It is generally accepted that CD26 functions as a co-stimulatory molecule in in vitro models of T cell activation.
  • a number of chemokines contain proline in the penultimate position, presumably to protect them from degradation by non-specific aminopeptidases.
  • cleavage results in an altered activity in chemotaxis and signaling assays.
  • Receptor selectivity also appears to be modified in some cases (RANTES).
  • Multiple N-terminally truncated forms of a number of chemokines have been identified in in vitro cell culture systems, including the predicted products of DP-TV hydrolysis.
  • DP-IV inhibitors have been shown to be efficacious immunosupressants in animal models of transplantation and arthritis.
  • Prodipine Pro- Pro-diphenyl-phosphonate
  • DP-IV inhibitors have been tested in collagen and alkyldiamine-induced arthritis in rats and showed a statistically significant attenuation of hind paw swelling in this model (Int. J. Immunopharmacology 19, 15-24 (1997), Immunopharmacology 40, 21-26 (1998)).
  • DP-IV is upregulated in a number of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, Graves' disease, and Hashimoto's thyroiditis (Immunology Today 20, 367-375 (1999)).
  • DP-TV inhibition may be useful for the treatment or prevention of HTV infection or AIDS because a number of chemokines which inhibit HIV cell entry are potential substrates for DP-TV (Immunology Today 20, 367-375 (1999)).
  • SDF-lalpha cleavage decreases antiviral activity (PNAS 95, 6331-6 (1998)).
  • stabilization of SDF-lalpha through inhibition of DP-TV would be expected to decrease HTV infectivity.
  • DP-TV inhibition may be useful for the treatment or prevention of hematopiesis because DP-TV may be involved in hematopoiesis.
  • a DP-TV inhibitor, Val-Boro-Pro stimulated hematopoiesis in a mouse model of cyclophosphamide- induced neutropenia (WO 99/56753).
  • DP-TV inhibition may be useful for the treatment or prevention of various neuronal or psychiatric disorders because a number of peptides implicated in a variety of neuronal processes are cleaved in vitro by DP-TV.
  • a DP-IV inhibitor thus may have a therapeutic benefit in the treatment of neuronal disorders.
  • Endomorphin-2, beta-casomorphin, and substance P have all been shown to be in vitro substrates for DP-TV. In all cases, in vitro cleavage is highly efficient, with cat /K m ⁇ 10 6 M ' V 1 or greater.
  • a DP-TV inhibitor showed a significant effect that was independent of the presence of exogenous endomorphin-2 (Brain Research 815, 278-286 (1999)).
  • DP-TV inhibition may be useful for the treatment or prevention of tumor invasion and metastasis because an increase or decrease in expression of several ectopeptidases including DP-TV has been observed during the transformation of normal cells to a malignant phenotype (J. Exp. Med. 190, 301-305 (1999)). Up- or down-regulation of these proteins appears to be tissue and cell-type specific. For example, increased CD26 DP-IV expression has been observed on T cell lymphoma, T cell acute lymphoblastic leukemia, cell-derived thyroid carcinomas, basal cell carcinomas, and breast carcinomas. Thus, DP-TV inhibitors may have utility in the treatment of such carcinomas.
  • Benign Prostatic Hypertrophy may be useful for the treatment of benign prostatic hypertrophy because increased DP-TV activity was noted in prostate tissue from patients with BPH (Eur. J. Clin. Chem. Clin. Biochem 30, 333-338 (1992)).
  • Sperm motility/male contraception DP-TV inhibition may be useful for the altering sperm motility and for male contraception because in seminal fluid, prostatosomes, prostate derived organelles important for sperm motility, possess very high levels of DP-TV activity (Eur. J. Clin. Chem. Clin. Biochem 30, 333-338 (1992)).
  • DP-TV inhibition may be useful for the treatment of gingivitis because DP-TV activity was found in gingival crevicular fluid and in some studies correlated with periodontal disease severity (Arch. Oral Biol. 37, 167-173 (1992)).
  • Osteoporosis may be useful for the treatment or prevention of osteoporosis because GIP receptors are present in osteoblasts.
  • Tthe compounds of the present invention have utility in treating or preventing one or more of the following conditions or diseases: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), (25) Type TJ diabetes, (26) growth hormone deficiency, (27) neutropenia, (28) neuronal disorders, (29) tumor metastas
  • the subject compounds are further useful in a method for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
  • the combination therapy may also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
  • Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition include, but are not limited to: (a) other dipeptidyl peptidase TV (DP-TV) inhibitors; (b) insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g.
  • troglitazone pioglitazone, englitazone, MCC-555, rosiglitazone, and the like
  • other PPAR ligands including PPAR ⁇ / ⁇ dual agonists, such as KRP- 297, and PPAR ⁇ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-lB (PTP-1B) inhibitors;
  • PTP-1B protein tyrosine phosphatase-lB
  • ⁇ -glucosidase inhibitors such as acarbose
  • glucagon receptor antagonists such as those disclosed in WO
  • GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists such as those disclosed in WO00/42026 and WOOO/59887;
  • GTP and GTP mimetics such as those disclosed in WO00/58360, and GIP receptor agonists;
  • PACAP PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as those disclosed in WO 01/23420;
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR ⁇ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR ⁇ / ⁇ dual agonists, such as KRP-297, (vi) inhibitors of cholesterol absorption, such as beta- sitosterol and ezetimibe, (vii) acyl CoA:cholesterol
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, and ⁇ 3 adrenergic receptor agonists;
  • an ileal bile acid transporter inhibitor (m) an ileal bile acid transporter inhibitor; and (n) agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo- oxygenase 2 selective inhibitors.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • Non-limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, other DP-TV inhibitors, and anti-obesity compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for use in humans.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drag.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical application For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of The present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention can be prepared from beta amino acid intermediates such as those of formula TJ and substituted heterocyclic intermediates such as those of formula m, using standard peptide coupling conditions followed by deprotection.
  • the preparation of these intermediates is described in the following schemes.
  • Ar, X and R 1 are as defined above and P is a suitable nitrogen protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, or 9-fluorenylmethoxycarbonyl.
  • Boc di-tert-butyl-dicarbonate
  • the resultant diazoketone is then treated with silver benzoate in a solvent such as methanol or aqueous dioxane and may be subjected to sonication following the procedure of Sewald et al., Synthesis, 837 (1997) in order to provide the beta amino acid TJ.
  • a solvent such as methanol or aqueous dioxane
  • sonication following the procedure of Sewald et al., Synthesis, 837 (1997) in order to provide the beta amino acid TJ.
  • enantiomerically pure alpha amino acids 1 may be used for the preparation of enantiomerically pure beta amino acids TJ. Alternate routes to these compounds can be found in the following reviews: E.
  • Compound 12 is then subjected to catalytic hydrogenation using a catalyst such as platinum oxide to provide Compound TJJb, as its monohydrochloride salt.
  • a catalyst such as platinum oxide
  • TJ and UI are coupled under standard peptide coupling conditions, for example, using l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBT), and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or dichloromethane for 3 to 48 hours at ambient temperature to provide intermediate 13 as shown in Scheme 6.
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • HOBT 1-hydroxybenzotriazole
  • a base generally diisopropylethylamine
  • DMF N,N-dimethylformamide
  • dichloromethane dichloromethane
  • the product is purified from unwanted side products, if necessary, by recrystalhzation, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, J. Org. Chem., 43, 2923 (1978), or HPLC.
  • Compounds which are purified by HPLC may be isolated as the corresponding salt.
  • Purification of intermediates is achieved in the same manner.
  • the intermediate 13 from the coupling reaction described in Scheme 6 may be further modified before removal of the protecting group, for example, by manipulation of substituents on X or Rl. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • Step A (R, l S')-N-(Ll-Dimethylethoxycarbonyl)-2.5-difluorophenylalanine
  • Step B (R,5)-3-r( l-Dimethylethoxycarbonyl)aminol-l-diazo-4-(2.5-difluoro- phenyl)butan-2-one
  • CDCI3 ⁇ 7.03-6.95 (m, IH), 6.95-6.88 (m, 2H), 5.43 (bs, IH), 5.18 (bs, IH), 4.45
  • Step C (3R)-3-r( l-Dimethylethoxycarbonyl)aminol-4-(2.5-difluorophenyl)butanoic acid
  • Step A (2R.5 )-2.5-Dihvdro-3.6-dimethoxy-2-(2'-fluoro-4'-(trifluoromethyl)benzyl)- 5-isopropylpyrazine
  • Step B (R)-N-(l.l-Dimethylethoxycarbonyl)-2-fluoro-4-trifluoromethyl)phenyl- alanine methyl ester
  • Step D (3J?)-3-r(Ll-Dimethylethoxycarbonyl)aminol-4-r2-fluoro-4-(trifluoromethyl)- phenyllbutanoic acid
  • Step A (25. 5R)-2,5-Dihvdro-3,6-dimethoxy-2-isopropyl-5-(2'.4',5'trifluorobenzyl)- pyrazine
  • Step B (R)-N-( l-Dimethylethoxycarbonyl)-2,4.5-trifluorophenylalanine methyl ester
  • Step D (3R)-3-f( l-Dimethylethoxycarbonyl)aminol-4-(2.4.5-trifluorophenyl)- butanoic acid
  • Step B (25. 5R)-2.5-Dihvdro-3.6-dimethoxy-2-isopro ⁇ yl-5-(4'-bromo-2 , .5'- difluorobenzyDpyrazine
  • the title compound (1.61 g) was prepared from 0.865 g (4.7 mmol) of
  • Step D (R)-N-(l.l-Dimethylethoxycarbonyl)-4-bromo-2.5-difluorophenylalanine
  • the title compound (1.34 g) was prepared from 1.4 g (3.5 mmol) of
  • Step E (3R)-3-r(Ll-Dimethylethoxycarbonyl)aminol-4-(4'-bromo-2'.5'- difluorophenvDbutanoic acid
  • Step B 2-(Trifluoromethyl)-5,6,7,8-tetrahvdroimidazo[T ,2- lpyrazine
  • Step C 7-l(3R)-3-r(Ll-dimethylethoxycarbonyl)aminol-4-(3.4- difluorophenyDbutanoyll -2-(trifluoromethyl)-5.6.7.8-tetrahydroimidazo ⁇ 1,2- lpyrazine
  • 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[l,2- ⁇ jpyrazine (64.3 mg, 0.34 mmol, from Step B) and (3R)-3-[(l,l- dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT (54.5 mg, 0.42 mmol) at 0 °C .
  • Step D 7-r(3R)-3-Amino-4-(3.4-difluorophenyl)butanoyll-2-(trifluoromethyl)- 5,6,7,8-tetrahvdroimidazori,2-.zlpyrazine, dihydrochloride
  • the title compound was prepared from 2-(trifluoromethyl)-5,6,7,8- tetrahydroimidazo[l,2- ⁇ ]pyrazine (277 mg, 1.45 mmol, from Example 1, Step B), (3R)-3-[(l , l-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 416 mg, 1.32 mmol), DTPEA (226 mg, 1.58 mol), HOBT (216 mg, 1.98 mol) and HATU (753 mg, 1.98 mol) in DMF (6 mL), using a procedure analogous to that described in Example 1 Step C, except for the purification method.
  • Step B 7-r(3i?)-3-Amino-4-(2,5-difluorophenyl)butanoyll-5,6,7.8- tetrahydroimidazolT ,2- ⁇ lpyrazine, dihydrochloride
  • the title compound was prepared from 2-(trifluoromefhyl)-5,6,7,8- tetrahydroimidazo[l,2- ⁇ ]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3R)-3-[(l,l-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol), HOBT (26.9 mg,0.199 ) mmol, and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C.
  • Step B 7-r(3R)-3-Amino-4-(2.4.5-trifluorophenyl)butanoyll-5,6,7,8- tetrahydroimidazori,2- ⁇ lpyrazine, dihydrochloride
  • Step B 5,6.7, 8-Tetrahydroimidazo
  • Step C 7-r(3J?)-3-r(l,l-dimethylethoxycarbonyl aminol-4-(3,4- difluorophenyl)butanovn-5 ,6,7, 8-tetrahydroimidazo I " 1 ,2-alpyrazine
  • Step B 3-Ethyl-5.6.7,8-tetrahydro-1.2.4-triazolor4,3- 1 pyrazine, hydrochloride
  • Step C 7-r(3J? -3-r(l,l-dimethylethoxycarbonyl)aminol-4-(3.4- difluoro ⁇ henyl)butanoyn-3-ethyl-5,6,7,8-tetrahydro-l,2,4-triazolor4,3- ⁇ lpyrazine
  • the title compound was prepared from 3-ethyl-5,6,7,8-tetrahydro- l,2,4-triazolo[4,3- ⁇ ]pyrazine hydrochloride (400 mg, 2.12 mmol, from Step B), (3i?)- 3-[(l,l-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (668 mg, 2.12 mmol), DIPEA (1.1 mL, 4.24 mmol), HOBT (343.8 mg, 2.54 mmol) and EDC (609.6 mg, 3.18 mmol) in 20 mL
  • Step D 7-r(3R)-3-Amino-4-(3,4-difluorophenyl)butanoyll-3-ethyl-5.6,7,8-tetrahvdro- L2,4-triazolo r 4,3- ⁇ 1 pyrazine, dihydrochloride
  • Step A 3-(Trifluoromethyl)-L2,4-triazolo r 4,3-fllpyrazine
  • Step B 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolor4,3- ⁇ lpyrazine
  • Step C 7-r(3R)-3-r(l,l-Dimethylethoxycarbonyl)aminol-4-(2.5- difluorophenyl)butanoyn-3-(trifluoromethyl)-5,6,7,8-tetrahvdro-l,2,4-triazolor4,3- alpyrazine
  • the title compound was prepared from (3i?)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 50 mg, 0.16 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3- ⁇ jpyrazine (30 mg, 0.16 mmol) using a procedure analogous to that described for Example 1, Step C.
  • the crude product was purified by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol/dichloromethane (2X)) to afford the title compound (38.1 mg) as a solid.
  • Step D 7-r(3R)-3-Amino-4-(2,5-difluorophenyl)butanovn-3-(trifluoromethyl)- 5,6,7, 8-tetrahydro-l,2,4-triazolo[4,3- ⁇ l pyrazine, hydrochloride
  • the title compound was prepared from 7-[(3R)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoyl]-3-(trifluoromethyl)- 5,6,7, 8-tetrahydro-l,2,4-triazolo[4,3- ⁇ ]pyrazine (19.1 mg, 0.039 mmol, from Step C) using a procedure analogous to that described for Example 1, Step D. Concentration afforded the title compound (16.1 mg) as a solid.
  • Step A 7-r(3Jg)-3-r(l,l-Dimethylethoxycarbonyl)aminol-4-(2.4.5-trifluorophenyl)- butanoyn-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolor4,3- lpyrazine
  • the title compound was prepared from (3R)-3-[(l,l-dimethylethoxy- carbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 50.1 mg, 0.15 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3- ⁇ ]pyrazine (39.2 mg, 0.20 mmol) using a procedure analogous to that described for Example 1, Step C.
  • the crude product was purified by preparative TLC (silica gel, 100% ethyl acetate) to afford the title compound (29 mg) as a solid.
  • Step B 7-r(3J? -3-Amino-4-(2.4.5-trifluorophenyl)butanoyll-3-(trifluoromethyl)- 5,6,7, 8-tetrahydro-l,2,4-triazolo[4,3-fll pyrazine, hydrochloride
  • the title compound was prepared from 7-[(3i?)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3- (trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3- ⁇ Jpyrazine (22 mg, 0.039 mmol, from Step A) using a procedure analogous to that described for Example 1, Step D.

Abstract

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ('DP-IV inhibitors') and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Description

BETA-AMINO TETRAHYDROIMIDAZO (1,2-A) PYRAZINES AND TETRAHYDROTRIAZOLO (4,3-A) PYRAZINES AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION
OF DIABETES
5 BACKGROUND OF THE INVENTION
Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature 0 morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral 5 vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (DDDM), patients produce little or no 0 insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NTDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and 5 adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin 0 activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
The available treatments for type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and 5 reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic β-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. However, the two biguanides, phenfor in and metformin, can induce lactic acidosis and nausea/diarrhea. Metformin has fewer side effects than phenformin and is often prescribed for the treatment of Type 2 diabetes. The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a more recently described class of compounds with potential for ameliorating many symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of Type TJ diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have occurred with some of the glitazones, such as troglitazone.
Additional methods of treating the disease are still under investigation. New biochemical approaches that have been recently introduced or are still under development include treatment with alpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosine phosphatase-lB (PTP-1B) inhibitors.
Compounds that are inhibitors of the dipeptidyl peptidase-IV ("DP-IV" or "DPP-IV") enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly type 2 diabetes. See for example WO 97/40832, WO 98/19998, U.S. Patent No. 5,939,560, Bioorg. Med. Chem. Lett., 6(10), 1163-1166 (1996); and Bioorg. Med. Chem. Lett., 6(22), 2745-2748 (1996). The usefulness of DP-IV inhibitors in the treatment of type 2 diabetes is based on the fact that DP-TV in vivo readily inactivates glucagon like peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are incretins and are produced when food is consumed. The incretins stimulate production of insulin. Inhibition of DP-TV leads to decreased inactivation of the incretins, and this in turn results in increased effectiveness of the incretins in stimulating production of insulin by the pancreas. DP-TV inhibition therefore results in an increased level of serum insulin. Advantageously, since the incretins are produced by the body only when food is consumed, DP-TV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycemia). Inhibition of DP-TV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of insulin secretagogues.
DP-IV inhibitors also have other therapeutic utilities, as discussed herein. DP-IV inhibitors have not been studied extensively to date, especially for utilities other than diabetes. New compounds are needed so that improved DP-TV inhibitors can be found for the treatment of diabetes and potentially other diseases and conditions.
SUMMARY OF THE INVENTION
The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of the formula I:
Figure imgf000005_0001
I wherein:
Ar is phenyl which is unsubstituted or substituted with 1-5 of R3, wherein R3 is independently selected from the group consisting of:
(1) halogen,
(2) Ci_6alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens,
(3) OCi-βalkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens, and
(4) CN;
X is selected from the group consisting of:
(1) N, and
(2) CR2;
Rl and R are independently selected from the group consisting of: (1) hydrogen,
(2) CN,
(3) Cι_ιoalkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H, and CO2Ci_6alkyl, wherein the CO2Ci_6 l yl is linear or branched,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H, and CO2Cι_6alkyl, wherein the CO2Ci-6alkyl is linear or branched, and (6) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, Ci_6alkyl, and OCι_6alkyl, wherein the Cj.βalkyl and OCι_6alkyl are linear or branched and optionally substituted with 1-5 halogens;
R4 is Cι_6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO2H, and CO Cι_6alkyl, wherein the CO2Cι_6alkyl is linear or branched;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
An embodiment of the present invention includes compounds of the formula la:
Figure imgf000006_0001
la wherein X, Ar and Ri are defined herein; and pharmaceutically acceptable salts and individual diastereomers thereof.
Another embodiment of the present invention includes compounds of the formula lb:
Figure imgf000006_0002
lb wherein Ar and R* are defined herein; and pharmaceutically acceptable salts and individual diastereomers thereof.
Another embodiment of the present invention includes compounds of the formula Ic:
Figure imgf000007_0001
Ic wherein Ar, Ri and R2 are defined herein; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
In the present invention it is preferred that Ar is phenyl which is unsubstituted or substituted with 1-5 substitutents which are independently selected from the group consisting of:
(1) fluoro,
(2) bromo, and (3) CF3.
In the present invention it is more preferred that Ar is selected from the group consisting of:
(1) phenyl, (2) 2-fluorophenyl,
3) 3,4-difluorophenyl,
4) 2,5-difluorophenyl,
5) 2,4,5-trifluorophenyl,
6) 2-fluoro-4-(triflouromethyl)phenyl, and (7) 4-bromo-2,5-difluorophenyl.
In the present invention it is preferred that R* is selected from the group consisting of:
(1) hydrogen, and (2) Ci_6alkyl, which is linear or branched and which is unsubstituted or substituted with phenyl or 1-5 fluoro.
In the present invention it is more preferred that R is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) ethyl,
(4) CF3,
(5) CH2CF3,
(5) CF2CF3
(6) phenyl, and
(7) benzyl.
In the present invention it is more preferred that R* is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) ethyl, (4) CF3, and
(5) CH2CF3.
In the present invention it is even more preferred that R is hydrogen or CF3.
In the present invention it is preferred that R2 is selected from:
(1) hydrogen,
(2) Ci_6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 fluoro, (3) phenyl, which is unsubstituted or substituted with 1-3 substituents independently selected from fluoro, OCH3, and
OCF3. In the present invention it is more preferred that R2 is selected from the
;roup consisting of:
(1) hydrogen,
(2) methyl,
(3) ethyl,
(4) CF3,
(5) CH2CF3,
(5) CF2CF3
(6) phenyl,
(7) (4-methoxy)phenyl,
(8) (4-trifluoromethoxy)phenyl,
(9) 4-fluorophenyl, and
(10) 3 ,4-difluorophenyl .
In the present invention it is even more preferred that R2 is CF3 or
CF2F .
In the present invention it is preferred that R3 is F, Br or CF3.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the instant invention have one asymmetric center at the beta carbon atom. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.
Formula I shows the structure of the class of compounds without preferred stereochemistry. Formula la shows the preferred sterochemistry at the carbon atom that is attached to the amine group of the beta amino acid from which these compounds are prepared.
The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylene- diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
As appreciated by those of skill in the art, halo or halogen as used herein are intended to include fluoro, chloro, bromo and iodo. Similarly, Ci_8, as in Ci_8alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that Cι_8aιkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. Likewise, Co, as in Coalkyl is defined to identify the presence of a direct covalent bond. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents. The term "heterocycle" as used herein is intended to include 5- or 6-membered ring systems which are within the following listing: benzimidazolyl, benzodioxanyl, benzofuranyl, benzopyrazolyl, benzothiadiazolyl, benzotriazolyl, benzothiophenyl, benzoxadiazolyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyi, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydroimidazolyl, tetrahydroisoquinolinyl, and tetrahydrothienyl.
Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
Specific compounds within the present invention include a compound which selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof. The subject compounds are useful in a method of inhibiting the dipeptidyl peptidase-IV enzyme in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as inhibitors of dipeptidyl peptidase-IV enzyme activity. In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
The present invention is further directed to a method for the manufacture of a medicament for inhibiting dipeptidyl peptidase-IV enzyme activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom inhibition of dipeptidyl peptidase- IV enzyme activity is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of" and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
The utility of the compounds in accordance with the present invention as inhibitors of dipeptidyl peptidase-IV enzyme activity may be demonstrated by methodology known in the art. Inhibition constants are determined as follows. A continuous fluorometric assay is employed with the substrate Gly-Pro-AMC, which is cleaved by DP-IV to release the fluorescent AMC leaving group. The kinetic parameters that describe this reaction are as follows: Km = 50 μM; kcat = 75 s"1; kc t/Km = 1.5 x 106 M'V1. A typical reaction contains approximately 50 pM enzyme, 50 μM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1 mg/ml BS A) in a total reaction volume of 100 μl. Liberation of AMC is monitored continuously in a 96-well plate fluorometer using an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Under these conditions, approximately 0.8 μM AMC is produced in 30 minutes at 25 degrees C. The enzyme used in these studies was soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculo virus expression system (Bac-To-Bac, Gibco BRL). The kinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found to be in accord with literature values for the native enzyme. To measure the dissociation constants for compounds, solutions of inhibitor in DMSO were added to reactions containing enzyme and substrate (final DMSO concentration is 1%). All experiments were conducted at room temperature using the standard reaction conditions described above. To determine the dissociation constants (Kj), reaction rates were fit by nonlinear regression to the Michaelis-Menton equation for competitive inhibition. The errors in reproducing the dissociation constants are typically less than two-fold. In particular, the compounds of the following examples had activity in inhibiting the dipeptidyl peptidase-IV enzyme in the aforementioned assays, generally with an IC50 of less than about 1 μM. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors the dipeptidyl peptidase-IV enzyme activity. Dipeptidyl peptidase-IV enzyme (DP-TV) is a cell surface protein that has been implicated in a wide range of biological functions. It has a broad tissue distribution (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, lymphoid and myeloid cells, serum), and distinct tissue and cell-type expression levels. DP-TV is identical to the T cell activation marker CD26, and it can cleave a number of immunoregulatory, endocrine, and neurological peptides in vitro. This has suggested a potential role for this peptidase in a variety of disease processes in humans or other species.
Accordingly, the subject compounds are useful in a method for the prevention or treatment of the following diseases, disorders and conditions.
Type TJ Diabetes and Related Disorders: It is well established that the incretins GLP-1 and GTP are rapidly inactivated in vivo by DP-TV. Studies with DP-TV^-deficient mice and preliminary clinical trials indicate that DP-TV inhibition increases the steady state concentrations of GLP-1 and GTP, resulting in improved glucose tolerance. By analogy to GLP-1 and GIP, it is likely that other glucagon family peptides involved in glucose regulation are also inactivated by DP-TV (eg. PACAP, glucagon). Inactivation of these peptides by DP-TV may also play a role in glucose homeostasis. The DP-IV inhibitors of the present invention therefore have utility in the treatment of type II diabetes and in the treatment and prevention of the numerous conditions that often accompany Type II diabetes, including metabolic syndrome X, reactive hypoglycemia, and diabetic dyslipidemia. Obesity, discussed below, is another condition that is often found with Type TJ diabetes that may respond to treatment with the compounds of this invention.
The following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component.
Obesity: DP-TV inhibitors may be useful for the treatment of obesity. This is based on the observed inhibitory effects on food intake and gastric emptying of GLP-1 and GLP-2. Exogenous administration of GLP-1 in humans significantly decreases food intake and slows gastric emptying (Am. J. Physiol. 277, R910-R916 (1999)). ICV administration of GLP-1 in rats and mice also has profound effects on food intake (Nature Medicine 2, 1254-1258 (1996)). This inhibition of feeding is not observed in GLP-IR^ mice, indicating that these effects are mediated through brain GLP-1 receptors. By analogy to GLP-1, it is likely that GLP-2 is also regulated by DP-TV. ICV administration of GLP-2 also inhibits food intake, analogous to the effects observed with GLP-1 (Nature Medicine 6, 802-807 (2000)).
Growth Hormone Deficiency: DP-IV inhibition may be useful for the treatment of growth hormone deficiency, based on the hypothesis that growth-hormone releasing factor (GRF), a peptide that stimulates release of growth hormone from the anterior pituitary, is cleaved by the DP-IV enzyme in vivo (WO 00/56297). The following data provide evidence that GRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitro to generate the inactive product GRF[3-44] (BBA 1122, 147-153 (1992)); (2) GRF is rapidly degraded in plasma to GRF[3-44]; this is prevented by the DP-TV inhibitor diprotin A; and (3) GRF[3-44] is found in the plasma of a human GRF transgenic pig (J. Clin. Invest. 83, 1533-1540 (1989)). Thus DP-TV inhibitors may be useful for the same spectrum of indications which have been considered for growth hormone secretagogues. Intestinal Injury: The potential for using DP-IV inhibitors for the treatment of intestinal injury is suggested by the results of studies indicating that glucagon-like peptide-2 (GLP-2), a likely endogenous substrate for DP-TV, may exhibit trophic effects on the intestinal epithelium (Regulatory Peptides 90, 27-32 (2000)). Administration of GLP-2 results in increased small bowel mass in rodents and attenuates intestinal injury in rodent models of colitis and enteritis.
Immunosuppression: DP-IV inhibition may be useful for modulation of the immune response, based upon studies implicating the DP-TV enzyme in T cell activation and in chemokine processing, and efficacy of DP-TV inhibitors in in vivo models of disease. ' DP-TV has been shown to be identical to CD26, a cell surface marker for activated immune cells. The expression of CD26 is regulated by the differentiation and activation status of immune cells. It is generally accepted that CD26 functions as a co-stimulatory molecule in in vitro models of T cell activation. A number of chemokines contain proline in the penultimate position, presumably to protect them from degradation by non-specific aminopeptidases. Many of these have been shown to be processed in vitro by DP-TV. In several cases (RANTES, LD78-beta, MDC, eotaxin, SDF-lalpha), cleavage results in an altered activity in chemotaxis and signaling assays. Receptor selectivity also appears to be modified in some cases (RANTES). Multiple N-terminally truncated forms of a number of chemokines have been identified in in vitro cell culture systems, including the predicted products of DP-TV hydrolysis.
DP-IV inhibitors have been shown to be efficacious immunosupressants in animal models of transplantation and arthritis. Prodipine (Pro- Pro-diphenyl-phosphonate), an irreversible inhibitor of DP-TV, was shown to double cardiac allograft survival in rats from day 7 to day 14 (Transplantation 63, 1495-1500 (1997)). DP-IV inhibitors have been tested in collagen and alkyldiamine-induced arthritis in rats and showed a statistically significant attenuation of hind paw swelling in this model (Int. J. Immunopharmacology 19, 15-24 (1997), Immunopharmacology 40, 21-26 (1998)). DP-IV is upregulated in a number of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, Graves' disease, and Hashimoto's thyroiditis (Immunology Today 20, 367-375 (1999)).
H V Infection: DP-TV inhibition may be useful for the treatment or prevention of HTV infection or AIDS because a number of chemokines which inhibit HIV cell entry are potential substrates for DP-TV (Immunology Today 20, 367-375 (1999)). In the case of SDF-lalpha, cleavage decreases antiviral activity (PNAS 95, 6331-6 (1998)). Thus, stabilization of SDF-lalpha through inhibition of DP-TV would be expected to decrease HTV infectivity.
Hematopoiesis: DP-TV inhibition may be useful for the treatment or prevention of hematopiesis because DP-TV may be involved in hematopoiesis. A DP-TV inhibitor, Val-Boro-Pro, stimulated hematopoiesis in a mouse model of cyclophosphamide- induced neutropenia (WO 99/56753).
Neuronal Disorders: DP-TV inhibition may be useful for the treatment or prevention of various neuronal or psychiatric disorders because a number of peptides implicated in a variety of neuronal processes are cleaved in vitro by DP-TV. A DP-IV inhibitor thus may have a therapeutic benefit in the treatment of neuronal disorders. Endomorphin-2, beta-casomorphin, and substance P have all been shown to be in vitro substrates for DP-TV. In all cases, in vitro cleavage is highly efficient, with cat/Km ~ 106 M'V1 or greater. In an electric shock jump test model of analgesia in rats, a DP-TV inhibitor showed a significant effect that was independent of the presence of exogenous endomorphin-2 (Brain Research 815, 278-286 (1999)).
Tumor Invasion and Metastasis: DP-TV inhibition may be useful for the treatment or prevention of tumor invasion and metastasis because an increase or decrease in expression of several ectopeptidases including DP-TV has been observed during the transformation of normal cells to a malignant phenotype (J. Exp. Med. 190, 301-305 (1999)). Up- or down-regulation of these proteins appears to be tissue and cell-type specific. For example, increased CD26 DP-IV expression has been observed on T cell lymphoma, T cell acute lymphoblastic leukemia, cell-derived thyroid carcinomas, basal cell carcinomas, and breast carcinomas. Thus, DP-TV inhibitors may have utility in the treatment of such carcinomas.
Benign Prostatic Hypertrophy: DP-TV inhibition may be useful for the treatment of benign prostatic hypertrophy because increased DP-TV activity was noted in prostate tissue from patients with BPH (Eur. J. Clin. Chem. Clin. Biochem 30, 333-338 (1992)). Sperm motility/male contraception: DP-TV inhibition may be useful for the altering sperm motility and for male contraception because in seminal fluid, prostatosomes, prostate derived organelles important for sperm motility, possess very high levels of DP-TV activity (Eur. J. Clin. Chem. Clin. Biochem 30, 333-338 (1992)).
Gingivitis: DP-TV inhibition may be useful for the treatment of gingivitis because DP-TV activity was found in gingival crevicular fluid and in some studies correlated with periodontal disease severity (Arch. Oral Biol. 37, 167-173 (1992)).
Osteoporosis: DP-IV inhibition may be useful for the treatment or prevention of osteoporosis because GIP receptors are present in osteoblasts.
Tthe compounds of the present invention have utility in treating or preventing one or more of the following conditions or diseases: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), (25) Type TJ diabetes, (26) growth hormone deficiency, (27) neutropenia, (28) neuronal disorders, (29) tumor metastasis, (30) benign prostatic hypertrophy, (32) gingivitis, (33) hypertension, (34) osteoporosis, and other conditions that may be treated or prevented by inhibition of DP-TV.
The subject compounds are further useful in a method for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition, include, but are not limited to: (a) other dipeptidyl peptidase TV (DP-TV) inhibitors; (b) insulin sensitizers including (i) PPARγ agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other PPAR ligands, including PPARα/γ dual agonists, such as KRP- 297, and PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-lB (PTP-1B) inhibitors;
(c) insulin or insulin mimetics;
(d) sulfonylureas and other insulin secretagogues such as tolbutamide and glipizide, meglitinide, and related materials;
(e) α-glucosidase inhibitors (such as acarbose); (f) glucagon receptor antagonists such as those disclosed in WO
98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists such as those disclosed in WO00/42026 and WOOO/59887;
(h) GTP and GTP mimetics such as those disclosed in WO00/58360, and GIP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as those disclosed in WO 01/23420;
(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ dual agonists, such as KRP-297, (vi) inhibitors of cholesterol absorption, such as beta- sitosterol and ezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe, and (viii) anti-oxidants, such as probucol;
(k) PPARδ agonists, such as those disclosed in WO97/28149;
(1) antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, and β3 adrenergic receptor agonists;
(m) an ileal bile acid transporter inhibitor; and (n) agents intended for use in inflammatory conditions such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo- oxygenase 2 selective inhibitors. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Non-limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, other DP-TV inhibitors, and anti-obesity compounds.
Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drag. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of The present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment or prevention of conditions which require inhibition of dipeptidyl peptidase-IV enzyme activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
When treating or preventing diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein.
The compounds of the present invention can be prepared from beta amino acid intermediates such as those of formula TJ and substituted heterocyclic intermediates such as those of formula m, using standard peptide coupling conditions followed by deprotection. The preparation of these intermediates is described in the following schemes.
Figure imgf000025_0001
II III
where Ar, X and R1 are as defined above and P is a suitable nitrogen protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, or 9-fluorenylmethoxycarbonyl.
SCHEME 1
Figure imgf000025_0002
Compounds of formula TJ are commercially available, known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One common route is illustrated in Scheme 1. Acid 1, which may be commercially available or readily prepared from the corresponding amino acid by protection using, for example, di-tert-butyl-dicarbonate (for P = Boc), carbobenzyloxy chloride (for P = Cbz), or N-(9-fluorenylmethoxycarbonyloxy)succinimide (for P = Fmoc), is treated with isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine, followed by diazomethane. The resultant diazoketone is then treated with silver benzoate in a solvent such as methanol or aqueous dioxane and may be subjected to sonication following the procedure of Sewald et al., Synthesis, 837 (1997) in order to provide the beta amino acid TJ. As will be understood by those skilled in the art, for the preparation of enantiomerically pure beta amino acids TJ, enantiomerically pure alpha amino acids 1 may be used. Alternate routes to these compounds can be found in the following reviews: E. Juaristi, Enantioselective Synthesis of β-Amino Acids, Ed., Wiley- VCH, New York: 1997, Juaristi et al., Aldrichimica Acta, 27, 3 (1994), Cole et al., Tetrahedron, 32, 9517 (1994).
SCHEME 2
Figure imgf000026_0001
2 III
Compounds HI are commercially available, known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One convenient method is shown in Scheme 2. Unsaturated derivative 2 is reduced, for example, by treatment with hydrogen gas and a catalyst such as palladium on carbon or platinum oxide in a solvent such as methanol or ethanol to provide Compound TJJ. SCHEME 3
Figure imgf000027_0001
Intermediates 2, from Scheme 2, are themselves commercially available, known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One such method when X is CR2 is illustrated in Scheme 3. Aminopyrazine 3 is treated with a 2-haloketone such as 2- bromoketone 4 in a solvent such as methanol or ethanol to provide intermediate 2a. Alternatively, for the preparation of intermediate 2a where R2 is H, 2-bromo- dimethylacetal 5 and a catalytic amount of acid such as hydrochloric acid may be employed instead of intermediate 4.
SCHEME 4
Figure imgf000027_0002
6 7
Figure imgf000027_0003
A convenient method for the preparation of intermediate 2b, where X is N, is illustrated in Scheme 4. Chloropyrazme 6 is treated with hydrazine to provide hydrazinopyrazine 7. Compound 7 may be condensed with either an orthoester such as triethyl orthoester 8 to give 2b or with a carboxylic acid 9 in polyphosphoric acid at elevated temperatures to give 2b. SCHEME 5
Figure imgf000028_0001
An alternate route for the preparation of Compound UJb wherein X is N is illustrated in Scheme 5. Compound 12 is prepared according to the method outlined above employing dichloropyrazine 10 instead of chloropyrazine 6.
Compound 12 is then subjected to catalytic hydrogenation using a catalyst such as platinum oxide to provide Compound TJJb, as its monohydrochloride salt.
SCHEME 6
Figure imgf000029_0001
deprotection e.g., TFA/CH2CI2 for P = Boc
Figure imgf000029_0002
Figure imgf000029_0003
Intermediates TJ and UI are coupled under standard peptide coupling conditions, for example, using l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBT), and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or dichloromethane for 3 to 48 hours at ambient temperature to provide intermediate 13 as shown in Scheme 6. The protecting group is then removed with, for example, trifluoroacetic acid or methanolic hydrogen chloride in the case of Boc to give the desired amine I. The product is purified from unwanted side products, if necessary, by recrystalhzation, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, J. Org. Chem., 43, 2923 (1978), or HPLC. Compounds which are purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner. In some cases the intermediate 13 from the coupling reaction described in Scheme 6 may be further modified before removal of the protecting group, for example, by manipulation of substituents on X or Rl. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
INTERMEDIATE 1
Figure imgf000030_0001
(3R)-3-r(l -Dimethylethoxycarbonyl)aminol-4-(2,5-difluorophenyl)butanoic acid
Step A. (R,lS')-N-(Ll-Dimethylethoxycarbonyl)-2.5-difluorophenylalanine
To a solution of 0.5 g (2.49 mmol) of 2,5-difluoro-DL-phenylalanine in 5 mL of tert-butanol were added sequentially 1.5 mL of 2N aqueous sodium hydroxide solution and 543 mg of di-tert-butyl dicarbonate. The reaction was stirred at ambient temperature for 16 h and diluted with ethyl acetate. The organic phase was washed sequentially with IN hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 97:2:1 dichloromethane:methanol: acetic acid) to afford 671 mg of the title compound. MS 302 (M + 1).
Step B. (R,5)-3-r( l-Dimethylethoxycarbonyl)aminol-l-diazo-4-(2.5-difluoro- phenyl)butan-2-one
To a solution of 2.23 g (7.4 mmol) of (R,S)-N-(l,l- dimethylethoxycarbonyl)-2,5-difluorophenylalanine in 100 mL of diethyl ether at 0 °C were added sequentially 1.37 mL (8.1 mmol) of triethylamine and 0.931 mL (7.5 mmol) of isobutyl chloroformate and the reaction was stirred at this temperature for 15 min. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for a further 16 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.5 g of diazoketone. H NMR (500 MHz,
CDCI3) δ 7.03-6.95 (m, IH), 6.95-6.88 (m, 2H), 5.43 (bs, IH), 5.18 (bs, IH), 4.45
(bs, IH), 3.19-3.12 (m, IH), 2.97-2.80 (m, IH), 1.38 (s, 9H).
Step C. (3R)-3-r( l-Dimethylethoxycarbonyl)aminol-4-(2.5-difluorophenyl)butanoic acid
To a solution of 2.14 g (6.58 mmol) of (R,S)-3-[(l,l- dimethylethoxycarbonyl)-amino]-l-diazo-4-(2,5-difluorophenyl)butan-2-one dissolved in 100 mL of methanol at -30 °C were added sequentially 3.3 mL (19 mmol) of diisopropylethylamine and 302 mg (1.32 mmol) of silver benzoate. The reaction was stirred for 90 min before diluting with ethyl acetate and washing sequentially with 2N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and the enantiomers were separated by preparative chiral HPLC (Chiralpak AD column, 5% ethanol in hexanes) to give 550 mg of the desired (R)-enantiomer, which eluted first. This material was dissolved in 50 mL of a mixture of tetrahydrofuran:methanol: IN aqueous lithium hydroxide (3:1:1) and stirred at 50 °C for 4 h. The reaction was cooled, acidified with 5% dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 360 mg of the title compound as a white foamy solid. 1H NMR (500 MHz, CDCI3) δ 7.21 (m, IH), 6.98
(m, 2H), 6.10 (bs, IH), 5.05 (m,lH), 4.21 (m, IH), 2.98 (m, 2H), 2.60 (m, 2H), 1.38 (s, 9H).
INTERMEDIATE 2
Figure imgf000032_0001
(3R)-3-r( l-Dimethylethoxycarbonyl)aminol-4-r2-fluoro-4-(trifluoromethyl)phenyll- butanoic acid
Step A. (2R.5 )-2.5-Dihvdro-3.6-dimethoxy-2-(2'-fluoro-4'-(trifluoromethyl)benzyl)- 5-isopropylpyrazine
To a solution of 3.32 g (18 mmol) of commercially available (2S)-2,5- dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL of tetrahydrofuran at -70 °C was added 12 mL (19 mmol) of a 1.6M solution of butyllithium in hexanes. After stirring at this temperature for 20 min, 5 g (19.5 mmol) of 2-fluoro-4- trifluoromethylbenzyl bromide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before warming the reaction to ambient temperature. The reaction was quenched with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-5% ethyl acetate in hexanes) afforded 5.5 g of the title compound. IH NMR (500 MHz, CDCI3) δ 7.33-
7.25 (m, 3H), 4.35-4.31 (m, IH), 3.75 (s, 3H), 3.65 (s, 3H), 3.60 (t, IH, J = 3.4 Hz), 3.33 (dd, IH, J = 4.6, 13.5 Hz), 3.03 (dd, IH, J = 7, 13.5 Hz), 2.25-2.15 (m, IH), 1.0 (d, 3H, J = 7 Hz), 0.66 (d, 3H, J = 7 Hz).
Step B. (R)-N-(l.l-Dimethylethoxycarbonyl)-2-fluoro-4-trifluoromethyl)phenyl- alanine methyl ester
To a solution of 5.5 g (15 mmol) of (2R,5S)-2,5-dihydro-3,6- dimethoxy-2-(2'-fluoro-4'-(trifluoromethyl)benzyl)-5-isopropylpyrazine in 50 mL of a mixture of acetonitrile:dichloromethane (10:1) was added 80 mL of IN aqueous trifluoroacetic acid. The reaction was stirred for 6 h and the organic solvents were removed in vacuo. Sodium carbonate was added until the solution was basic (>pH 8), and then the reaction was diluted with 100 mL of tetrahydrofuran and 10 g (46 mmol) of di-tert-butyl dicarbonate was added. The resulting slurry was stirred for 16 h, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography (silica gel, 20% ethyl acetate in hexanes) afforded 5.1 g of the title compound. XH NMR (500 MHz, CDCI3) δ 7.38-7.28 (m, 3H), 5.10 (bd, IH), 4.65-
3.98 (m, IH), 3.76 (s, 3H), 3.32-3.25 (m, IH), 3.13-3.05 (m, IH), 1.40 (s, 9H).
Step C. (J?)-N-(Ll-Dimethylethoxycarbonyl)-2-fluoro-4-trifluoromethyl)phenyl- alanine
A solution of 5.1 g (14 mmol) of (R,S)-N-(1,1- dimethylethoxycarbonyl)-2-fluoro-4-trifluoromethyl)phenylalanine methyl ester in 350 mL of a mixture of tetrahydrofuran: methanol: IN lithium hydroxide (3:1:1) was stirred at 50 °C for 4 h. The reaction was cooled, acidified with 5% dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4.8 g of the title compound. IH NMR (500 MHz, CD3OD) δ 7.45-7.38 (m, 3H),
4.44.4.4O (m, IH), 3.38-3.33 (m, IH), 2.98 (dd, IH, J = 9.6, 13.5 Hz), 1.44 (s, 9H).
Step D. (3J?)-3-r(Ll-Dimethylethoxycarbonyl)aminol-4-r2-fluoro-4-(trifluoromethyl)- phenyllbutanoic acid
To a solution of 3.4 g (9.7 mmol) of the product from Step C in 60 mL of tetrahydrofuran at 0 °C were added sequentially 2.3 mL (13 mmol) of diisopropylethylamine and 1.7 mL (13 mmol) of isobutyl chloroformate and the reaction was stirred at this temperature for 30 min. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for a further 16 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo.
Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 0.5 g of diazoketone. To a solution of 0.5 g (1.33 mmol) of the diazoketone dissolved in 100 mL of methanol at 0 °C were added sequentially 0.7 mL (4 mmol) of diisopropylethylamine and 32 mg (0.13 mmol) of silver benzoate. The reaction was stirred for 2 h before diluting with ethyl acetate and washing sequentially with 2N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and dissolved in 50 mL of a mixture of tetrahydrofura methanol: IN aqueous lithium hydroxide (3:1:1) and stirred at 50 °C for 3 h. The reaction was cooled, acidified with 5% dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 410 mg of the title compound as a white foamy solid. H NMR (500 MHz, CD3OD) δ 7.47-7.33 (m, 3H), 4.88 (bs, IH), 4.26-3.98 (m, IH), 3.06-3.01 (m, IH),
2.83-2.77 (m, IH), 2.58-2.50 (m, 2H), 1.29 (s, 9H).
INTERMEDIATE 3
Figure imgf000034_0001
(3R)-3-r(l.l-Dimethylethoxycarbonyl)aminol-4-(2.4,5-trifluorophenyl)butanoic acid
Step A. (25. 5R)-2,5-Dihvdro-3,6-dimethoxy-2-isopropyl-5-(2'.4',5'trifluorobenzyl)- pyrazine
The title compound (3.81 g) was prepared from 3.42 g (18.5 mmol) of (25)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine using the procedure described for Intermediate 2, Step A. 1H NMR (500 MHz, CDCI3) δ 7.01 (m, IH), 6.85 (m,
IH), 4.22 (m, IH), 3.78 (m, 3H), 3.64 (m, 3H), 3.61 (m, IH), 3.20 (m, IH), 2.98 (m, IH), 2.20 (m, IH), 0.99 (d, 3H, J = 8 Hz), 0.62 (d, 3H, J = 8 Hz).
Step B. (R)-N-( l-Dimethylethoxycarbonyl)-2,4.5-trifluorophenylalanine methyl ester
To a solution of 3.81 g (11.6 mmol) of (25, 5R)-2,5-dihydro-3,6- dimethoxy-2-isopropyl-5-(2',4',5'trifluoro-benzyl)pyrazine in 20 mL of acetonitrile was added 20 mL of 2N hydrochloric acid. The reaction was stirred for 72 h and concentrated in vacuo. The residue was dissolved in 30 mL of dichloromethane and 10 mL (72 mmol) of triethylamine and 9.68 g (44.8 mmol) of di-tert-butyldicarbonate were added. The reaction was stirred for 16 h, diluted with ethyl acetate and washed sequentially with IN hydrochloric acid and brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 9:1 hexanes:ethyl acetate) to afford 2.41 g of the title compound. IH NMR (500 MHz, CDCI3) δ 6.99 (m, IH), 6.94 (m, IH), 5.08 (m, IH), 4.58 (m, IH), 3.78 (m,
3H), 3.19 (m, IH), 3.01 (m, IH), 1.41 (s, 9H).
Step C. (R)-N-( l-Dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine
The title compound (2.01 g) was prepared from 2.41 g (7.5 mol) of (R)-N-(l,l-dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine methyl ester using the procedure described for Intermediate 2, Step C. MS (M + l)-BOC 220.9.
Step D. (3R)-3-f( l-Dimethylethoxycarbonyl)aminol-4-(2.4.5-trifluorophenyl)- butanoic acid
To a solution of 0.37 g (1.16 mmol) of (R)-N~(l,l- dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine in 10 mL of diethyl ether at -20 °C were added sequentially 0.193 mL (1.3 mmol) of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate, and the reaction was stirred at this temperature for 15 min. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for a further 1 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo.
Purification by flash chromatography (silica gel, 3:1 hexane: ethyl acetate) afforded 0.36 g of diazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketone dissolved in 12 mL of 1,4-dioxane: water (5:1) was added 26 mg (0.113 mmol) of silver benzoate. The resultant solution was sonicated for 2 h before diluting with ethyl acetate and washing sequentially with IN hydrochloric acid and brine, drying over magnesium sulfate and concentrating in vacuo. Purification by flash chromatography (silica gel, 97:2:1 dichloromethane:methanol: acetic acid) afforded 401 mg of the title compound. 4ϊ NMR (500 MHz, CDCI3) δ 7.06 (m, IH), 6.95 (m,
IH), 5.06 (bs, IH), 4.18 (m, IH), 2.98 (m, 2H), 2.61 (m, 2H), 1.39 (s, 9H). INTERMEDIATE 4
Figure imgf000036_0001
(3R)-3-r(Ll-Dimethylethoxycarbonyl)aminol-4-(4-bromo-2.5-difluorophenyl)- butanoic acid
Step A. 4-Bromo-2.5-difluorobenzyl bromide
To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of Ishikawa et al., Kogyo Kagaku Zasshi, pg 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a IM solution of borane-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to ambient temperature and 100 mL of methanol was added. The reaction was then heated for a further 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 1.6 g of 4-bromo-2,5- difluorobenzyl alcohol. To a solution of 1.3 g (5.6 mmol) of 4-bromo-2,5- difluorobenzyl alcohol in 20 mL of dichloromethane at 0 °C was added 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 9:1 hexane: ethyl acetate) to afford 1.5 g of the title compound.
Step B. (25. 5R)-2.5-Dihvdro-3.6-dimethoxy-2-isoproρyl-5-(4'-bromo-2,.5'- difluorobenzyDpyrazine The title compound (1.61 g) was prepared from 0.865 g (4.7 mmol) of
(2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazme and 1.5 g (5.2 mmol) of 4- bromo-2,5-difhιorobenzyl bromide using the procedure described for Intermediate 2, Step A. IH NMR (400 MHz, CDCI3) δ 7.21 (m, IH), 6.97 (m, IH), 4.25 (m, IH), 3.78 (s, 3H), 3.70-3.64 (m, 4H), 3.25-3.18 (m, IH), 2.96-2.90 (m, IH), 2.25-2.16 (m, IH), 1.01 (d, 3H, J = 8 Hz), 0.65 (d, 3H, J = 8 Hz).
Step C. (R)-N-(l, l-Dimethylethoxycarbonyl)-4-bromo-2.5-difluorophenylalanine methyl ester
To a solution of 1.61 g (4.14 mmol) of (25, 5R)-2,5-dihydro-3,6- dimethoxy-2-isopropyl-5-(4'-bromo-2',5'-difluorobenzyl)pyrazine in 10 mL of acetonitrile was added 10 mL of 2N hydrochloric acid. The reaction was stirred for 16 h and concentrated in vacuo. The residue was dissolved in 30 mL of dichloromethane and 5.6 mL (40 mmol) of triethylamine and 2.2 g (10 mmol) of di- tert-butyldicarbonate were added. The reaction was stirred for 16 h, diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 9:1 hexanes:ethyl acetate) to afford 1.22 g of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.27-7.15 (m,
IH), 6.98-6.93 (m, IH), 5.08 (bs, IH), 4.61-4.55 (m, IH), 3.78 (s, 3H), 3.23-3.18 (m, IH), 3.05-2.95 (m, IH), 1.41 (s, 9H).
Step D. (R)-N-(l.l-Dimethylethoxycarbonyl)-4-bromo-2.5-difluorophenylalanine The title compound (1.34 g) was prepared from 1.4 g (3.5 mmol) of
(R)-N-(l , 1 -dimethylethoxycarbonyl)-4-bromo-2,5-diifluorophenylalanine methyl ester using the procedure described for Intermediate 2, Step C. MS (M + 1) 380.3 and 382.3.
Step E. (3R)-3-r(Ll-Dimethylethoxycarbonyl)aminol-4-(4'-bromo-2'.5'- difluorophenvDbutanoic acid
The title compound (0.36 g) was prepared from 0.6 g (1.57 mmol) of (R)-N-(l, l-dimethylethoxycarbonyl)-4-bromo-2,5-diifluorophenylalanine using the procedure described for Intermediate 3, Step D. MS (M + 1) 394.1 and 396.1.
EXAMPLE 1
Figure imgf000038_0001
7-r(3R)-3-Amino-4-(3.4-difluorophenyl)butanoyll-2-(trifluoromethyl)-5.6.7.8- tetrahydroimidazor 1 ,2- lpyrazine, dihydrochloride
Step A. 2-(Trifluoromethyl)imidazo[T,2-αlpyrazine
To a solution of 2-aminopyrazine (5.25 g, 55.2 mmol) in ethanol (120 mL) was added l-bromo-3,3,3-trifluoroacetone (5.73 mL, 55.2 mmol). The reaction was stirred at reflux for 20 h. After evaporation of solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution.
The aqueous layer was extracted with ethyl acetate (3x). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexane, then 100% ι ethyl acetate) to give 2.35 g of the title compound as a solid. H NMR (500 MHz, CDC13) 6 8.02 (m, 2H), 8.13(m, IH), 9.22 (s, IH). ESI-MS 188 (M+1).
Step B. 2-(Trifluoromethyl)-5,6,7,8-tetrahvdroimidazo[T ,2- lpyrazine
To a solution of 2-(trifluoromethyl)imidazo[l,2-α]pyrazine (2.0 g, 10.46 mmol, from Step A) in methanol (100 mL) was added 10% palladium on carbon (400 mg). The mixture was stirred under atmospheric hydrogen at ambient temperature for 14 h. The mixture was filtered through Celite and washed with methanol (3X). The filtrate was concentrated and purified by flash chromatography (silica gel, 10% methanol in ethyl acetate, then 15% methanol in chloroform with 1% aqueous ammonium hydroxide) to give 1.33 g of the title compound as a solid. H NMR (500 MHz, CDC13) δ 1.93 (bs, IH), 3.26 (t, 2H, J=5.5 Hz), 3.99 (t, 2H, J=5.5 Hz), 4.10 (s, IH), 7.16 (s, IH). ESI-MS 192 (M+1).
Step C. 7-l(3R)-3-r(Ll-dimethylethoxycarbonyl)aminol-4-(3.4- difluorophenyDbutanoyll -2-(trifluoromethyl)-5.6.7.8-tetrahydroimidazo \ 1,2- lpyrazine To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[l,2- αjpyrazine (64.3 mg, 0.34 mmol, from Step B) and (3R)-3-[(l,l- dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT (54.5 mg, 0.42 mmol) at 0 °C . The reaction was stirred at 0 °C for 10 min, then EDC (96.6 mg, 0.50 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 14 h. The mixture was concentrated and purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100 x 20 mm ID.; solvent gradient from 10% acetonitrile, 90% water, and 0.1 % trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1 % trifluoroacetic acid) to give 115 mg of the title compound as a foamy solid. *H NMR (500 MHz, CDC13) δ 1.36 (s, 9H), 2.62 (m, 2H), 2..86 (m, 2H) 3.34 (bs, IH), 3.86 (m, IH), 4.05 (m, 4H). 4.85 (m, IH) 5.30-5.38 (m, IH) 6.97 (m, 3H), 7.28 (m, IH). LC/MS 489 (M+1).
Step D. 7-r(3R)-3-Amino-4-(3.4-difluorophenyl)butanoyll-2-(trifluoromethyl)- 5,6,7,8-tetrahvdroimidazori,2-.zlpyrazine, dihydrochloride
To 7-[(3R)-3-[(l,l-dimethylethoxycarbonyl)amino]-4-(3,4- difluorophenyl)butanoyl]-2-(Mfluoromethyl)-5,6,7,8-tetrahyα oimidazo[l,2- αjpyrazine (110.8 mg, 0.226 mmol, from Step C) was added 2 mL of methanol saturated with hydrogen chloride. The reaction was stirred at ambient temperature for 1 h. Concentration gave 89.5 mg of the title compound as a foamy solid. IH NMR (500 MHz, CD3OD) δ 2.97-3.10 (m, 4H), 3.91-4.34 (m, 5H), 4.90-5.04 (m, 2H), 7.16-
7.33 (m, 2H), 8.01-8.08 (m, IH). ESI-MS 389 (M+1).
EXAMPLE 2
Figure imgf000039_0001
7-r(3i?)-3-Amino-4-(2.5-difluorophenyl)butanoyll-2-(trifluoromethyl)-5.6.7.8- tetrahydroimidazori.2-αlpyrazine, dihydrochloride Step A. 7-r(3J?)-3-r(l.l-dimethylethoxycarbonyl)aminol-4-(2.5- difluorophenyl)butanoyll-5,6,7,8-tetrahydroimidazori.2-αlpyrazine
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8- tetrahydroimidazo[l,2-α]pyrazine (277 mg, 1.45 mmol, from Example 1, Step B), (3R)-3-[(l , l-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 416 mg, 1.32 mmol), DTPEA (226 mg, 1.58 mol), HOBT (216 mg, 1.98 mol) and HATU (753 mg, 1.98 mol) in DMF (6 mL), using a procedure analogous to that described in Example 1 Step C, except for the purification method. The compound was purified by preparative TLC (silica gel, 20% hexane in ethyl acetate, then 10% methanol in dichloromethane) to give 360 mg of the title compound as a foamy solid. H NMR (500 MHz, CDC13) δ 1.35 (s, 9H), 2.62 (m, 2H), 2.88 (m, 2H) 3.88-4.16 (m, 5H), 4.73 (s, IH), 4.85 (m, IH) 5.26-5.39 (m, IH) 6.90 (bs, IH), 7.06(m, 2H), 7.24(m, IH). ESI-MS 489 (M+1).
Step B. 7-r(3i?)-3-Amino-4-(2,5-difluorophenyl)butanoyll-5,6,7.8- tetrahydroimidazolT ,2-αlpyrazine, dihydrochloride
The title compound was prepared from 7-[(3R)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoyl]-5,6,7,8- tetrahydroimidazo[l,2-α]pyrazine (349.8 mg, 0.72 mol, from Step A) in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent gave 299 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD): δ 3.10-3.17 (m, 2H),
2.89-2.99 (m, 2H), 3.94-4.22 (m, 4H), 4.33 (m, IH), 4.91-5.48 (m, 2H), 7.07-7.23 (m, 3H), 8.05 (m, IH). ESI-MS 389(M+1).
EXAMPLE 3
Figure imgf000040_0001
7-r(3^)-3-Amino-4-(2.4,5-trifluorophenyl)butanoyll-2-(trifluoromethyl)-5,6,7,8- tetrahydroimidazoll,2- lpyrazine, dihydrochloride Step A. 7-r(3R)-3-r(l.l-dimethylethoxycarbonyl)aminol-4-(2,4.5- trifluorophenyDbutanoyπ -5,6,7 , 8-tetrahvdroimidazo I" 1 ,2-αlpyrazine
The title compound was prepared from 2-(trifluoromefhyl)-5,6,7,8- tetrahydroimidazo[l,2-α]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3R)-3-[(l,l-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol), HOBT (26.9 mg,0.199 ) mmol, and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol in dichloromethane) gave 40 mg of the title compound as a foamy solid. XH NMR (500 MHz, CDC13) δ 1.35 (s, 9H), 3.00 (m, 2H), 3.30 (m, 2H), 3.93 ( , IH) 4.04-4.24 (m, 2H), 4.23 (s, IH), 4.35 (m, IH) 4.97- 5.48 (m, 2H) 7.22 (m, IH), 7.44 (m, IH), 8.04 (m, IH). ESI-MS 507 (M+1).
Step B. 7-r(3R)-3-Amino-4-(2.4.5-trifluorophenyl)butanoyll-5,6,7,8- tetrahydroimidazori,2-αlpyrazine, dihydrochloride
The title compound was prepared from 7-[(3R)-3-[(l,l- dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-5,6,7,8- tetrahydroimidazo[l,2- ]pyrazme (38 mg, 0.075 mmol, from Step A), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent gave 34 mg of the title compound as a foamy solid. H NMR (500 MHz, CD3OD): δ 2.59-2.66 (m, 2H),
2.92 (m, 2H), 3.89-4.16-4.22 (m, 5H), 4.70-4.84 (m, 2H), 5.42 (m, IH), 6.86 (m, IH), 7.06 (m, IH), 7.24 (m, IH). ESI-MS 407(M+1).
EXAMPLE 4
Figure imgf000041_0001
7-r(3R)-3-Amino-4-(3.4-difluorophenyl)butanoyl1-5,6.7.8-tetrahvdroimidazori.2- αlpyrazine, dihydrochloride Step A. Imidazori,2- lpyrazine
To a solution of 2-aminopyrazine (2.0 g, 21.03 mmol) in ethanol (40 mL) was added 2-bromo-l,l-dimethoxyethane (2.5 mL, 21.03 mmol) followed by 5 drops of concentrated hydrochloric acid. After refluxing for 14 hours, the solvent was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3x). The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (100% ethyl acetate, 10% methanol in ethyl acetate, then 10% methanol in dichloromethane) to give 536 mg of the title compound as a solid. *H NMR (500 MHz, CDC13) δ 7.70 (bs, IH), 7.82 (bs, IH), 7.89 (d, IH, J=4.4 Hz), 8.10 (d, IH, J=4.6 Hz), 9.12 (s, IH).
Step B. 5,6.7, 8-Tetrahydroimidazo|T,2-fllpyrazine
The title compound was prepared from imidazo[l,2-α]pyrazine (500 mg, 4.20 mmol, from Step A) and platinum oxide (250 mg) in methanol (50 mL), using a procedure analogous to that described in Example 1, Step B. Concentration
1 gave the title compound (512 mg) as a viscous oil. H NMR (500 MHz, CD3OD) δ 3.37 (t, IH, J=5.5 Hz), 4.18 (t, 2H, J=5.6 Hz), 4.88 (s, IH), 7.27 (d, J=1.6 Hz, IH), 7.33 (d, IH).
Step C. 7-r(3J?)-3-r(l,l-dimethylethoxycarbonyl aminol-4-(3,4- difluorophenyl)butanovn-5 ,6,7, 8-tetrahydroimidazo I" 1 ,2-alpyrazine
The title compound was prepared from 5,6,7,8-tetrahydroimidazo[l,2- αjpyrazine (31.3 mg, 0.254 mmol, from Step B), (3R)-3-[(l,l- dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (80 mg, mmol),
DTPEA (32.8 mg, 0.254 mmol), HOBT (41.2 mg, 0.305 mmol) and EDC (73 mg,
0.381 mmol) in 5 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by HPLC (Gilson; YMC-Pack Pro C18 column, 100 x 20 mm ID.; solvent gradient system from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic
I acid) gave 75 mg of the title compound as a viscous oil. H NMR (500 MHz, CDC13) δ 1.38 (s, 9H), 2.05 (bs, IH), 2.62 (m, 2H), 2.89 (m, 2H) 3.81-4.04 (m, 5H), 4.64-4.88
(m, 2H). 5.38 (m, IH) 6.88 (m, 2H), 7.0 5(m, 3H). ESI-MS 421 (M+1). Step P. 7-r(3R)-3-Amino-4-(3.4-difluorophenyl)butanoyll-5,6.7.8- tetrahydroimidazoπ,2-fl1pyrazine, dihydrochloride
The title compound was prepared from 7-[(3R)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl]-5,6,7,8- tetrahydroimidazo[l,2-α]pyrazine (72 mg, 0.171 mmol, from Step C), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Concentration gave 66 mg of the title compound as a foamy solid. IH NMR (500 MHz, CD3OD) δ 2.96-3.13 (m, 4H), 3.93 (m, IH), 4.13
(m, 2H), 4.26-4.38 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.04 (m, 2H), 7.19-7.36 (m, 3H), 7.58 (m, IH). ESI-MS 321 (M+1).
EXAMPLE 5
Figure imgf000043_0001
7-I(3J? -3-Amino-4-(3,4-difluorophenvDbutanoyll-3-ethyl-5,6,7.8-tetrahvdro-l,2,4- triazolor4,3- lpyrazine, dihydrochloride
Step A. 8-Chloro-3-ethyl-l,2,4-triazolor4,3- 1pyrazine
To 3-chloro-2-hydrazinopyrazine (3.0 g, 20.75 mmol), prepared from 2,3-dichloropyrazine and hydrazine using a procedure analogous to that described in the literature (Huynh-Dinh et al, J. Org. Chem. 1979, 44, 1028), was added 8 mL of triethyl orthopropionate. After refluxing for 10 h, the reaction was cooled down to ambient temperature and the precipitate was filtered. The solid was purified by flash chromatography (100% ethyl acetate, then 10% methanol in ethyl acetate) to give 2.73 g of the title compound as a solid. *H NMR (500 MHz, CDC13) δ 1.54 (t, 3H, J=7.6 Hz), 3.16 (q, 2H, J=7.8 Hz), 7.70 (d, IH, J=4.5 Hz), 7.83 (d, IH, J=4.8 Hz).
Step B. 3-Ethyl-5.6.7,8-tetrahydro-1.2.4-triazolor4,3- 1 pyrazine, hydrochloride
The title compound was prepared from 8-chloro-3-ethyl- 1,2,4- triazolo[4,3-α]pyrazine (2.70 g, 14.8 mmol, from Step A) and platinum oxide (0.4 g) in 200 mL of methanol in a paar shaker under hydrogen (50 psi) for 14 hours. Filtration through Celite followed by concentration gave the title compound as a solid. *H NMR (500 MHz, CD3OD) δ 1.36 (t, 3H, J=6.0 Hz), 2.84 (q, 2H, J=6.0 Hz), 3.70 (t, 2H, J=8.0 Hz), 4.28 (t, 2H, J=8.0 Hz). 4.06(s, 2H). ESI-MS 153 (M+1).
Step C. 7-r(3J? -3-r(l,l-dimethylethoxycarbonyl)aminol-4-(3.4- difluoroρhenyl)butanoyn-3-ethyl-5,6,7,8-tetrahydro-l,2,4-triazolor4,3-αlpyrazine The title compound was prepared from 3-ethyl-5,6,7,8-tetrahydro- l,2,4-triazolo[4,3-α]pyrazine hydrochloride (400 mg, 2.12 mmol, from Step B), (3i?)- 3-[(l,l-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (668 mg, 2.12 mmol), DIPEA (1.1 mL, 4.24 mmol), HOBT (343.8 mg, 2.54 mmol) and EDC (609.6 mg, 3.18 mmol) in 20 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. The crude product was purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100 x 20 mm ID.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0. % trifluoroacetic acid) to give 366.3 mg of the title compound as a viscous oil. XH NMR (500 MHz, CDC13) δ 1.31-1.34 (m, 12H), 2.67-2.92 (m, 6H), 4.03-4.12 (m, 4H), 5.03-5.31 (m, 3H), 6.93 (s, IH), 7.05 (m, 2H). ESI-MS 450 (M+1).
Step D. 7-r(3R)-3-Amino-4-(3,4-difluorophenyl)butanoyll-3-ethyl-5.6,7,8-tetrahvdro- L2,4-triazolor4,3-α1 pyrazine, dihydrochloride
The title compound was prepared from 7-[(3R)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl]-3-ethyl-5,6,7,8- tetrahydro-l,2,4-triazolo[4,3-α]ρyrazine (30 mg, 0.067 mmol from Step C), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent afforded 28 mg of the title compound as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 1.45 (t, 3H), 2.93-3.07
(m, 6H), 3.90-4.31 (m, 5H), 5.08 (m, 2H), 7.16 (s, IH), 7.31 (m, 2H). ESI-MS 350 (M+H). EXAMPLE 6
Figure imgf000045_0001
7-r(3ig)-3-Amino-4-(2,5-difluorophenyl)butanoyll-3-(trifluoromethyl)-5,6,7,8- tetrahydro- 1 ,2,4-triazolo r4,3-alpyrazine, hydrochloride
Step A. 3-(Trifluoromethyl)-L2,4-triazolor4,3-fllpyrazine
A mixture of 2-hydrazinopyrazine (820 mg, 7.45 mmol), prepared from 2-chloropyrazine and hydrazine using a procedure analogous to that described in the literature (P.J. Nelson and K.T. Potts, J. Org. Chem. 1962, 27, 3243, except that the crude product was extracted into 10%methanol/dichloromethane and filtered, and the filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate followed by 10% methanol in dichloromethane), TFA (2.55 g, 22.4 mmol), and polyphosphoric acid (10 mL) was heated to 140 °C with stirring for 18 h. The solution was added to ice and neutralized by the addition of ammonium hydroxide. The aqueous solution was extracted with ethyl acetate (3X), washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (silica gel, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded the title compound as a solid (861 mg). 1H NMR (500 MHz, CDC13) δ 8.17-8.20 (m, 2H), 9.54 (s, IH). LC/MS (M+1) 189.
Step B. 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolor4,3-αlpyrazine
3-(Trifluoromethyl)-l,2,4-triazolo[4,3-α] pyrazine (540 mg, 2.87 mmol, from Step A) was hydrogenated under atmospheric hydrogen with 10% Pd/C (200 mg) as a catalyst in ethanol (10 mL) at ambient temperature for 18 h. Filtration through Celite followed by concentration gave a dark colored oil. Dichloromethane was added to the above oil and the insoluble black precipitate was filtered off. Concentration of the filtrate gave the title compound as an oil (495 mg). 1H NMR (500 MHz, CDC13) δ 2.21 (br, IH), 3.29 (t, 2H, J = 5.5 Hz), 4.09 (t, 2H, J = 5.5 Hz), 4.24 (s, 2H). LC/MS (M+1) 193.
Step C. 7-r(3R)-3-r(l,l-Dimethylethoxycarbonyl)aminol-4-(2.5- difluorophenyl)butanoyn-3-(trifluoromethyl)-5,6,7,8-tetrahvdro-l,2,4-triazolor4,3- alpyrazine
The title compound was prepared from (3i?)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 50 mg, 0.16 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3- αjpyrazine (30 mg, 0.16 mmol) using a procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol/dichloromethane (2X)) to afford the title compound (38.1 mg) as a solid. 1H NMR (500 MHz, CDC13) δ 1.38 (s, 9H), 2.57-3.05 (m, 4H), 3.85-4.30 (m, 5H), 4.90 (s, IH), 4.95-5.15 (m, IH), 5.22-5.40 (br, IH), 6.86-7.24 (m, 3H). LC/MS (M+1-t-Boc) 390.
Step D. 7-r(3R)-3-Amino-4-(2,5-difluorophenyl)butanovn-3-(trifluoromethyl)- 5,6,7, 8-tetrahydro-l,2,4-triazolo[4,3-αl pyrazine, hydrochloride
The title compound was prepared from 7-[(3R)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoyl]-3-(trifluoromethyl)- 5,6,7, 8-tetrahydro-l,2,4-triazolo[4,3-α]pyrazine (19.1 mg, 0.039 mmol, from Step C) using a procedure analogous to that described for Example 1, Step D. Concentration afforded the title compound (16.1 mg) as a solid. 1H NMR (500 MHz, CD3OD) δ 2.75-3.16 (m, 4H), 3.86-4.35 (m, 5H), 4.95-5.05 (m, 2H), 7.03-7.20 (m, 3H). LC/MS (M+1) 390.
EXAMPLE 7
Figure imgf000047_0001
7-r(3R -3-Amino-4-(2,4.5-trifluorophenyl butanoyll-3-(trifluoromethyl)-5,6,7,8- tetrahydro-l,2,4-triazolor4.3-fllpyrazine, hydrochloride
Step A. 7-r(3Jg)-3-r(l,l-Dimethylethoxycarbonyl)aminol-4-(2.4.5-trifluorophenyl)- butanoyn-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolor4,3- lpyrazine
The title compound was prepared from (3R)-3-[(l,l-dimethylethoxy- carbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 50.1 mg, 0.15 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-α]pyrazine (39.2 mg, 0.20 mmol) using a procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate) to afford the title compound (29 mg) as a solid. 1H NMR (500 MHz, CDC13) δ 1.37 (s, 9H), 2.61-3.00 (m, 4H), 3.92-4.30 (m, 5H), 4.93 (s, IH), 4.95-5.12 (m, IH), 5.22-5.35 (br, IH), 6.83-6.95 (m, IH), 7.02-7.12 (m, IH). LC/MS (M+l-t-Bu) 452.
Step B. 7-r(3J? -3-Amino-4-(2.4.5-trifluorophenyl)butanoyll-3-(trifluoromethyl)- 5,6,7, 8-tetrahydro-l,2,4-triazolo[4,3-fll pyrazine, hydrochloride The title compound was prepared from 7-[(3i?)-3-[(l,l- dimethylethoxycarbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3- (trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-ΩJpyrazine (22 mg, 0.039 mmol, from Step A) using a procedure analogous to that described for Example 1, Step D. Concentration afforded the title compound (16.5 mg) as a solid. 1H NMR (500 MHz, CD3OD) δ 2.75-3.15 (m, 4H), 3.82-4.35 (m, 5H), 4.90-5.05 (m, 2H), 7.16-7.25 (m, IH), 7.30-7.42 (m, IH). LC/MS (M+1) 408. Essentially following the procedures outlined for Examples 1-7, the compounds listed in Table 1 were prepared.
TABLE 1
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0001
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. The specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula I:
Figure imgf000051_0001
I wherein:
Ar is phenyl which is unsubstituted or substituted with 1-5 of R3, wherein R3 is independently selected from the group consisting of: (1) halogen, (2) Cι_6alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens,
(3) OCi_6alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens, and
(4) CN;
X is selected from the group consisting of:
(1) N, and
(2) CR2;
Rl and R2 are independently selected from the group consisting of:
(1) hydrogen,
(2) CN,
(3) Ci-ioalkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen,
CN, OH, R4, OR4, NHS02R4 SO2R4, CO H, and CO2Ci-6alkyl, wherein the CO2Ci~6alkyl is linear or branched,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4 NHS02R4, SO2R4, CO2H, and CO2Ci_6alkyl, wherein the CO2Ci_6al yl is linear or branched, and (6) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, Ci_6alkyl, and OCi-βalkyl, wherein the Cι_6alkyl and OCι_6alkyl are linear or branched and optionally substituted with 1-5 halogens;
R4 is Cι_6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO2H, and CO2Ci-6alkyl, wherein the CO2Cι_6alkyl is linear or branched;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
2. The compound of Claim 1 of the formula la:
Figure imgf000052_0001
la wherein X, Ar and Ri are defined in Claim 1 ; and pharmaceutically acceptable salts and individual diastereomers thereof.
The compound of Claim 1 of the formula lb:
Figure imgf000052_0002
lb wherein Ar and Ri are defined in Claim 1; and pharmaceutically acceptable salts and individual diastereomers thereof.
4. The compound of Claim 1 of the formula Ic:
Figure imgf000053_0001
Ic wherein Ar , Ri and R are defined in Claim 1; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
5. The compound of Claim 1 wherein Ar is phenyl which is unsubstituted or substituted with 1-5 substitutents which are independently selected from the group consisting of:
(1) fluoro,
(2) bromo, and (3) CF3.
6. The compound of Claim 1 wherein Ar is selected from the group consisting of:
(1) phenyl, (2) 2-fluorophenyl,
(3) 3,4-difluorophenyl,
(4) 2,5-difluorophenyl,
(5) 2,4,5-trifluorophenyl,
(6) 2-fluoro-4-(triflouromethyl)phenyl, and (7) 4-bromo-2,5-difluorophenyl.
7. The compound of Claim 1 wherein Ri is selected from the group consisting of:
(1) hydrogen, and (2) Ci-galkyl, which is linear or branched and which is unsubstituted or substituted with phenyl or 1-5 fluoro.
8. The compound of Claim 1 wherein Rl is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) ethyl,
(4) CF3, (5) CH2CF3,
(5) CF2CF3
(6) phenyl, and
(7) benzyl.
9. The compound of Claim 1 wherein Rl is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) ethyl, (4) CF3, and
(5) CH2CF3.
10. The compound of Claim 1 wherein Rl is hydrogen or CF3.
11. The compound of Claim 1 wherein R is selected from:
(1) hydrogen,
(2) Ci_6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 fluoro,
(3) phenyl, which is unsubstituted or substituted with 1-3 substituents independently selected from fluoro, OCH3, and
OCF3.
12. The compound of Claim 1 wherein R2 is selected from the group consisting of: (1) hydrogen,
(2) methyl,
(3) ethyl,
(4) CF3,
(5) CH2CF3,
(5) CF2CF3
(6) phenyl,
(7) (4-methoxy)phenyl,
(8) (4-trifluoromefhoxy)phenyl,
(9) 4-fluorophenyl, and
(10) 3,4-difluorophenyl.
13. The compound of Claim 1 wherein R2 is CF3 or CF2F3.
14. The compound of Claim 1 wherein R3 is F, Br or CF3.
15. A compound which is selected from the group consisting of:
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0001
and pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition which comprises an inert carrier and a compound of Claim 1.
17. A method for inhibition of dipeptidyl peptidase-IV enzyme activity in a mammal which comprises the administration of an effective amount of the compound of Claim 1.
18. A method for treating, controlling, or preventing diabetes comprising the administration to a patient of an effective amount of the compound of Claim 1.
19. A method for treating, controlling, or preventing non-insulin dependent (Type 2) diabetes mellitus in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
20. A method for treating, controlling or preventing hyperglycemia in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
21. A method for treating, controlling or preventing obesity in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
22. A method for treating, controlling or preventing insulin resistance in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
23. A method for treating, controlling or preventing one or more lipid disorders selected from the group conisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
24. A method for treating, controlling or preventing atherosclerosis in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
25. A method for treating or controlling growth hormone deficiency in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
26. A method for modulating the immune response in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
27. A method for treating or controlling HTV infection in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
28. A method for treating, controlling or preventing in a mammalian patient in need of treatment one or more disorders selected from the group consisting of neutropenia, neuronal disorders, tumor metastasis, benign prostatic hypertrophy, gingivitis, hypertension and osteoporosis which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
29. A method for reducing sperm motility in a male mammalian patient which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1.
30. A method for treating, controlling or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisitng of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component, wherein the method comprises the administration to the patient of a therapeutically effective amount of a compound of Claim 1.
31. A method for treating, controlling or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), (25) Type TJ diabetes, (26) growth hormone deficiency, (27) neutropenia, (28) neuronal disorders, (29) tumor metastasis, (30) benign prostatic hypertrophy, (32) gingivitis, (33) hypertension, (34) osteoporosis, and other conditions that may be treated by inhibition of DP-TV, wherein the treatment comprises the administration to the patient of a therapeutically effective amount of a first compound of Claim 1, or a pharmaceutically acceptable salt thereof, and one or more other compounds selected from the group consisting of: (a) other dipeptidyl peptidase TV (DP-TV) inhibitors, (b) insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein tyrosine phosphatase-lB (PTP-1B) inhibitors;
(c) insulin or insulin mimetics;
(d) sulfonylureas or other insulin secretagogues; (e) α-glucosidase inhibitors;
(f) glucagon receptor agonists;
(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (h) GIP, GTP mimetics, and GTP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) cholesterol lowering agents selected from the group consisting of
(i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants; (k) PPARδ agonists; (1) antiobesity compounds;
(m) an ileal bile acid transporter inhibitor; and
(n) anti-inflammatory agents.
32. A method for the treatment, control, or prevention of one or more conditions selected from intestinal injury, inflammatory bowel disease, Crohn's disease, and ulcerative colitis, which method comprises administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of Claim 1.
33. A method for the treatment, control, or prevention of one or more conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia, which method comprises administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of Claim 1 and an HMG-CoA reductase inhibitor.
34. The method of Claim 33, wherein the HMG-CoA reductase inhibitor is a statin.
35. The method of Claim 34, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
36. A method for the treatment, control, or prevention of atherosclerosis in a mammalian patient in need of such treatment comprising the administration to the patient of an effective amount of a compound of Claim 1 and an effective amount of an HMG-CoA reductase inhibitor.
37. The method as recited in Claim 36, wherein the HMG-CoA reductase inhibitor is a statin.
38. The method as recited in Claim 37, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
39. A pharmaceutical composition for the treatment, prevention or control of atherosclerosis, comprising: (1) a compound of Claim 1, (2) an HMG- CoA reductase inhibitor, and (3) a pharmaceutically acceptable carrier.
40. A pharmaceutical composition comprising
(1) a compound of Claim 1,
(2) one or more compounds selected from the group consisting of :
(a) other dipeptidyl peptidase TV (DP-TV) inhibitors; (b) insulin sensitizers selected from the group consisting of (i) PPARγ agonists, other PPAR ligands, PPARα/γ dual agonists, and PPARα agonists, (ii) biguanides, and (iii) protein tyrosine phosphatase-lB (PTP-IB) inhibitors;
(b) insulin or insulin mimetics;
(c) sulfonylureas or other insulin secretagogues; (d) α-glucosidase inhibitors;
(f) glucagon receptor agonists;
(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (h) GTP, GTP mimetics, and GTP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) cholesterol lowering agents selected from the group consisting of
(i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoAxholesterol acyltransferase inhibitors, and (viii) anti-oxidants; (k) PPARδ agonists;
(1) antiobesity compounds;
(m) an ileal bile acid transporter inhibitor; and
(n) anti-inflammatory agents; and
(3) a pharmaceutically acceptable carrier.
PCT/US2002/021349 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes WO2003004498A1 (en)

Priority Applications (42)

Application Number Priority Date Filing Date Title
UA2004020837A UA74912C2 (en) 2001-07-06 2002-05-07 Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
BRPI0210866A BRPI0210866B8 (en) 2001-07-06 2002-07-05 beta-amino tetrahydroimidazo (1,2-a) pyrazine and tetrahydrotriazole (4.3-a) pyrazine compounds, uses thereof and pharmaceutical composition
NZ529833A NZ529833A (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-A) pyrazines and tetrahydrotrioazolo (4, 3-A) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
AU2002320303A AU2002320303B2 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-A) pyrazines and tetrahydrotrioazolo (4, 3-A) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
HU0401104A HU225695B1 (en) 2001-07-06 2002-07-05 Beta-aminoacyl tetrahydroimidazo[1,2-a]pyrazines and tetrahydrotriazolo[4,3-a]pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes and pharmaceutical compositions containing them
DE200712000056 DE122007000056I1 (en) 2001-07-06 2002-07-05 Beta-amino-tetrahydroimidazo (1,2-A) pyrazines and -tetrahydrotriazolo (4,3-A) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
IL15910902A IL159109A0 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1,2-a) pyrazines and tetrahydrotriazolo (4,3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
CA002450740A CA2450740C (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
DE122008000046C DE122008000046I1 (en) 2001-07-06 2002-07-05 BETA-AMINO-TETRAHYDROIMIDAZO (1,2-A) PYRAZINE AND -ETRAHYDROTRIAZOLO (4,3-A) PYRAZINE AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
PL367279A PL196278B6 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
DE60210093T DE60210093T2 (en) 2001-07-06 2002-07-05 BETA-AMINO-TETRAHYDROIMIDAZO (1,2-A) PYRAZINE AND -ETRAHYDROTRIAZOLO (4,3-A) PYRAZINE AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
US10/481,353 US7125873B2 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
MEP-2008-667A ME00439B (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
MXPA04000018A MXPA04000018A (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes.
JP2003510665A JP3762407B2 (en) 2001-07-06 2002-07-05 Β-aminotetrahydroimidazo (1,2-A) pyrazines and tetrahydrotriazolo (4,3-A) pyrazines as dipeptidyl peptidase inhibitors for treating or preventing diabetes
SI200230301T SI1412357T1 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo(1,2-a)pyrazines and tetrahydrotriazolo(4,3-a)pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
KR1020047000166A KR100606871B1 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo 1,2-a pyrazines and tetrahydrotriazolo 4, 3-a pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP02749813A EP1412357B1 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo(1,2-a)pyrazines and tetrahydrotriazolo(4,3-a)pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EA200400153A EA006845B1 (en) 2001-07-06 2002-07-05 Beta-amino tetrahydroimidazo(1, 2-a) pyrazines and tetrahydrotrioazolo (4, 3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
IL159109A IL159109A (en) 2001-07-06 2003-11-27 Dipeptidyl peptidase inhibiting 7-(3-amino-4-arylbutanoyl)tetrahydroimidazo (1,2-a) pyrazine and tetrahydrotriazolo (4,3-a) pyrazine derivatives and pharmaceutical compositions containing them
IS7062A IS2218B (en) 2001-07-06 2003-11-28 Beta-amino tetrahydroimidazo (1,2-a) pyrazine and tetrahydrotriazolo (4,3-a) pyrazine which dipeptidylpeptidase inhibits the treatment or prevention of diabetes.
HR20031098A HRP20031098B1 (en) 2001-07-06 2003-12-30 Beta-amino tetrahydroimidazo (1,2-a) pyrazines and tetrahydrotrioazolo (4,3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
NO20040021A NO321999B1 (en) 2001-07-06 2004-01-05 Beta-amino-tetrahydroimidaz (1,2-a) pyrazines and tetrahydrotriazolo (4,3-a) pyrazines, pharmaceutical compositions comprising the compounds, and use of the compounds in the manufacture of medicaments for use in the treatment of type II diabetes.
HK05101300A HK1068882A1 (en) 2001-07-06 2005-02-16 Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4,3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US11/500,252 US20060270679A1 (en) 2001-07-06 2006-08-07 Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
IL178307A IL178307A (en) 2001-07-06 2006-09-26 PHARMACEUTICAL COMPOSITION COMPRISING A TETRAHYDROTRIAZOLO[4,3-a]PYRAZINE
IS8617A IS2964B (en) 2001-07-06 2007-03-06 Beta-amino tetrahydroimidazo (1,2-a) pyrazine and tetrahydrotiazolo (4,3-a) pyrazine for use in the treatment of type II diabetes
NL300287C NL300287I2 (en) 2001-07-06 2007-08-16 Beta-amino tetrahydroimidazo (1,2-A) pyrazines and tetrehydrotriazolo (4,3-A) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
CY200700019C CY2007019I1 (en) 2001-07-06 2007-08-23 B-AMINO-TETRAHYDROIMIDAZO-(1,2-A)-PYRASINES AND TETRAHYDROTRIAZOLE-(4,3-A)-PYRASINES AS DIPEPTIDYLPEPTIDASE INHIBITORS FOR THE INDUCTION OR PREVENTION OF DIABETES
FR07C0041C FR07C0041I2 (en) 2001-07-06 2007-08-27 BETA-AMINO-TETRAHYDROIMIDAZO(1, 2-A)PYRAZINES AND BETA-AMINO-TETRAHYDROTRIOAZOLO(4, 3-A)PYRAZINES USED AS DIPEPTIDYL PEPTIDASE INHIBITORS IN THE TREATMENT OR PREVENTION OF DIABETES
LU91360C LUC91360I2 (en) 2001-07-06 2007-09-05
NO2007010C NO2007010I2 (en) 2001-07-06 2007-09-06 Sitagliptin, optionally in the form of a pharmaceutically acceptable salt
LTPA2007006C LTC1412357I2 (en) 2001-07-06 2007-09-12 Beta-amino tetrahydroimidazo (1,2-a) pyrazines and tetrahydrotrazole (4,3-A) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
BE2007C047C BE2007C047I2 (en) 2001-07-06 2007-09-13
NL300357C NL300357I2 (en) 2001-07-06 2008-08-15 Beta-amino tetrahydroimidazo (1,2-A) pyrazines and
LU91470C LU91470I2 (en) 2001-07-06 2008-08-18 Beta-amino-tetrahydroimidazo (1,2-A) pyrazines and betaamino-tetrahydrotrioazolo (4,3-A) pyrazines used as inhibitors of dipeptidyl peptibase in the treatment or prevention of diabetes
FR08C0033C FR08C0033I2 (en) 2001-07-06 2008-08-21 BETA-AMINO-TETRAHYDROIMIDAZO(1, 2-A)PYRAZINES AND BETA-AMINO-TETRAHYDROTRIOAZOLO(4, 3-A)PYRAZINES USED AS DIPEPTIDYL PEPTIDASE INHIBITORS IN THE TREATMENT OR PREVENTION OF DIABETES
NO2008013C NO2008013I2 (en) 2001-07-06 2008-08-22 Sitagliptin, optionally in the form of a pharmaceutically acceptable salt, especially the monophosphate, plus metformin hydrochloride.
CY200800014C CY2008014I1 (en) 2001-07-06 2008-09-09 B-AMINO-TETRAHYDROIMIDAZO-(1,2-A)-PYRASINES AND TETRAHYDROTRIAZOLE-(4,3-A)-PYRASINES AS DIPEPTIDYLPEPTIDASE INHIBITORS FOR THE INDUCTION OR PREVENTION OF DIABETES
US12/694,758 US8168637B2 (en) 2001-07-06 2010-01-27 Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment of diabetes
US13/086,563 US8440668B2 (en) 2001-07-06 2011-04-14 Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment of type 2 diabetes
NO2020007C NO2020007I1 (en) 2001-07-06 2020-03-19 Sitagliptin, optionally in the form of a pharmaceutically acceptable salt

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Cited By (231)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002986A2 (en) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Novel benzimidazole derivatives
WO2004052362A1 (en) * 2002-12-10 2004-06-24 Novartis Ag Combination of an dpp-iv inhibitor and a ppar-alpha compound
WO2004069162A2 (en) 2003-01-31 2004-08-19 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004080958A2 (en) * 2003-03-07 2004-09-23 Merck & Co. Inc. Process to tetrahydrotriazolopyrazines and intermediates
WO2004083212A1 (en) * 2003-03-18 2004-09-30 Merck & Co., Inc. Process to beta-ketoamide intermediates to dipeptidyl peptidase inhibitors
WO2004085661A2 (en) * 2003-03-24 2004-10-07 Merck & Co., Inc Process to chiral beta-amino acid derivatives
WO2004087650A2 (en) * 2003-03-27 2004-10-14 Merck & Co. Inc. Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
WO2004098591A2 (en) 2003-05-05 2004-11-18 Probiodrug Ag Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases
WO2004103276A2 (en) 2003-05-14 2004-12-02 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1490335A2 (en) * 2002-03-25 2004-12-29 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2005003135A1 (en) * 2003-06-24 2005-01-13 Merck & Co., Inc. Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005028438A1 (en) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
EP1554280A2 (en) * 2002-10-07 2005-07-20 Merck & Co., Inc. Antidiabetic beta-amino heterocyclic dipeptidyl peptidase inhibitors
WO2005072530A1 (en) * 2004-01-16 2005-08-11 Merck & Co., Inc. Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor
WO2005075436A2 (en) 2004-02-05 2005-08-18 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
EP1583534A1 (en) * 2002-12-20 2005-10-12 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2005097759A1 (en) 2004-03-29 2005-10-20 Merck & Co., Inc. Diaryltriazoles as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
EP1589969A2 (en) * 2003-01-17 2005-11-02 Merck & Co. Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2006017542A1 (en) 2004-08-06 2006-02-16 Merck & Co., Inc. Sulfonyl compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
EP1662876A2 (en) * 2003-09-02 2006-06-07 Merck & Co., Inc. Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
EP1667524A2 (en) * 2003-09-23 2006-06-14 Merck & Co., Inc. Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
US7098239B2 (en) 2001-06-20 2006-08-29 Merck & Co., Inc Dipeptidyl peptidase inhibitors for the treatment of diabetes
JP2006521354A (en) * 2003-03-19 2006-09-21 メルク エンド カムパニー インコーポレーテッド Process for producing chiral beta amino acid derivatives by asymmetric hydrogenation
US7132443B2 (en) 2001-06-27 2006-11-07 Smithklinebeecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
WO2006129826A1 (en) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
US7157490B2 (en) 2002-11-07 2007-01-02 Merck & Co., Inc. Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2007018248A1 (en) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Pyridone compound
WO2007024004A1 (en) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
WO2007029847A1 (en) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Bicyclic aromatic substituted pyridone derivative
WO2007035198A2 (en) * 2005-07-25 2007-03-29 Merck & Co., Inc. Dodecylsulfate salt of a dipeptidyl peptidase-iv inhibitor
WO2007041052A2 (en) 2005-09-29 2007-04-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
WO2007049798A1 (en) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Novel benzoxathiin derivative
EP1784188A2 (en) * 2004-08-23 2007-05-16 Merck & Co., Inc. Fused triazole derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2007055418A1 (en) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Aza-substituted spiro derivative
EP1796671A1 (en) * 2004-09-15 2007-06-20 Merck & Co., Inc. Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
EP1801098A1 (en) 2005-12-16 2007-06-27 Merck Sante 2-Adamantylurea derivatives as selective 11B-HSD1 inhibitors
WO2007072083A1 (en) 2005-12-23 2007-06-28 Prosidion Limited Treatment of type 2 diabetes with a combination of dpiv inhibitor and metformin or thiazolidinedione
WO2007077508A2 (en) 2005-12-30 2007-07-12 Ranbaxy Laboratories Limited Derivatives of beta-amino acid as dipeptidyl peptidase-iv inhibitors
US7253172B2 (en) 2001-06-20 2007-08-07 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
WO2007120702A2 (en) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
KR100776623B1 (en) 2005-04-01 2007-11-15 주식회사 엘지생명과학 Dipeptidyl Peptidase-IV Inhibiting Compounds, Methods of Preparing the Same, and Pharmaceutical Compositions Containing the Same as an Active Agent
EP1888066A2 (en) * 2005-05-25 2008-02-20 Merck and Co., Inc. Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2008038692A1 (en) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. Diaryl ketimine derivative
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
WO2007078726A3 (en) * 2005-12-16 2008-06-12 Merck & Co Inc Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
WO2008074384A1 (en) 2006-12-21 2008-06-26 Merck Patent Gmbh 2-ADAMANTYL-BUTYRAMIDE DERIVATIVES AS SELECTIVE 11βETA-HSD1 INHIBITORS
WO2008093960A1 (en) * 2007-01-30 2008-08-07 Lg Life Sciences, Ltd. Novel dipeptidyl peptidase-iv inhibitors
WO2008120653A1 (en) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Indoledione derivative
WO2008120813A1 (en) 2007-04-03 2008-10-09 Mitsubishi Tanabe Pharma Corporation Combined use of dipeptidyl peptidase iv inhibitor compound and sweetener
WO2008137105A1 (en) 2007-05-07 2008-11-13 Merck & Co., Inc. Method of treatment using fused aromatic compounds having anti-diabetic activity
US7495123B2 (en) 2004-04-05 2009-02-24 Solvias Ag Process for the preparation of enantiomerically enriched beta amino acid derivatives
WO2009082881A1 (en) 2007-12-26 2009-07-09 Shanghai Hengrui Pharmaceutical Co., Ltd. Tetrahydro-imidazo[1,5-a]pyrazine derivatives, preparation methods and medical uses thereof
WO2009093269A1 (en) * 2008-01-24 2009-07-30 Panacea Biotec Limited Novel heterocyclic compounds
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2009110510A1 (en) 2008-03-06 2009-09-11 萬有製薬株式会社 Alkylaminopyridine derivative
WO2009082134A3 (en) * 2007-12-21 2009-09-24 Lg Life Sciences, Ltd. Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent
WO2009119726A1 (en) 2008-03-28 2009-10-01 萬有製薬株式会社 Diarylmethylamide derivative having antagonistic activity on melanin-concentrating hormone receptor
EP2110374A1 (en) 2008-04-18 2009-10-21 Merck Sante Benzofurane, benzothiophene, benzothiazol derivatives as FXR modulators
EP2116235A1 (en) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
WO2009154132A1 (en) 2008-06-19 2009-12-23 萬有製薬株式会社 Spirodiamine-diarylketoxime derivative
WO2010013595A1 (en) 2008-07-30 2010-02-04 萬有製薬株式会社 (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative
EP2165703A2 (en) 2004-01-20 2010-03-24 Novartis Pharma AG. Direct compression formulation and process
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US7709468B2 (en) 2005-09-02 2010-05-04 Abbott Laboratories Imidazo based heterocycles
WO2010051236A1 (en) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Isonicotinamide orexin receptor antagonists
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010056717A1 (en) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Substituted bicyclic amines for the treatment of diabetes
EP2191824A1 (en) 2005-06-10 2010-06-02 Novartis AG Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation
WO2010079197A1 (en) 2009-01-07 2010-07-15 Boehringer Ingelheim International Gmbh Treatment of diabetes in patients with inadequate glycemic control despite metformin therapy comprising a dpp-iv inhibitor
EP2213289A1 (en) 2006-09-07 2010-08-04 Nycomed GmbH Combination treatment for diabetes mellitus
WO2010086411A1 (en) 2009-01-29 2010-08-05 Boehringer Ingelheim International Gmbh Dpp-iv inhibitors for treatment of diabetes in paediatric patients
EP2218721A1 (en) 2009-02-11 2010-08-18 LEK Pharmaceuticals d.d. Novel salts of sitagliptin
WO2010092125A1 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
WO2010032264A3 (en) * 2008-08-27 2010-08-19 Cadila Healthcare Limited Improved process for preparation of (2r)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro [1,2,4]-triazolo[4,3-a]pyrazin- 7(8h)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine & new impurities in preparation thereof
WO2010092163A2 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Antidiabetic medications
EP2223923A1 (en) 2009-02-25 2010-09-01 Esteve Química, S.A. Process for the preparation of a chiral beta aminoacid derivative and intermediates thereof
WO2010114292A2 (en) 2009-03-30 2010-10-07 동아제약 주식회사 Improved method for manufacturing dipeptidyl peptidase-iv inhibitor and intermediate
WO2010114291A2 (en) 2009-03-30 2010-10-07 동아제약 주식회사 Improved method for preparing dipeptidyl peptidase-iv inhibitor and intermediate
US7820666B2 (en) * 2007-05-08 2010-10-26 Concert Pharmaceuticals, Inc. Tetrahydrotriazolopyrazine derivatives and uses thereof
WO2010131025A1 (en) * 2009-05-11 2010-11-18 Generics [Uk] Limited Sitagliptin synthesis
US7838525B2 (en) 2003-07-11 2010-11-23 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
WO2010135944A1 (en) 2009-05-27 2010-12-02 江苏恒瑞医药股份有限公司 Salts of methyl (r)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate
WO2011005929A1 (en) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Piperidine derivative and its use for the treatment of diabets and obesity
WO2011006143A2 (en) 2009-07-09 2011-01-13 Irm Llc Compounds and compositions for the treatment of parasitic diseases
WO2011011506A1 (en) 2009-07-23 2011-01-27 Schering Corporation Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
WO2011011508A1 (en) 2009-07-23 2011-01-27 Schering Corporation Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
US7884104B2 (en) 2004-10-01 2011-02-08 Merck Sharp & Dohme Corp. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US7888351B2 (en) 2006-04-11 2011-02-15 Novartis Ag Organic compounds
WO2011018494A1 (en) 2009-08-13 2011-02-17 Sandoz Ag Crystalline compound of 7-[(3r)-3-amino-1-oxo-4-(2, 4, 5-trifluorphenyl)butyl]-5, 6, 7, 8-tetrahydro-3-(tri fluormethyl)-1, 2, 4 -triazolo[4,3-a]pyrazine
EP2295083A1 (en) 2009-09-15 2011-03-16 Ratiopharm GmbH Pharmaceutical composition comprising active agents metformin and sitagliptin or vildagliptin
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
EP2308847A1 (en) 2009-10-09 2011-04-13 EMC microcollections GmbH Substituted pyridines as inhibitors of dipeptidyl peptidase IV and their application for the treatment of diabetes and related diseases
CN101397300B (en) * 2007-09-04 2011-04-27 山东轩竹医药科技有限公司 Dipeptidase-IV inhibitor derivates
US7943584B2 (en) 2004-07-29 2011-05-17 Sankyo Company, Limited Medicinal composition containing diabetes remedy
WO2011058193A1 (en) 2009-11-16 2011-05-19 Mellitech [1,5]-diazocin derivatives
WO2011064352A1 (en) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2338490A2 (en) 2003-11-03 2011-06-29 Probiodrug AG Combinations Useful for the Treatment of Neuronal Disorders
EP2351567A2 (en) * 2008-10-17 2011-08-03 Dong-A Pharmaceutical Co., Ltd. Pharmaceutical composition for prevention and treatment of diabetes or obesity comprising a compound that inhibits activity of dipeptidyl peptidase-iv, and other antidiabetic or antiobesity agents as active ingredients
CN102159578A (en) * 2009-03-05 2011-08-17 江苏恒瑞医药股份有限公司 Salts of tetrahydroimidazo [1,5-a] pyrazine derivatives, preparation methods and pharmaceutical use thereof
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
WO2011135586A2 (en) 2010-04-28 2011-11-03 Sun Pharmaceutical Industries Ltd. Process for the preparation of chiral beta amino carboxamide derivatives
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
EP2392575A1 (en) 2010-06-04 2011-12-07 LEK Pharmaceuticals d.d. A novel synthetic approach to ß-aminobutyryl substituted compounds
WO2011151443A1 (en) 2010-06-04 2011-12-08 Lek Pharmaceuticals D.D. A NOVEL SYNTHETIC APPROACH TO ß-AMINOBUTYRYL SUBSTITUTED COMPOUNDS
US8076514B2 (en) 2005-07-20 2011-12-13 Eli Lilly And Company Phenyl compounds and their use in the treatment of Type II diabetes
EP2397141A1 (en) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Process for the synthesis of beta-amino acids and derivatives thereof
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2011161161A1 (en) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Diabetes therapy
US20120010211A1 (en) * 2009-03-31 2012-01-12 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition for treatment of type 2 diabetes
EP2407469A1 (en) 2010-07-13 2012-01-18 Chemo Ibérica, S.A. Salt of sitagliptin
US8106090B2 (en) 2005-07-20 2012-01-31 Eli Lilly And Company 1-amino linked compounds
EP2423178A1 (en) 2010-07-28 2012-02-29 Chemo Ibérica, S.A. Process for the production of sitagliptin
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US8133907B2 (en) 2005-07-20 2012-03-13 Eli Lilly And Company Pyridine derivatives as dipeptedyl peptidase inhibitors
WO2012035549A2 (en) 2010-09-13 2012-03-22 Panacea Biotec Ltd An improved process for the synthesis of beta amino acid derivatives
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012046254A2 (en) 2010-10-08 2012-04-12 Cadila Healthcare Limited Process for preparing an intermediate of sitagliptin via enzymatic conversion
KR101156587B1 (en) 2010-02-19 2012-06-20 한미사이언스 주식회사 Preparation method of sitagliptin and amine salt intermediate used therein
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012118972A2 (en) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Process of preparing guanylate cyclase c agonists
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
US8278486B2 (en) 2008-12-31 2012-10-02 Chiral Quest, Inc. Process and intermediates for the preparation of N-acylated-4-aryl beta-amino acid derivatives
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012131005A1 (en) 2011-03-29 2012-10-04 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical composition of sitagliptin
EP2508506A1 (en) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Preparation of sitagliptin intermediates
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
CN102757431A (en) * 2011-04-24 2012-10-31 浙江华海药业股份有限公司 Novel method for synthesizing sitagliptin
WO2012147092A2 (en) 2011-03-03 2012-11-01 Cadila Healthcare Limited Novel salts of dpp-iv inhibitor
ITMI20110765A1 (en) * 2011-05-05 2012-11-06 Chemo Iberica Sa PROCESS FOR SITAGLIPTINA PRODUCTION
EP2527320A1 (en) 2011-05-27 2012-11-28 LEK Pharmaceuticals d.d. Preparation of Sitagliptin Intermediates
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013013833A1 (en) 2011-07-27 2013-01-31 Farma Grs, D.O.O. Process for the preparation of sitagliptin and its pharmaceutically acceptable salts
US8410119B2 (en) 2003-07-14 2013-04-02 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013059222A1 (en) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. 2-pyridyloxy-4-nitrile orexin receptor antagonists
EP2586782A1 (en) 2008-07-03 2013-05-01 Ratiopharm GmbH Crystalline salts of sitagliptin
US8466145B2 (en) 2009-01-09 2013-06-18 Orchid Chemicals & Pharmaceuticals Limited Dipeptidyl peptidase IV inhibitors
EP2615080A1 (en) 2012-01-12 2013-07-17 LEK Pharmaceuticals d.d. Preparation of Optically Pure ß-Amino Acid Type Active Pharmaceutical Ingredients and Intermediates thereof
WO2013128000A1 (en) 2012-03-02 2013-09-06 Moehs Iberica S.L. Novel crystalline form of sitagliptin sulfate
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
US8551524B2 (en) 2008-03-14 2013-10-08 Iycus, Llc Anti-diabetic combinations
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
EP2674432A1 (en) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. New synthetic route for the preparation of ß aminobutyryl substituted 5,6,7,8-tetrahydro[1,4]diazolo[4,3-alpha]pyrazin-7-yl compounds
US8637079B2 (en) 2007-02-01 2014-01-28 Takeda Pharmaceutical Company Limited Solid preparation comprising alogliptin and pioglitazone
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US8648073B2 (en) 2009-12-30 2014-02-11 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
EP2698152A1 (en) 2007-08-16 2014-02-19 Boehringer Ingelheim International GmbH Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
EP2698157A1 (en) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
US8691832B2 (en) 2010-12-06 2014-04-08 Merck Sharp & Dohme Corp. Tricyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
US20140187558A1 (en) * 2011-05-27 2014-07-03 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
EP2769712A1 (en) 2013-02-21 2014-08-27 Siegfried International AG Pharmaceutical formulation comprising DPP-IV inhibitor agglomerates and DPP-IV inhibitor particles
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
US8853385B2 (en) 2008-01-17 2014-10-07 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising SGLT inhibitors and DPP4 inhibitors
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US8895603B2 (en) 2011-06-29 2014-11-25 Merck Sharp & Dohme Corp. Crystalline forms of a dipeptidyl peptidase-IV inhibitor
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
EP2839832A2 (en) 2003-11-17 2015-02-25 Novartis AG Use of dipeptidyl peptidase IV inhibitors
US8980929B2 (en) 2010-05-21 2015-03-17 Merck Sharp & Dohme Corp. Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
WO2015062562A1 (en) 2013-11-01 2015-05-07 Zentiva, K.S. A stable polymorph of the salt of (2r)-4-oxo-4-[3-(trifiuoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-l-(2,4,54rifluorophenyl)butan-2-amine with l-tartaric acid
WO2015068156A1 (en) 2013-11-05 2015-05-14 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
US9050292B2 (en) 2011-01-07 2015-06-09 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US9051329B2 (en) 2011-07-05 2015-06-09 Merck Sharp & Dohme Corp. Tricyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
EP2766369A4 (en) * 2011-10-14 2015-07-01 Laurus Labs Private Ltd Novel salts of sitagliptin, process for the preparation and pharmaceutical composition thereof
US9073930B2 (en) 2012-02-17 2015-07-07 Merck Sharp & Dohme Dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
TWI494313B (en) * 2010-12-29 2015-08-01 Jiangsu Hengrui Medicine Co Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings
US9156848B2 (en) 2012-07-23 2015-10-13 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-IV inhibitors
WO2015160678A1 (en) 2014-04-17 2015-10-22 Merck Sharp & Dohme Corp. Sitagliptin tannate complex
US9211263B2 (en) 2012-01-06 2015-12-15 Elcelyx Therapeutics, Inc. Compositions and methods of treating metabolic disorders
EP2990037A1 (en) 2008-08-06 2016-03-02 Boehringer Ingelheim International GmbH Treatment for diabetes in patients inappropriate for metformin therapy
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2016046679A1 (en) * 2014-09-28 2016-03-31 Mohan M Alapati Compositions and methods for the treatment of diabetes and pre-diabetes
US9315508B2 (en) 2012-07-23 2016-04-19 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-IV inhibitors
WO2016112879A1 (en) 2015-01-13 2016-07-21 Zentiva, K.S. CRYSTALLINE MODIFICATION 2 OF (3/R)-3-AMINO-1-[3-(TRIFLUOROMETHYL)-6,8-DIHYDRO-5H-[1,2,4]TRIAZOLO[4,3-α]PYRAZIN-7-YL]-4-(2,4,5-TRIFLUOROPHENYL)BUTAN-1-ONE L-TARTRATE
WO2016112880A1 (en) 2015-01-13 2016-07-21 Zentiva, K.S Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate
US9399051B2 (en) 2009-08-03 2016-07-26 Kaneka Corporation Dipeptidyl peptidase-4 inhibitor
CZ306115B6 (en) * 2012-12-04 2016-08-10 Zentiva, K.S. Process for preparing derivatives of 3-amino-4-(2,4,5-trifluorophenyl)-butanoic acid
WO2016168535A1 (en) * 2015-04-15 2016-10-20 Valent Biosciences Corporation (s)-2'-vinyl-abscisic acid derivatives
US9480663B2 (en) 2011-01-07 2016-11-01 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US9481642B2 (en) 2011-01-07 2016-11-01 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
EP3087975A1 (en) 2004-08-27 2016-11-02 Novartis Ag Treatment with vildagliptin
KR20160146124A (en) 2015-06-11 2016-12-21 동방에프티엘(주) Improved method of sitagliptin
KR20160148371A (en) 2015-06-16 2016-12-26 경동제약 주식회사 Novel intermediates for preparing DPP-IV inhibitors, preparing method thereof and preparing method of DPP-IV inhibitors using the same
US9572784B2 (en) 2011-01-07 2017-02-21 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
KR20170036288A (en) 2015-09-24 2017-04-03 주식회사 종근당 Novel Salts of Sitagliptin and Preparation Method thereof
EP3159343A1 (en) * 2015-10-22 2017-04-26 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Improved process for the preparation of triazole and salt thereof
US9663448B2 (en) 2007-06-04 2017-05-30 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
US9862725B2 (en) 2014-07-21 2018-01-09 Merck Sharp & Dohme Corp. Process for preparing chiral dipeptidyl peptidase-IV inhibitors
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US10047094B1 (en) 2017-02-10 2018-08-14 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Process for the preparation of triazole and salt thereof
WO2018162722A1 (en) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Dpp-4 inhibitors for use in treating bone fractures
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
KR20190060235A (en) 2017-11-24 2019-06-03 제일약품주식회사 Preparation Method Camphorsulfonic acid Salt of Sitagliptin
US10450315B2 (en) 2015-01-08 2019-10-22 Lee Pharma Limited Process for the preparation of dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
EP3626238A1 (en) 2008-08-15 2020-03-25 Boehringer Ingelheim International GmbH Dpp-4 inhibitors for use for the treatment of wound healing in diabetic patients
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
WO2020167706A1 (en) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. 5-alkyl pyrrolidine orexin receptor agonists
WO2021026047A1 (en) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Heteroaryl pyrrolidine and piperidine orexin receptor agonists
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
KR20210057603A (en) 2019-11-12 2021-05-21 제이투에이치바이오텍 (주) Process for preparing sitagliptin
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
WO2022040070A1 (en) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Bicycloheptane pyrrolidine orexin receptor agonists
EP4000630A1 (en) 2014-09-03 2022-05-25 Invex Therapeutics Ltd Elevated intracranial pressure treatment
KR20220145631A (en) 2021-04-22 2022-10-31 주식회사 메디켐코리아 Improved manufacturing method of sitagliptin phosphate salt
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
WO2023139276A1 (en) 2022-01-24 2023-07-27 Zaklady Farmaceutyczne Polpharma S.A. Process for preparing crystalline sitagliptin hydrochloride monohydrate
US11738028B2 (en) 2017-04-24 2023-08-29 Novartis Ag Therapeutic regimen
US11759441B2 (en) 2011-01-07 2023-09-19 Anji Pharmaceuticals Inc. Biguanide compositions and methods of treating metabolic disorders
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Families Citing this family (190)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020006899A1 (en) * 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
US7544511B2 (en) * 1996-09-25 2009-06-09 Neuralstem Biopharmaceuticals Ltd. Stable neural stem cell line methods
US20030176357A1 (en) * 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
RU2241712C9 (en) * 1998-12-31 2006-04-20 Сосьете Де Консей Де Решерш Э Д`Аппликасьон Сьентификс Сас Derivatives of imidazole as inhibitors of prenyl transferase, pharmaceutical composition and methods for treatment based on thereof
UA74912C2 (en) * 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
AU2003219787A1 (en) * 2002-02-14 2003-09-04 Bayer Pharmaceuticals Corporation Formulation strategies in stabilizing peptides in organic solvents and in dried states
CA2490818A1 (en) * 2002-07-15 2004-01-22 Merck & Co., Inc. Piperidino pyrimidine dipeptidyl peptidase inhibitors for the treatment of diabetes
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
KR20050067418A (en) * 2002-10-18 2005-07-01 머크 앤드 캄파니 인코포레이티드 Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7309714B2 (en) * 2002-12-04 2007-12-18 Merck & Co., Inc. Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US8293488B2 (en) 2002-12-09 2012-10-23 Neuralstem, Inc. Method for screening neurogenic agents
US20040185429A1 (en) * 2002-12-09 2004-09-23 Judith Kelleher-Andersson Method for discovering neurogenic agents
US20040242568A1 (en) * 2003-03-25 2004-12-02 Syrrx, Inc. Dipeptidyl peptidase inhibitors
GB0310593D0 (en) * 2003-05-08 2003-06-11 Leuven K U Res & Dev Peptidic prodrugs
EP1625122A1 (en) 2003-05-14 2006-02-15 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
CA2526770A1 (en) * 2003-06-06 2004-12-23 Merck & Co., Inc. Fused indoles as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1635832A2 (en) * 2003-06-06 2006-03-22 Merck & Co., Inc. Combination therapy for the treatment of diabetes
CA2527806A1 (en) * 2003-06-17 2004-12-29 Merck & Co., Inc. Cyclohexylglycine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
BRPI0412252A (en) * 2003-07-25 2006-09-19 Conjuchem Inc long-term insulin derivatives and their methods
JP2007500704A (en) * 2003-07-31 2007-01-18 メルク エンド カムパニー インコーポレーテッド Hexahydrodiazepinone as a dipeptidyl peptidase IV-inhibitor for the treatment or prevention of diabetes
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US20050065148A1 (en) * 2003-08-13 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP1697342A2 (en) * 2003-09-08 2006-09-06 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP2007505121A (en) * 2003-09-08 2007-03-08 武田薬品工業株式会社 Dipeptidyl peptidase inhibitor
US20070123470A1 (en) * 2003-10-24 2007-05-31 Wladimir Hogenhuis Enhancement of growth hormone levels with a dipeptidyl peptidase IV inhibitor and a growth hormone secretagogue
JP2007510651A (en) * 2003-11-04 2007-04-26 メルク エンド カムパニー インコーポレーテッド Fused phenylalanine derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US7317109B2 (en) * 2003-11-12 2008-01-08 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
BRPI0416444B8 (en) * 2003-11-12 2021-05-25 Chiesi Farm Spa heterocyclic boronic acid compound, pharmaceutical composition, and, pharmaceutical combination comprising the same
US7767828B2 (en) * 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US7576121B2 (en) * 2003-11-12 2009-08-18 Phenomix Corporation Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
ATE537141T1 (en) * 2004-02-05 2011-12-15 Kyorin Seiyaku Kk BICYCLOESTER DERIVATIVE
CN1922139B (en) * 2004-02-18 2010-12-29 杏林制药株式会社 Bicyclic amide derivatives
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
CA2557275C (en) * 2004-02-27 2012-06-05 Kyorin Pharmaceutical Co., Ltd. Bicyclo derivative
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
KR101071390B1 (en) 2004-03-15 2011-10-07 다케다 야쿠힌 고교 가부시키가이샤 dipeptidyl peptidase inhibitors
JP2007536234A (en) * 2004-05-04 2007-12-13 メルク エンド カムパニー インコーポレーテッド 1,2,4-oxadiazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
JP2007538079A (en) * 2004-05-18 2007-12-27 メルク エンド カムパニー インコーポレーテッド Cyclohexylalanine derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US7687638B2 (en) * 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
AU2005265148B2 (en) * 2004-06-21 2011-01-20 Merck Sharp & Dohme Corp. Aminocyclohexanes as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2006019965A2 (en) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7842707B2 (en) * 2004-07-23 2010-11-30 Nuada, Llc Peptidase inhibitors
US20070259927A1 (en) * 2004-08-26 2007-11-08 Takeda Pharmaceutical Company Limited Remedy for Diabetes
US20060063719A1 (en) * 2004-09-21 2006-03-23 Point Therapeutics, Inc. Methods for treating diabetes
KR20070073887A (en) * 2004-10-12 2007-07-10 그렌마크 파머수티칼스 에스. 아. Novel dipeptidyl peptidase iv inhibitors, pharmaceutical compositions containing them, and process for their preparation
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
US7691629B2 (en) 2004-11-17 2010-04-06 Neuralstem, Inc. Transplantation of human neural cells for treatment of neurodegenerative conditions
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8017633B2 (en) * 2005-03-08 2011-09-13 Nycomed Gmbh Roflumilast for the treatment of diabetes mellitus
EP1879582A4 (en) * 2005-05-02 2009-05-13 Merck & Co Inc Combination of dipeptidyl peptidase-iv inhibitor and a cannabinoid cb1 receptor antagonist for the treatment of diabetes and obesity
US7825139B2 (en) * 2005-05-25 2010-11-02 Forest Laboratories Holdings Limited (BM) Compounds and methods for selective inhibition of dipeptidyl peptidase-IV
JP4915833B2 (en) * 2005-07-01 2012-04-11 雪印メグミルク株式会社 Dipeptidyl peptidase IV inhibitor
DE102005035891A1 (en) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals
CN102908350B (en) * 2005-09-14 2014-07-23 武田药品工业株式会社 Dipeptidyl peptidase inhibitors for treating diabetes
TW200745079A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
TW200745080A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of tartrate salt of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile and methods of use therefor
TW200738266A (en) * 2005-09-29 2007-10-16 Sankyo Co Pharmaceutical agent containing insulin resistance improving agent
US20090156579A1 (en) * 2005-10-25 2009-06-18 Hasegawa Philip A Combination of a Dipeptidyl Peptidase-4 Inhibitor and an Anti-Hypertensive Agent for the Treatment of Diabetes and Hypertension
CA2635777A1 (en) * 2005-12-28 2007-07-05 Takeda Pharmaceutical Company Limited Combination therapy for diabetes
AP2008004537A0 (en) * 2005-12-30 2008-08-31 Ranbaxy Lab Ltd Muscarinic receptor antagonists
CA2636757A1 (en) * 2006-01-25 2007-08-02 Tesfaye Biftu Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
JP5101489B2 (en) * 2006-03-08 2012-12-19 杏林製薬株式会社 Process for producing aminoacetylpyrrolidinecarbonitrile derivative and its production intermediate
EP1999108A1 (en) * 2006-03-28 2008-12-10 Takeda Pharmaceutical Company Limited Preparation of (r)-3-aminopiperidine dihydrochloride
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CL2007001011A1 (en) * 2006-04-11 2008-05-16 Arena Pharm Inc METHOD FOR THE IDENTIFICATION OF GIP SECRETAGOGS, GASTRIC INHIBITOR POLYPEPTIDE; AND USE OF A PROTEIN G COUPLED RECEIVER TO CLASSIFY TEST COMPOUNDS AS GIP SECRETAGOGS.
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20080251A1 (en) 2006-05-04 2008-04-25 Boehringer Ingelheim Int USES OF DPP IV INHIBITORS
NZ600394A (en) 2006-05-04 2014-04-30 Boehringer Ingelheim Int Polymorphs of a dpp-iv enzyme inhibitor
CN101616673A (en) * 2006-09-13 2009-12-30 武田药品工业株式会社 2-[6-(3-amino-piperadine-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl]-purposes of 4-fluoro-benzonitrile
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US20070172525A1 (en) * 2007-03-15 2007-07-26 Ramesh Sesha Anti-diabetic combinations
US20080064701A1 (en) * 2007-04-24 2008-03-13 Ramesh Sesha Anti-diabetic combinations
JPWO2008114857A1 (en) * 2007-03-22 2010-07-08 杏林製薬株式会社 Process for producing aminoacetylpyrrolidinecarbonitrile derivative
CN101318922B (en) * 2007-06-08 2010-11-10 上海阳帆医药科技有限公司 Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof
WO2009024542A2 (en) * 2007-08-17 2009-02-26 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases
US20090076013A1 (en) * 2007-09-17 2009-03-19 Protia, Llc Deuterium-enriched sitagliptin
CN101417999A (en) * 2007-10-25 2009-04-29 上海恒瑞医药有限公司 Piperazines derivates, preparation method thereof and application thereof in medicine
US8334385B2 (en) * 2007-11-02 2012-12-18 Glenmark Generics Limited Process for the preparation of R-sitagliptin and its pharmaceutically acceptable salts thereof
US20090192326A1 (en) * 2007-11-13 2009-07-30 Nurit Perlman Preparation of sitagliptin intermediate
US8309724B2 (en) * 2007-12-20 2012-11-13 Dr. Reddy's Laboratories Limited Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof
AU2009210641A1 (en) * 2008-02-05 2009-08-13 Merck Sharp & Dohme Corp. Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-IV inhibitor
CN101959406A (en) * 2008-03-04 2011-01-26 默沙东公司 Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-IV inhibitor
US20090247532A1 (en) * 2008-03-28 2009-10-01 Mae De Ltd. Crystalline polymorph of sitagliptin phosphate and its preparation
AR071175A1 (en) * 2008-04-03 2010-06-02 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITION THAT INCLUDES AN INHIBITOR OF DIPEPTIDIL-PEPTIDASA-4 (DPP4) AND A COMPARING PHARMACO
US20090264476A1 (en) * 2008-04-18 2009-10-22 Mckelvey Craig CB-1 receptor modulator formulations
US8003672B2 (en) * 2008-04-21 2011-08-23 Merck Sharp & Dohme Corp. CB-1 receptor modulator formulations
PE20100156A1 (en) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int NAFLD TREATMENT
EP2324027B1 (en) * 2008-07-29 2016-02-24 Medichem, S.A. New crystalline salt forms of a 5,6,7,8-tetrahydro-1,2,4- triazolo[4,3-a]pyrazine derivative
KR20190016601A (en) 2008-08-06 2019-02-18 베링거 인겔하임 인터내셔날 게엠베하 Treatment for diabetes in patients inappropriate for metformin therapy
EP2322499A4 (en) * 2008-08-07 2011-12-21 Kyorin Seiyaku Kk Process for production of bicycloý2.2.2¨octylamine derivative
CN102186474A (en) * 2008-08-14 2011-09-14 杏林制药株式会社 Uchida hiroshi [jp]; fukuda mamoru [jp]; aritomi seigo
EP2344195A2 (en) 2008-09-10 2011-07-20 Boehringer Ingelheim International GmbH Combination therapy for the treatment of diabetes and related conditions
AU2009298617A1 (en) 2008-10-03 2010-04-08 Schering Corporation Spiro-imidazolone derivatives as glucagon receptor antagonists
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
JO2870B1 (en) 2008-11-13 2015-03-15 ميرك شارب اند دوهم كورب Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
TWI508965B (en) 2008-12-23 2015-11-21 Boehringer Ingelheim Int Salt forms of organic compound
WO2010079433A2 (en) * 2009-01-07 2010-07-15 Glenmark Pharmaceuticals, S.A. Pharmaceutical composition that includes a dipeptidyl peptidase-iv inhibitor
WO2010122578A2 (en) * 2009-04-20 2010-10-28 Msn Laboratories Limited Process for the preparation of sitagliptin and its intermediates
CN101899047B (en) * 2009-05-26 2016-01-20 盛世泰科生物医药技术(苏州)有限公司 Be used for the treatment of as depeptidyl peptidase inhibitors or the beta-amino tetrahydrochysene pyrazine of prevent diabetes, tetrahydropyrimidine and tetrahydropyridine
EP2440553B1 (en) 2009-06-12 2017-08-23 Merck Sharp & Dohme Corp. Thiophenes as glucagon receptor antagonists, compositions, and methods for their use
IT1395596B1 (en) 2009-06-30 2012-10-16 Dipharma Francis Srl PROCEDURE FOR THE PREPARATION OF SITAGLIPTIN
US8552022B2 (en) 2009-08-13 2013-10-08 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
KR20120092096A (en) 2009-09-02 2012-08-20 머크 샤프 앤드 돔 코포레이션 Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
CN102030683B (en) * 2009-09-27 2013-07-31 浙江九洲药业股份有限公司 Sitagliptin intermediate and preparation method and application thereof
US8853212B2 (en) 2010-02-22 2014-10-07 Merck Sharp & Dohme Corp Substituted aminotetrahydrothiopyrans and derivatives thereof as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes
CZ303113B6 (en) 2010-03-16 2012-04-11 Zentiva, K.S. Process for preparing sitagliptin
EP2547682A1 (en) 2010-03-31 2013-01-23 Teva Pharmaceutical Industries Ltd. Solid state forms of sitagliptin salts
EP2555617A4 (en) * 2010-04-05 2013-08-14 Cadila Pharmaceuticals Ltd Novel hypoglycemic compounds
CN102260265B (en) 2010-05-24 2015-09-02 上海阳帆医药科技有限公司 Hexahydropyrrolo [3,4-b] pyrrole derivative, Its Preparation Method And Use
KR101765980B1 (en) 2010-07-28 2017-08-07 뉴럴스템, 인크. Methods for treating and/or reversing neurodegenerative diseases and/or disorders
EP2418196A1 (en) * 2010-07-29 2012-02-15 IMTM GmbH Dual alanyl-aminopeptidase and dipeptidyl-peptidase IV inhibitors
US8742110B2 (en) 2010-08-18 2014-06-03 Merck Sharp & Dohme Corp. Spiroxazolidinone compounds
US20130158265A1 (en) 2010-08-27 2013-06-20 Dhananjay Govind Sathe Sitagliptin, salts and polymorphs thereof
WO2012049566A1 (en) 2010-10-14 2012-04-19 Japan Tobacco Inc. Combination therapy for use in treating diabetes
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
CN102485718B (en) 2010-12-03 2014-03-26 浙江海翔药业股份有限公司 Sitagliptin intermediate and its preparation method
WO2012076973A2 (en) 2010-12-09 2012-06-14 Aurobindo Pharma Limited Novel salts of dipeptidyl peptidase iv inhibitor
KR101290029B1 (en) * 2011-01-20 2013-07-30 에스티팜 주식회사 Preparation method of intermediate of sitagliptin
KR101733414B1 (en) 2011-01-31 2017-05-10 카딜라 핼쓰캐어 리미티드 Treatment for lipodystrophy
US8957062B2 (en) 2011-04-08 2015-02-17 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
KR101369584B1 (en) 2011-04-19 2014-03-06 일양약품주식회사 Phenyl-isoxazol derivatives and preparation process thereof
US8524936B2 (en) 2011-05-18 2013-09-03 Milan Soukup Manufacturing process for sitagliptin from L-aspartic acid
JP2014518890A (en) 2011-06-02 2014-08-07 インターベット インターナショナル ベー. フェー. Imidazole derivatives
AR086675A1 (en) * 2011-06-14 2014-01-15 Merck Sharp & Dohme PHARMACEUTICAL COMPOSITIONS OF COMBINATIONS OF INHIBITORS OF DIPEPTIDIL PEPTIDASA-4 WITH SIMVASTATIN
US9006228B2 (en) 2011-06-16 2015-04-14 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds, and methods of treatment
AU2012277373A1 (en) 2011-06-29 2014-01-30 Sun Pharmaceutical Industries Limited Solid dispersions of sitagliptin and processes for their preparation
AU2012277403A1 (en) 2011-06-30 2014-01-30 Ranbaxy Laboratories Limited Novel salts of sitagliptin
BR112014000938A2 (en) 2011-07-15 2017-01-10 Boehringer Ingelheim Int substituted quinazolines, their preparation and their use in pharmaceutical compositions
EP2753328A1 (en) 2011-09-07 2014-07-16 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dpp-iv inhibitor formulations
EP2760855B1 (en) 2011-09-30 2017-03-15 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds as well as their use in treating type-2 diabetes
EP2578208B1 (en) 2011-10-06 2014-05-21 Sanovel Ilac Sanayi ve Ticaret A.S. DPP-IV inhibitor solid dosage formulations
EP2771000B1 (en) 2011-10-24 2016-05-04 Merck Sharp & Dohme Corp. Substituted piperidinyl compounds useful as gpr119 agonists
CN102603749B (en) * 2011-10-27 2017-02-08 浙江华海药业股份有限公司 Synthesis method of sitagliptin intermediate
WO2013065066A1 (en) 2011-11-02 2013-05-10 Cadila Healthcare Limited Processes for preparing 4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [l,2,41-triazolo[43-a]pyrazin-7(8h)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine
WO2013068328A1 (en) 2011-11-07 2013-05-16 Intervet International B.V. Bicyclo [2.2.2] octan-1-ylcarboxylic acid compounds as dgat-1 inhibitors
WO2013068439A1 (en) 2011-11-09 2013-05-16 Intervet International B.V. 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazepine compounds as dgat1 inhibitors
EP2780337B1 (en) 2011-11-15 2017-12-20 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds useful as gpr119 agonists
EP2788352A1 (en) 2011-12-08 2014-10-15 Ranbaxy Laboratories Limited Amorphous form of sitagliptin salts
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
CA2870488A1 (en) 2012-04-16 2013-10-24 Kaneq Pharma Inc. Fused aromatic phosphonate derivatives as precursors to ptp-1b inhibitors
TWI469785B (en) 2012-04-25 2015-01-21 Inovobiologic Inc Dietary fiber compositions for the treatment of metabolic disease
JP6224084B2 (en) 2012-05-14 2017-11-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Xanthine derivatives as DPP-4 inhibitors for the treatment of glomerular epithelial cell related disorders and / or nephrotic syndrome
AU2013301410A1 (en) 2012-08-08 2015-02-26 Cipla Limited Process for the preparation of sitagliptin and intermediate compounds
CN102898387B (en) * 2012-09-26 2015-01-07 浙江工业大学 Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine
TWI500613B (en) 2012-10-17 2015-09-21 Cadila Healthcare Ltd Novel heterocyclic compounds
CN103788070B (en) * 2012-10-26 2017-10-20 南京华威医药科技开发有限公司 The inhibitor class polymers of DPP 4
CN103319487B (en) * 2013-01-10 2015-04-01 药源药物化学(上海)有限公司 Preparation method of sitagliptin and intermediate of sitagliptin
WO2014127745A1 (en) * 2013-02-22 2014-08-28 成都先导药物开发有限公司 Dpp-iv-inhibiting compounds and intermediates thereof
IN2013MU00916A (en) 2013-03-20 2015-06-26 Cadila Healthcare Ltd
GEP201706663B (en) 2013-04-22 2017-05-10 Cadila Healthcare Ltd Novel composition for nonalcoholic fatty liver disease (nafld
US20160107989A1 (en) 2013-05-30 2016-04-21 Cadila Healthcare Limited A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
WO2015001568A2 (en) * 2013-07-01 2015-01-08 Laurus Labs Private Limited Sitagliptin lipoate salt, process for the preparation and pharmaceutical composition thereof
TW201513857A (en) 2013-07-05 2015-04-16 Cadila Healthcare Ltd Synergistic compositions
IN2013MU02470A (en) 2013-07-25 2015-06-26 Cadila Healthcare Ltd
US10112898B2 (en) 2013-09-06 2018-10-30 Cadila Healthcare Limited Process for the preparation of saroglitazar pharmaceutical salts
CN103626775B (en) * 2013-12-02 2015-05-20 南京华威医药科技开发有限公司 DPP-4 inhibitor with diazine structure
WO2015089809A1 (en) 2013-12-19 2015-06-25 Merck Sharp & Dohme Corp. Antidiabetic substituted heteroaryl compounds
IN2014MU00212A (en) 2014-01-21 2015-08-28 Cadila Healthcare Ltd
EP3097101B1 (en) 2014-01-24 2020-12-23 Merck Sharp & Dohme Corp. Isoquinoline derivatives as mgat2 inhibitors
IN2014MU00651A (en) 2014-02-25 2015-10-23 Cadila Healthcare Ltd
EP3110449B1 (en) 2014-02-28 2023-06-28 Boehringer Ingelheim International GmbH Medical use of a dpp-4 inhibitor
WO2015145333A1 (en) 2014-03-26 2015-10-01 Sun Pharmaceutical Industries Limited Process for the preparation of sitagliptin and its intermediate
WO2015162506A1 (en) 2014-04-21 2015-10-29 Suven Life Sciences Limited Process for the preparation of sitagliptin and novel intermediates
WO2015170340A2 (en) * 2014-05-06 2015-11-12 Laurus Labs Private Limited Novel polymorphs of sitagliptin hydrochloride, processes for its preparation and pharmaceutical composition thereof
EP3177285B1 (en) 2014-08-08 2020-09-23 Merck Sharp & Dohme Corp. [5,6]-fused bicyclic antidiabetic compounds
US10968193B2 (en) 2014-08-08 2021-04-06 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
CN104140430B (en) * 2014-08-08 2016-07-13 广东东阳光药业有限公司 A kind of racemization method of isomer
WO2016022448A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
CN107148275A (en) 2014-10-20 2017-09-08 神经干细胞公司 The NSC of the stabilization of exogenous polynucleotide comprising encoding growth hormone and its application method
CN105017260B (en) * 2015-07-30 2017-04-19 新发药业有限公司 Preparation method of sitagliptin intermediate triazolopyrazine derivative
WO2017020974A1 (en) 2015-08-03 2017-02-09 Institut Pasteur Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy
WO2017064635A2 (en) 2015-10-14 2017-04-20 Cadila Healthcare Limited Pyrrole compound, compositions and process for preparation thereof
US20190382363A1 (en) 2015-11-30 2019-12-19 Merck Sharp & Dohme Corp. Aryl sulfonamides as blt1 antagonists
EP3383869B1 (en) 2015-11-30 2023-06-28 Merck Sharp & Dohme LLC Aryl sulfonamides as blt1 antagonists
WO2017201683A1 (en) 2016-05-25 2017-11-30 Merck Sharp & Dohme Corp. Substituted tetrahydroisoquinoline compounds useful as gpr120 agonists
BR112018072401A2 (en) 2016-06-10 2019-02-19 Boehringer Ingelheim International Gmbh combinations of linagliptin and metformin
WO2018034917A1 (en) 2016-08-15 2018-02-22 Merck Sharp & Dohme Corp. Compounds useful for altering the levels of bile acids for the treatment of diabetes and cardiometabolic disease
WO2018034918A1 (en) 2016-08-15 2018-02-22 Merck Sharp & Dohme Corp. Compounds useful for altering the levels of bile acids for the treatment of diabetes and cardiometabolic disease
CN106124667B (en) * 2016-08-29 2018-07-31 上海应用技术学院 A kind of methods of the separation determination Xi Gelieting in relation to substance
MX2016016260A (en) 2016-12-08 2018-06-07 Alparis Sa De Cv New solid forms of sitagliptin.
US20180243263A1 (en) 2016-12-09 2018-08-30 Cadila Healthcare Ltd. Treatment for primary biliary cholangitis
WO2018107415A1 (en) 2016-12-15 2018-06-21 Merck Sharp & Dohme Corp. Hydroxy isoxazole compounds useful as gpr120 agonists
US11197949B2 (en) * 2017-01-19 2021-12-14 Medtronic Minimed, Inc. Medication infusion components and systems
US11096890B2 (en) 2017-09-29 2021-08-24 Merck Sharp & Dohme Corp. Chewable dosage forms containing sitagliptin and metformin
TR201722603A2 (en) 2017-12-28 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Tablet formulations comprising metformin and sitagliptin processed with hot-melt extrusion
CN108586346B (en) 2018-05-10 2019-10-01 北京富盛嘉华医药科技有限公司 A kind of method that biocatalysis synthesizes sitagliptin and its intermediate
US20220177465A1 (en) 2019-04-04 2022-06-09 Merck Sharp & Dohme Corp. Inhibitors of histone deacetylase-3 useful for the treatment of cancer, inflammation, neurodegeneration diseases and diabetes
CN113979896A (en) * 2021-11-18 2022-01-28 浙江永太手心医药科技有限公司 Sitagliptin impurity I and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997030053A1 (en) * 1996-02-16 1997-08-21 Biomeasure Incorporated Farnesyl transferase inhibitors
WO1997040832A1 (en) * 1996-04-25 1997-11-06 Probiodrug Gesellschaft für Arzneimittelforschung mbH Use of dipeptidyl peptidase iv effectors for lowering the blood glucose level in mammals

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4166452A (en) 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
US4256108A (en) 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
IL111785A0 (en) 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
GB9324803D0 (en) * 1993-12-03 1994-01-19 Ferring Bv Enzyme inhibitors
US5705483A (en) * 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
AU1856997A (en) 1996-02-02 1997-08-22 Merck & Co., Inc. Method for raising hdl cholesterol levels
AR008789A1 (en) 1996-07-31 2000-02-23 Bayer Corp PIRIDINES AND SUBSTITUTED BIPHENYLS
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
US6613942B1 (en) 1997-07-01 2003-09-02 Novo Nordisk A/S Glucagon antagonists/inverse agonists
AU749271B2 (en) 1997-07-01 2002-06-20 Agouron Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
HUP0004359A3 (en) 1997-11-11 2001-12-28 Ono Pharmaceutical Co Fused pyrazine derivatives and pharmaceutical compositions containing them
BR9910251A (en) 1998-05-04 2001-01-02 Point Therapeutics Inc Hematopoietic stimulation
DE19823831A1 (en) 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim New pharmaceutical use of isoleucyl thiazolidide and its salts
DE19828114A1 (en) * 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs of unstable inhibitors of dipeptidyl peptidase IV
FR2780974B1 (en) 1998-07-08 2001-09-28 Sod Conseils Rech Applic USE OF IMIDAZOPYRAZINE DERIVATIVES FOR THE PREPARATION OF A MEDICAMENT FOR TREATING CONDITIONS RESULTING FROM THE FORMATION OF HETEROTRIMETER G PROTEIN
CO5150173A1 (en) 1998-12-10 2002-04-29 Novartis Ag COMPOUNDS N- (REPLACED GLYCLE) -2-DIPEPTIDYL-IV PEPTIDASE INHIBITING CYANOPIRROLIDINS (DPP-IV) WHICH ARE EFFECTIVE IN THE TREATMENT OF CONDITIONS MEDIATED BY DPP-IV INHIBITION
WO2000042026A1 (en) 1999-01-15 2000-07-20 Novo Nordisk A/S Non-peptide glp-1 agonists
GB9906715D0 (en) 1999-03-23 1999-05-19 Ferring Bv Compositions for promoting growth
CA2367856C (en) 1999-03-29 2013-10-15 Uutech Limited Analogs of gastric inhibitory peptide and their use for treatment of diabetes
EP1165519A1 (en) 1999-04-02 2002-01-02 Neurogen Corporation Aryl and heteroaryl fused aminoalkyl-imidazole derivatives and their use as antidiabetics
ES2250128T3 (en) 1999-05-17 2006-04-16 Novo Nordisk A/S ANTIGONISTS / INVESTED AGONISTS OF GLUCAGON.
AU7726600A (en) 1999-09-28 2001-04-30 Bayer Corporation Pituitary adenylate cyclase activating peptide (pacap) receptor 3 (r3) agonists and their pharmacological methods of use
CA2390231A1 (en) 1999-11-12 2001-05-17 Paul Jackson Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors
TW583185B (en) 2000-06-13 2004-04-11 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines and pharmaceutical composition for inhibiting dipeptidyl peptidase-IV (DPP-IV) or for the prevention or treatment of diseases or conditions associated with elevated levels of DPP-IV comprising the same
EP1301187B1 (en) 2000-07-04 2005-07-06 Novo Nordisk A/S Purine-2,6-diones which are inhibitors of the enzyme dipeptidyl peptidase iv (dpp-iv)
UA74912C2 (en) * 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
WO2003082817A2 (en) * 2002-03-25 2003-10-09 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
ES2291680T3 (en) * 2002-10-07 2008-03-01 MERCK & CO., INC. BETA-AMINO HETEROCICLIC INHIBITING ANTIDIABETICS OF DIPEPTIDIL PEPTIDASA.
JP2006516573A (en) * 2003-01-31 2006-07-06 メルク エンド カムパニー インコーポレーテッド 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment and prevention of diabetes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997030053A1 (en) * 1996-02-16 1997-08-21 Biomeasure Incorporated Farnesyl transferase inhibitors
WO1997040832A1 (en) * 1996-04-25 1997-11-06 Probiodrug Gesellschaft für Arzneimittelforschung mbH Use of dipeptidyl peptidase iv effectors for lowering the blood glucose level in mammals

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STOECKEL-MASCHEK A ET AL: "POTENT INHIBITORS OF DIPEPTIDYL PEPTIDASE IV AND THEIR MECHANISMS OF INHIBITION", ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, SPRING ST., NY, US, vol. 477, 2000, pages 117 - 123, XP008000943, ISSN: 0065-2598 *

Cited By (382)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7253172B2 (en) 2001-06-20 2007-08-07 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
US7098239B2 (en) 2001-06-20 2006-08-29 Merck & Co., Inc Dipeptidyl peptidase inhibitors for the treatment of diabetes
US7132443B2 (en) 2001-06-27 2006-11-07 Smithklinebeecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
EP1490335A4 (en) * 2002-03-25 2006-02-08 Merck & Co Inc Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7307164B2 (en) 2002-03-25 2007-12-11 Merck & Co., Inc. β-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1490335A2 (en) * 2002-03-25 2004-12-29 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004002986A2 (en) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Novel benzimidazole derivatives
EP1554280A2 (en) * 2002-10-07 2005-07-20 Merck & Co., Inc. Antidiabetic beta-amino heterocyclic dipeptidyl peptidase inhibitors
EP1554280A4 (en) * 2002-10-07 2006-07-05 Merck & Co Inc Antidiabetic beta-amino heterocyclic dipeptidyl peptidase inhibitors
US7390809B2 (en) 2002-10-07 2008-06-24 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for diabetes
US7157490B2 (en) 2002-11-07 2007-01-02 Merck & Co., Inc. Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004052362A1 (en) * 2002-12-10 2004-06-24 Novartis Ag Combination of an dpp-iv inhibitor and a ppar-alpha compound
EP1583534A1 (en) * 2002-12-20 2005-10-12 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1583534A4 (en) * 2002-12-20 2007-08-29 Merck & Co Inc 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
EP1589969A4 (en) * 2003-01-17 2008-08-13 Merck & Co Inc 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1589969A2 (en) * 2003-01-17 2005-11-02 Merck & Co. Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
JP2006516975A (en) * 2003-01-17 2006-07-13 メルク エンド カムパニー インコーポレーテッド 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment and prevention of diabetes
EP1592689A4 (en) * 2003-01-31 2008-12-24 Merck & Co Inc 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004069162A2 (en) 2003-01-31 2004-08-19 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1592689A2 (en) * 2003-01-31 2005-11-09 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
JP2006516573A (en) * 2003-01-31 2006-07-06 メルク エンド カムパニー インコーポレーテッド 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment and prevention of diabetes
WO2004080958A2 (en) * 2003-03-07 2004-09-23 Merck & Co. Inc. Process to tetrahydrotriazolopyrazines and intermediates
WO2004080958A3 (en) * 2003-03-07 2004-12-23 Merck & Co Inc Process to tetrahydrotriazolopyrazines and intermediates
WO2004083212A1 (en) * 2003-03-18 2004-09-30 Merck & Co., Inc. Process to beta-ketoamide intermediates to dipeptidyl peptidase inhibitors
JP2013237674A (en) * 2003-03-19 2013-11-28 Merck Sharp & Dohme Corp Process for preparation of chiral beta amino acid derivatives by asymmetric hydrogenation
AU2009202775B2 (en) * 2003-03-19 2011-07-28 Merck Sharp & Dohme Llc Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation
US7468459B2 (en) 2003-03-19 2008-12-23 Merck & Co., Inc. Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation
JP2006521354A (en) * 2003-03-19 2006-09-21 メルク エンド カムパニー インコーポレーテッド Process for producing chiral beta amino acid derivatives by asymmetric hydrogenation
JP2010155857A (en) * 2003-03-19 2010-07-15 Merck Sharp & Dohme Corp Method for producing chiral beta amino acid derivative by asymmetric hydrogenation
WO2004085661A3 (en) * 2003-03-24 2005-03-10 Merck & Co Inc Process to chiral beta-amino acid derivatives
WO2004085661A2 (en) * 2003-03-24 2004-10-07 Merck & Co., Inc Process to chiral beta-amino acid derivatives
WO2004087650A2 (en) * 2003-03-27 2004-10-14 Merck & Co. Inc. Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
WO2004087650A3 (en) * 2003-03-27 2005-01-13 Merck & Co Inc Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
WO2004098591A2 (en) 2003-05-05 2004-11-18 Probiodrug Ag Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases
EP1624874A2 (en) * 2003-05-14 2006-02-15 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
JP2006528693A (en) * 2003-05-14 2006-12-21 メルク エンド カムパニー インコーポレーテッド 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for treating or preventing diabetes
WO2004103276A2 (en) 2003-05-14 2004-12-02 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EP1624874A4 (en) * 2003-05-14 2006-11-22 Merck & Co Inc 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
EA009042B1 (en) * 2003-06-24 2007-10-26 Мерк Энд Ко., Инк. Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
KR101013431B1 (en) 2003-06-24 2011-02-14 머크 샤프 앤드 돔 코포레이션 Crystalline monohydrate of a phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
AU2004253889B2 (en) * 2003-06-24 2008-04-24 Merck Sharp & Dohme Llc Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
KR101016569B1 (en) * 2003-06-24 2011-02-22 머크 샤프 앤드 돔 코포레이션 Phosphoric acid salt of a dipeptidyl-peptidase-IV inhibitor
WO2005003135A1 (en) * 2003-06-24 2005-01-13 Merck & Co., Inc. Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
NO335371B1 (en) * 2003-06-24 2014-12-01 Merck Sharp & Dohme Dihydrogen phosphate salt of a dipeptidyl peptidase IV inhibitor, process for the preparation of the salt, a pharmaceutical preparation thereof, a drug substance thereof for use as a medicament and the use of the salt in the manufacture of a medicament for the treatment of type 2 diabetes.
CN100430397C (en) * 2003-06-24 2008-11-05 默克公司 Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
US8546429B2 (en) 2003-07-11 2013-10-01 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7838525B2 (en) 2003-07-11 2010-11-23 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US8410119B2 (en) 2003-07-14 2013-04-02 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
CN100457108C (en) * 2003-09-02 2009-02-04 默克公司 Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
JP2007504230A (en) * 2003-09-02 2007-03-01 メルク エンド カムパニー インコーポレーテッド A novel crystalline form of phosphate of dipeptidyl peptidase-IV inhibitor
EP1662876A2 (en) * 2003-09-02 2006-06-07 Merck & Co., Inc. Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
EP1662876A4 (en) * 2003-09-02 2009-01-14 Merck & Co Inc Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005028438A1 (en) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
EP1667524A2 (en) * 2003-09-23 2006-06-14 Merck & Co., Inc. Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
EP1667524A4 (en) * 2003-09-23 2009-01-14 Merck & Co Inc Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
EP2338490A2 (en) 2003-11-03 2011-06-29 Probiodrug AG Combinations Useful for the Treatment of Neuronal Disorders
EP2839832A2 (en) 2003-11-17 2015-02-25 Novartis AG Use of dipeptidyl peptidase IV inhibitors
WO2005072530A1 (en) * 2004-01-16 2005-08-11 Merck & Co., Inc. Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor
EP3738585A1 (en) 2004-01-20 2020-11-18 Novartis Ag Direct compression formulation and process
EP3023095A1 (en) 2004-01-20 2016-05-25 Novartis AG Direct compression formulation and process
EP2165703A2 (en) 2004-01-20 2010-03-24 Novartis Pharma AG. Direct compression formulation and process
EP3366283A1 (en) 2004-01-20 2018-08-29 Novartis AG Direct compression formulation and process
WO2005075436A2 (en) 2004-02-05 2005-08-18 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
US7897633B2 (en) 2004-02-05 2011-03-01 Probiodrug Ag Inhibitors of glutaminyl cyclase
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2005097759A1 (en) 2004-03-29 2005-10-20 Merck & Co., Inc. Diaryltriazoles as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
US7495123B2 (en) 2004-04-05 2009-02-24 Solvias Ag Process for the preparation of enantiomerically enriched beta amino acid derivatives
US7943584B2 (en) 2004-07-29 2011-05-17 Sankyo Company, Limited Medicinal composition containing diabetes remedy
WO2006017542A1 (en) 2004-08-06 2006-02-16 Merck & Co., Inc. Sulfonyl compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
EP1784188A4 (en) * 2004-08-23 2009-06-24 Merck & Co Inc Fused triazole derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
US7625888B2 (en) 2004-08-23 2009-12-01 Merck & Co., Inc. Fused triazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
EP1784188A2 (en) * 2004-08-23 2007-05-16 Merck & Co., Inc. Fused triazole derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
EP3087975A1 (en) 2004-08-27 2016-11-02 Novartis Ag Treatment with vildagliptin
US7612072B2 (en) 2004-09-15 2009-11-03 Merck & Co., Inc. Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
EP1796671A1 (en) * 2004-09-15 2007-06-20 Merck & Co., Inc. Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
EP1796671A4 (en) * 2004-09-15 2009-01-21 Merck & Co Inc Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
US7884104B2 (en) 2004-10-01 2011-02-08 Merck Sharp & Dohme Corp. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
EP2116235A1 (en) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
EP2322157A1 (en) 2005-01-10 2011-05-18 Arena Pharmaceuticals, Inc. Composition for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
JP2008534581A (en) * 2005-04-01 2008-08-28 エルジー ライフ サイエンス リミテッド Dipeptidyl peptidase-IV inhibitory compound, method for producing the same, and pharmaceutical composition comprising the same as an active substance
US7879848B2 (en) 2005-04-01 2011-02-01 Lg Life Sciences, Ltd. Dipeptidyl Peptidase-IV inhibiting compounds, method of preparing the same, and pharmaceutical compositions containing the same as an active agent
KR100776623B1 (en) 2005-04-01 2007-11-15 주식회사 엘지생명과학 Dipeptidyl Peptidase-IV Inhibiting Compounds, Methods of Preparing the Same, and Pharmaceutical Compositions Containing the Same as an Active Agent
KR100794184B1 (en) * 2005-04-01 2008-01-11 주식회사 엘지생명과학 Dipeptidyl Peptidase-IV Inhibiting Compounds, Methods of Preparing the Same, and Pharmaceutical Compositions Containing the Same as an Active Agent
EP1888066A2 (en) * 2005-05-25 2008-02-20 Merck and Co., Inc. Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
EP1888066A4 (en) * 2005-05-25 2010-06-09 Merck Sharp & Dohme Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2006129826A1 (en) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
EP2191824A1 (en) 2005-06-10 2010-06-02 Novartis AG Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation
US8076514B2 (en) 2005-07-20 2011-12-13 Eli Lilly And Company Phenyl compounds and their use in the treatment of Type II diabetes
US8106090B2 (en) 2005-07-20 2012-01-31 Eli Lilly And Company 1-amino linked compounds
US8133907B2 (en) 2005-07-20 2012-03-13 Eli Lilly And Company Pyridine derivatives as dipeptedyl peptidase inhibitors
WO2007035198A3 (en) * 2005-07-25 2007-07-19 Merck & Co Inc Dodecylsulfate salt of a dipeptidyl peptidase-iv inhibitor
WO2007035198A2 (en) * 2005-07-25 2007-03-29 Merck & Co., Inc. Dodecylsulfate salt of a dipeptidyl peptidase-iv inhibitor
WO2007018248A1 (en) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Pyridone compound
WO2007024004A1 (en) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
US7709468B2 (en) 2005-09-02 2010-05-04 Abbott Laboratories Imidazo based heterocycles
WO2007029847A1 (en) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Bicyclic aromatic substituted pyridone derivative
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2007041052A2 (en) 2005-09-29 2007-04-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
WO2007049798A1 (en) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Novel benzoxathiin derivative
WO2007055418A1 (en) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Aza-substituted spiro derivative
US8414921B2 (en) 2005-12-16 2013-04-09 Merck Sharp & Dohme Corp. Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
JP2009519934A (en) * 2005-12-16 2009-05-21 メルク エンド カムパニー インコーポレーテッド Pharmaceutical composition comprising a combination of a dipeptidyl peptidase-4 inhibitor and metformin
AU2006333151B2 (en) * 2005-12-16 2010-03-04 Merck Sharp & Dohme Llc Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
WO2007078726A3 (en) * 2005-12-16 2008-06-12 Merck & Co Inc Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
EP1801098A1 (en) 2005-12-16 2007-06-27 Merck Sante 2-Adamantylurea derivatives as selective 11B-HSD1 inhibitors
WO2007072083A1 (en) 2005-12-23 2007-06-28 Prosidion Limited Treatment of type 2 diabetes with a combination of dpiv inhibitor and metformin or thiazolidinedione
WO2007077508A2 (en) 2005-12-30 2007-07-12 Ranbaxy Laboratories Limited Derivatives of beta-amino acid as dipeptidyl peptidase-iv inhibitors
EP2253311A3 (en) * 2006-04-11 2011-06-22 Arena Pharmaceuticals, Inc. Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto
EP2253311A2 (en) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto
WO2007120702A2 (en) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
US7888351B2 (en) 2006-04-11 2011-02-15 Novartis Ag Organic compounds
WO2007120702A3 (en) * 2006-04-11 2008-05-22 Arena Pharm Inc Use of gpr119 receptor agonists for increasing bone mass and for treating osteoporosis, and combination therapy relating thereto
EP2213289A1 (en) 2006-09-07 2010-08-04 Nycomed GmbH Combination treatment for diabetes mellitus
EP2946778A1 (en) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
EP2698157A1 (en) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
WO2008038692A1 (en) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. Diaryl ketimine derivative
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
WO2008074384A1 (en) 2006-12-21 2008-06-26 Merck Patent Gmbh 2-ADAMANTYL-BUTYRAMIDE DERIVATIVES AS SELECTIVE 11βETA-HSD1 INHIBITORS
WO2008093960A1 (en) * 2007-01-30 2008-08-07 Lg Life Sciences, Ltd. Novel dipeptidyl peptidase-iv inhibitors
US8637079B2 (en) 2007-02-01 2014-01-28 Takeda Pharmaceutical Company Limited Solid preparation comprising alogliptin and pioglitazone
WO2008120653A1 (en) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Indoledione derivative
WO2008120813A1 (en) 2007-04-03 2008-10-09 Mitsubishi Tanabe Pharma Corporation Combined use of dipeptidyl peptidase iv inhibitor compound and sweetener
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
WO2008137105A1 (en) 2007-05-07 2008-11-13 Merck & Co., Inc. Method of treatment using fused aromatic compounds having anti-diabetic activity
US7820666B2 (en) * 2007-05-08 2010-10-26 Concert Pharmaceuticals, Inc. Tetrahydrotriazolopyrazine derivatives and uses thereof
US9670138B2 (en) 2007-06-04 2017-06-06 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US9663448B2 (en) 2007-06-04 2017-05-30 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US10214481B2 (en) 2007-06-04 2019-02-26 Ben-Gurion University Of The Negev Research And Development Aithority Telomerase activating compounds and methods of use thereof
EP2698152A1 (en) 2007-08-16 2014-02-19 Boehringer Ingelheim International GmbH Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
EP3939577A1 (en) 2007-08-16 2022-01-19 Boehringer Ingelheim International GmbH Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
CN101397300B (en) * 2007-09-04 2011-04-27 山东轩竹医药科技有限公司 Dipeptidase-IV inhibitor derivates
WO2009082134A3 (en) * 2007-12-21 2009-09-24 Lg Life Sciences, Ltd. Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent
US8470836B2 (en) 2007-12-21 2013-06-25 Lg Life Sciences, Ltd. Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent
US8207161B2 (en) 2007-12-26 2012-06-26 Jiangsu Hengrui Medicine Co. Ltd. Tetrahydro-imidazo[1,5-α]pyrazine derivatives, preparation process and medicinal use thereof
WO2009082881A1 (en) 2007-12-26 2009-07-09 Shanghai Hengrui Pharmaceutical Co., Ltd. Tetrahydro-imidazo[1,5-a]pyrazine derivatives, preparation methods and medical uses thereof
US8513411B2 (en) 2007-12-26 2013-08-20 Jiangsu Hengrui Medicine Co., Ltd. Tetrahydro-imidazo[1,5-α] pyrazine derivatives, preparation process and medicinal use thereof
US20100273786A1 (en) * 2007-12-26 2010-10-28 Peng Cho Tang Tetrahydro-imidaz0[1,5-a]pyrazine derivatives, preparation process and medicinal use thereof
US8853385B2 (en) 2008-01-17 2014-10-07 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising SGLT inhibitors and DPP4 inhibitors
WO2009093269A1 (en) * 2008-01-24 2009-07-30 Panacea Biotec Limited Novel heterocyclic compounds
EA018612B1 (en) * 2008-01-24 2013-09-30 Панацеа Биотек Лимитед Novel heterocyclic compounds
US8455479B2 (en) 2008-01-24 2013-06-04 Panacea Biotec Limited Heterocyclic compounds
WO2009110510A1 (en) 2008-03-06 2009-09-11 萬有製薬株式会社 Alkylaminopyridine derivative
US8551524B2 (en) 2008-03-14 2013-10-08 Iycus, Llc Anti-diabetic combinations
WO2009119726A1 (en) 2008-03-28 2009-10-01 萬有製薬株式会社 Diarylmethylamide derivative having antagonistic activity on melanin-concentrating hormone receptor
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
WO2009127321A1 (en) 2008-04-18 2009-10-22 Merck Patent Gmbh, Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators
EP2110374A1 (en) 2008-04-18 2009-10-21 Merck Sante Benzofurane, benzothiophene, benzothiazol derivatives as FXR modulators
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2009154132A1 (en) 2008-06-19 2009-12-23 萬有製薬株式会社 Spirodiamine-diarylketoxime derivative
EP2650298A1 (en) 2008-07-03 2013-10-16 Ratiopharm GmbH Crystalline salts of sitagliptin
EP2650299A1 (en) 2008-07-03 2013-10-16 Ratiopharm GmbH Crystalline salts of sitagliptin
EP2915814A2 (en) 2008-07-03 2015-09-09 Ratiopharm GmbH Crystalline salts of sitagliptin
EP2586782A1 (en) 2008-07-03 2013-05-01 Ratiopharm GmbH Crystalline salts of sitagliptin
EP2650296A1 (en) 2008-07-03 2013-10-16 Ratiopharm GmbH Crystalline salts of sitagliptin
EP2650297A1 (en) 2008-07-03 2013-10-16 Ratiopharm GmbH Crystalline salts of sitagliptin
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2010013595A1 (en) 2008-07-30 2010-02-04 萬有製薬株式会社 (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative
EP3598974A1 (en) 2008-08-06 2020-01-29 Boehringer Ingelheim International GmbH Treatment for diabetes in patients inappropriate for metformin therapy
EP2990037A1 (en) 2008-08-06 2016-03-02 Boehringer Ingelheim International GmbH Treatment for diabetes in patients inappropriate for metformin therapy
EP3626238A1 (en) 2008-08-15 2020-03-25 Boehringer Ingelheim International GmbH Dpp-4 inhibitors for use for the treatment of wound healing in diabetic patients
US8476437B2 (en) 2008-08-27 2013-07-02 Cadila Healthcare Limited Process for preparation of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine and new impurities in preparation thereof
WO2010032264A3 (en) * 2008-08-27 2010-08-19 Cadila Healthcare Limited Improved process for preparation of (2r)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro [1,2,4]-triazolo[4,3-a]pyrazin- 7(8h)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine & new impurities in preparation thereof
EP2351567A4 (en) * 2008-10-17 2013-12-04 Dong A Pharm Co Ltd Pharmaceutical composition for prevention and treatment of diabetes or obesity comprising a compound that inhibits activity of dipeptidyl peptidase-iv, and other antidiabetic or antiobesity agents as active ingredients
EP2351567A2 (en) * 2008-10-17 2011-08-03 Dong-A Pharmaceutical Co., Ltd. Pharmaceutical composition for prevention and treatment of diabetes or obesity comprising a compound that inhibits activity of dipeptidyl peptidase-iv, and other antidiabetic or antiobesity agents as active ingredients
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051236A1 (en) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Isonicotinamide orexin receptor antagonists
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010056717A1 (en) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Substituted bicyclic amines for the treatment of diabetes
US8278486B2 (en) 2008-12-31 2012-10-02 Chiral Quest, Inc. Process and intermediates for the preparation of N-acylated-4-aryl beta-amino acid derivatives
WO2010079197A1 (en) 2009-01-07 2010-07-15 Boehringer Ingelheim International Gmbh Treatment of diabetes in patients with inadequate glycemic control despite metformin therapy comprising a dpp-iv inhibitor
US8466145B2 (en) 2009-01-09 2013-06-18 Orchid Chemicals & Pharmaceuticals Limited Dipeptidyl peptidase IV inhibitors
WO2010086411A1 (en) 2009-01-29 2010-08-05 Boehringer Ingelheim International Gmbh Dpp-iv inhibitors for treatment of diabetes in paediatric patients
CN102388047A (en) * 2009-02-11 2012-03-21 力奇制药公司 Novel salts of sitagliptin
WO2010092090A2 (en) 2009-02-11 2010-08-19 Lek Pharmaceuticals D.D. Novel salts of sitagliptin
EP2218721A1 (en) 2009-02-11 2010-08-18 LEK Pharmaceuticals d.d. Novel salts of sitagliptin
WO2010092125A1 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
WO2010092163A2 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Antidiabetic medications
EP2223923A1 (en) 2009-02-25 2010-09-01 Esteve Química, S.A. Process for the preparation of a chiral beta aminoacid derivative and intermediates thereof
WO2010097420A1 (en) 2009-02-25 2010-09-02 Esteve Química, S.A. Process for the preparation of a chiral beta aminoacid derivative and intermediates thereof
CN102159578B (en) * 2009-03-05 2013-04-10 江苏恒瑞医药股份有限公司 Salts of tetrahydroimidazo [1,5-a] pyrazine derivatives, preparation methods and pharmaceutical use thereof
CN102159578A (en) * 2009-03-05 2011-08-17 江苏恒瑞医药股份有限公司 Salts of tetrahydroimidazo [1,5-a] pyrazine derivatives, preparation methods and pharmaceutical use thereof
WO2010114291A2 (en) 2009-03-30 2010-10-07 동아제약 주식회사 Improved method for preparing dipeptidyl peptidase-iv inhibitor and intermediate
EP2669266A1 (en) 2009-03-30 2013-12-04 Dong-A Pharmaceutical Co., Ltd. Improved Method for Manufacturing Dipeptidyl Peptidase-IV Inhibitor and Intermediate
WO2010114292A2 (en) 2009-03-30 2010-10-07 동아제약 주식회사 Improved method for manufacturing dipeptidyl peptidase-iv inhibitor and intermediate
US20120010211A1 (en) * 2009-03-31 2012-01-12 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition for treatment of type 2 diabetes
US8476272B2 (en) * 2009-03-31 2013-07-02 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition for treatment of type 2 diabetes
CN102574856A (en) * 2009-05-11 2012-07-11 基因里克斯(英国)有限公司 Sitagliptin synthesis
WO2010131025A1 (en) * 2009-05-11 2010-11-18 Generics [Uk] Limited Sitagliptin synthesis
AU2010247193B2 (en) * 2009-05-11 2016-05-19 Generics [Uk] Limited Sitagliptin synthesis
CN102574856B (en) * 2009-05-11 2016-09-21 基因里克斯(英国)有限公司 The synthesis of sitagliptin
US8846916B2 (en) 2009-05-11 2014-09-30 Generics [Uk] Limited Sitagliptin synthesis
WO2010135944A1 (en) 2009-05-27 2010-12-02 江苏恒瑞医药股份有限公司 Salts of methyl (r)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate
EP2436684A4 (en) * 2009-05-27 2012-12-19 Jiangsu Hengrui Medicine Co Salts of methyl (r)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate
KR101769775B1 (en) 2009-05-27 2017-08-21 지앙수 헨그루이 메디슨 컴퍼니 리미티드 SALTS OF METHYL (R)-7-[3-AMINO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRYL]-3- TRIFLUOROMETHYL-5,6,7,8-TETRAHYDRO-IMIDAZO[1,5-a]PYRAZINE-1-CARBOXYLATE
EP2436684A1 (en) * 2009-05-27 2012-04-04 Jiangsu Hengrui Medicine Co., Ltd. Salts of methyl (r)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate
US20120122875A1 (en) * 2009-05-27 2012-05-17 Jiangsu Hengrui Medicine Co., Ltd. Salts of Methyl (R)-7-[3-Amino-4-(2,4,5-Trifluoro-Phenyl)-Butyryl]-3-Trifluoromethyl-5,6,7,8-Tetrahydro-Imidazo[1,5-A]Pyrazine-1-Carboxylate
US8618104B2 (en) 2009-05-27 2013-12-31 Jiangsu Hengrui Medicine Co., Ltd. Salts of methyl (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-A]pyrazine-1-carboxylate
CN102471341A (en) * 2009-07-09 2012-05-23 Irm责任有限公司 Compounds and compositions for the treatment of parasitic diseases
US9963454B2 (en) 2009-07-09 2018-05-08 Novartis Ag Compounds and compositions for the treatment of parasitic disease
TWI421252B (en) * 2009-07-09 2014-01-01 Irm Llc Compounds and compositions for the treatment of parasitic diseases
WO2011005929A1 (en) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Piperidine derivative and its use for the treatment of diabets and obesity
WO2011006143A2 (en) 2009-07-09 2011-01-13 Irm Llc Compounds and compositions for the treatment of parasitic diseases
EA019655B1 (en) * 2009-07-09 2014-05-30 Айрм Ллк Fused imidazoles and compositions comprising them for the treatment of parasitic diseases, such as e.g. malaria
AU2010271247B2 (en) * 2009-07-09 2013-07-18 Novartis Ag Fused imidazoles and compositions comprising them for the treatment of parasitic diseases, such as e.g. malaria
KR101378666B1 (en) 2009-07-09 2014-03-26 아이알엠 엘엘씨 Fused imidazoles and compositions comprising them for the treatment of parasitic diseases, such as e.g. malaria
US8557801B2 (en) 2009-07-09 2013-10-15 Irm Llc Compounds and compositions useful for the treatment of parasitic diseases
CN102471341B (en) * 2009-07-09 2014-07-02 Irm责任有限公司 Compounds and compositions for the treatment of parasitic diseases
WO2011006143A3 (en) * 2009-07-09 2011-06-09 Irm Llc Fused imidazoles and compositions comprising them for the treatment of parasitic diseases, such as e.g. malaria
US9469645B2 (en) 2009-07-09 2016-10-18 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
WO2011011508A1 (en) 2009-07-23 2011-01-27 Schering Corporation Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
WO2011011506A1 (en) 2009-07-23 2011-01-27 Schering Corporation Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
US9399051B2 (en) 2009-08-03 2016-07-26 Kaneka Corporation Dipeptidyl peptidase-4 inhibitor
CN102471344A (en) * 2009-08-13 2012-05-23 桑多斯股份公司 Crystalline compound of 7-[(3r)-3-amino-1-oxo-4-(2, 4, 5-trifluorphenyl)butyl]-5, 6, 7, 8-tetrahydro-3-(tri fluormethyl)-1, 2, 4 -triazolo[4, 3-a]pyrazine
US8916559B2 (en) 2009-08-13 2014-12-23 Sandoz Ag Crystalline compound of 7-[(3R)-3-amino-1-oxo-4-(2, 4, 5-trifluorophenyl)butyl]-5, 6, 7, 8-tetrahydro-3-(tri fluoromethyl)-1, 2, 4 -triazolo[4,3-A]pyrazin
WO2011018494A1 (en) 2009-08-13 2011-02-17 Sandoz Ag Crystalline compound of 7-[(3r)-3-amino-1-oxo-4-(2, 4, 5-trifluorphenyl)butyl]-5, 6, 7, 8-tetrahydro-3-(tri fluormethyl)-1, 2, 4 -triazolo[4,3-a]pyrazine
EA022485B1 (en) * 2009-08-13 2016-01-29 Сандоз Аг CRYSTALLINE COMPOUND OF 7-[(3R)-3-AMINO-1-OXO-4-(2,4,5-TRIFLUORPHENYL)BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUORMETHYL)-1,2,4-TRIAZOLO[4,3-a]PYRAZINE
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011032912A1 (en) 2009-09-15 2011-03-24 Ratiopharm Gmbh Pharmaceutical composition having the active substances metformin and sitagliptin or vildaliptin
EP2295083A1 (en) 2009-09-15 2011-03-16 Ratiopharm GmbH Pharmaceutical composition comprising active agents metformin and sitagliptin or vildagliptin
EP2308847A1 (en) 2009-10-09 2011-04-13 EMC microcollections GmbH Substituted pyridines as inhibitors of dipeptidyl peptidase IV and their application for the treatment of diabetes and related diseases
WO2011058193A1 (en) 2009-11-16 2011-05-19 Mellitech [1,5]-diazocin derivatives
US8765728B2 (en) 2009-11-16 2014-07-01 Mellitech [1,5]-diazocin derivatives
EP3646859A1 (en) 2009-11-27 2020-05-06 Boehringer Ingelheim International GmbH Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
WO2011064352A1 (en) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US9340523B2 (en) 2009-12-30 2016-05-17 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
US8648073B2 (en) 2009-12-30 2014-02-11 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
KR101156587B1 (en) 2010-02-19 2012-06-20 한미사이언스 주식회사 Preparation method of sitagliptin and amine salt intermediate used therein
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
EP2566843A4 (en) * 2010-04-28 2013-10-02 Sun Pharmaceutical Ind Ltd Process for the preparation of chiral beta amino carboxamide derivatives
EP2566843A2 (en) * 2010-04-28 2013-03-13 Sun Pharmaceutical Industries Limited Process for the preparation of chiral beta amino carboxamide derivatives
WO2011135586A2 (en) 2010-04-28 2011-11-03 Sun Pharmaceutical Industries Ltd. Process for the preparation of chiral beta amino carboxamide derivatives
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
US8980929B2 (en) 2010-05-21 2015-03-17 Merck Sharp & Dohme Corp. Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes
US8765668B2 (en) 2010-06-04 2014-07-01 Lek Pharmaceuticals D.D. Methods of synthesis of β-aminobutyryl substituted compounds
US20130130974A1 (en) * 2010-06-04 2013-05-23 Damjan Sterk NOVEL SYNTHETIC APPROACH TO beta-AMINOBUTYRYL SUBSTITUTED COMPOUNDS
WO2011151443A1 (en) 2010-06-04 2011-12-08 Lek Pharmaceuticals D.D. A NOVEL SYNTHETIC APPROACH TO ß-AMINOBUTYRYL SUBSTITUTED COMPOUNDS
EP2392575A1 (en) 2010-06-04 2011-12-07 LEK Pharmaceuticals d.d. A novel synthetic approach to ß-aminobutyryl substituted compounds
EP2397141A1 (en) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Process for the synthesis of beta-amino acids and derivatives thereof
WO2011161161A1 (en) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Diabetes therapy
WO2012007455A1 (en) 2010-07-13 2012-01-19 Chemo Iberica, S.A. Process for the preparation of organic salts
EP2407469A1 (en) 2010-07-13 2012-01-18 Chemo Ibérica, S.A. Salt of sitagliptin
EP2423178A1 (en) 2010-07-28 2012-02-29 Chemo Ibérica, S.A. Process for the production of sitagliptin
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
WO2012035549A2 (en) 2010-09-13 2012-03-22 Panacea Biotec Ltd An improved process for the synthesis of beta amino acid derivatives
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
EP3323818A1 (en) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2012046254A2 (en) 2010-10-08 2012-04-12 Cadila Healthcare Limited Process for preparing an intermediate of sitagliptin via enzymatic conversion
JP2013541942A (en) * 2010-10-08 2013-11-21 カディラ ヘルスケア リミティド Methods for producing sitagliptin intermediates by enzymatic conversion
US8691832B2 (en) 2010-12-06 2014-04-08 Merck Sharp & Dohme Corp. Tricyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
TWI494313B (en) * 2010-12-29 2015-08-01 Jiangsu Hengrui Medicine Co Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings
US9481642B2 (en) 2011-01-07 2016-11-01 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US9463170B2 (en) 2011-01-07 2016-10-11 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US11065215B2 (en) 2011-01-07 2021-07-20 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US9480663B2 (en) 2011-01-07 2016-11-01 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10201511B2 (en) 2011-01-07 2019-02-12 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
US10159658B2 (en) 2011-01-07 2018-12-25 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US10028923B2 (en) 2011-01-07 2018-07-24 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US11759441B2 (en) 2011-01-07 2023-09-19 Anji Pharmaceuticals Inc. Biguanide compositions and methods of treating metabolic disorders
US10610500B2 (en) 2011-01-07 2020-04-07 Anji Pharma (Us) Llc Chemosensory receptor ligand-based therapies
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US9050292B2 (en) 2011-01-07 2015-06-09 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US9572784B2 (en) 2011-01-07 2017-02-21 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US9962344B2 (en) 2011-01-07 2018-05-08 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
EP3243385A1 (en) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012118972A2 (en) 2011-03-01 2012-09-07 Synegy Pharmaceuticals Inc. Process of preparing guanylate cyclase c agonists
EP2899194A1 (en) 2011-03-03 2015-07-29 Cadila Healthcare Limited Amorphous besylate salt of a dpp-iv inhibitor
EP2789616A1 (en) 2011-03-03 2014-10-15 Cadila Healthcare Limited A novel gentisate salt of a DPP-IV inhibitor
CN104788456A (en) * 2011-03-03 2015-07-22 卡迪拉保健有限公司 Novel salts of DDP-IV inhibitor
WO2012147092A3 (en) * 2011-03-03 2013-03-14 Cadila Healthcare Limited Novel salts of dpp-iv inhibitor
WO2012147092A2 (en) 2011-03-03 2012-11-01 Cadila Healthcare Limited Novel salts of dpp-iv inhibitor
US9108972B2 (en) 2011-03-03 2015-08-18 Cadila Healthcare Limited Salts of DPP-IV inhibitor
AU2012247127B2 (en) * 2011-03-03 2016-01-28 Cadila Healthcare Limited Novel salts of DPP-IV inhibitor
EP2860180A1 (en) 2011-03-03 2015-04-15 Cadila Healthcare Limited Novel gentisate salts of DPP-IV inhibitor
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
WO2012131005A1 (en) 2011-03-29 2012-10-04 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical composition of sitagliptin
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9174930B2 (en) 2011-04-08 2015-11-03 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
WO2012136383A2 (en) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
EP2508506A1 (en) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Preparation of sitagliptin intermediates
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
CN102757431A (en) * 2011-04-24 2012-10-31 浙江华海药业股份有限公司 Novel method for synthesizing sitagliptin
US8912327B2 (en) 2011-05-05 2014-12-16 Chemo Iberica, S.A. Process for the production of sitagliptin
WO2012150328A1 (en) 2011-05-05 2012-11-08 Chemo Iberica, S.A. Process for the production of sitagliptin
ITMI20110765A1 (en) * 2011-05-05 2012-11-06 Chemo Iberica Sa PROCESS FOR SITAGLIPTINA PRODUCTION
EP2527320A1 (en) 2011-05-27 2012-11-28 LEK Pharmaceuticals d.d. Preparation of Sitagliptin Intermediates
WO2012163815A1 (en) 2011-05-27 2012-12-06 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
US20140187558A1 (en) * 2011-05-27 2014-07-03 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
US9359385B2 (en) * 2011-05-27 2016-06-07 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9527855B2 (en) 2011-06-29 2016-12-27 Merck Sharp & Dohme Corp. Process for preparing chiral dipeptidyl peptidase-IV inhibitors
US9181262B2 (en) 2011-06-29 2015-11-10 Merck Sharp & Dohme Corp Crystalline forms of a dipeptidyl peptidase-IV inhibitors
US8895603B2 (en) 2011-06-29 2014-11-25 Merck Sharp & Dohme Corp. Crystalline forms of a dipeptidyl peptidase-IV inhibitor
US9187488B2 (en) 2011-06-29 2015-11-17 Merck Sharp & Dohme Corp Process for preparing chiral dipeptidyl peptidase-IV inhibitors
US9051329B2 (en) 2011-07-05 2015-06-09 Merck Sharp & Dohme Corp. Tricyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
WO2013013833A1 (en) 2011-07-27 2013-01-31 Farma Grs, D.O.O. Process for the preparation of sitagliptin and its pharmaceutically acceptable salts
EA024688B1 (en) * 2011-07-27 2016-10-31 ФАРМА ДжРС, Д.О.О. Process for the preparation of sitagliptin and its pharmaceutically acceptable salts
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
EP2766369A4 (en) * 2011-10-14 2015-07-01 Laurus Labs Private Ltd Novel salts of sitagliptin, process for the preparation and pharmaceutical composition thereof
WO2013059222A1 (en) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. 2-pyridyloxy-4-nitrile orexin receptor antagonists
US9211263B2 (en) 2012-01-06 2015-12-15 Elcelyx Therapeutics, Inc. Compositions and methods of treating metabolic disorders
US10603291B2 (en) 2012-01-06 2020-03-31 Anji Pharma (Us) Llc Compositions and methods for treating metabolic disorders
US9770422B2 (en) 2012-01-06 2017-09-26 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
EP2615080A1 (en) 2012-01-12 2013-07-17 LEK Pharmaceuticals d.d. Preparation of Optically Pure ß-Amino Acid Type Active Pharmaceutical Ingredients and Intermediates thereof
WO2013104774A1 (en) 2012-01-12 2013-07-18 Lek Pharmaceuticals D.D. PREPARATION OF OPTICALLY PURE ß-AMINO ACID TYPE ACTIVE PHARMACEUTICAL INGREDIENTS AND INTERMEDIATES THEREOF
US9073930B2 (en) 2012-02-17 2015-07-07 Merck Sharp & Dohme Dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2013128000A1 (en) 2012-03-02 2013-09-06 Moehs Iberica S.L. Novel crystalline form of sitagliptin sulfate
US9181260B2 (en) 2012-03-02 2015-11-10 Moehs Iberica, S.L. Crystalline form of sitagliptin sulfate
EP4309673A2 (en) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
EP3708179A1 (en) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
US9388188B2 (en) 2012-06-14 2016-07-12 Lek Pharmaceuticals D.D. Synthetic route for the preparation of β-aminobutyryl substituted 5,6,7,8-tetrahydro[1,4]diazolo[4,3-alpha ]pyrazin-7-yl compounds
WO2013186326A1 (en) 2012-06-14 2013-12-19 Lek Pharmaceuticals D.D. NEW SYNTHETIC ROUTE FOR THE PREPARATION OF ß-AMINOBUTYRYL SUBSTITUTED 5,6,7,8-TETRAHYDRO[1,4]DIAZOLO[4,3-alpha]PYRAZIN-7-YL COMPOUNDS
EP2674432A1 (en) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. New synthetic route for the preparation of ß aminobutyryl substituted 5,6,7,8-tetrahydro[1,4]diazolo[4,3-alpha]pyrazin-7-yl compounds
US9156848B2 (en) 2012-07-23 2015-10-13 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-IV inhibitors
US9315508B2 (en) 2012-07-23 2016-04-19 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-IV inhibitors
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
CZ306115B6 (en) * 2012-12-04 2016-08-10 Zentiva, K.S. Process for preparing derivatives of 3-amino-4-(2,4,5-trifluorophenyl)-butanoic acid
EP2769712A1 (en) 2013-02-21 2014-08-27 Siegfried International AG Pharmaceutical formulation comprising DPP-IV inhibitor agglomerates and DPP-IV inhibitor particles
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US9862723B2 (en) 2013-11-01 2018-01-09 Zentiva K.S. Stable polymorph of the salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-anime with L-tartaric acid
WO2015062562A1 (en) 2013-11-01 2015-05-07 Zentiva, K.S. A stable polymorph of the salt of (2r)-4-oxo-4-[3-(trifiuoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-l-(2,4,54rifluorophenyl)butan-2-amine with l-tartaric acid
US10111880B2 (en) 2013-11-05 2018-10-30 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
WO2015068156A1 (en) 2013-11-05 2015-05-14 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
WO2015160678A1 (en) 2014-04-17 2015-10-22 Merck Sharp & Dohme Corp. Sitagliptin tannate complex
US9833463B2 (en) 2014-04-17 2017-12-05 Merck Sharp & Dohme Corp. Sitagliptin tannate complex
US10053466B2 (en) 2014-07-21 2018-08-21 Merck Sharp & Dohme Corp. Process for preparing chiral dipeptidyl peptidase-IV inhibitors
US9862725B2 (en) 2014-07-21 2018-01-09 Merck Sharp & Dohme Corp. Process for preparing chiral dipeptidyl peptidase-IV inhibitors
EP4000630A1 (en) 2014-09-03 2022-05-25 Invex Therapeutics Ltd Elevated intracranial pressure treatment
WO2016046679A1 (en) * 2014-09-28 2016-03-31 Mohan M Alapati Compositions and methods for the treatment of diabetes and pre-diabetes
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US10450315B2 (en) 2015-01-08 2019-10-22 Lee Pharma Limited Process for the preparation of dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor
WO2016112879A1 (en) 2015-01-13 2016-07-21 Zentiva, K.S. CRYSTALLINE MODIFICATION 2 OF (3/R)-3-AMINO-1-[3-(TRIFLUOROMETHYL)-6,8-DIHYDRO-5H-[1,2,4]TRIAZOLO[4,3-α]PYRAZIN-7-YL]-4-(2,4,5-TRIFLUOROPHENYL)BUTAN-1-ONE L-TARTRATE
WO2016112880A1 (en) 2015-01-13 2016-07-21 Zentiva, K.S Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
WO2016168535A1 (en) * 2015-04-15 2016-10-20 Valent Biosciences Corporation (s)-2'-vinyl-abscisic acid derivatives
KR101772898B1 (en) 2015-06-11 2017-08-31 동방에프티엘(주) Improved method of sitagliptin
KR20160146124A (en) 2015-06-11 2016-12-21 동방에프티엘(주) Improved method of sitagliptin
KR20160148371A (en) 2015-06-16 2016-12-26 경동제약 주식회사 Novel intermediates for preparing DPP-IV inhibitors, preparing method thereof and preparing method of DPP-IV inhibitors using the same
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
KR20170036288A (en) 2015-09-24 2017-04-03 주식회사 종근당 Novel Salts of Sitagliptin and Preparation Method thereof
EP3159343A1 (en) * 2015-10-22 2017-04-26 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Improved process for the preparation of triazole and salt thereof
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US10047094B1 (en) 2017-02-10 2018-08-14 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Process for the preparation of triazole and salt thereof
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
WO2018162722A1 (en) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Dpp-4 inhibitors for use in treating bone fractures
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
US11738028B2 (en) 2017-04-24 2023-08-29 Novartis Ag Therapeutic regimen
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
KR20190060235A (en) 2017-11-24 2019-06-03 제일약품주식회사 Preparation Method Camphorsulfonic acid Salt of Sitagliptin
WO2020167706A1 (en) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. 5-alkyl pyrrolidine orexin receptor agonists
WO2021026047A1 (en) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Heteroaryl pyrrolidine and piperidine orexin receptor agonists
KR20210057603A (en) 2019-11-12 2021-05-21 제이투에이치바이오텍 (주) Process for preparing sitagliptin
WO2022040070A1 (en) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Bicycloheptane pyrrolidine orexin receptor agonists
KR20220145631A (en) 2021-04-22 2022-10-31 주식회사 메디켐코리아 Improved manufacturing method of sitagliptin phosphate salt
WO2023139276A1 (en) 2022-01-24 2023-07-27 Zaklady Farmaceutyczne Polpharma S.A. Process for preparing crystalline sitagliptin hydrochloride monohydrate

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