WO2004087053A9 - Dipeptidyl peptidase inhibitors - Google Patents
Dipeptidyl peptidase inhibitorsInfo
- Publication number
- WO2004087053A9 WO2004087053A9 PCT/US2004/009217 US2004009217W WO2004087053A9 WO 2004087053 A9 WO2004087053 A9 WO 2004087053A9 US 2004009217 W US2004009217 W US 2004009217W WO 2004087053 A9 WO2004087053 A9 WO 2004087053A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound according
- ring
- unsubstituted
- phenyl
- Prior art date
Links
- 0 C*(*C=CC)C(*1)=C(*)*=C(*(C)N)*1=* Chemical compound C*(*C=CC)C(*1)=C(*)*=C(*(C)N)*1=* 0.000 description 5
- ZEMQJWXNDNHYJX-UHFFFAOYSA-N CC(N1CCCC1)SC Chemical compound CC(N1CCCC1)SC ZEMQJWXNDNHYJX-UHFFFAOYSA-N 0.000 description 1
- OCEOBNNIDOBMSF-UHFFFAOYSA-N CC(NC1=O)=Nc2c1nc[n]2COCc1ccccc1 Chemical compound CC(NC1=O)=Nc2c1nc[n]2COCc1ccccc1 OCEOBNNIDOBMSF-UHFFFAOYSA-N 0.000 description 1
- XJINZNWPEQMMBV-UHFFFAOYSA-N CCCCCCNC Chemical compound CCCCCCNC XJINZNWPEQMMBV-UHFFFAOYSA-N 0.000 description 1
- LNFLATPDVKDNKC-UHFFFAOYSA-N COC(CC1NC1CC(N1c2ccccc2)=Nc2ccccc2C1=O)=O Chemical compound COC(CC1NC1CC(N1c2ccccc2)=Nc2ccccc2C1=O)=O LNFLATPDVKDNKC-UHFFFAOYSA-N 0.000 description 1
- NGWOMNGDMOOJQD-UHFFFAOYSA-N COc(cc1C(N2Cc(cccc3)c3C#N)=O)ccc1N=C2Cl Chemical compound COc(cc1C(N2Cc(cccc3)c3C#N)=O)ccc1N=C2Cl NGWOMNGDMOOJQD-UHFFFAOYSA-N 0.000 description 1
- BKDANTHIHWWSIU-MRXNPFEDSA-N COc(nc1)cc(C(N2Cc3ccccc3C#N)=O)c1N=C2N(CCC1)C[C@@H]1N Chemical compound COc(nc1)cc(C(N2Cc3ccccc3C#N)=O)c1N=C2N(CCC1)C[C@@H]1N BKDANTHIHWWSIU-MRXNPFEDSA-N 0.000 description 1
- BROCCMHDEBWCSI-UHFFFAOYSA-N C[n]1c(N=C(N(Cc2ccccc2C#N)C2=O)N(CCC3)CC3N)c2nc1 Chemical compound C[n]1c(N=C(N(Cc2ccccc2C#N)C2=O)N(CCC3)CC3N)c2nc1 BROCCMHDEBWCSI-UHFFFAOYSA-N 0.000 description 1
- YNXUTUJCKRGCDF-UHFFFAOYSA-N Clc1c2nc[n](COCc3ccccc3)c2nc(Cl)n1 Chemical compound Clc1c2nc[n](COCc3ccccc3)c2nc(Cl)n1 YNXUTUJCKRGCDF-UHFFFAOYSA-N 0.000 description 1
- WYEIHVJOOZCGMD-UHFFFAOYSA-N N#Cc1c(CN2C(Cl)=Nc(ccc(Cl)c3)c3C2=O)cccc1 Chemical compound N#Cc1c(CN2C(Cl)=Nc(ccc(Cl)c3)c3C2=O)cccc1 WYEIHVJOOZCGMD-UHFFFAOYSA-N 0.000 description 1
- DPJXTBPIDMNEQR-UHFFFAOYSA-N N#Cc1ccccc1CN(C(c1c2)=O)C(Cl)=Nc1ccc2Br Chemical compound N#Cc1ccccc1CN(C(c1c2)=O)C(Cl)=Nc1ccc2Br DPJXTBPIDMNEQR-UHFFFAOYSA-N 0.000 description 1
- IZVBVAHHSUXPDZ-UHFFFAOYSA-N N#Cc1ccccc1CN(C1=O)C(Cl)=Nc2c1nc[n]2COCc1ccccc1 Chemical compound N#Cc1ccccc1CN(C1=O)C(Cl)=Nc2c1nc[n]2COCc1ccccc1 IZVBVAHHSUXPDZ-UHFFFAOYSA-N 0.000 description 1
- GXDMWXPYCUYFDK-UHFFFAOYSA-N N#Cc1ccccc1CN1C(Cl)=Nc(c(Cl)ccc2)c2C1=O Chemical compound N#Cc1ccccc1CN1C(Cl)=Nc(c(Cl)ccc2)c2C1=O GXDMWXPYCUYFDK-UHFFFAOYSA-N 0.000 description 1
- QPRAFCFDOZPSSH-MRXNPFEDSA-N N[C@H](CCC1)CN1C(N1Cc2ccccc2C#N)=Nc2cccc(F)c2C1=O Chemical compound N[C@H](CCC1)CN1C(N1Cc2ccccc2C#N)=Nc2cccc(F)c2C1=O QPRAFCFDOZPSSH-MRXNPFEDSA-N 0.000 description 1
- VOIFPEGZIPOIGK-UHFFFAOYSA-N O=C(c(cc(cc1Cl)Cl)c1N1)NC1=O Chemical compound O=C(c(cc(cc1Cl)Cl)c1N1)NC1=O VOIFPEGZIPOIGK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention relates to compounds that may be used to inhibit dipeptidyl peptidases as well as compositions of matter and kits comprising these compounds.
- the present invention also relates to methods for inhibiting dipeptidyl peptidases as well as treatment methods using compounds according to the present invention.
- Dipeptidyl Peptidase IN (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type H membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAPTV, FAP ⁇ , adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl- aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GP110; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glyc
- DPP-IV is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-Gly or X-Ser has also been reported for some naturally occurring peptides.
- DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of disease states, some of which are discussed below.
- DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1 (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.
- GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine; GLP-1 (7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying.
- DPP-IV has been shown to be the primary degrading enzyme of GLP-1 (7-36) in vivo.
- GLP-1 (7-36) is degraded by DPP-IV efficiently to GLP-1 (9-36), which has been speculated to act as a physiological antagonist to GLP-1 (7-36).
- Inhibiting DPP-IV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-1 (7-36) and attenuating the formation of its antagonist GLP-1 (9-36).
- DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
- diabetes in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
- ITT impaired glucose tolerance
- IGF impaired fasting plasma glucose
- metabolic acidosis ketosis
- ketosis ketosis
- appetite regulation and obesity are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose
- DPP-IV expression is increased in T-cells upon mitogenic or antigenic stimulation (Mattem, T submit et al., Scand. J. Immunol., 1991, 33, 737). It has been reported that inhibitors of DPP-IV and antibodies to DPP-IV suppress the proliferation of mitogen-stimulated and antigen-stimulated T-cells in a dose-dependant manner (Schon, E., et al., Biol. Chem., 1991, 372, 305). Various other functions of T-lymphocytes such as cytokine production, IL-2 mediated cell proliferation and B-cell helper activity have been shown to be dependent on DPP-IV activity (Schon, E., et al., Scand. J.
- DPP-IV inhibitors based on boroProline, (Flentke, G. R., et al., Proc. Nat. Acad. Sci. USA, 1991, 88, 1556) although unstable, were effective at inhibiting antigen-induced lymphocyte proliferation and IL-2 production in murine CD4+ T-helper cells.
- Such boronic acid inhibitors have been shown to have an effect in vivo in mice causing suppression of antibody production induced by immune challenge (Kubota, T. et al., Clin. Exp. ⁇ rnmun., 1992, 89, 192).
- DPP-IV The role of DPP- IV in regulating T lymphocyte activation may also be attributed, in part, to its cell-surface association with the transmembrane phosphatase, CD45. DPP-IV inhibitors or non-active site ligands may possibly disrupt the CD45-DPP-IV association.
- CD45 is known to be an integral component of the T-cell signaling apparatus. It has been reported that DPP-IV is essential for the penetration and infectivity of UPV-l and HTV-2 viruses in CD4+ T-cells (Wakselman, M., Nguyen, C, Mazaleyrat, J.-P., Callebaut, C, Krust, B., Hovanessian, A.
- inhibitors of DPP-IV may be useful immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
- lung endothelial cell DPP-IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells (Johnson, R. C, et al., J. Cell. Biol., 1993, 121, 1423). DPP-IV is known to bind to fibronectin and some metastatic tumor cells are known to carry large amounts of fibronectin on their surface. Potent DPP-IV inhibitors may be useful as drugs to prevent metastases of, for example, breast and prostrate tumors to the lungs.
- DPP-IV inhibitors may be useful as agents to treat dermatological diseases such as psoriasis and lichen planus.
- DPP-IV inhibitors may also act to suppress sperm motility and therefore act as a male contraceptive agent.
- DPP-JN inhibitors have been implicated as novel for treatment of infertility, and particularly human female infertility due to Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) which is a condition characterized by thickening of the ovarian capsule and formation of multiple follicular cysts. It results in infertility and amenorrhea.
- PCOS Polycystic ovary syndrome
- DPP-IV is thought to play a role in the cleavage of various cytokines (stimulating hematopoietic cells), growth factors and neuropeptides.
- Stimulated hematopoietic cells are useful for the treatment of disorders that are characterized by a reduced number of hematopoietic cells or their precursors in vivo. Such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer. It was discovered that inhibitors of dipeptidyl peptidase type IV are useful for stimulating the growth and differentiation of hematopoietic cells in the absence of exogenously added cytokines or other growth factors or stromal cells.
- DPP-IV in human plasma has been shown to cleave N-terminal Tyr- Ala from growth hormone-releasing factor and cause motivation of this hormone. Therefore, inhibitors of DPP-IV may be useful in the treatment of short stature due to growth hormone deficiency (Dwarfism) and for promoting GH-dependent tissue growth or re-growth.
- Dwarfism growth hormone deficiency
- DPP-TV can also cleave neuropeptides and has been shown to modulate the activity of neuroactive peptides substance P, neuropeptide Y and CLP (Mentlein, R., Dahms, P., Grandt, D., Kruger, R., Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV, Regul. Pept, 49, 133, 1993; Wetzel, W., Wagner, T., Vogel, D., Demuth, H.-U., Balschun, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes, Neuropeptides, 31, 41, 1997).
- DPP-IV inhibitors may also be useful agents for the regulation or normalization of neurological disorders.
- Several compounds have been shown to inhibit DPP-JN. Nonetheless, a need still exists for new DPP-JN inhibitors that have advantageous potency, stability, selectivity, toxicity and or pharmacodynamics properties. In this regard, a novel class of DPP-JN inhibitors are provided herein.
- the present invention relates to compounds that have activity for inhibiting DPP- JN. It is noted that these compounds may also have activity for inhibiting other S9 proteases and thus may be used against these other S9 proteases as well as DPP-JN.
- the present invention also provides compositions, articles of manufacture and kits comprising these compounds.
- a pharmaceutical composition that comprises a DPP-JN inhibitor according to the present invention as an active ingredient.
- Pharmaceutical compositions according to the invention may optionally comprise 0.001 %-100% of one or more DPP-JN inhibitors of this invention.
- compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
- routes including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
- routes including for example, orally, parenterally, intra
- the invention is also directed to kits and other articles of manufacture for treating disease states associated with DPP-JN.
- a kit comprising a composition comprising at least one DPP-JN inhibitor of the present invention in combination with instructions.
- the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to a ⁇ ninister the composition.
- the kit may also comprise packaging materials.
- the packaging material may comprise a container for housing the composition.
- the kit may also optionally comprise additional components, such as syringes for administration of the composition.
- the kit may comprise the composition in single or multiple dose forms.
- an article of manufacture comprises a composition comprising at least one DPP-JN inhibitor of the present invention in combination with packaging materials.
- the packaging material may comprise a container for housing the composition.
- the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
- the kit may also optionally comprise additional components, such as syringes for administration of the composition.
- the kit may comprise the composition in single or multiple dose forms.
- the compounds, compositions, kits and articles of manufacture are used to inhibit DPP-JN.
- the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which DPP-JN possesses activity that contributes to the pathology and/or symptomology of the disease state.
- a compound is administered to a subject wherein DPP-JN activity within the subject is altered, preferably reduced.
- a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits DPP-JN.
- a method of inhibiting DPP-JN comprises contacting DPP-JN with a compound according to the present invention.
- a method of inhibiting DPP-IV comprises causing a compound according to the present invention to be present in a subject in order to inhibit DPP-JN in vivo.
- a method of inhibiting DPP-JN comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits DPP-JN in vivo.
- the compounds of the present invention may be the first or second compounds.
- a therapeutic method comprises administering a compound according to the present invention.
- a method of inhibiting cell proliferation comprises contacting a cell with an effective amount of a compound according to the present invention.
- a method of inhibiting cell proliferation in a patient comprises administering to the patient a therapeutically effective amount of a compound according to the present invention.
- a method of treating a condition in a patient which is known to be mediated by DPP-JN, or which is known to be treated by DPP-JN inhibitors comprising administering to the patient a therapeutically effective amount of a compound according to the present invention.
- a method for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of disease state which is known to be mediated by DPP-JN, or which is known to be treated by DPP-JN inhibitors.
- DPP-JN possesses activity that contributes. to the pathology and/or symptomology of the disease state, the method comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
- DPP-JN possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state.
- the compounds of the present invention may be the first or second compounds.
- DPP-IN possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state.
- a method for treating a cell proliferative disease state comprising treating cells with a compound according to the present invention in combination with an anti-proliferative agent, wherein the cells are treated with the compound according to the present invention before, at the same time, and/or after the cells are treated with the anti-proliferative agent, referred to herein as combination therapy.
- combination therapy is intended to cover when agents are administered before or after each other (sequential therapy) as well as when the agents are administered at the same time.
- diabetes more particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (TFG), metabolic acidosis, ketosis, appetite regulation, obesity, immunosuppressants or
- the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well known in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers.
- pharmaceutically acceptable ionized forms e.g., salts
- solvates e.g., hydrates
- prodrugs may also be administered which are altered in vivo and become a compound according to the present invention.
- the various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention.
- certain compounds of the present invention may be altered in vivo prior to inhibiting DPP-JN and thus may themselves be prodrugs for another compound. Such prodrugs of another compound may or may not themselves independently have DPP-IN inhibitory activity.
- Figure 1 illustrates a ribbon diagram overview of the structure of DPP-JN, highlighting the secondary structural elements of the protein.
- Figure 2 depicts different, representative 5 membered ring structures that may be formed when R3 and R4 are taken together to form a substituted or unsubstituted ring.
- Figure 3 depicts different, representative 6 membered ring structures that may be formed when R3 and R4 are taken together to form a substituted or unsubstituted ring.
- Figure 4 depict additional representative 5 or 6 membered ring structures that may be formed when R3 and R4 are taken together to form a substituted or unsubstituted ring.
- the rings shown in Figures 2, 3 and 4 are unsubstituted. It is noted that the rings may optionally be further substituted by one or more substituents.
- Alicyclic means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quaternerized or oxidized and the sulfur atoms can be optionally oxidized.
- alicyclic moieties include, but are not limited to moieties with C 3 - C 8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
- "Aliphatic" means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
- Alkenyl represented by itself means a straight or branched, unsaturated, aliphatic radical having a chain of carbon atoms having at least one double bond between adjacent carbon atoms.
- Cx alkenyl and C ⁇ . ⁇ alkenyl are typically used where X and Y indicate the number of carbon atoms in the chain.
- C 2- alkenyl includes alkenyls that have a chain of between 2 and 6 carbons.
- Alkoxy means an oxygen moiety having a further alkyl substituent.
- the alkoxy groups of the present invention can be optionally substituted.
- Alkyl represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See “aminoalkyl”) between the carbon atoms.
- oxaalkyl oxygen
- aminoalkyl nitrogen atoms between the carbon atoms.
- Cx alkyl and C ⁇ . ⁇ alkyl are typically used where X and Y indicate the number of carbon atoms in the chain.
- C ⁇ -6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, .fee-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-methylalTyl, ethynyl, 1-propynyl, 2-propynyl, and the like).
- 1 and 6 carbons e.g., methyl, ethyl, propyl, isopropyl, butyl, .fee-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-methylalTyl
- Alkyl represented along with another radical means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6- ⁇ o)aryl(C 1- 3)alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2- thienylmethyl, 2-pyridinylmethyl and the like).
- Alkylene unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical.
- Cx alkylene and C ⁇ . ⁇ alkylene are typically used where X and Y indicate the number of carbon atoms in the chain.
- 2-methyltetramethylene (-CH 2 CH(CH 3 )CH 2 CH 2 -), pentamethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) and the like).
- Alkylidene means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond.
- Cx alkylidene and C ⁇ . ⁇ alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain.
- Alkynyl represented by itself means a straight or branched, unsaturated, aliphatic radical having a chain of carbon atoms having at least one triple bond between adjacent carbon atoms.
- Cx alkynyl and C ⁇ . ⁇ alkynyl are typically used where X and Y indicate the number of carbon atoms in the chain.
- C 2 ⁇ alkynyl includes alkynyls that have a chain of between 2 and 6 carbons.
- amino means a nitrogen moiety having two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
- representative amino groups include -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHC 1-3 -alkyl, -N(C ⁇ . 3 -alkyl) 2 and the like.
- the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, arid the like.
- Aminoalkyl means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between carbon atoms of the alkyl.
- an (C 2-6 ) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
- "Animal” includes humans, non-human mammals (e.g. , dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
- Aromatic means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp hybridized and the total number of pi electrons is equal to 4n+2.
- An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
- Aryl means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl.
- Aryloxy means an oxygen moiety having a further aryl substituent.
- the aryloxy groups of the present invention can be optionally substituted.
- Bicycloalkyl means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
- Bicycloaryl means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic.
- Cx bicycloaryl and C ⁇ . ⁇ bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
- “Bridging ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other.
- Non-exclusive examples of common compounds having a bridging ring include bor ⁇ eol, norbornane, 7-oxabicyclo[2.2. ljheptane, and the like.
- One or both rings of the bicyclic system may also comprise heteroatoms.
- Carbamoyl means the radical -OC(O)NR a Rb where R a and Rt, are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
- Carbocycle means a ring consisting of carbon atoms.
- Carbocyclic ketone derivative means a carbocyclic derivative wherein the ring contains a -CO- moiety.
- Carbonyl means the radical -CO-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
- Carboxy means the radical -CO 2 -. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
- Cyano means the radical -CN.
- Cycloalkyl means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly.
- C x cycloalkyl and C ⁇ -Y cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
- C3.10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,
- Cycloalkylene means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly. Cx cycloalkylene and C ⁇ . ⁇ cycloalkylene are typically used where
- X and Y indicate the number of carbon atoms in the ring assembly.
- Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, Le., the "side effects" of such therapy.
- fused ring refers to a ring that is bonded to another ring to form a compound haying a bicyclic structure where the ring atoms that are common to both rings are directly bound to each other.
- Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like.
- Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like.
- Halo means fluoro, chloro, bromo or iodo.
- Halo-substituted alkyl as an isolated group or part of a larger group, means
- alkyl substituted by one or more "halo" atoms, as such terms are defined in this Application.
- Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like
- halo-substituted (C ⁇ alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).
- Heteroaryl means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon.
- the nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized.
- Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.
- Heteroaryl also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring.
- bicyclic or tricyclic heteroaryls include, but are not limited to, those derived frombenzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, imidazo[l,2-a]pyrirmdine, imidazo[l,2- c]pyrimidine, imidazo[
- the bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused.
- the heteroaryl groups of this invention can be substituted or unsubstituted.
- Heteroaryloxy means an oxygen moiety having a further heteroaryl substituent.
- heteroaryloxy groups of the present invention can be optionally substituted.
- Heteroatom refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur.
- Heteroatom moiety includes a moiety where the atom by which the moiety is attached is not a carbon.
- Heterobicycloalkyl means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
- hetero(C 9-12 )bicycloalkyl as used in this application includes, but is not limited to, 3-aza- bicyclo[4.1.0]he ⁇ t-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl , 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
- Heterobicycloaryl means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
- hetero(C -1 o)bicycloaryl as used in this Application includes, but is not limited to, 2-amino-
- Heterocycloalkyl means cycloalkyl, as defined in this AppHcation, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S.
- Non-exclusive examples of heterocycloalkyl include piperidyl, 4-morpholyl, 4- piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4- dioxanyl and the like.
- Heterocycloalkylene means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
- Heterocycloalkylene means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
- “Hydroxy” means the radical -OH.
- Jminoketone derivative means a derivative comprising the moiety -C(NR)-, wherein R comprises a hydrogen or carbon atom attached to the nitrogen.
- “Isomers” mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space.
- stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”
- stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers.”
- a carbon atom bonded to four nonidentical substituents is termed a “chiral center.”
- a compound with one chiral center has two enantiomeric forms of opposite chirality.
- a mixture of the two enantiomeric forms is termed a "racemic mixture.”
- a compound that has more than one chiral center has 2 n ⁇ enantiomeric pairs, where n is the number of chiral centers.
- Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture.”
- a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
- Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog.
- Oxaalkyl means an alkyl, as defined above, except where one or more oxygen atoms (-O-) are positioned between carbon atoms of the alkyl.
- an (C 2- 6)oxaaikyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
- Oxoalkyl means an alkyl, further substituted with a carbonyl group.
- the carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
- “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
- “Pharmaceutically acceptable salts” means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
- Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, ⁇ -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
- Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
- Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
- Acceptable organic bases include emanolamine, diethanolamine, triethanolamine, tromethamine, N-memylglucamine and the like.
- Prodrug means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention. The prodrug itself may or may not also have DPP-JN inhibitory activity.
- an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
- Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
- an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
- Protected derivatives means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
- Substituted or unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
- isopropyl is an example of an ethylene moiety that is substituted by -CH 3 .
- a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
- substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
- Sulfinyl means the radical -SO-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
- Sulfonyl means the radical -SO 2 -. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
- “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
- Thiocarbonyl means the radical -CS-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
- Treatment or “treating” means any administration of a compound of the present invention and includes:
- a alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom.
- a alkyl comprises methyl (i.e., -CH 3 ) as well as -R a RbRc where R a , R b , and R c may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano.
- CF 3 , CH 2 OH and CH 2 CN for example, are all alkyls.
- DPP- IV dipeptidyl peptidases JN
- DPP-JN EC.3.4.14.5 also known as DPP4, DP4, DAP-TV, adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp) or CD26
- ADAbp adenosine deaminase binding protein
- CD26 CD26
- DPP-TV has a serine type mechanism of protease activity, cleaving off dipeptides from the ammo-terminus of peptides with proline or alanine at the penultimate position. In addition the slow release of dipeptides of the type X-Gly or X-Ser is reported for some naturally occurring peptides.
- DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids.
- DPP-JN is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26.
- DPP-JN The wild-type form of full length DPP-JN is described in GenBank Accession Number NM_001935 ("Dipeptidyl peptidase TV (CD 26) gene expression in enterocyte-like colon cancer cell lines HT-29 and Caco-2. Cloning of the complete human coding sequence and changes of dipeptidyl peptidase TN mR ⁇ A levels during cell differentiation", Darmoul, D., Lacasa, M., Baricault, L., Marguet, D., Sapin, C, Trotot, P., Barbat, A. and Trugnan, G., J. Biol. Chem., 267 (7), 4824-4833, 1992).
- DPP-JN is a member of the S9 family of serine proteases, more particularly the S9B family.
- Other members of the S9 family include, but are not limited to:
- Subfamily S9A Dipeptidyl-peptidase; Oligopeptidase B (EC 3.4.21.83): Oligopeptidase B; Prolyl oligopeptidase (EC 3.4.21.26): Subfamily S9B: Dipeptidyl aminopeptidase A; Dipeptidyl aminopeptidase B Dipeptidyl-peptidase TV (EC 3.4.14.5): Dipeptidyl-peptidase V Fibroblast activation protein alpha subunit; Seprase Subfamily S9C: Acvlaminoacvl-peptidase (EC 3.4.19.1) [0108] It is noted that the compounds of the present invention may also possess inhibitory activity for other S9 family members and thus maybe used to address disease states associated with these other family members.
- FIG. 1 illustrates a ribbon diagram overview of the structure of DPP-TV, highlighting secondary structural elements of the protein.
- DPP-TV is a cylindrical shaped molecule with an approximate height of 70 A and a diameter of 60 A.
- the catalytic triad of DPP-IN (Ser642, Asp720 and His752) is illustrated in the center of the figure by a "ball and stick" representation. This triad of amino acids is located in the peptidase domain or catalytic domain of DPP-TV.
- the catalytic domain is covalently linked to the ⁇ -propeller domain.
- the catalytic domain of DPP-TV includes residues 1-67 and 511-778.
- the catalytic domain of DPP-IN adopts a characteristic ⁇ / ⁇ hydrolase fold.
- the core of this domain contains an 8- stranded ⁇ -sheet with all strands being parallel except one.
- the ⁇ -sheet is significantly twisted and is flanked by three ⁇ -helices on one side and five ⁇ -helices on the other.
- the topology of the ⁇ -strands is 1, 2, -lx, 2x and (lx) (J. S. Richardson: The anatomy and taxonomy of protein structure; (1981) Adv. Protein Chem.269, 15076-15084.).
- a number of residues were identified that contribute to the shape and charge characteristics of the active site. Knowledge of these residues has been an important contribution to the design of DPP-JN inhibitors of the present invention.
- DPP-TV inhibitors of the present invention comprise Formula I:
- Ri is hydrogen or is selected from the group consisting of (C ⁇ - 1 o)alkyl, (C 3 -i 2 )cycloalkyl, (C3 -12 )cycloalkyl(C 1 - 5 )alkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(C 1 - 10 )alkyl, (C 9- i 2 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C ⁇ -3)alkyl, thiocarbonyl (C ⁇ -3 )alkyl, sulfonyl (C 1- 3)alkyl, sulfinyl amino, cyano, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- R 2 is selected from the group consisting of halo, perhalo(C ⁇ - 1 o)alkyl, amino, cyano, thio, (C ⁇ -io)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C ⁇ . 3 )alkyl, thiocarbonyl sulfinyl (C ⁇ . 3 )alkyl, imino alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring;
- R 3 and R 4 are taken together to form a substituted or unsubstituted 5 or 6 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-JN inhibitors of the present invention comprise Formula JJ:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C or N;
- Ri is hydrogen or is selected from the group consisting of (C 1 - ⁇ o)alkyl, (C3-i2)cycloalkyl, (C3- 1 2)cycloalkyl(C 1 - 5 )alkyl, hetero(C3- 12 )cycloalkyl, aryl(C 1 - 1 o)alkyl, (Cg- ⁇ bicycloaryl, hetero(C -i 2 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )a ⁇ kyl, sulfonyl (C 1 -3)alkyl, sulfinyl (Ci ⁇ alkyl, imino (C ⁇ .
- R 2 is selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, amino, cyano, thio, (C ⁇ - ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C ⁇ - 3 )alkyl, thiocarbonyl (Ci ⁇ alkyl, sulfonyl (C ⁇ -3 )alkyl, sulfinyl (C ⁇ .
- R is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-JN inhibitors of the present invention having particular substitution patterns have significantly improved stability in biological assays. Improvement in the stabilities of the compounds in rat liver microsomes, for example, as demonstrated by the increase in the half life of the test compound in microsomal assays, has been demonstrated in particular substitutions of the DPP-IN inhibitors of the present invention.
- DPP-IV inhibitors comprising the Formula JJ with substitution at the 6 and/or the 7-positions result in enhanced stability as demonstrated in biological assays.
- compounds of the Formula JJ comprise quinazolinones that are substituted at the 6-position, the 7-position, or both the 6 and 7 positions of the compound of Formula TJ. ⁇ on-limiting examples of the compounds of the Formula JI include quinazolinone derivatives, naphthyridine derivatives, 4H-pyrido[3,4- d]pyrimidine derivatives, etc.
- DPP-JN inhibitors comprise compounds of the Formula JJ wherein K is CR12, where R12 is independently selected from the group consisting of halo, perhalo(Cl-10)alkyl, CF3, cyano, nitro, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- R12 is independently selected from the group consisting of halo, perhalo(Cl-10)alkyl, CF3, cyano, nitro, alkyl, aryl, heteroaryl, aminosulfon
- K is CR12 where R12 is independently selected from the group consisting of halo, perhalo(Cl-10)alkyl, CF3, cyano, nitro, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and L is nitrogen.
- R12 is independently selected from the group consisting of halo, perhalo(Cl-10)alkyl, CF3, cyano, nitro, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl
- K is CR 12 , where R 12 is independently selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, CF 3 , cyano, nitro, alkyl, aryloxy, heteroaryloxy, amino, and alkoxy, each substituted or unsubstituted;
- Ri is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl, -(CH 2 )-(3-cyano)phenyl, -(CH 2 )-(2-hydroxy)phenyl, -(CH 2 )-(3-hydroxy)phenyl, -(CH 2 )-(2- alkenyl)phenyl, -(CH 2 )-(3-alkenyl)phenyl, -(CH 2 )-(2-alkynyl)phenyl, -(CH 2 )-(3- alkynyl)phenyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(3-nitro)phenyl, -(CH 2 )-(2-carboxy)phenyl, -(CH 2 )-(3-carboxy)phenyl, -(CH 2 )-(2-carboxamido) ⁇ henyl, -(CH 2
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrrolidin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrolidin- 1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0118] In yet another variation,
- K is CRi 2 , where R 12 is independently selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, CF 3 , cyano, nitro, alkyl, aryloxy, heteroaryloxy, amino, and alkoxy, each substituted or unsubstituted;
- Ri is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl, -(CH 2 )-(3-cyano) ⁇ henyl, -(CH 2 )-(2-hydroxy) ⁇ henyl, -(CH 2 )-(3-hydroxy)phenyl, -(CH 2 )-(2- alkenyl) ⁇ henyl, -(CH 2 )-(3-alkenyl) ⁇ henyl, -(CH 2 )-(2-alkynyl)phenyl, -(CH 2 )-(3 ⁇ alkynyl)phenyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(3-nitro) ⁇ henyl, -(CH 2 )-(2-carboxy)phenyl, -(CH 2 )-(3-carboxy)phenyl, -(CH 2 )-(2-carboxamido)phenyl, -
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrrolidin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrolidin- 1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted.
- DPP-IN inhibitors of the present invention comprise a member selected from the group consisting of Formulae HJa, JJIb, T
- Ri is hydrogen or is selected from the group consisting of (C ⁇ -io)alkyl, (C3 -1 2)cycloalkyl, (C 3 . 12 )cycloalkyl(C 1 - 5 )alkyl, hetero(C 3 -i2)cycloalkyl, aryl(C ⁇ - 10 )alkyl, (Cg- ⁇ bicycloaryl, hetero(C -12 )bicycloaryl, carbonyl (C ⁇ alkyl, thiocarbonyl (C ⁇ alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C ⁇ alkyl, imino (C 1-3 )alkyl, amino, cyano, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- R 2 is selected from the group consisting of halo, perhalo(C ⁇ - 1 o)alkyl, amino, cyano, thio, (C 1 - 1 o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl ( ⁇ alkyl, thiocarbonyl sulfinyl (C ⁇ - 3 )alkyl, imino (C ⁇ - 3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R ⁇ 9 is independently selected from the group consisting of hydrogen, halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or
- DPP-JN inhibitors of the present invention comprise Formula TN:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is hydrogen or is selected from the group consisting of (C ⁇ - ⁇ o)alkyl, (C 3- i 2 )cycloalkyl, (C3-i 2 )cycloalkyl(C 1 - 5 )alkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 -io)alkyl, (C 9 - ⁇ 2 )bicycloaryl, hetero(C , 12 )bicycloaryl, carbonyl sulfonyl (C 1 -3)alkyl, sulfinyl ( ⁇ alkyl, imino (C ⁇ aHcyl, amino, cyano, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- R 2 is selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, amino, cyano, thio, (C 1 - 1 o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C ⁇ - 3 )alkyl, thiocarbonyl hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring; and R is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-IV inhibitors of the present invention comprise Formulae Va, Vb or Vc:
- Ri is hydrogen or is selected from the group consisting of (Ci-io)alkyl, (C 3 - 12 )cycloalkyl, (C 3- i 2 )cycloalkyl(C ⁇ - 5 )alkyl, hetero(C 3 - 12 )cycloalkyl, aryl(Ci-io)alkyl, (C 9-12 )bicycloaryl, hetero(C -12 )bicycloaryl, carbonyl (C ⁇ alkyl, thiocarbonyl ( ⁇ alkyl, sulfonyl (C ⁇ .
- R 2 is selected from the group consisting of halo, perhalo(Ci- 1 o)alkyl, amino, cyano, thio, (C ⁇ - 1 o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl ( ⁇ alkyl, thiocarbonyl sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R ⁇ 9 is independently selected from the group consisting of hydrogen, halo, ⁇ erhalo(C 1 - 1 o)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group,
- DPP-IV inhibitors of the present invention comprise Formula Via or Formula VJb:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is hydrogen or is selected from the group consisting of (Ci-io)alkyl, (C 3- i 2 )cycloalkyl, (C 3- i 2 )cycloalkyl(Ci- 5 )alkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C 1 - 1 o)alkyl, (C 9- ⁇ 2 )bicycloaryl, hetero(C -i 2 )bicycloaryl, carbonyl ( ⁇ alkyl, thiocarbonyl (C ⁇ -3 )alkyl, sulfonyl (Ci- 3 )alkyl, sulfinyl (Chalky!, imino ( ⁇ alkyl, amino, cyano, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or
- R 2 is selected from the group consisting of halo, perhalo(Ci-io)alkyl, amino, cyano, thio, (Ci- 1 o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (Ci ⁇ alkyl, thiocarbonyl hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring; and
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-IV inhibitors of the present invention comprise Formulae Vila, VHb, or VJJc: wherein
- X is selected from the group of moieties where the ring atom is either C, N, O or S in Formula VTJa, or X is selected from the group of moieties where the ring atom is either C or N in Formula VTJb or Formula VTJc;
- Ri is hydrogen or is selected from the group consisting of (Ci- 10 )alkyl, (C 3 -i 2 )cycloalkyl, (C 3 .i 2 )cycloalkyl(Ci- 5 )alkyl, hetero(C 3 - 12 )cycloaIkyl, aryl(C ⁇ - ⁇ o)alkyl, C 9- i 2 )bicycloaryl, hetero(C 4 .
- R 2 is selected from the group consisting of halo, ⁇ erhalo(Ci-io)alkyl, amino, cyano, thio, (Cr ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C 1- 3)alkyl, thiocarbonyl (Ci- 3 )alkyl, sulfonyl alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring;
- R is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 19 is independently selected from the group consisting of hydrogen, halo, perhalo(Ci-io)alkyl, CF3, cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstit
- DPP-TV inhibitors of the present invention comprise Formulae Villa VTUb and VTTIc:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is hydrogen or is selected from the group consisting of (C ⁇ -io)alkyl, (C 3 - ⁇ 2 )cycloalkyl, (C 3- i 2 )cycloalkyl(Ci- 5 )alkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C ⁇ -i 0 )alkyl, (C 9- ⁇ 2 )bicycloaryl, hetero(C 4 .i 2 )bicycloaryl, carbonyl sulfonyl sulfinyl (Ci.
- R 2 is selected from the group consisting of halo, perhalo(C ⁇ - ⁇ 0 )alkyl, amino, cyano, thio, (C ⁇ - ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl thiocarbonyl sulfinyl (Ci_ 3 )alkyl, imino hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring; and
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-JV inhibitors of the present invention comprise Formula TX:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is hydrogen or is selected from the group consisting of (Ci-io)alkyl, (C 3 -i 2 )cycloalkyl, (C 3- i 2 )cycloalkyl(Ci- 5 )alkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(Ci-io)alkyl, (C 9 .i 2 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (Ci ⁇ alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C ⁇ - 3 )alkyl, sulfinyl (Ci ⁇ alkyl, imino (Chalky!, amino, cyano, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsub
- R 2 is selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, amino, cyano, thio, (C ⁇ -io)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (Ci.3)alkyl, thiocarbonyl sulfonyl (C 1-3 )alkyl, sulfinyl (Ci_ 3 )alkyl, imino alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring; and
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formula X:
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C3- )cycloalkyl and aryl;
- R2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 3 and R 4 are taken together to form a substituted or unsubstituted 5 or 6 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formula XI:
- J, K, L, and M are each independently selected from the group of CR ⁇ 2 and N;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C 3 - 7 )cycloalkyl and aryl;
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R12 is hydrogen or is independently selected from the group consisting of halo, perhalo(Ci-io)alkyl, CF3, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- DPP-IV inhibitors of the present invention comprise
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R ra and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C 3 - 7 )cycloalkyl and aryl;
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted;
- each R 19 is independently selected from the group consisting of hydrogen, halo, perhalo(Ci-io)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio,
- DPP-IN inhibitors of the present invention comprise Formula XTJJ:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZRm, where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C3- 7 )cycloalkyl and aryl;
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formulae XTVa, XTVb, and XTVc:
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C3- )cycloalkyl and aryl;
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R ⁇ 9 is independently selected from the group consisting of hydrogen, halo, perhalo(Ci-io)alkyl, CF3, cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsub
- DPP-JV inhibitors of the present invention comprise Formulae XVa and XVb:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formulae XVIa, XVTb, and XVIc:
- X is selected from the group of moieties where the ring atom is either C, N, O or S in Formula XVIa, or X is selected from the group of moieties where the ring atom is either C or N in Formula XVTb or Formula XVTc;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- Rg is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted;
- each R 19 is independently selected from the group consisting of hydrogen, halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio,
- DPP-IN inhibitors of the present invention comprise Formulae XVJJa, XVJJb, and XVHc:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C3- 7 )cycloalkyl and aryl; and
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring.
- DPP-I inhibitors of the present invention comprise Formula XV : xvm wherein
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which.Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formula XIX:
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; R 3 and R 4 are taken together to form a substituted or unsubstituted 5 or 6 membered ring; and
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-IN inhibitors of the present invention comprise Formula XX:
- J, K, L, and M are each independently selected from the group of CR 12 and N;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R ⁇ 2 is hydrogen or is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF3, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- DPP-IV inhibitors of the present invention comprise Formulae XXIa, XXIb, XXIc, XXId, XXIe, and XXJf:
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 19 is independently selected from the group consisting of hydrogen, halo, perhalo(Ci-io)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or un
- DPP-TV inhibitors of the present invention comprise Formula XXII:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C3- )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; and
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-IV inhibitors of the present invention comprise Formulae XXTHa, XXJJIb, and XXTHc:
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 19 is independently selected from the group consisting of hydrogen, halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or un
- DPP-IN inhibitors of the present invention comprise Formulae XXINa and XXIVb:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - 7 )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; and
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-IV inhibitors of the present invention comprise Formulae XXVa, XXVb, and XXVc:
- X is selected from the group of moieties where the ring atom is either C, N, O or S in Formula XXVa, or X is selected from the group of moieties where the ring atom is either C or N in Formula XXVb or Formula XXVc;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - 7 )cycloalkyl and aryl;
- R 2 is -UN, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- Rg is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 19 is independently selected from the group consisting of hydrogen, halo, perhalo(C ⁇ - ⁇ o)alkyl, CF3, cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, irnine group, sulfonyl group and sulfinyl group, each substituted or
- DPP-TV inhibitors of the present invention comprise Formulae XXVIa, XXVIb, and XXVIc:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - 7 )cycloalkyl and aryl; and R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein.
- DPP-TV inhibitors of the present invention comprise Formula XXVTT:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and -R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; and
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formula XXVTJJ:
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- R 3 and R 4 are taken together to form a substituted or unsubstituted 5 or 6 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-IV inhibitors of the present invention comprise Formula XXIX:
- J, K, L, and M are each independently selected from the group of CR 12 and N;
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 12 is hydrogen or is independently selected from the group consisting of halo, perhalo(Ci-io)alkyl, CF 3 , alkyl, aryl; heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- DPP-IN inhibitors of the present invention comprise Formulae XXXa, XXXb, XXXc, XXXd, XXXe, and XXXf:
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 19 is independently selected from the group consisting of hydrogen, halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or un
- DPP-IN inhibitors of the present invention comprise Formula XXXI:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UN, where U is a moiety providing 1-6 atom separation between N and the ring to which R 2 is attached and N comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; and R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-IN inhibitors of the present invention comprise Formulae XXXJJa, XXXTIb, and XXXIJc:
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- Rg is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each Rig is independently selected from the group consisting of hydrogen, halo, perhalo(Ci-io)alkyl, CF 3 , cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or un
- DPP-IV inhibitors of the present invention comprise Formulae XXXJJJa and XXXITJb:
- W, X, and Y are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; and
- Rg is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formulae XXXJNa, XXXIVb, and XXXTNc:
- X is selected from the group of moieties where the ring atom is either C, N, O or S in Formula XXXTVa, or X is selected from the group of moieties where the ring atom is either C or N in Formula XXXIVb or Formula XXXTVc;
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 1 9 is independently selected from the group consisting of hydrogen, halo, perhalo(C ⁇ - ⁇ o)alkyl, CF3, cyano, nitro, alkyl, alkene, alkyne, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsub
- DPP-TV inhibitors of the present invention comprise Formulae XXXVa, XXXVb, and XXXVc:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring; and R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein.
- DPP-TV inhibitors of the present invention comprise Formula XXXVI:
- J, K, L, and M are each independently selected from the group of moieties where the ring atom is either C, N, O or S;
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; and
- R9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formula XXXVII:
- J, K, L, and M are each independently selected from the group of CR12 and N, provided that at least one of K and L is CR 12 where R ⁇ 2 is not hydrogen;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C3- )cycloalkyl and aryl;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein;
- Rg is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 12 is hydrogen or is independently selected from the group consisting of halo, perhalo(Ci-io)alkyl, CF 3 , alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- DPP-TV inhibitors of the present invention comprise Formula XXXVHI:
- J, K, L, and M are each independently selected from the group of CR ⁇ 2 and N, provided that at least one of K and L is CR 12 where R 12 is not hydrogen;
- Ri is -ZR m , where Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and R m is selected from the group consisting of a substituted or unsubstituted (C 3 - )cycloalkyl and aryl; R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R 12 is hydrogen or is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- DPP-IN inhibitors of the present invention comprise Formula XXXIX:
- J, K, L, and M are each independently selected from the group of CR 12 and N, provided that at least one of K and L is CR 12 where R 12 is not hydrogen;
- Ri is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
- R 2 is -UV, where U is a moiety providing 1-6 atom separation between V and the ring to which R 2 is attached and V comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein; and
- Rg is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted; and each R12 is hydrogen or is independently selected from the group consisting of halo, perhalo(Ci-io)alkyl, CF 3 , alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- R 3 and R 4 are taken together to form an unsubstituted or substituted 5 or 6 membered cycloalkyl or heterocycloalkyl ring.
- R 3 and R 4 are taken together to form a substituted or unsubstituted phenyl ring.
- R3 and R 4 are taken together to form a substituted or unsubstituted heteroaryl ring.
- R3 and R 4 are taken together to form a substituted or unsubstituted heteroaryl selected from the group consisting of substituted or unsubstituted furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline, phthalazine, and benzothiazole.
- R3 and R are taken together to form a 5 or 6-membered ring where the ring comprises at least one CO group.
- R 3 and R 4 are taken together to form a 5 or 6-membered ring comprising of 1-3 nitrogen ring atoms.
- R 3 and j are taken together to form a 5 or 6-membered ring where the ring comprises a sulfur atom.
- the ring sulfur atom is in an oxidized form as SO or SO 2 .
- R 3 and R 4 are taken together to form a ring system such that the compound formed is selected from the group consisting of substituted or unsubstituted 4-oxo-4H-quinazoline, 3H-pvrido[2,3-d]pyrir din-4-one, 3H-pyrido[3,2-d]pyrimidin-4-one, 3H-pyrido[3,4-d]pyrimidin-4-one and 3H-pyrido[4,3-d]pyrimidin-4-one.
- the ring formed by R3 and R4 comprises substituents that form a ring fused to the ring formed by R 3 and R 4 .
- the fused ring may be further substituted or unsubstituted, and may be a saturated or unsaturated ring.
- the fused ring is a heterocyclic ring.
- the 5 or 6 membered ring is further substituted such that a 3 , 4, 5, 6 or 7 membered bridging ring is formed with the 5 or 6 membered ring.
- the 3, 4, 5, 6 or 7 membered ring may be further substituted or unsubstituted, and may be a saturated or unsaturated ring.
- the 3, 4, 5, 6 or 7 membered bridged ring may be a heterocyclic ring.
- J, K, L and M each comprises a carbon ring atom.
- J comprises a nitrogen ring atom.
- K comprises a nitrogen ring atom.
- L comprises a nitrogen ring atom.
- M comprises a nitrogen ring atom.
- J and L each comprise a nitrogen ring atom or J and K each comprise a nitrogen ring atom.
- K and L each comprise a nitrogen ring atom.
- K and M each comprise a nitrogen ring atom.
- J and M each comprise a nitrogen ring atom, or L and M each comprise a nitrogen ring atom. ;
- At least one of J, K, L and M comprise a nitrogen ring atom.
- at least two of J, K, L and M comprise a nitrogen ring atom.
- at least three of J, K, L and M comprise a nitrogen ring atom.
- at least three of J, K, L and M comprise a nitrogen ring atom.
- the ring formed by J, K, L, and M may comprise substituents that form a ring fused or bridged (e.g., through available valencies) to the ring formed by J, K, L, and M.
- Jn particular with respect to the case of Formula VTJJib, J and M optionally form a fused or bridged ring relative to the ring formed by J, K, L, and M.
- K is CR12, where R ⁇ is independently selected from the group consisting of halo, perhalo(C 1 -io)alkyl, CF 3 , alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- R ⁇ is independently selected from the group consisting of halo, perhalo(C 1 -io)alkyl, CF 3 , alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl,
- K is CR ⁇ 2 , where R 12 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyan ⁇ , nitro, alkyl, aryloxy, heteroaryloxy, amino, and alkoxy, each substituted or unsubstituted.
- K is CR 12 , where R ⁇ 2 is independently selected from the group consisting of heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, thio, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- K is CR 12 , where R12 is independently selected from the group consisting of chloro, bromo, fluoro, iodo, methoxy, morpholin-4-yl, and pyrrolidin- 1-yl, each substituted or unsubstituted.
- L comprises a nitrogen ring atom.
- L is CRu, where R12 is independently selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, CF3, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- R12 is independently selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, CF3, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, ary
- L is CR12, where R 12 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF3, cyano, nitro, alkyl, aryloxy, heteroaryloxy, amino, morpholin-
- J, K, L and M at least one of J, K, L and M is SO.
- at least one of J, K, L and M is SO 2 .
- J and M form a bridged ring relative to the ring formed by J, K, L, and M
- K and L are independently CR 12 , where R 12 is independently selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, CF 3 , cyano, nitro, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- R 12 is independently selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, CF 3 , cyano, nitro, alkyl, aryl, heteroaryl, aminosulfon
- K is CR 12 , where R 12 is independently selected from the group consisting of halo, perhalo(Ci-io)alkyl, CF 3 , cyano, nitro, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, a carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; and
- At least one R ⁇ 2 is fluorine.
- At least one of W, X, and Y is CO. In another variation, at least one of W, X, and Y is SO. In another variation, at least one of W, X, and Y is SO 2 . In one variation of each of the above embodiments and variations comprising W, W is selected from the group consisting of CO, SO or SO 2 . In one variation of each of the above embodiments and variations comprising Y, Y is selected from the group consisting of CO, SO or SO 2 . [0181] In another variation, at least one of W, X, and Y comprises a ring nitrogen atom. In yet another variation, at least two of W, X, and Y comprises a ring nitrogen atom. In yet another variation, W comprises a ring nitrogen atom. In still variation, X comprises a ring nitrogen atom. In a further variation, Y comprises a ring nitrogen atom.
- W and Y are taken together to form a substituted or unsubstituted bridged ring relative to the ring formed by W, X and Y.
- at least two (t'.e., two or three) of W, X, and Y are taken together to form a substituted or unsubstituted ring fused or bridged (e.g., by substitution through available valencies) to the ring formed by W, X and Y.
- W, X, and Y are selected such that the compound comprises a ring system selected from the group consisting of 4-oxo-4H-tMeno[3,2-d]pvrimidine, 7-oxo- l,2,3,7-tefrahydro-8-tMa-4,6-diaza-cyclopenta[a]mdene,7-memyl-6-oxo-6,7-dmydro-p ⁇ rm and 6-oxo-6,9-dihydro-purine, each substituted or unsubstituted.
- a ring system selected from the group consisting of 4-oxo-4H-tMeno[3,2-d]pvrimidine, 7-oxo- l,2,3,7-tefrahydro-8-tMa-4,6-diaza-cyclopenta[a]mdene,7-memyl-6-oxo-6,7-dmydro-p ⁇ rm and 6-oxo-6,
- Ri is selected from the group consisting of -NH2, -NHCH3, -N(CH 3 ) 2 , -NHC ⁇ -3-alkyl, and -N(C ⁇ -3-alkyl) 2 , each unsubstituted or substituted through available valencies.
- Ri is selected from the group consisting of a ( .
- alkyl an amino, alkyl, or alkoxy carbonyl (C ⁇ -3 )alkyl; an amino, alkyl, or alkoxy thiocarbonyl (Ci ⁇ alkyl; an amino, alkyl, or alkoxy sulfonyl (C ⁇ -3)alkyl; an amino, alkyl, or alkoxy sulfinyl (C ⁇ - 3 )alkyl; an amino, alkyl, or alkoxy imino (Ci ⁇ alkyl; and an aryl ( . 5 )alkyl, each unsubstituted or substituted through available valencies.
- Ri is selected from the group consisting of a (C 2 - ⁇ o)alkenyl; an amino, alkyl, or alkoxy carbonyl (Ci ⁇ alkenyl; an amino, alkyl, or alkoxy thiocarbonyl ( . 3 )alkenyl; an amino, alkyl, or alkoxy sulfonyl (Ci ⁇ alkenyl; an amino, alkyl, or alkoxy sulfinyl and a heteroaryl ( . 5 ) alkenyl, each unsubstituted or substituted through available valencies.
- Ri is selected from the group consisting of a (C 2- io)alkynyl; an amino, alkyl, or alkoxy carbonyl (Ci ⁇ alkynyl; an amino, alkyl, or alkoxy thiocarbonyl (C ⁇ . 3 )alkynyl; an amino, alkyl, or alkoxy sulfonyl an amino, alkyl, or alkoxy sulfinyl ( . 3 )alkynyl; an amino, alkyl, or alkoxy imino an aryl ( ..
- Ri is substituted or unsubstituted (C 3 . 7 )cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted phenyl.
- Ri is hydroxy. Jn yet another variation, Ri is
- Rn is selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl.
- Ri is a carbonyl group.
- Rl is selected from the group consisting of an aldehyde, acid, amide, and ester.
- Ri is selected from the group consisting of py ⁇ olidin- 1 - ylcarbonyl, piperidin-1 -ylcarbonyl, and morpholin-4-ylcarbonyl, each unsubstituted or substituted through available valencies.
- Ri is -Z-R m , where
- Z is a moiety having a chain of 1-6 atoms selected from the group consisting of substituted or unsubstituted C, N, O, and S, attaching -R m to the ring, or Z is a unsubstituted or substituted -(Ci- 3 )alkylene optionally interrupted by O, N(O), -NH, SO, SO 2 , or carbonyl; and
- -R m is selected from the group consisting of a substituted or unsubstituted (Ci- )alkyl, -(C 2 - 7 )alkene, -(C 2 - 7 )alkyne, -(C 3 - 7 )cycloalkyl, and aryl.
- Z is a moiety providing 1-6 atom separation between R m and the ring to which Ri is attached, and
- R m is selected from the group consisting of a substituted or unsubstituted (C 3 - 7 )cycloalkyl and aryl.
- the 1-6 atoms of Z comprise of carbon atoms.
- the 1-6 atoms of Z are selected from the group consisting of at least one oxygen, or at least one nitrogen atom.
- Z comprises of 1 atom.
- Z is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH2CH2CH2-, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -CH 2 CH 2 C(O)-, -O-, -OCH2-, -CH 2 O-, -CH 2 OCH 2 -, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -N(CH 3 )-, -NHCH2-, -CH2NH-, -CH2NHCH2-, -NHCH 2 CH 2 -, -CH 2 CH 2 NH-, -NH-C(O)-, -NCH 3 -C(O)-, -C(O)NH-, -C(O)NCH 3 -, -
- Z is selected from the group consisting of -CH 2 -, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, and -CH 2 CH 2 C(O)-, each substituted or unsubstituted.
- Z provides 1-3 atom separation between R m and the ring.
- Z provides 1 atom separation between R m and the ring.
- the 1 atom separation is provided by an atom selected from the group consisting of C, N, O, and S.
- the 1 atom separation is provided by a carbon atom.
- the 1 atom separation is provided by an oxygen atom.
- the 1 atom separation is provided by a nitrogen atom.
- Z is selected from the group consisting of -CH 2 -, -CHR 9 -, -C(R 9 )(R 9 )-, -C(O)-, -C(S)-, -C(NH)-, -C(NR 9 )-, -O-, -N(H)-, -N(R 9 )-, and -S-.
- Z is a carbonyl
- R m is a substituted or unsubstituted (C3 -7 )cycloalkyl.
- R m is a substituted or unsubstituted aryl.
- R m is a substituted or unsubstituted phenyl.
- R m is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring.
- R m has a non- hydrogen substituent at a 2 or 3 position of the ring selected from.the group consisting of ( - 10 )alkyl, (C 3- ⁇ 2 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C ⁇ - ⁇ o)alkyl, heteroaryl(Ci-5)alkyl, (C 9- i 2 )bicycloaryl, hetero(C - ⁇ 2 )bicycloaryl, carbonyl (Ci ⁇ alkyl, thiocarbonyl (Ci ⁇ alkyl, sulfonyl (C ⁇ -3)alkyl, sulfinyl imino (C ⁇ .
- R m is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and bicycloaryl, each substituted or unsubstituted.
- R m is selected from the group consisting of (2-cyano)phenyl, (3-cyano)phenyl, (2- hydroxy)phenyl, (3-hydroxy)phenyl, (2-alkenyl)phenyl, (3-alkenyl)phenyl, (2-alkynyl)phenyl, (3-alkynyl)phenyl, (2-nitro)phenyl, (3-nitro)phenyl, (2-carboxy)phenyl, (3-carboxy)phenyl, (2-carboxamido)phenyl, (3-carboxamido) ⁇ henyl, (2-sulfonamido)phenyl,
- Ri is -(CR 5 R 6 )o -2 -(R 7 ) 0 . 2 -R 8 , where
- R5 and R ⁇ are each independently hydrogen, halo or substituted or unsubstituted (C ⁇ -8 )alkyl or R 5 and R 6 are taken together to form a (C 3 - 6 )cycloalkyl ring;
- R 7 is selected from the group consisting of CO; CS; (C ⁇ - ⁇ o)alkylene, hetero(C3- ⁇ 2 )cycloalkylene, amino, arylene, heteroarylene, imine, sulfonyl, and sulfinyl, each substituted or unsubstituted; and
- R 8 is hydrogen or is selected from the group consisting of (C ⁇ - 7 )alkyl, (C 2 - 7 )alkenyl, (C 2 - 7 )alkynyl, (C3- 7 )cycloalkyl, (C 3 - 7 )heterocycloalkyl, aryl, aryl(Ci- 3 )alkyl, heteroaryl(C ⁇ - 2 )alkyl, heteroaryl, -SH, (C ⁇ - 7 )alkyl-S-, (Ci- 7 )alkyl-SO-, (C ⁇ - 7 )alkyl-SO 2 -, CO, CS, NHCONNH2, -NHCSNH2, -NHCONH2, -NHCO(C ⁇ - 7 )alkyl, -NHS02(C ⁇ - 7 )alkyl, -OCO-(Q- 5 )alkyl, cyano, nitro, halo, hydroxy, perhalo(C ⁇ -
- Ri is selected from the group consisting of -(CH 2 )-(2-cyano) ⁇ henyl, -(CH 2 )-(3-cyano)phenyl, -(CH 2 )-(2-hydroxy)phenyl, -(CH 2 )-(3- hydroxy) ⁇ henyl, -(CH 2 )-(2-alkenyl)phenyl, -(CH 2 )-(3-alkeny ⁇ ) ⁇ henyl, -(CH 2 )-(2- alkynyl)phenyl, -(CH2)-(3-alkynyl) ⁇ henyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(3-nitro)phenyl, -(CH 2 )-(2-carboxy)phenyl, -(CH 2 )-(3-carboxy)phenyl, -(CH 2 )-(2-carboxamido)
- -(CH 2 )-(3-CO 2 (C ⁇ - 7 )alkyl)phenyl -CH 2 -NH 2 , -CH 2 -OH, -CH 2 -(C 3 - 7 )alkyl, -CH 2 -alkene, -CH 2 -alkyne, -CH 2 -CCH, -CH 2 -(C 3 - 7 )cycloalkyl, and -CH 2 -aryl, each substituted or unsubstituted.
- Ri is selected from the group consisting of -(C ⁇ )alkyl-aryl, -(C ⁇ )alkyl-bicycloaryl, -aminoaryl, -aminoheteroaryl, -aminobicycloaryl, -aminoheterobicycloaryl, -O-aryl, -O- heteroaryl, -O-bicycloaryl, -O-heterobicycloaryl, -(S)-aryl, -(S)-heteroaryl, -(S)-bicycloaryl, - S-heterobicycloaryl, -C(O)-aryl, -C(O)-heteroaryl, - ., C(O)-bicycloaryl, -C(O)- heterobicycloaryl, -C(S)-aryl, -C(S)-heteroaryl, - ., C(O)-bicycloaryl,
- Ri is a substituted or unsubstituted aryl. In a further variation of each of the above embodiments and variations comprising Ri, Ri is a substituted or unsubstituted phenyl. In yet another variation of each of the above embodiments and variations comprising Ri, Ri is a substituted or unsubstituted heteroaryl.
- R 2 is selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, amino, cyano, thio, (Cr ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl thiocarbonyl (C ⁇ . 3 )alkyl, sulfonyl (C ⁇ -3)alkyl, sulfinyl (Ci.
- R 2 is selected from the group consisting of (C 3 -i 2 )cycloalkyl(C ⁇ .
- R 2 is selected from the group consisting of I, Br, CI, and F.
- R 2 is selected from the group consisting of -SH, -SCH3, and -S(C ⁇ . 3 )alkyl unsubstituted or substituted through available valencips.
- R 2 is selected from the group consisting of -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH(C ⁇ -3 )alkyl, -N(C ⁇ .3-alkyl) 2 , -NR14R15, where R M is selected from the group consisting of a substituted or unsubstituted (Cs- ⁇ cycloalkyl, hetero(C 3 . ⁇ 2 )cycloalkyl, (C 6 - ⁇ 2 )aryl, hetero(C 5 - ⁇ 2 )aryl, (C 9- ⁇ 2 )bicycloaryl and hetero(C 4- ⁇ 2 )bicycloaryl, and R 15 is selected from the group consisting of hydrogen and a substituted or unsubstituted (C ⁇ -8 )alkyl, and -NR 1 0R11, where Rio and -Rn together are -(CEJ ⁇ s- optionally interrupted by one O,
- R 2 is selected from the group consisting of a (Ci ⁇ alkyl; an amino, alkyl, or alkoxy carbonyl (Ci ⁇ alkyl; an amino, alkyl, or alkoxy thiocarbonyl (C ⁇ -3 )alkyl; an amino, alkyl, or alkoxy sulfonyl (C ⁇ .3)alkyl; an amino, alkyl, or alkoxy sulfinyl (C ⁇ .
- R 2 is selected from the group consisting of a (C 2 - ⁇ o)alkenyl; an amino, alkyl, or alkoxy carbonyl (C ⁇ -3)alkenyl; an amino, alkyl, or alkoxy thiocarbonyl (C ⁇ -3 )alkenyl; an amino, alkyl, or alkoxy sulfonyl (Q.
- alkenyl an amino, alkyl, or alkoxy sulfinyl (Ci ⁇ alkenyl; an amino, alkyl, or alkoxy imino (C ⁇ -3)alkenyl; an aryl (C ⁇ - 5 )alkenyl, and a heteroaryl (C ⁇ - 5 )alkenyl, each unsubstituted or substituted through available valencies.
- R 2 is selected from the group consisting of a (C 2 - ⁇ o)alkynyl; an amino, alkyl, or alkoxy carbonyl (C ⁇ _3)alkynyl; an amino, alkyl, or alkoxy thiocarbonyl (C ⁇ . 3 )alkynyl; an amino, alkyl, or alkoxy sulfonyl ( . 3)alkynyl; an amino, alkyl, or alkoxy sulfinyl (Ci ⁇ alkynyl; an amino, alkyl, or alkoxy imino (C ⁇ . 3 )alkynyl; an aryl (C 1 - 5 ) alkynyl; and a heteroaryl (C ⁇ -5)alkynyl, each unsubstituted or substituted through available valencies.
- a (C 2 - ⁇ o)alkynyl an amino, alkyl, or alkoxy carbonyl (C ⁇ _3)alky
- R 2 is a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring.
- R 2 is substituted or unsubstituted (C3 -7 )cycloalkyl (i.e., a substituted or unsubstituted 3, 4, 5, 6, or 7 membered cycloalkyl).
- R 2 is substituted or unsubstituted (C 3-7 )heterocycloalkyl (e.g., a substituted or unsubstituted 4, 5,
- R 2 is substituted or unsubstituted aryl. In another variation, R 2 is substituted or unsubstituted phenyl. In yet another variation,
- R 2 is substituted or unsubstituted heteroaryl.
- R 2 is hydroxy
- R 2 is -ORn, where Rn is selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl.
- R 2 is a carbonyl group.
- R 2 is selected from the group consisting of an aldehyde, acid, amide, ketone and ester.
- R 2 is selected from the group consisting of pyrrolidin- 1 -ylcarbonyl, piperidin-1 -ylcarbonyl, and morpholin-4- ylcarbonyl, each unsubstituted or substituted through available valencies.
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl-pyrrolidin-l-yl, azetidin-1-yl, 3- aminoazetidin-1-yl, pyrrolidin- 1-yl, 3-aminocyclopent-l-yl, 3-aminomethylcyclopent-l-yl, 3- aminomethylcyclohex-1-yl, hexahydroazepin-1-yl, 3-aminohexahydroazepin-l-yl, 3-amino- cyclohex-1-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3-amino-pyrrolidin-l-yl, and R-3- aminopiperidin-1-yl, each substituted or unsubstituted.
- R 2 is MR a Rb, where
- M is CH or N, R a is H or (C ⁇ -6 )alkyl, and R is amino(Co 4 )alkyl; or
- R 2 comprises a primary or secondary amine where the nitrogen of the arnine is 1-6 atoms from the nearest ring atom.
- R 2 comprises a primary or secondary amine where the nitrogen of the amine is 2-5 atoms from the nearest ring atom.
- R 2 comprises a primary or secondary amine where the nitrogen of the amine is 3-4 atoms from the nearest ring atom.
- R 2 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring wherein at least one substituent is selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom.
- R 2 is selected from the group consisting of
- each R 8 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF3, cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- R 2 is selected from the group consisting of
- each R 8 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF3, cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
- R 2 , R 2 is a substituted or unsubstituted heteroaryl selected from the group consisting of furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline, phthalazine, and benzothiazole, each substituted or unsubstituted.
- R 2 is selected from the group consisting of (C 3 .. ⁇ 2 )cycloalkyl, hetero(C 3 -i 2 )cycloalkyl, aryl(C ⁇ - ⁇ o)alkyl, heteroaryl (C ⁇ -5)alkyl, (Cg- ⁇ bicycloaryl, and hetero(C 4 .i 2 )bicycloaryl, each substituted or unsubstituted.
- R 2 , R 2 is a substituted or unsubstituted (C 3 - )cycloalkyl ring, optionally comprising O, N(O),
- R 1 9, two Rig are taken together to form a substituted or unsubstituted fused or bridged ring.
- U provides 1-4 atom separation between V and the ring. In another variation, U provides 1-3 atom separation between V and the ring.
- U is selected from the group consisting of -CH 2 -,
- U is selected from the group consisting of -CH 2 -, -CHR 9 -, -C(R 9 )(R 9 )-, -O-, -N(H)-,
- V is selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom
- V is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring wherein at least one substituent is selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom.
- V the basic nitrogen of V forms part of a primary, secondary or tertiary amine.
- the basic nitrogen of V is a nitrogen ring atom of a heterocycloalkyl comprising a nitrogen ring atom or a heteroaryl comprising a nitrogen ring atom.
- -UV, -UV is selected from the group consisting of
- each R 8 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that at least one R 8 serves as V.
- -UV is selected from the group consisting of
- each R 8 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that at least one R 8 serves as V.
- At least one R 8 is a primary, secondary or tertiary amine.
- R 8 at least one R 8 is a substituted or unsubstituted heterocycloalkyl comprising a nitrogen ring atom or a substituted or unsubstituted heteroaryl comprising a nitrogen ring atom.
- At least one R 8 is selected from the group consisting of -NH 2 , -NH(C ⁇ _s alkyl), -
- N(C ⁇ - 5 alkyl) 2 piperazine, imidazole, and pyridine.
- Ri is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl,
- -(CH 2 )-(3-CO 2 (Ci- 7 )alkyl)phenyl -CH 2 -NH 2 , -CH 2 -OH, -CH 2 -(C 3 - 7 )alkyl, -CH 2 -alkene, -CH 2 -alkyne, -CH 2 -CCH, -CH 2 -(C 3 - 7 )cycloalkyl, and -CH 2 -aryl, each substituted or unsubstituted, and
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrrolidin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrohdin-1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0246] In another particular variation according to the present invention,
- Ri is selected from the group consisting of -NH 2 , -NHCH 3 , -N(CH 3 )2, -NHCi- 3 -alkyl, and -N(C ⁇ -3-alkyl) 2 each unsubstituted or substituted through available valencies, and
- R2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrrolidin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrolidin- 1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0247] In another variation according to the present invention,
- Ri is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl, -(CH 2 )-(3-cyano)phenyl, -(CH )-(2-hydroxy)phenyl, -(CH 2 )-(3-hydroxy)phenyl, -(CH 2 )-(2- alkenyl)phenyl, -(CH 2 )-(3-alkenyl)phenyl, -(CH 2 )-(2-alkynyl)phenyl, -(CH 2 )-(3- alkynyl) ⁇ henyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(3-nitro) ⁇ henyl, -(CH 2 )-(2-carboxy) ⁇ henyl, -(CH 2 )-(3-carboxy)phenyl, -(CH 2 )-(2-carboxamido)phenyl, -(CH 2
- -(CH 2 )-(3-CO 2 (C ⁇ - 7 )alkyl)phenyl -CH 2 -NH 2 , -CH 2 -OH, -CH 2 -(C 3 - 7 )alkyl, -CH 2 -alkene, -CH 2 -alkyne, -CH 2 -CCH, -CH 2 -(C 3 - 7 )cycloalkyl, and -CH 2 -aryl, each substituted or unsubstituted, and
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrrolidin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrolidin- 1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-py ⁇ Olidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0248] In another variation according to the present invention,
- Ri is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl, -(CH 2 )-(3-cyano) ⁇ henyl, -(CH 2 )-(2-hydroxy) ⁇ henyl, -(CH 2 )-(3-hydroxy)phenyl, -(CH 2 )-(2- alkenyl)phenyl, -(CH 2 )-(3-alkenyl)phenyl, -(CH 2 )-(2-alkynyl)phenyl, -(CH 2 )-(3- alkynyl)phenyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(3-nitro)phenyl, -(CH 2 )-(2-carboxy)phenyl, -(CH 2 )-(3-carboxy)phenyl, -(CH 2 )-(2-carboxamido)phenyl, -(CH 2
- -(CH 2 )-(3-CO 2 (C ⁇ - 7 )alkyl)phenyl -CH 2 -NH 2 , -CH 2 -OH, -CH 2 -(C 3 - 7 )alkyl, -CH 2 -alkene, -CH 2 -alkyne, -CH 2 -CCH, -CH 2 -(C 3 - )cycloalkyl, and -CH 2 -aryl, each substituted or unsubstituted, and
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrcolidin-1-yl, azetidin-1-yl, 3-ammoazetidin-l-yl, pyrrohdin-1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- ammo-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0249] In yet another variation according to the present invention,
- Ri is selected from the group consisting of-(CH 2 )-(2-cyano)phenyl, -(CH 2 )-(3-cyano)phenyl, -(CH 2 )-(2-hydroxy)phenyl, -(CH 2 )-(3-hydroxy)phenyl, -(CH 2 )-(2- alkenyl) ⁇ henyl, -(CH 2 )-(3-alkenyl)phenyl, -(CH 2 )-(2-alkynyl)phenyl, -(CH 2 )-(3- alkynyl)phenyl, -(CH 2 )-(2-nitro)phenyl, -(CH 2 )-(3-nitro)phenyl, -(CH 2 )-(2-carboxy)phenyl, -(CH 2 )-(3-carboxy)phenyl, -(CH 2 )-(2-carboxarmdo)phenyl, -(CH 2 )
- -(CH 2 )-(3-CO 2 (Ci- 7 )alkyl)phenyl -CH 2 -NH 2 , -CH 2 -OH, -CH 2 -(C 3 - 7 )alkyl, -CH 2 -alkene, -CH 2 -alkyne, -CH 2 -CCH, -CH 2 -(C 3 - )cycloalkyl, and -CH 2 -aryl, each substituted or unsubstituted, and
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrrohdin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrroUdin-1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-py ⁇ olidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0250] In yet another variation according to the present invention,
- Q is CO
- Ri is selected from the group consisting of -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHC ⁇ . 3 -alkyl, and -N(C ⁇ - 3 -alkyl) 2 each unsubstituted or substituted through available valencies, and
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrrohdin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrohdin-1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0251] In another variation according to the present invention,
- Ri is selected from the group consisting of -NH 2 , -NHCH3, -N(CH 3 ) 2 , -NHC 1 . 3 -a.kyl, and -N(Ci- 3 -alkyl) 2 each unsubstituted or substituted through available valencies, and
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrcolidin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrolidin- 1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted. [0252] In another variation according to the present invention,
- Ri is selected from the group consisting of -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHC ⁇ . 3 -alkyl, and -N(C ⁇ - 3 -alkyl) 2 each unsubstituted or substituted through available valencies, and
- R 2 is selected from the group consisting of 3-amino-piperidin-l-yl, 3-aminomethyl- pyrcolidin-1-yl, azetidin-1-yl, 3-aminoazetidin-l-yl, pyrrolidin- 1-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-l-yl, hexahydroazepin-1-yl, 3- aminohexahydroazepin-1-yl, 3-amino-cyclohex-l-yl, piperazin- 1-yl, homopiperazin- 1-yl, 3- amino-pyrrolidin-1-yl, and R-3-aminopiperidin-l-yl, each substituted or unsubstituted.
- DPP-TV inhibitors include:
- the present invention provides the compounds in the form of a pharmaceutically acceptable salt.
- the present invention provides the compounds present in a mixture of stereoisomers. In yet another embodiment, the present invention provides the compounds as a single stereoisomer.
- the present invention provides pharmaceutical compositions comprising the compound as an active ingredient.
- the present invention provides pharmaceutical compositions wherein the composition is a solid formulation adapted for oral administration.
- the present invention provides pharmaceutical composition wherein the composition is a tablet.
- the present invention provides the pharmaceutical composition wherein the composition is a liquid formulation adapted for oral administration.
- the present invention provides pharmaceutical composition wherein the composition is a liquid formulation adapted for parenteral administration.
- the present invention provides the pharmaceutical composition comprising the compound of the invention wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.
- the present invention provides a kit comprising a compound of the present invention and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.
- the present invention provides the kit that comprises the compound in a multiple dose form.
- the present invention provides an article of manufacture comprising a compound of the present invention, and packaging materials.
- the packaging material comprises a container for housing the compound.
- the invention provides the article of manufacture wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
- the present invention provides the article of manufacture wherein the article of manufacture comprises the compound in a multiple dose form.
- the present invention provides a method of inhibiting DPP-IN comprising contacting DPP-IN with a compound according to the present invention.
- the present invention provides a method of inhibiting DPP-IN comprising causing a compound according to the present invention to be present in a subject in order to inhibit DPP-IN in vivo.
- the present invention provides a method of inhibiting DPP-IN comprising: administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits DPP-IN in vivo, the second compound being a compound of the present invention.
- the present invention provides therapeutic method comprising: administering a compound according to the present invention to a subject.
- the present invention provides a method of treating a disease state for which DPP-IN possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising causing a compound of the present invention to be present in a subject in a therapeutically effective amount for the disease state.
- the present invention provides a method of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
- the present invention provides a method of treating a disease where the disease is type I or type U diabetes.
- the present invention provides a method of treating autoimmune disorders such as, but not limited to, rheumatoid arthritis, psoriasis, and multiple sclerosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
- the present invention provides a method of treating cancer where the cancer treated is colorectal, prostate, breast, thyroid, skin, lung, or head and neck.
- the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
- the present invention provides a method of treating HTV infection in a patient in need thereof, comprising admimstering to said patient a therapeutically effective amount of a compound according to the present invention.
- the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, wherein the condition is a side effect of chemotherapy or radiation therapy.
- the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, wherein the condition is a result of kidney failure.
- the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, wherein the condition is a result of a bone marrow disorder.
- the present invention provides a method of treating a condition characterized by immunodeficiency symptoms in a patient in need thereof, comprising adrninistering to said patient a therapeutically effective amount of a compound according to the present invention.
- the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention.
- the compounds of the present invention possess a free base form the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g.
- hydrohalides such as hydrochloride, hydrobromide, hydroiodide
- other mineral acids and their conesponding salts such as sulfate, nitrate, phosphate, etc.
- alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate andbenzenesulfonate
- other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
- Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (frommucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso- butyrate, lactate, lactobionate, malate, malonate,
- a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
- bases are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g.
- potassium ethanolate and sodium propanolate potassium ethanolate and sodium propanolate
- various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine.
- aluminum salts of the compounds of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts.
- Organic base salts include, but are not l mited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), chcyclohexylamine, diemylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylene ⁇ iamine, N-emylmo holine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, tri
- N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
- N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C.
- an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like
- a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
- the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
- Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention.
- prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., l -acyloxyalkylcarbonochloridate.p ⁇ r ⁇ -nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
- Compounds of the present invention may also be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by reciystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
- a "pharmaceutically acceptable salt”, as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound.
- the pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
- An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound.
- the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized.
- an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid adsorption of the compound.
- DPP-TV is believed to contribute to the pathology and/or symptomology of several different diseases such that reduction of the activity of DPP-TV in a subject through inhibition maybe used to therapeutically address these disease states. Examples of various diseases that may be treated using the DPP-TV inhibitors of the present invention are described herein. It is noted that additional diseases beyond those disclosed herein may be later identified as the biological roles that DPP-TV plays in various pathways becomes more fully understood.
- DPP-TV inhibitors of the present invention maybe used to treat are those involving the prevention and treatment of diabetes and obesity, in particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
- ITT impaired glucose tolerance
- IGF impaired fasting plasma glucose
- metabolic acidosis ketosis
- appetite regulation and obesity are those involving the prevention and treatment of diabetes and obesity, in particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
- DPP-IN inhibitors of the present invention may also be used as immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
- DPP-TV inhibitors of the present invention may also be used for treating various cancers including breast cancer, lung cancer and prostate cancer.
- DPP-IN inhibitors of the present invention may also be used to treat dermatological diseases such as psoriasis, rheumatoid arthritis (RA) and lichen planus. [0291] DPP-IN inhibitors of the present invention may also be used to treat infertility and amenorrhea.
- DPP-IN inhibitors of the present invention may also be used to modulate cleavage of various cytokines (stimulating hematopoietic cells), growth factors and neuropeptides. For example, such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer.
- DPP-IN inhibitors of the present invention may also be used prevent or reduce cleavage of ⁇ -terminal Tyr- Ala from growth hormone-releasing factor. Accordingly, these inhibitors may be used in the treatment of short stature due to growth hormone deficiency (Dwarfism) and for promoting GH-dependent tissue growth or re-growth.
- DPP-TV inhibitors of the present invention may also be used to address disease states associated with cleavage of neuropeptides and thus may be useful for the regulation or normalization of neurological disorders.
- DPP-TV inhibitors of the present invention may be used in conjunction with other agents to inhibit undesirable and uncontrolled cell proliferation.
- examples of other anti-cell proliferation agents that may be used in conjunction with the DPP- IN inhibitors of the present invention include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, A ⁇ GIOSTATT ⁇ TM protein, E ⁇ DOSTATI ⁇ TM protein, suramin, squalamine, tissue inhibitor of metalloproteinase-I, tissue inhibitor of metalloprote ase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((l-
- anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5, VEGF isoforms, NEGF-C, HGF/SF and Ang- l/Ang-2.
- Ferrara ⁇ . and Alitalo, K. “Clinical application of angiogenic growth factors and their inhibitors” (1999) Nature Medicine 5:1359-1364.
- compositions and administration methods may be used in conjunction with the DPP-JN inhibitors of the present invention.
- Such compositions may include, in addition to the DPP-IN inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents.
- the compositions may include active agents in addition to the DPP-IN inhibitors of the present invention. These additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents.
- the compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral aciministration, capsules and tablets are typically used.
- compositions comprising DPP-IN inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
- the compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
- the DPP-JN inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form.
- Co-administration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a DPP-IN inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome.
- Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
- Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid.
- Parenteral preparations may optionally be enclosed in ampules
- DPP-TV inhibitors according to the present invention exhibit insufficient solubility
- methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEE ⁇ , or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
- DMSO dimethylsulfoxide
- TWEE ⁇ surfactants
- Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
- a solution, suspension, emulsion or the like may be formed. The fonn of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle. The effective concentration needed to ameliorate the disease being treated may be empirically determined.
- compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof.
- the pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms.
- Unit- dose forms refers to physically discrete units suitable for human and aiiimal subjects and packaged individually as is known in the art.
- Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
- unit-dose forms include ampoules and syringes individually packaged tablet or capsule.
- Unit-dose forms may be administered in fractions or multiples thereof.
- a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form.
- Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons.
- multiple dose form is a multiple of unit-doses that are not segregated in packaging.
- the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
- a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
- a lubricant such as magnesium stearate, calcium stearate and talc
- a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders
- Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension.
- a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like
- the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
- composition or formulation to be administered will, in any event, contain a sufficient quantity of a DPP-JN inhibitor of the present invention to reduce DPP-JN activity in vivo, thereby treating the disease state of the subject.
- Dosage forms or compositions may optionally comprise one or more DPP-TV inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein.
- a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum.
- compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art.
- the compositions may optionally contain 0.01%- 100% (weight/weight) of one or more DPP-IN inhibitors, optionally 0.1-95%, and optionally 1-95%.
- Salts, preferably sodium salts, of the DPP-IN inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
- the formulations may further include other active compounds to obtain desired combinations of properties.
- Oral pharmaceutical dosage fonns may be as a solid, gel or liquid.
- solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated.
- capsules include hard or soft gelatin capsules. Granules and powders may be provided in non-effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
- DPP-IN inhibitors according to the present invention are provided as solid dosage forms, preferably capsules or tablets.
- the tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
- binders examples include, but are not limited to, microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
- lubricants examples include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
- diluents examples include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
- glidants examples include, but are not limited to, colloidal silicon dioxide.
- disintegrating agents examples include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
- coloring agents examples include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble
- sweetening agents examples include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
- flavoring agents examples include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
- wetting agents examples include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
- anti-emetic coatings examples include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
- film coatings examples include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
- the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach.
- the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
- the composition may also be formulated in combination with an antacid or other such ingredient.
- dosage unit form When the dosage unit form is a capsule, it may optionally additionally comprise a liquid canier such as a fatty oil.
- dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
- Compounds according to the present invention may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
- a syrup may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
- the DPP-IN inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
- active materials such as antacids, H2 blockers, and diuretics.
- Examples of pharmaceutically acceptable carriers that may be included in tablets comprising DPP-IN inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents .
- Enteric-coated tablets because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
- Sugar-coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
- Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned.
- Coloring agents may also be used in tablets..
- Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges.
- liquid oral dosage forms examples include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
- aqueous solutions examples include, but are not limited to, elixirs and syrups.
- elixirs refer to clear, sweetened, hydroalcoholic preparations.
- pharmaceutically acceptable carriers examples include, but are not limited to solvents.
- solvents include glycerin, sorbitol, ethyl alcohol and syrup.
- syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
- Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in-water or water-in-oil emulsions .
- Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
- Examples of pharmaceutically acceptable substances that may be used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
- Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic adds and a source of carbon dioxide.
- Coloring and flavoring agents may optionally be used in all of the above dosage forms.
- Particular examples of preservatives that may be used include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
- emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
- suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Neegum and acacia.
- Diluents include lactose and sucrose.
- Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
- wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
- organic acids that may be used include citric and tartaric acid.
- S ources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate.
- Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
- flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds that produce a pleasant taste sensation.
- the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
- a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. ⁇ os.
- the solution e.g. , for example, in a polyethylene glycol
- a pharmaceutically acceptable liquid carrier e.g. water
- liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
- Other useful formulations include those set forth in U.S. Pat. Nos. Re 28,819 and 4,358,603.
- compositions designed to administer the DPP-TV inhibitors of the present invention by parenteral administration generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
- injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
- excipients examples include, but are not limited to water, saline, dextrose, glycerol or ethanol.
- the injectable compositions may also optionally comprise minor amounts of non- toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
- Implantation of a slow- release or sustained-release system, such that a constant level of dosage is maintained see, e.g., U.S. Pat. No.
- Parenteral adininistration of the formulations includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
- suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
- pharmaceutically acceptable earners that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
- aqueous vehicles examples include Sodium
- nonaqueous parenteral vehicles examples include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
- Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed.
- antimicrobial agents include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
- Examples of isotonic agents that may be used include sodium chloride and dextrose.
- Examples of buffers that may be used include phosphate and citrate.
- antioxidants that may be used include sodium bisulfate.
- Examples of local anesthetics that may be used include procaine hydrochloride.
- Examples of suspending and dispersing agents that may be used include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpynolidone.
- Examples of emulsifying agents that may be used include Polysorbate
- TWEEN 80 TWEEN 80
- a sequestering or chelating agent of metal ions include EDTA.
- Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
- the concentration of a DPP-IN inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect.
- concentration of a DPP-IN inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art.
- Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
- Injectables may be designed for local and systemic administration.
- a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1 % w/w up to about 90% w/w or more, preferably more than 1% w/w of the DPP-TV inhibitor to the treated tissue(s).
- the DPP-TV inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data.
- concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.
- the DPP-TV inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
- the DPP-IN inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures.
- the lyophilized powders may also be formulated as solids or gels.
- Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation.
- the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
- a suitable buffer such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
- a DPP-JN inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35 °C, and st red until it dissolves.
- the resulting mixture is diluted by adding more buffer to a desired concentration.
- the resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization.
- Each vial
- the DPP-TV inhibitors of the present invention may also be administered as topical mixtures.
- Topical mixtures may be used for local and systemic administration.
- the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical admiriistration.
- the DPP-IN inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat. ⁇ os. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma).
- These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
- the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
- the DPP-IN inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application.
- Topical administration is contemplated for transdermal delivery and also for admiiiistration to the eyes or mucosa, or for inhalation therapies.
- Nasal solutions of the DPP-TV inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
- Formulations for other routes of administration can also be administered.
- rectal administration may also be used.
- pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect.
- Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
- Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
- bases examples include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used.
- Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
- oral, intravenous and tablet formulations that may optionally be used with compounds of the present invention. It is noted that these formulations may be varied depending on the particular compound being used and the indication for which the formulation is going to be used.
- the invention is also directed to kits and other articles of manufacture for treating diseases associated with DPP-JN. It is noted that diseases are intended to cover all conditions for which the DPP-IN possesses activity that contributes to the pathology and/or symptomology of the condition.
- a kit comprising a composition comprising at least one DPP-IN inhibitor of the present invention in combination with instructions.
- the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
- the kit may also comprise packaging materials.
- the packaging material may comprise a container for housing the composition.
- the kit may also optionally comprise additional components, such as syringes for administration of the composition.
- the kit may comprise the composition in single or multiple dose forms.
- an article of manufacture comprises a composition comprising at least one DPP-JN inhibitor of the present invention in combination with packaging materials.
- the packaging material may comprise a container for housing the composition.
- the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
- the kit may also optionally comprise additional components, such as syringes for administration of the composition.
- the kit may comprise the composition in single or multiple dose forms.
- the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet.
- the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
- a pharmaceutically acceptable material for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
- the container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in
- ⁇ ie kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
- different dosage forms e.g., oral, topical, transdermal and parenteral
- Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
- kits are a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
- the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
- a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed.
- a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
- the diastereomers may then be separated in order to recover the optically pure enantiomers.
- Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
- Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities.
- diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility.
- a more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
- Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
- a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
- Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application.
- the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
- the free acid or free base forms of the compounds can be prepared from the conesponding base addition salt or acid addition salt form.
- a compound in an acid addition salt form can be converted to the conesponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
- a compound in a base addition salt form can be converted to the conesponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
- N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
- N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C.
- an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like
- a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
- the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
- Compounds in an unoxidized form can be prepared from N-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 °C.
- a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
- an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, or the like
- Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et ⁇ Z.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
- appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate,/? ⁇ r ⁇ -nitrophenyl carbonate, or the like).
- a suitable carbamylating agent e.g., l,l-acyloxyalkylcarbonochloridate,/? ⁇ r ⁇ -nitrophenyl carbonate, or the like.
- Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3 rd edition,
- Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
- Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds, dissociable complexes are prefened (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g. , melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
- the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
- the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
- a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981). [0379]
- the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.
- M molar
- mM millimolar
- i.v. intravenous
- Hz Hertz
- Tr retention time
- RP reverse phase
- TEA triethylamine
- TFA trifluoroacetic acid
- TFAA trifluoroacetic anhydride
- THF tetrahydrofuran
- DME (1,2-dimethoxyethane); DCM (dichloromethane);
- DCE dichloroethane
- DMF N,N-dimethylformamide
- DMPU N,N'-dimethylpropyleneurea
- CDI 1,1-carbonyldiimidazole
- IBCF isobutyl chloroformate
- HO Ac acetic acid
- HOSu N-hydroxysuccinimino
- HOBT 1-hydroxybenzotriazole
- Et 2 O diethyl ether
- EDCI ethylcarbodnmino hydrochloride
- TJPS triisopropylsilyl
- TBS t-butyldimethylsilyl
- DMAP 4-dimethylam opyridine
- Me methyl
- HPLC high pressure liquid chomatography
- BOP bis(2-oxo-3-oxazolidinyl)phosphinic chloride
- TBAF tetra-n-butylammonium fluoride
- mCPB A metal-chloroperbenzoic acid.
- MS mass spectra
- compound purity data were acquired on a Waters ZQ LC/MS single quadrupole system equipped with electrospray ionization (EST) source, UN detector (220 and 254 nm), and evaporative light scattering detector (ELSD).
- EST electrospray ionization
- UN detector 220 and 254 nm
- ELSD evaporative light scattering detector
- Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UN light, 5% ethanolic phosphomolybdic acid, ⁇ inhydrin or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
- DPP-IN inhibitors according to the present invention may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided herein in the examples. Other reaction schemes could be readily devised by those skilled in the art. [0384] In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
- Example 7 2-[2-(3-Amino-piperidin- l-yl)-7-methyl-6-oxo-6,7-dihydro-purin- 1- ylmethylj-benzonitrile
- Example 8 2-[2-(3-Amino-piperidin- 1 -yl)-9-methyl-6-oxo-6,9-dihydro-purin- 1 - ylmethyl] -benzonitrile
- Tne crude products 7A and 8A were converted to 7B and 8B as a mixture by the method used for the preparation of IC in 82% yield.
- Example 7C 2-(2-CMoro-7-methyl-6-oxo-6,7-dmydro-purin-l-ylmethyl)- benzonitrile
- a mixture of title compounds 7C and 8C was prepared by the method used in the preparation of ID.
- Example 7 NMR (400 MHz CDQ 3 -CD 3 OD 10: 1): ⁇ 7.9 (br s, IH), 7.63 (d, IH, J
- Example 9A A mixture of Example 9A and Example 9B was synthesized from 2,6-Dichloro- 7H-purine by the method described in syntheses of Example 7A and 8A.
- Example 9B NMR (400 MHz CDC1 3 ): ⁇ 8.2 (s, IH), 7.3 (m, 5H), 5.70 (s, 2H), 4.63 (s, 2H).
- MS (ES) [m+H] calculated for C ⁇ 3 H ⁇ 0 Cl 2 N 4 O+H, 309; found 309.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04758366A EP1608317B1 (en) | 2003-03-25 | 2004-03-24 | Dipeptidyl peptidase inhibitors |
CA002518465A CA2518465A1 (en) | 2003-03-25 | 2004-03-24 | Dipeptidyl peptidase inhibitors |
JP2006509315A JP4887139B2 (en) | 2003-03-25 | 2004-03-24 | Dipeptidyl peptidase inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US45778503P | 2003-03-25 | 2003-03-25 | |
US60/457,785 | 2003-03-25 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2004087053A2 WO2004087053A2 (en) | 2004-10-14 |
WO2004087053A9 true WO2004087053A9 (en) | 2004-11-11 |
WO2004087053A3 WO2004087053A3 (en) | 2006-08-31 |
Family
ID=33131718
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/009217 WO2004087053A2 (en) | 2003-03-25 | 2004-03-24 | Dipeptidyl peptidase inhibitors |
Country Status (7)
Country | Link |
---|---|
US (4) | US20040242566A1 (en) |
EP (1) | EP1608317B1 (en) |
JP (1) | JP4887139B2 (en) |
KR (1) | KR20050122220A (en) |
CN (1) | CN1894234A (en) |
CA (1) | CA2518465A1 (en) |
WO (1) | WO2004087053A2 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
US8906901B2 (en) | 2005-09-14 | 2014-12-09 | Takeda Pharmaceutical Company Limited | Administration of dipeptidyl peptidase inhibitors |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
US9533954B2 (en) | 2010-12-22 | 2017-01-03 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US9533984B2 (en) | 2013-04-19 | 2017-01-03 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
Families Citing this family (122)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2518465A1 (en) | 2003-03-25 | 2004-10-14 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
EP1911754B1 (en) * | 2003-08-13 | 2013-10-09 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
KR20060041309A (en) | 2003-08-13 | 2006-05-11 | 다케다 야쿠힌 고교 가부시키가이샤 | 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors |
US7169926B1 (en) | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
WO2005026148A1 (en) * | 2003-09-08 | 2005-03-24 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
CN102134231B (en) | 2004-03-15 | 2020-08-04 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
JP2008501714A (en) | 2004-06-04 | 2008-01-24 | 武田薬品工業株式会社 | Dipeptidyl peptidase inhibitor |
WO2006019965A2 (en) | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
AR051596A1 (en) * | 2004-10-26 | 2007-01-24 | Irm Llc | CONDENSED HETEROCICLIC COMPOUNDS NITROGENATED AS INHIBITORS OF THE ACTIVITY OF THE CANABINOID RECEIVER 1; PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR EMPLOYMENT IN THE PREPARATION OF MEDICINES FOR THE TREATMENT OF FOOD DISORDERS |
JP2008520744A (en) | 2004-11-19 | 2008-06-19 | ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア | Anti-inflammatory pyrazolopyrimidine |
AU2011201488B2 (en) * | 2004-11-29 | 2011-11-17 | Merck Sharp & Dohme Corp. | Fused aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
US7872124B2 (en) | 2004-12-21 | 2011-01-18 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
DOP2006000008A (en) | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | COMBINED THERAPY FOR THE TREATMENT OF DIABETES AND RELATED AFFECTIONS AND FOR THE TREATMENT OF AFFECTIONS THAT IMPROVE THROUGH AN INCREASE IN THE BLOOD CONCENTRATION OF GLP-1 |
EP2390264A1 (en) | 2005-02-11 | 2011-11-30 | Amylin Pharmaceuticals Inc. | GIP analog and hybrid polypeptides with selectable propperties |
WO2007022946A1 (en) | 2005-08-21 | 2007-03-01 | Abbott Gmbh & Co. Kg | Heterocyclic compounds and their use as binding partners for 5-ht5 receptors |
ATE549926T1 (en) | 2005-08-26 | 2012-04-15 | Merck Sharp & Dohme | CONDENSED AMINOPIPERIDINES AS DIPEPTIDYLPEPTIDASE IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES |
BRPI0616077B8 (en) † | 2005-09-14 | 2021-05-25 | Takeda Pharmaceuticals Co | pharmaceutical composition formulated in a single dose, kit, article of manufacture, use of the pharmaceutical composition and use of one or more antidiabetic compounds |
CA2622642C (en) | 2005-09-16 | 2013-12-31 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
AU2006327069A1 (en) * | 2005-12-23 | 2007-06-28 | Novartis Ag | Condensed heterocyclic compounds useful as DPP-IV inhibitors |
WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
EP1999108A1 (en) * | 2006-03-28 | 2008-12-10 | Takeda Pharmaceutical Company Limited | Preparation of (r)-3-aminopiperidine dihydrochloride |
GB2453058A (en) | 2006-04-04 | 2009-03-25 | Univ California | Kinase antagonists |
PE20071221A1 (en) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | GPR119 RECEPTOR AGONISTS IN METHODS TO INCREASE BONE MASS AND TO TREAT OSTEOPOROSIS AND OTHER CONDITIONS CHARACTERIZED BY LOW BONE MASS, AND COMBINED THERAPY RELATED TO THESE AGONISTS |
KR20090004950A (en) | 2006-04-12 | 2009-01-12 | 프로비오드룩 아게 | Enzyme inhibitors |
JP5421108B2 (en) * | 2006-08-23 | 2014-02-19 | ニューロジェン・コーポレーション | 2-phenoxypyrimidinone analogs |
WO2008024433A2 (en) * | 2006-08-23 | 2008-02-28 | Neurogen Corporation | Haloalkyl-substituted pyrimidinone derivatives |
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 |
KR101129868B1 (en) | 2006-10-04 | 2012-04-12 | 화이자 프로덕츠 인코포레이티드 | Pyrido[4,3-d]pyrimidin-43h-one derivatives as calcium receptor antagonists |
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 |
TW200838536A (en) * | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | 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 |
US9126987B2 (en) | 2006-11-30 | 2015-09-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
KR20120030570A (en) | 2007-04-03 | 2012-03-28 | 미쓰비시 타나베 파마 코퍼레이션 | Combined use of dipeptidyl peptidase iv inhibitor compound and sweetener |
JP5667440B2 (en) | 2007-04-18 | 2015-02-12 | プロビオドルグ エージー | Thiourea derivatives as glutaminyl cyclase inhibitors |
SI2152712T1 (en) | 2007-05-11 | 2012-03-30 | Pfizer | Amino-heterocyclic compounds |
WO2009046448A1 (en) | 2007-10-04 | 2009-04-09 | Intellikine, Inc. | Chemical entities and therapeutic uses thereof |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
CN101965336B (en) | 2008-01-04 | 2015-06-17 | 英特利凯恩有限责任公司 | Certain chemical entities, compositions and methods |
US8993580B2 (en) | 2008-03-14 | 2015-03-31 | Intellikine Llc | Benzothiazole kinase inhibitors and methods of use |
WO2009114870A2 (en) | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Kinase inhibitors and methods of use |
US20090257979A1 (en) * | 2008-04-15 | 2009-10-15 | Intermune, Inc. | Novel Inhibitors of Hepatitis C Virus Replication |
WO2010006072A2 (en) | 2008-07-08 | 2010-01-14 | The Regents Of The University Of California | Mtor modulators and uses thereof |
MX2011000216A (en) | 2008-07-08 | 2011-03-29 | Intellikine Inc | Kinase inhibitors and methods of use. |
US20100029371A1 (en) * | 2008-08-01 | 2010-02-04 | Gennady Medvinsky | Personal Game Services Commerce System (PGSCS) |
CA2738429C (en) | 2008-09-26 | 2016-10-25 | Intellikine, Inc. | Heterocyclic kinase inhibitors |
DK2358720T3 (en) | 2008-10-16 | 2016-06-06 | Univ California | Heteroarylkinaseinhibitorer fused-ring |
US8476431B2 (en) | 2008-11-03 | 2013-07-02 | Itellikine LLC | Benzoxazole kinase inhibitors and methods of use |
CN101817833B (en) * | 2009-02-26 | 2013-03-06 | 中国科学院广州生物医药与健康研究院 | DPP-IV inhibitor |
EP2427195B1 (en) | 2009-05-07 | 2019-05-01 | Intellikine, LLC | Heterocyclic compounds and uses thereof |
AR077642A1 (en) | 2009-07-09 | 2011-09-14 | Arena Pharm Inc | METABOLISM MODULATORS AND THE TREATMENT OF DISORDERS RELATED TO THE SAME |
EP2475428B1 (en) | 2009-09-11 | 2015-07-01 | Probiodrug AG | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
US8980899B2 (en) | 2009-10-16 | 2015-03-17 | The Regents Of The University Of California | Methods of inhibiting Ire1 |
TW201121968A (en) * | 2009-11-09 | 2011-07-01 | Intermune Inc | Novel inhibitors of hepatitis C virus replication |
ES2567168T3 (en) | 2009-11-12 | 2016-04-20 | F. Hoffmann-La Roche Ag | N7-substituted purine and pyrazolopyrimidine compounds, compositions and methods of use |
EA021568B1 (en) | 2009-12-23 | 2015-07-30 | Такеда Фармасьютикал Компани Лимитед | Fused heteroaromatic pyrrolidinones as syk inhibitors |
US8648073B2 (en) | 2009-12-30 | 2014-02-11 | Fochon Pharma, Inc. | Certain dipeptidyl peptidase inhibitors |
WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
CA2789440C (en) | 2010-03-10 | 2020-03-24 | Probiodrug Ag | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
JP5945532B2 (en) | 2010-04-21 | 2016-07-05 | プロビオドルグ エージー | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
AU2011255218B2 (en) | 2010-05-21 | 2015-03-12 | Infinity Pharmaceuticals, Inc. | Chemical compounds, compositions and methods for kinase modulation |
CN102311448B (en) * | 2010-07-07 | 2014-02-19 | 中国科学院广州生物医药与健康研究院 | Thieno-pyrimidone DPP-IV (dipeptidyl peptidase) inhibitor |
CN102311447B (en) * | 2010-07-07 | 2013-11-27 | 中国科学院广州生物医药与健康研究院 | Heterocyclo pyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitor |
EA201390421A1 (en) | 2010-09-22 | 2013-09-30 | Арена Фармасьютикалз, Инк. | GPR119 RECEPTOR MODULATORS AND TREATMENT OF RELATED DISORDERS |
WO2012064973A2 (en) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
AR084824A1 (en) | 2011-01-10 | 2013-06-26 | Intellikine Inc | PROCESSES TO PREPARE ISOQUINOLINONES AND SOLID FORMS OF ISOQUINOLINONAS |
JP6130305B2 (en) | 2011-02-23 | 2017-05-17 | インテリカイン, エルエルシー | Combinations of kinase inhibitors and their use |
US8907086B2 (en) | 2011-03-03 | 2014-12-09 | Merck Sharp & Dohme Corp. | Fused bicyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors |
ES2570167T3 (en) | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Benzimidazole derivatives as glutaminyl cyclase inhibitors |
US20140018371A1 (en) | 2011-04-01 | 2014-01-16 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
US20140066369A1 (en) | 2011-04-19 | 2014-03-06 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
US20140051714A1 (en) | 2011-04-22 | 2014-02-20 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
US20140038889A1 (en) | 2011-04-22 | 2014-02-06 | Arena Pharmaceuticals, Inc. | Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
JP6026525B2 (en) | 2011-06-22 | 2016-11-16 | 武田薬品工業株式会社 | Substituted 6-aza-isoindoline-1-one derivatives |
EP2734520B1 (en) | 2011-07-19 | 2016-09-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
JP6027611B2 (en) | 2011-07-19 | 2016-11-16 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | Heterocyclic compounds and uses thereof |
BR112014003981A2 (en) | 2011-08-23 | 2017-03-07 | Endo Pharmaceuticals Inc | pyrimido-pyridazinone compounds and their use |
US8785470B2 (en) | 2011-08-29 | 2014-07-22 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
JP6342805B2 (en) | 2011-09-02 | 2018-06-13 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Substituted pyrazolo [3,4-D] pyrimidine and uses thereof |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
CN103130819B (en) * | 2011-12-01 | 2016-01-20 | 中国科学院上海药物研究所 | Thiophene [3,2-d] pyrimidin-4-one compounds, its preparation method, pharmaceutical composition and purposes |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
NZ730134A (en) | 2012-06-13 | 2018-07-27 | Incyte Holdings Corp | Substituted tricyclic compounds as fgfr inhibitors |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
AU2013323426A1 (en) | 2012-09-26 | 2015-04-23 | The Regents Of The University Of California | Modulation of ire1 |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
UY35675A (en) | 2013-07-24 | 2015-02-27 | Novartis Ag | SUBSTITUTED DERIVATIVES OF QUINAZOLIN-4-ONA |
PL3052485T3 (en) | 2013-10-04 | 2022-02-28 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
WO2015051241A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US20160187724A1 (en) * | 2013-10-08 | 2016-06-30 | Sharp Kabushiki Kaisha | Image display device |
CA2943075C (en) | 2014-03-19 | 2023-02-28 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders |
US20150320755A1 (en) | 2014-04-16 | 2015-11-12 | Infinity Pharmaceuticals, Inc. | Combination therapies |
KR101739003B1 (en) * | 2014-07-11 | 2017-05-23 | 에스티팜 주식회사 | Novel triazolopyrimidinone or triazolopyridone derivatives, and use thereof |
GB201415598D0 (en) | 2014-09-03 | 2014-10-15 | Univ Birmingham | Elavated Itercranial Pressure Treatment |
US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
MA41551A (en) | 2015-02-20 | 2017-12-26 | Incyte Corp | BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS |
TWI712601B (en) | 2015-02-20 | 2020-12-11 | 美商英塞特公司 | Bicyclic heterocycles as fgfr inhibitors |
KR20220070057A (en) | 2015-03-09 | 2022-05-27 | 인테크린 테라퓨틱스, 아이엔씨. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
MX2018003058A (en) | 2015-09-14 | 2018-08-01 | Infinity Pharmaceuticals Inc | Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same. |
KR101730790B1 (en) | 2015-12-24 | 2017-04-28 | 한국과학기술연구원 | 5,6,7,8-Tetrahydroquinazolin-2-amine compounds having inhibitory activity of serotonine 5-HT6 |
WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
WO2017223422A1 (en) | 2016-06-24 | 2017-12-28 | Infinity Pharmaceuticals, Inc. | Combination therapies |
TW201825465A (en) | 2016-09-23 | 2018-07-16 | 美商基利科學股份有限公司 | Phosphatidylinositol 3-kinase inhibitors |
TW201815787A (en) | 2016-09-23 | 2018-05-01 | 美商基利科學股份有限公司 | Phosphatidylinositol 3-kinase inhibitors |
TW201813963A (en) | 2016-09-23 | 2018-04-16 | 美商基利科學股份有限公司 | Phosphatidylinositol 3-kinase inhibitors |
MX2019011867A (en) | 2017-04-03 | 2020-01-09 | Coherus Biosciences Inc | Pparî³ agonist for treatment of progressive supranuclear palsy. |
AR111960A1 (en) | 2017-05-26 | 2019-09-04 | Incyte Corp | CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION |
ES2812698T3 (en) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Glutaminyl cyclase inhibitors |
MA52494A (en) | 2018-05-04 | 2021-03-10 | Incyte Corp | SOLID FORMS OF FGFR INHIBITOR AND THEIR PREPARATION PROCEDURES |
CR20200591A (en) | 2018-05-04 | 2021-03-31 | Incyte Corp | Salts of an fgfr inhibitor |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
BR112022007163A2 (en) | 2019-10-14 | 2022-08-23 | Incyte Corp | BICYCLIC HETEROCYCLES AS FGFR INHIBITORS |
CA3162010A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Derivatives of an fgfr inhibitor |
WO2021113479A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
WO2021127071A1 (en) * | 2019-12-18 | 2021-06-24 | Merck Sharp & Dohme Corp. | Bicyclic heterocycle compounds methods of use thereof for the treatment of herpes viruses |
TW202313611A (en) | 2021-06-09 | 2023-04-01 | 美商英塞特公司 | Tricyclic heterocycles as fgfr inhibitors |
Family Cites Families (308)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US150343A (en) * | 1874-04-28 | Ezra milleb | ||
US114141A (en) * | 1871-04-25 | Improvement in steam-traps | ||
US150344A (en) * | 1874-04-28 | Improvement in fluid-meters | ||
US150353A (en) * | 1874-04-28 | Improvement in bearing-bars for furnace-grates | ||
CH317122A (en) * | 1952-09-03 | 1956-11-15 | Basf Ag | Process for the production of vat dyes |
DE1249281B (en) * | 1963-05-18 | |||
DE1670912C3 (en) | 1967-08-18 | 1981-06-11 | Bayer Ag, 5090 Leverkusen | Herbicidal agents based on 1,2,4-triazin-5-ones |
GB1377642A (en) * | 1971-01-14 | 1974-12-18 | Koninklijke Gist Spiritus | Penicillanic and cephalosporanic acid derivatives |
US3960949A (en) * | 1971-04-02 | 1976-06-01 | Schering Aktiengesellschaft | 1,2-Biguanides |
DE2150686A1 (en) | 1971-10-12 | 1973-04-19 | Basf Ag | 6-amino-uracil-5-carboxylic acid thioamides - inters for dyestuffs and pharmaceuticals |
AU5996573A (en) | 1972-09-11 | 1975-03-06 | Commonwealth Scientific And Industrial Research Organisation | Pyridinium salts |
US3823135A (en) | 1972-12-26 | 1974-07-09 | Shell Oil Co | Pyrimidone herbicides |
GB1464248A (en) | 1973-11-01 | 1977-02-09 | Ici Ltd | Substituted triazinediones their preparation and use as herbicides |
DE2361551A1 (en) | 1973-12-11 | 1975-06-19 | Basf Ag | Watersol. azo dyes derived from substd. pyridinium chlorides - dyeing natural and synthetic polyamides yellow-violet shades |
DE2500024A1 (en) | 1975-01-02 | 1976-07-08 | Basf Ag | Soluble azo dyes for dying polyamides - prepd. by coupling of 4,6-diaminopyridone derivs |
JPS535180A (en) | 1976-07-01 | 1978-01-18 | Sumitomo Chem Co Ltd | Preparation of 3,4-dihydro-2 (1h) quinazoline derivatives |
DE2720085A1 (en) | 1977-05-05 | 1978-11-16 | Hoechst Ag | PYRIMIDO (6.1-A) ISOCHINOLIN-2-ON DERIVATIVES |
US4494978A (en) * | 1976-12-30 | 1985-01-22 | Chevron Research Company | Herbicidal N-(N'-hydrocarbyloxycarbamylalkyl)-2,6-dialkyl-alpha-haloacetanilides |
CH657851A5 (en) * | 1983-06-28 | 1986-09-30 | Ciba Geigy Ag | CHROMOGENEOUS CHINAZOLONE COMPOUNDS. |
AR240698A1 (en) | 1985-01-19 | 1990-09-28 | Takeda Chemical Industries Ltd | Process for the preparation of 5-(4-(2-(5-ethyl-2-pyridil)-ethoxy)benzyl)-2,4-thiazolodinedione and their salts |
US5614492A (en) * | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
EP0842925A1 (en) | 1987-09-04 | 1998-05-20 | Beecham Group Plc | Substituted thiazolidinedione derivatives |
US4935493A (en) * | 1987-10-06 | 1990-06-19 | E. I. Du Pont De Nemours And Company | Protease inhibitors |
GB8900382D0 (en) | 1989-01-09 | 1989-03-08 | Janssen Pharmaceutica Nv | 2-aminopyrimidinone derivatives |
US5433955A (en) * | 1989-01-23 | 1995-07-18 | Akzo N.V. | Site specific in vivo activation of therapeutic drugs |
IE63502B1 (en) | 1989-04-21 | 1995-05-03 | Zeneca Ltd | Aminopyrimidine derivatives useful for treating cardiovascular disorders |
US5366862A (en) | 1990-02-14 | 1994-11-22 | Receptor Laboratories, Inc. | Method for generating and screening useful peptides |
US5814460A (en) | 1990-02-14 | 1998-09-29 | Diatide, Inc. | Method for generating and screening useful peptides |
ATE169915T1 (en) | 1990-02-15 | 1998-09-15 | Takeda Chemical Industries Ltd | PYRIMIDINEDIONE DERIVATIVES, THEIR PREPARATION AND USE |
US5462928A (en) | 1990-04-14 | 1995-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type IV |
DE4110019C2 (en) | 1991-03-27 | 2000-04-13 | Merck Patent Gmbh | Imidazopyridines, processes for their production and pharmaceutical preparations containing them |
US5387512A (en) * | 1991-06-07 | 1995-02-07 | Merck & Co. Inc. | Preparation of 3-[z-benzoxazol-2-yl)ethyl]-5-(1-hydroxyethyl)-6-methyl-2-(1H)-pyridinone by biotransformation |
EP0610317B1 (en) | 1991-10-22 | 2001-01-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
US5350752A (en) | 1991-12-16 | 1994-09-27 | E. R. Squibb & Sons, Inc. | Dihydropyrimidine derivatives |
DE4141788A1 (en) | 1991-12-18 | 1993-06-24 | Merck Patent Gmbh | imidazopyridines |
EP0626964A1 (en) * | 1992-02-19 | 1994-12-07 | Pfizer Inc. | Heterocyclic compounds for enhancing antitumor activity |
DE4305602A1 (en) | 1992-06-17 | 1993-12-23 | Merck Patent Gmbh | imidazopyridines |
EP0915090A1 (en) | 1992-09-10 | 1999-05-12 | Eli Lilly And Company | Compounds useful as hypoglycemic agents and for treating Alzheimer's disease |
IL106998A0 (en) | 1992-09-17 | 1993-12-28 | Univ Florida | Brain-enhanced delivery of neuroactive peptides by sequential metabolism |
US5811281A (en) | 1993-07-12 | 1998-09-22 | Cornell Research Foundation, Inc. | Immortalized intestinal epithelial cell lines |
IL111785A0 (en) * | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
DE4341453A1 (en) | 1993-12-06 | 1995-06-08 | Merck Patent Gmbh | imidazopyridines |
CN1066739C (en) | 1994-03-08 | 2001-06-06 | 株式会社大塚制药工场 | Phosphonic diester deriv |
US5580979A (en) | 1994-03-15 | 1996-12-03 | Trustees Of Tufts University | Phosphotyrosine peptidomimetics for inhibiting SH2 domain interactions |
US5543396A (en) | 1994-04-28 | 1996-08-06 | Georgia Tech Research Corp. | Proline phosphonate derivatives |
US6090786A (en) | 1994-06-10 | 2000-07-18 | Fondatech Benelux N.V. | Serine proteases, their activity and their synthetic inhibitors |
US5601986A (en) * | 1994-07-14 | 1997-02-11 | Amgen Inc. | Assays and devices for the detection of extrahepatic biliary atresia |
DE4432860A1 (en) | 1994-09-15 | 1996-03-21 | Merck Patent Gmbh | imidazopyridines |
US5512549A (en) * | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
US5864468A (en) * | 1995-01-13 | 1999-01-26 | Methode Electronics, Inc. | Removable optoelectronic module with grounding means |
US5879173A (en) * | 1995-01-13 | 1999-03-09 | Methode Electronics, Inc. | Removable transceiver module and receptacle |
US5717533A (en) * | 1995-01-13 | 1998-02-10 | Methode Electronics Inc. | Removable optoelectronic module |
US5734558A (en) * | 1995-01-13 | 1998-03-31 | Poplawski; Daniel S. | Removable optoelectronic module |
US5614379A (en) | 1995-04-26 | 1997-03-25 | Eli Lilly And Company | Process for preparing anti-obesity protein |
US6265551B1 (en) | 1995-06-01 | 2001-07-24 | Dana-Farber Cancer Institute, Inc. | Form of dipeptidylpeptidase IV (CD26) found in human serum, antibodies thereto, and uses thereof |
US6325989B1 (en) | 1995-06-01 | 2001-12-04 | Dana-Farber Cancer Institute, Inc. | Form of dipeptidylpeptidase IV (CD26) found in human serum |
ATE201016T1 (en) | 1995-06-09 | 2001-05-15 | Hoffmann La Roche | PYRIMIDINDIONE, PYRIMIDINDRION, TRIAZINDIONE DERIVATIVES AS ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISTS |
JPH0928376A (en) | 1995-07-21 | 1997-02-04 | Ajinomoto Co Inc | New dipeptidyl peptidase iv and its production |
TW445263B (en) * | 1996-02-29 | 2001-07-11 | Janssen Pharmaceutica Nv | Novel esters of 1,4-disubstituted piperidine derivatives |
DE122010000020I1 (en) | 1996-04-25 | 2010-07-08 | Prosidion Ltd | Method for lowering the blood glucose level in mammals |
US20020006899A1 (en) * | 1998-10-06 | 2002-01-17 | Pospisilik Andrew J. | Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals |
US5965532A (en) | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
US5885997A (en) * | 1996-07-01 | 1999-03-23 | Dr. Reddy's Research Foundation | Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases |
CA2258949C (en) | 1996-07-01 | 2008-05-06 | Dr. Reddy's Research Foundation | Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases |
US6458924B2 (en) | 1996-08-30 | 2002-10-01 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
US7235627B2 (en) | 1996-08-30 | 2007-06-26 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6011155A (en) | 1996-11-07 | 2000-01-04 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
GB9702701D0 (en) | 1997-02-01 | 1997-04-02 | Univ Newcastle Ventures Ltd | Quinazolinone compounds |
JP3468007B2 (en) * | 1997-02-05 | 2003-11-17 | 住友電装株式会社 | Lever connector |
US20030060434A1 (en) * | 1997-02-18 | 2003-03-27 | Loretta Nielsen | Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms |
US6100234A (en) | 1997-05-07 | 2000-08-08 | Tufts University | Treatment of HIV |
DE69840230D1 (en) | 1997-05-16 | 2009-01-02 | Novozymes Inc | POLYPEPTIDES WITH PROLYLDIPEPTIDYLAMINOPEPTIDASE ACTIVITY AND NUCLEIC ACIDS THAT CODE FOR IT |
EP0897012A1 (en) | 1997-07-05 | 1999-02-17 | Societe Des Produits Nestle S.A. | Cloning of the prolyl-dipeptidyl-peptidase from aspergillus oryzae |
US6235493B1 (en) | 1997-08-06 | 2001-05-22 | The Regents Of The University Of California | Amino acid substituted-cresyl violet, synthetic fluorogenic substrates for the analysis of agents in individual in vivo cells or tissue |
IL125950A0 (en) * | 1997-09-05 | 1999-04-11 | Pfizer Prod Inc | Methods of administering ampa receptor antagonists to treat dyskinesias associated with dopamine agonist therapy |
JP2001518290A (en) | 1997-09-29 | 2001-10-16 | ポイント セラピューティクス, インコーポレイテッド | Stimulation of hematopoietic cells in vitro |
US6485955B1 (en) | 1997-10-06 | 2002-11-26 | The Trustees Of Tufts University | Quiescent cell dipeptidyl peptidase: a novel cytoplasmic serine protease |
US6342611B1 (en) * | 1997-10-10 | 2002-01-29 | Cytovia, Inc. | Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for capsases and other enzymes and the use thereof |
JP4095772B2 (en) * | 1997-11-18 | 2008-06-04 | 財団法人微生物化学研究会 | Novel bioactive substance sulfostine, its production method and its use |
FR2771004B1 (en) | 1997-11-19 | 2000-02-18 | Inst Curie | USE OF BENZHYDRYL SULFINYL DERIVATIVES FOR THE MANUFACTURE OF MEDICINAL PRODUCTS HAVING A WAKING EFFECT IN SITUATIONS OF DRUG-BASED VIGILANCE DISORDERS |
US6380357B2 (en) | 1997-12-16 | 2002-04-30 | Eli Lilly And Company | Glucagon-like peptide-1 crystals |
KR100556071B1 (en) * | 1997-12-16 | 2006-03-10 | 노보자임스 에이/에스 | Polypeptides having signal peptide activity and nucleic acids encoding same |
EP1052994A2 (en) | 1998-02-02 | 2000-11-22 | Trustees Of Tufts College | Use of dipeptidylpetidase inhibitors to regulate glucose metabolism |
US20020061839A1 (en) * | 1998-03-09 | 2002-05-23 | Scharpe Simon Lodewijk | Serine peptidase modulators |
FR2777283B1 (en) | 1998-04-10 | 2000-11-24 | Adir | NOVEL GLUCAGON-PEPTIDE- 1 (7-37) ANALOGUE PEPTIDE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
DE19823831A1 (en) * | 1998-05-28 | 1999-12-02 | Probiodrug Ges Fuer Arzneim | New pharmaceutical use of isoleucyl thiazolidide and its salts |
JP2002517401A (en) * | 1998-06-05 | 2002-06-18 | ポイント セラピューティクス, インコーポレイテッド | Cyclic boroproline compound |
DE19828114A1 (en) | 1998-06-24 | 2000-01-27 | Probiodrug Ges Fuer Arzneim | Produgs of unstable inhibitors of dipeptidyl peptidase IV |
DE19828113A1 (en) * | 1998-06-24 | 2000-01-05 | Probiodrug Ges Fuer Arzneim | Prodrugs of Dipeptidyl Peptidase IV Inhibitors |
US6129911A (en) | 1998-07-10 | 2000-10-10 | Rhode Island Hospital, A Lifespan Partner | Liver stem cell |
DE19834591A1 (en) * | 1998-07-31 | 2000-02-03 | Probiodrug Ges Fuer Arzneim | Use of substances that decrease the activity of dipeptidyl peptidase IV to increase blood sugar levels, e.g. for treating hypoglycemia |
DE19844693A1 (en) * | 1998-09-29 | 2000-03-30 | Delphi Automotive Systems Gmbh | Two part electrical connector |
US20030176357A1 (en) | 1998-10-06 | 2003-09-18 | Pospisilik Andrew J. | Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels |
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 |
GB9906715D0 (en) * | 1999-03-23 | 1999-05-19 | Ferring Bv | Compositions for promoting growth |
US6548529B1 (en) | 1999-04-05 | 2003-04-15 | Bristol-Myers Squibb Company | Heterocyclic containing biphenyl aP2 inhibitors and method |
AU3958100A (en) | 1999-04-20 | 2000-11-02 | Novo Nordisk A/S | New compounds, their preparation and use |
CN1191273C (en) | 1999-05-17 | 2005-03-02 | 康久化学公司 | Long lasting insulinotropic peptides |
DE19926233C1 (en) * | 1999-06-10 | 2000-10-19 | Probiodrug Ges Fuer Arzneim | Production of thiazolidine, useful as pharmaceutical intermediate, comprises reacting hexamethylenetetramine with cysteamine |
US6172081B1 (en) * | 1999-06-24 | 2001-01-09 | Novartis Ag | Tetrahydroisoquinoline 3-carboxamide derivatives |
US6107317A (en) | 1999-06-24 | 2000-08-22 | Novartis Ag | N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
US6110949A (en) | 1999-06-24 | 2000-08-29 | Novartis Ag | N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
US6528486B1 (en) * | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
US6617340B1 (en) | 1999-07-29 | 2003-09-09 | Novartis Ag | N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
DE19940130A1 (en) | 1999-08-24 | 2001-03-01 | Probiodrug Ges Fuer Arzneim | New effectors of Dipeptidyl Peptidase IV for topical use |
WO2001016114A2 (en) * | 1999-08-27 | 2001-03-08 | Chemocentryx, Inc. | Heterocyclic compounds and methods for modulating cxcr3 function |
ES2234662T3 (en) * | 1999-09-16 | 2005-07-01 | Curis, Inc. | HEDGEHOG SIGNALING ROUTE MEDIATORS, COMPOSITIONS AND USES RELATED TO THEMSELVES. |
US6559188B1 (en) * | 1999-09-17 | 2003-05-06 | Novartis Ag | Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes |
US6414002B1 (en) * | 1999-09-22 | 2002-07-02 | Bristol-Myers Squibb Company | Substituted acid derivatives useful as antidiabetic and antiobesity agents and method |
WO2001023364A1 (en) | 1999-09-28 | 2001-04-05 | Merck Patent Gmbh | Quinazolinones |
US6447772B1 (en) | 1999-10-01 | 2002-09-10 | Klaire Laboratories, Inc. | Compositions and methods relating to reduction of symptoms of autism |
US6251391B1 (en) * | 1999-10-01 | 2001-06-26 | Klaire Laboratories, Inc. | Compositions containing dipepitidyl peptidase IV and tyrosinase or phenylalaninase for reducing opioid-related symptons |
JP2001172257A (en) * | 1999-10-05 | 2001-06-26 | Fujisawa Pharmaceut Co Ltd | Organic sulfonamide compound |
WO2001027090A1 (en) | 1999-10-08 | 2001-04-19 | Meiji Seika Kaisha, Ltd. | m-SUBSTITUTED BENZOIC ACID DERIVATIVES EXHIBITING INTEGRINαvβ3 ANTAGONISM |
US6261794B1 (en) | 1999-10-14 | 2001-07-17 | Saint Louis University | Methods for identifying inhibitors of methionine aminopeptidases |
US7230000B1 (en) * | 1999-10-27 | 2007-06-12 | Cytokinetics, Incorporated | Methods and compositions utilizing quinazolinones |
KR20050049562A (en) * | 1999-10-27 | 2005-05-25 | 싸이토키네틱스, 인코포레이티드 | Methods and compositions utilizing quinazolinones |
US20040152745A1 (en) | 1999-11-12 | 2004-08-05 | Guilford Pharmaceuticals, Inc. | Dipeptidyl peptidase IV inhibitors and methods of making and using dipeptidyl peptidase IV inhibitors |
CA2390231A1 (en) | 1999-11-12 | 2001-05-17 | Paul Jackson | Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors |
GB9928330D0 (en) * | 1999-11-30 | 2000-01-26 | Ferring Bv | Novel antidiabetic agents |
US6517382B2 (en) * | 1999-12-01 | 2003-02-11 | Tyco Electronics Corporation | Pluggable module and receptacle |
AU2020501A (en) * | 1999-12-08 | 2001-06-18 | 1149336 Ontario Inc. | Chemotherapy treatment |
US6380398B2 (en) | 2000-01-04 | 2002-04-30 | Novo Nordisk A/S | Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
ATE385421T1 (en) | 2000-01-21 | 2008-02-15 | Novartis Pharma Gmbh | COMPOSITIONS CONSISTING OF DIPEPTIDYLPEPTIDASE-IV INHIBITORS AND ANTIDIABETICS |
CA2396920A1 (en) * | 2000-01-27 | 2001-08-02 | Eli Lilly And Company | Process for solubilizing glucagon-like peptide 1 (glp-1) compounds |
US6569901B2 (en) | 2000-01-28 | 2003-05-27 | Novo Nordisk A/S | Alkynyl-substituted propionic acid derivatives, their preparation and use |
US7217722B2 (en) | 2000-02-01 | 2007-05-15 | Kirin Beer Kabushiki Kaisha | Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same |
US6395767B2 (en) * | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US6448045B1 (en) | 2000-03-10 | 2002-09-10 | The Regents Of The University Of California | Inducing insulin gene expression in pancreas cells expressing recombinant PDX-1 |
US6608038B2 (en) | 2000-03-15 | 2003-08-19 | Novartis Ag | Methods and compositions for treatment of diabetes and related conditions via gene therapy |
EP1136482A1 (en) | 2000-03-23 | 2001-09-26 | Sanofi-Synthelabo | 2-Amino-3-(alkyl)-pyrimidone derivatives as GSK3beta inhibitors |
US6555519B2 (en) * | 2000-03-30 | 2003-04-29 | Bristol-Myers Squibb Company | O-glucosylated benzamide SGLT2 inhibitors and method |
CZ20023234A3 (en) * | 2000-03-31 | 2003-01-15 | Probiodrug Ag | Medicament against diabetes mellitus |
US6573096B1 (en) | 2000-04-01 | 2003-06-03 | The Research Foundation At State University Of New York | Compositions and methods for inhibition of cancer invasion and angiogenesis |
US6545170B2 (en) * | 2000-04-13 | 2003-04-08 | Pharmacia Corporation | 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
ES2567260T3 (en) * | 2000-04-25 | 2016-04-21 | Icos Corporation | Human phosphatidylinositol 3-kinase delta inhibitors |
GB0010183D0 (en) | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
GB0010188D0 (en) * | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
US6783757B2 (en) * | 2000-06-01 | 2004-08-31 | Kirkman Group, Inc. | Composition and method for increasing exorphin catabolism to treat autism |
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 |
US6432969B1 (en) | 2000-06-13 | 2002-08-13 | Novartis Ag | N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
US6627636B2 (en) | 2000-06-15 | 2003-09-30 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
US6620821B2 (en) | 2000-06-15 | 2003-09-16 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
GB0014969D0 (en) | 2000-06-19 | 2000-08-09 | Smithkline Beecham Plc | Novel method of treatment |
US7078397B2 (en) | 2000-06-19 | 2006-07-18 | Smithkline Beecham Corporation | Combinations of dipeptidyl peptidase IV inhibitors and other antidiabetic agents for the treatment of diabetes mellitus |
MXPA02012272A (en) * | 2000-07-04 | 2003-04-25 | Novo Nordisk As | Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv. |
JP2002042960A (en) * | 2000-07-25 | 2002-02-08 | Yazaki Corp | Connector support mechanism |
AU2001281083A1 (en) | 2000-08-01 | 2002-02-13 | Pharmacia Corporation | Hexahydro-7-1h-azepin-2-yl-haxanoic acid derivatives as inhibitors of inducible nitric oxide synthase |
US7022711B2 (en) | 2000-08-04 | 2006-04-04 | Warner-Lambert Company | 2-(4-Pyridyl)amino-6-dialkoxyphenyl-pyrido[2,3-d]pyrimidin-7-ones |
JP4101053B2 (en) | 2000-08-10 | 2008-06-11 | 田辺三菱製薬株式会社 | Proline derivative and its pharmaceutical use |
US20020165237A1 (en) | 2000-08-11 | 2002-11-07 | Fryburg David Albert | Treatment of the insulin resistance syndrome |
US20020037829A1 (en) * | 2000-08-23 | 2002-03-28 | Aronson Peter S. | Use of DPPIV inhibitors as diuretic and anti-hypertensive agents |
US6900226B2 (en) * | 2000-09-06 | 2005-05-31 | Hoffman-La Roche Inc. | Neuropeptide Y antagonists |
US20020064736A1 (en) * | 2000-09-27 | 2002-05-30 | Fuji Photo Film Co., Ltd. | Dye-forming coupler, silver halide photographic light-sensitive material, and method for producing an azomethine dye |
EP1324995A2 (en) * | 2000-09-27 | 2003-07-09 | Merck & Co., Inc. | Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders |
IL154893A0 (en) * | 2000-10-06 | 2003-10-31 | Tanabe Seiyaku Co | Aliphatic nitrogen-containing cyclic compounds, methods for the preparation thereof and pharmaceutical compositions containing the same |
RU2305133C2 (en) | 2000-10-12 | 2007-08-27 | Ферринг Бв | Dppiv-cognated new serine protease gene |
AUPR107800A0 (en) * | 2000-10-27 | 2000-11-23 | University Of Sydney, The | Peptide and nucleic acid molecule ii |
JP2004512300A (en) | 2000-10-27 | 2004-04-22 | プロバイオドラッグ アーゲー | Methods of treating neurological and neuropsychological disorders |
EP1333887B1 (en) * | 2000-10-30 | 2006-08-02 | Ortho-McNeil Pharmaceutical, Inc. | Combination therapy comprising anti-diabetic and anticonvulsant agents |
CA2427610A1 (en) | 2000-10-31 | 2002-08-08 | Merck & Co., Inc. | Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders |
WO2002059343A2 (en) | 2000-10-31 | 2002-08-01 | Vanderbilt University | Biological markers and diagnostic tests for angiotensin converting enzyme inhibitor- and vasopeptidase inhibitor-associated angioedema |
US6864363B2 (en) | 2000-11-08 | 2005-03-08 | University Of Georgia Research Foundation, Inc. | Dipeptidylpeptidases and methods of use |
US20020155565A1 (en) | 2000-11-10 | 2002-10-24 | Pilar Garin-Chesa | FAP-activated anti-tumor compounds |
TWI243162B (en) * | 2000-11-10 | 2005-11-11 | Taisho Pharmaceutical Co Ltd | Cyanopyrrolidine derivatives |
US20030055052A1 (en) * | 2000-11-10 | 2003-03-20 | Stefan Peters | FAP-activated anti-tumor compounds |
US20030203946A1 (en) | 2000-11-17 | 2003-10-30 | Carsten Behrens | Glucagon antagonists/inverse agonists |
WO2002040448A1 (en) | 2000-11-20 | 2002-05-23 | Bristol-Myers Squibb Company | Pyridone derivatives as ap2 inhibitors |
NZ526622A (en) | 2000-12-11 | 2006-07-28 | Amgen Sf Llc | CXCR3 antagonists |
JPWO2002051836A1 (en) | 2000-12-27 | 2004-04-22 | 協和醗酵工業株式会社 | Dipeptidyl peptidase-IV inhibitor |
DE10100053A1 (en) | 2001-01-02 | 2002-08-22 | Keyneurotek Ag I G | Use of enzyme inhibitors of dipeptidyl peptidase IV and aminopeptidase N and pharmaceutical preparations therefrom for the prevention and / or therapy of ischemia-related acute and chronic neurodegenerative processes and diseases |
BR0206831A (en) * | 2001-02-02 | 2004-07-06 | Takeda Chemical Industries Ltd | Compound, crystal, pharmaceutical agent, agents for the prophylaxis or treatment of diabetes, diabetic complications, impaired glucose tolerance and obesity, peptidase inhibitor, use of a compound, and method of producing a compound |
WO2002062798A2 (en) * | 2001-02-05 | 2002-08-15 | Dr. Reddy's Laboratories Ltd. | Salts of pyrimidine derivatives for use against coronary heart disease and atherosclerose |
TWI255817B (en) | 2001-02-14 | 2006-06-01 | Kissei Pharmaceutical | Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof |
CZ301487B6 (en) * | 2001-02-24 | 2010-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, process of their preparation and use as a medicament |
US6337069B1 (en) | 2001-02-28 | 2002-01-08 | B.M.R.A. Corporation B.V. | Method of treating rhinitis or sinusitis by intranasally administering a peptidase |
US6371787B1 (en) * | 2001-03-07 | 2002-04-16 | International Business Machines Corporation | Pull-to-release type latch mechanism for removable small form factor electronic modules |
PT1372650E (en) * | 2001-03-19 | 2009-02-25 | Novartis Ag | Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative |
US7026316B2 (en) | 2001-03-27 | 2006-04-11 | Merck & Co., Inc. | Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
FR2822826B1 (en) | 2001-03-28 | 2003-05-09 | Servier Lab | NOVEL ALPHA-AMINO ACID SULPHONYL DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
DE10115921A1 (en) | 2001-03-30 | 2002-10-02 | Boehringer Ingelheim Pharma | Process for the preparation of 4,6-diaminopyrimido [5,4-d] pyrimidines |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
GB0109146D0 (en) | 2001-04-11 | 2001-05-30 | Ferring Bv | Treatment of type 2 diabetes |
PE20021080A1 (en) * | 2001-04-12 | 2003-02-12 | Boehringer Ingelheim Int | A SPECIFIC ANTIBODY FAPO BIBH1 IN THE TREATMENT OF CANCER |
US6573287B2 (en) | 2001-04-12 | 2003-06-03 | Bristo-Myers Squibb Company | 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method |
FR2824825B1 (en) * | 2001-05-15 | 2005-05-06 | Servier Lab | NOVEL ALPHA-AMINOACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US20030060494A1 (en) | 2001-05-18 | 2003-03-27 | Nobuyuki Yasuda | Pharmaceutical use of N-carbamoylazole derivatives |
US7105556B2 (en) * | 2001-05-30 | 2006-09-12 | Bristol-Myers Squibb Company | Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method |
US6794379B2 (en) * | 2001-06-06 | 2004-09-21 | Tularik Inc. | CXCR3 antagonists |
KR100490048B1 (en) * | 2001-06-19 | 2005-05-17 | 삼성전자주식회사 | In-line system for manufacturing liquid crystal display and method of manufacturing liquid crystal display using the same |
JP2004535433A (en) | 2001-06-20 | 2004-11-25 | メルク エンド カムパニー インコーポレーテッド | Dipeptidyl peptidase inhibitors for the treatment of diabetes |
ATE318139T1 (en) | 2001-06-20 | 2006-03-15 | Merck & Co Inc | DIPEPTIDYLPEPTIDASE INHIBITORS FOR THE TREATMENT OF DIABETES |
ES2296962T3 (en) | 2001-06-27 | 2008-05-01 | Smithkline Beecham Corporation | PIRROLIDINS AS INHIBITORS OF DIPEPTIDIL PEPTIDASA. |
US7183290B2 (en) | 2001-06-27 | 2007-02-27 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
DE10150203A1 (en) | 2001-10-12 | 2003-04-17 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitor in treatment of cancer |
US20030135023A1 (en) | 2001-06-27 | 2003-07-17 | Hans-Ulrich Demuth | Peptide structures useful for competitive modulation of dipeptidyl peptidase IV catalysis |
WO2003002593A2 (en) | 2001-06-27 | 2003-01-09 | Probiodrug Ag | Peptide structures useful for competitive modulation of dipeptidyl peptidase iv catalysis |
US7368421B2 (en) * | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
EP1406873B1 (en) | 2001-06-27 | 2007-09-26 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
US20030130199A1 (en) * | 2001-06-27 | 2003-07-10 | Von Hoersten Stephan | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
DE10154689A1 (en) | 2001-11-09 | 2003-05-22 | Probiodrug Ag | Substituted amino ketone compounds |
CA2418543A1 (en) | 2001-06-27 | 2003-01-09 | Probiodrug Ag | New dipeptidyl peptidase iv inhibitors and their uses as anti-cancer agents |
US6869947B2 (en) * | 2001-07-03 | 2005-03-22 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme 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 |
US20030144350A1 (en) | 2001-07-20 | 2003-07-31 | Adipogenix, Inc. | Fat accumulation-modulation compounds |
EP1285922A1 (en) | 2001-08-13 | 2003-02-26 | Warner-Lambert Company | 1-Alkyl or 1-cycloalkyltriazolo[4,3-a]quinazolin-5-ones as phosphodiesterase inhibitors |
WO2003016335A2 (en) | 2001-08-13 | 2003-02-27 | Probiodrug Ag | Irreversible cysteine protease inhibitors of legumain |
US6844316B2 (en) * | 2001-09-06 | 2005-01-18 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
DE10143840A1 (en) | 2001-09-06 | 2003-03-27 | Probiodrug Ag | New acylated hydroxamates useful for the treatment of e.g. wound healing |
US6673829B2 (en) * | 2001-09-14 | 2004-01-06 | Novo Nordisk A/S | Aminoazetidine,-pyrrolidine and -piperidine derivatives |
CA2460512A1 (en) | 2001-09-14 | 2003-03-27 | Mitsubishi Pharma Corporation | Thiazolidine derivatives and medicinal use thereof |
US20030186963A1 (en) | 2001-09-14 | 2003-10-02 | Dorwald Florencio Zaragoza | Substituted piperidines |
AU2002331311A1 (en) | 2001-09-19 | 2003-04-01 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
EA007224B1 (en) | 2001-09-21 | 2006-08-25 | Мицубиси Фарма Корпорейшн | 3-substituted-4-pyrimidone derivatives |
NZ531636A (en) | 2001-09-21 | 2005-11-25 | Mitsubishi Pharma Corp | 3-substituted-4-pyrimidone derivatives as tau protein kinase 1 inhibitor |
SI1427415T1 (en) | 2001-09-21 | 2009-12-31 | Bristol Myers Squibb Co | Lactam-containing compounds and derivatives thereof as factor xa inhibitors |
US7019010B2 (en) * | 2001-09-27 | 2006-03-28 | Novertis Ag | Combinations |
MXPA04002993A (en) * | 2001-10-01 | 2004-07-15 | Bristol Myers Squibb Co | Spiro-hydantoin compounds useful as anti-inflammatory agents. |
WO2003030946A1 (en) | 2001-10-09 | 2003-04-17 | Novartis Ag | Regulation of insulin production |
US7064135B2 (en) | 2001-10-12 | 2006-06-20 | Novo Nordisk Inc. | Substituted piperidines |
TWI301834B (en) | 2001-10-22 | 2008-10-11 | Eisai R&D Man Co Ltd | Pyrimidone compound and pharmaceutical composition including the same |
GB0125445D0 (en) * | 2001-10-23 | 2001-12-12 | Ferring Bv | Protease Inhibitors |
US6861440B2 (en) | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
EP1442028A4 (en) * | 2001-11-06 | 2009-11-04 | Bristol Myers Squibb Co | Substituted acid derivatives useful as antidiabetic and antiobesity agents and method |
WO2003039460A2 (en) * | 2001-11-07 | 2003-05-15 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
US20030125304A1 (en) * | 2001-11-09 | 2003-07-03 | Hans-Ulrich Demuth | Substituted amino ketone compounds |
US20030089935A1 (en) * | 2001-11-13 | 2003-05-15 | Macronix International Co., Ltd. | Non-volatile semiconductor memory device with multi-layer gate insulating structure |
IL161717A0 (en) | 2001-11-26 | 2004-09-27 | Schering Corp | Piperidine-based mch antagonists for treatment of obesity and cns disorders |
EP2769715A3 (en) | 2001-11-26 | 2014-09-17 | Trustees Of Tufts College | Methods for treating autoimmune disorders, and reagents related thereto |
EP1469873A4 (en) | 2001-11-26 | 2007-10-03 | Tufts College | Peptidomimetic inhibitors of post-proline cleaving enzymes |
AU2002350217A1 (en) | 2001-12-04 | 2003-06-17 | Bristol-Myers Squibb Company | Glycinamides as factor xa inhibitors |
DE60222302T2 (en) * | 2001-12-06 | 2008-05-29 | Merck & Co., Inc. | INHIBITORS OF MITOTIC KINESINE |
CZ2004714A3 (en) | 2001-12-14 | 2004-10-13 | Novoánordiskáa@S | Compounds and uses thereof for decreasing activity of hormone-sensitive lipase |
JP2005518391A (en) | 2001-12-21 | 2005-06-23 | ノボ ノルディスク アクティーゼルスカブ | Amide derivatives as GK activators |
TW200301698A (en) | 2001-12-21 | 2003-07-16 | Bristol Myers Squibb Co | Acridone inhibitors of IMPDH enzyme |
US6727261B2 (en) * | 2001-12-27 | 2004-04-27 | Hoffman-La Roche Inc. | Pyrido[2,1-A]Isoquinoline derivatives |
DE60217918T2 (en) | 2001-12-29 | 2007-11-15 | Novo Nordisk A/S | COMBINED USE OF A GLP-1 COMPOUND AND AN ALDOSE REDUCTASE INHIBITOR |
ATE409466T1 (en) | 2002-01-11 | 2008-10-15 | Novo Nordisk As | METHOD AND COMPOSITION FOR TREATING DIABETES, HYPERTENSION, CHRONIC HEART FAILURE AND CONDITIONS ASSOCIATED WITH FLUID RETENTION |
WO2003063903A2 (en) | 2002-02-01 | 2003-08-07 | Probiodrug Ag | Modulation of t lymphocytes using dp iv inhibitors |
US7101898B2 (en) | 2002-02-01 | 2006-09-05 | Novo Nordisk A/S | Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes |
BR0307665A (en) * | 2002-02-13 | 2005-01-04 | Hoffmann La Roche | Compounds, process for their manufacture, pharmaceutical compositions comprising them, method for treating and / or prophylaxis of diseases associated with dpp iv and use of the compounds |
MXPA04007743A (en) | 2002-02-13 | 2004-10-15 | Hoffmann La Roche | Novel pyridine- and quinoline-derivatives. |
EA200400980A1 (en) | 2002-02-27 | 2005-02-24 | Пфайзер Продактс Инк. | ACC INHIBITORS |
ATE349435T1 (en) | 2002-02-28 | 2007-01-15 | Prosidion Ltd | GLUTAMINE-BASED DPIV INHIBITORS |
US20080070864A1 (en) | 2002-03-07 | 2008-03-20 | X-Ceptor Therapeutics, Inc. | Quinazolinone Modulators Of Nuclear Receptors |
US20030232761A1 (en) | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
EP1492777A1 (en) | 2002-04-08 | 2005-01-05 | Torrent Pharmaceuticals Ltd | Thiazolidine-4-carbonitriles and analogues and their use as dipeptidyl-peptidase inhibitors |
US20040106802A1 (en) * | 2002-04-08 | 2004-06-03 | Torrent Pharmaceuticals Ltd. | Novel compounds and therapeutic uses thereof |
JP2003300977A (en) | 2002-04-10 | 2003-10-21 | Sumitomo Pharmaceut Co Ltd | Xanthine derivative |
EP2204181A3 (en) | 2002-04-30 | 2010-09-22 | Trustees Of Tufts College | Protease inhibitors |
TW200307667A (en) * | 2002-05-06 | 2003-12-16 | Bristol Myers Squibb Co | Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors |
US7057046B2 (en) * | 2002-05-20 | 2006-06-06 | Bristol-Myers Squibb Company | Lactam glycogen phosphorylase inhibitors and method of use |
MXPA04011557A (en) | 2002-05-23 | 2005-07-05 | Chiron Corp | Substituted quinazolinone compounds. |
GB0212412D0 (en) | 2002-05-29 | 2002-07-10 | Novartis Ag | Combination of organic compounds |
US6710040B1 (en) | 2002-06-04 | 2004-03-23 | Pfizer Inc. | Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors |
AU2003233010A1 (en) | 2002-06-04 | 2003-12-19 | Pfizer Products Inc. | Process for the preparation of 3,3,4,4-tetrafluoropyrrolidine and derivatives thereof |
CN100469778C (en) * | 2002-06-06 | 2009-03-18 | 卫材R&D管理有限公司 | New fused imidazole derivative |
WO2003106628A2 (en) * | 2002-06-17 | 2003-12-24 | Bristol-Myers Squibb Company | Benzodiazepine inhibitors of mitochondial f1f0 atp hydrolase and methods of inhibiting f1f0 atp hydrolase |
CA2489648A1 (en) | 2002-06-17 | 2003-12-24 | Smithkline Beecham Corporation | Chemical process |
SE0201976D0 (en) | 2002-06-24 | 2002-06-24 | Astrazeneca Ab | Novel compounds |
US20040054171A1 (en) * | 2002-07-04 | 2004-03-18 | Jensen Anette Frost | Polymorphic forms of a 4H-thieno[3,2-E]-1,2,4-thiadiazine 1,1-dioxide derivative |
AU2002331226A1 (en) | 2002-08-09 | 2004-03-11 | Prosidion Ltd. | Methods for improving islet signaling in diabetes mellitus and for its prevention |
AU2003262747A1 (en) * | 2002-08-21 | 2004-03-11 | Cytokinetics, Inc. | Compounds, compositions, and methods |
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 |
DE10238477A1 (en) * | 2002-08-22 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New purine derivatives, their production and their use as medicines |
US7495005B2 (en) | 2002-08-22 | 2009-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
US6998502B1 (en) | 2002-09-05 | 2006-02-14 | Sabinsa Corporation | Convenient process of manufacture for difluoromethylornithine and related compounds |
EP1398032A1 (en) | 2002-09-10 | 2004-03-17 | PheneX Pharmaceuticals AG | 4-Oxo-quinazolines as LXR nuclear receptor binding compounds |
EP1407774A1 (en) * | 2002-09-10 | 2004-04-14 | LION Bioscience AG | 2-Amino-4-quinazolinones as LXR nuclear receptor binding compounds |
JP2004123738A (en) | 2002-09-11 | 2004-04-22 | Takeda Chem Ind Ltd | Sustained-release preparation |
EP1543023B1 (en) | 2002-09-18 | 2010-03-17 | Prosidion Limited | Secondary binding site of dipeptidyl peptidase iv (dp iv) |
US20040058876A1 (en) * | 2002-09-18 | 2004-03-25 | Torsten Hoffmann | Secondary binding site of dipeptidyl peptidase IV (DP IV) |
US7262207B2 (en) | 2002-09-19 | 2007-08-28 | Abbott Laboratories | Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV) |
US6869966B2 (en) * | 2002-09-30 | 2005-03-22 | Banyu Pharmaceutical Co., Ltd. | N-substituted-2-oxodihydropyridine derivatives |
DE60320008T2 (en) | 2002-10-18 | 2009-06-18 | Merck & Co., Inc. | HETEROCYCLIC BETA-AMINO COMPOUNDS AS INHIBITORS OF DIPEPTIDYLPEPTIDASE FOR TREATMENT OR PREVENTION OF DIABETES |
AU2003301662A1 (en) | 2002-10-21 | 2004-05-13 | Bristol-Myers Squibb Company | Quinazolinones and derivatives thereof as factor xa inhibitors |
DE60332856D1 (en) | 2002-10-23 | 2010-07-15 | Bristol Myers Squibb Co | GLYCINNITRIL BASED DIPEPTIDYLPEPTIDASE IV INHIBITORS |
US7482337B2 (en) | 2002-11-08 | 2009-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
CA2502068A1 (en) * | 2002-11-18 | 2004-06-03 | Pfizer Products Inc. | Dipeptidyl peptidase iv inhibiting fluorinated cyclic amides |
DE10254304A1 (en) | 2002-11-21 | 2004-06-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New xanthine derivatives, their production and their use as medicines |
DE10256264A1 (en) | 2002-12-03 | 2004-06-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New trisubstituted dihydro-imidazo-pyridazinone or imidazo-pyridinone derivatives, useful as dipeptidylpeptidase-IV inhibitors for e.g. treating diabetes mellitus type I or II, arthritis or obesity |
US7109192B2 (en) * | 2002-12-03 | 2006-09-19 | Boehringer Ingelheim Pharma Gmbh & Co Kg | Substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions |
UY28103A1 (en) * | 2002-12-03 | 2004-06-30 | Boehringer Ingelheim Pharma | NEW IMIDAZO-PIRIDINONAS REPLACED, ITS PREPARATION AND ITS EMPLOYMENT AS MEDICATIONS |
WO2004062613A2 (en) | 2003-01-13 | 2004-07-29 | Bristol-Myers Squibb Company | Hiv integrase inhibitors |
US7148246B2 (en) | 2003-02-27 | 2006-12-12 | Sanofi-Aventis Deutschland Gmbh | Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals |
WO2004078758A1 (en) * | 2003-03-07 | 2004-09-16 | Astrazeneca Ab | Novel fused heterocycles and uses thereof |
US20050014732A1 (en) * | 2003-03-14 | 2005-01-20 | Pharmacia Corporation | Combination of an aldosterone receptor antagonist and an anti-diabetic agent |
CA2518465A1 (en) | 2003-03-25 | 2004-10-14 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
TWI357408B (en) | 2003-03-26 | 2012-02-01 | Mitsubishi Tanabe Pharma Corp | 3-substituted-4-pyrimidone derivatives |
EP1961416B1 (en) * | 2003-05-05 | 2013-01-23 | Probiodrug AG | Use of inhibitors of glutaminyl cyclase for treating psoriasis, rheumatoid arthritis or atherosclerosis. |
WO2004098591A2 (en) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases |
US20040229848A1 (en) | 2003-05-05 | 2004-11-18 | Hans-Ulrich Demuth | Glutaminyl based DP IV-inhibitors |
WO2004103993A1 (en) | 2003-05-14 | 2004-12-02 | Syrrx, Inc. | Dipeptidyl peptidase inhibitors |
US7566707B2 (en) * | 2003-06-18 | 2009-07-28 | Boehringer Ingelheim International Gmbh | Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions |
NZ544221A (en) | 2003-06-20 | 2009-05-31 | Hoffmann La Roche | Pyrido[2,1-a]-isoquinoline derivatives as DPP-IV inhibitors |
MXPA05013734A (en) | 2003-06-20 | 2006-03-08 | Hoffmann La Roche | Hexahydropyridoisoqinolines as dpp-iv inhibitors. |
JO2625B1 (en) * | 2003-06-24 | 2011-11-01 | ميرك شارب اند دوم كوربوريشن | Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor |
US6995183B2 (en) * | 2003-08-01 | 2006-02-07 | Bristol Myers Squibb Company | Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods |
KR20060041309A (en) | 2003-08-13 | 2006-05-11 | 다케다 야쿠힌 고교 가부시키가이샤 | 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors |
WO2005019168A2 (en) * | 2003-08-20 | 2005-03-03 | Pfizer Products Inc. | Fluorinated lysine derivatives as dipeptidyl peptidase iv inhibitors |
WO2005026148A1 (en) | 2003-09-08 | 2005-03-24 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
JP2007513058A (en) | 2003-09-08 | 2007-05-24 | 武田薬品工業株式会社 | Dipeptidyl peptidase inhibitor |
AU2004293012A1 (en) * | 2003-11-19 | 2005-06-09 | Rustum S. Boyce | Quinazolinone compounds with reduced bioaccumulation |
US7304086B2 (en) | 2004-02-05 | 2007-12-04 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
CN102134231B (en) | 2004-03-15 | 2020-08-04 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
US7872124B2 (en) | 2004-12-21 | 2011-01-18 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
-
2004
- 2004-03-24 CA CA002518465A patent/CA2518465A1/en not_active Abandoned
- 2004-03-24 JP JP2006509315A patent/JP4887139B2/en not_active Expired - Fee Related
- 2004-03-24 KR KR1020057018103A patent/KR20050122220A/en not_active Application Discontinuation
- 2004-03-24 US US10/809,638 patent/US20040242566A1/en not_active Abandoned
- 2004-03-24 US US10/809,637 patent/US7687625B2/en not_active Expired - Fee Related
- 2004-03-24 US US10/809,636 patent/US20040242568A1/en not_active Abandoned
- 2004-03-24 EP EP04758366A patent/EP1608317B1/en not_active Expired - Lifetime
- 2004-03-24 CN CNA2004800119000A patent/CN1894234A/en active Pending
- 2004-03-24 WO PCT/US2004/009217 patent/WO2004087053A2/en active Search and Examination
- 2004-03-24 US US10/809,635 patent/US7550590B2/en not_active Expired - Fee Related
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8906901B2 (en) | 2005-09-14 | 2014-12-09 | Takeda Pharmaceutical Company Limited | Administration of dipeptidyl peptidase inhibitors |
US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
US9533954B2 (en) | 2010-12-22 | 2017-01-03 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
US9533984B2 (en) | 2013-04-19 | 2017-01-03 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
Also Published As
Publication number | Publication date |
---|---|
US20040259870A1 (en) | 2004-12-23 |
CN1894234A (en) | 2007-01-10 |
CA2518465A1 (en) | 2004-10-14 |
KR20050122220A (en) | 2005-12-28 |
US20040242566A1 (en) | 2004-12-02 |
US20040242568A1 (en) | 2004-12-02 |
EP1608317A2 (en) | 2005-12-28 |
JP4887139B2 (en) | 2012-02-29 |
WO2004087053A3 (en) | 2006-08-31 |
WO2004087053A2 (en) | 2004-10-14 |
US7550590B2 (en) | 2009-06-23 |
EP1608317B1 (en) | 2012-09-26 |
US20050004117A1 (en) | 2005-01-06 |
US7687625B2 (en) | 2010-03-30 |
JP2007524600A (en) | 2007-08-30 |
EP1608317A4 (en) | 2006-12-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7550590B2 (en) | Dipeptidyl peptidase inhibitors | |
US7872124B2 (en) | Dipeptidyl peptidase inhibitors | |
EP1506967B1 (en) | Dipeptidyl peptidase inhibitors | |
US7825242B2 (en) | Dipeptidyl peptidase inhibitors | |
EP1697342A2 (en) | Dipeptidyl peptidase inhibitors | |
WO2005095381A1 (en) | Dipeptidyl peptidase inhibitors | |
US7550598B2 (en) | Kinase inhibitors | |
EP1911754B1 (en) | Dipeptidyl peptidase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
COP | Corrected version of pamphlet |
Free format text: PAGE 173, CLAIMS, REPLACED BY A NEW PAGE 173 |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2518465 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006509315 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020057018103 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004758366 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 20048119000 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2004758366 Country of ref document: EP Ref document number: 1020057018103 Country of ref document: KR |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) |