WO2005021024A1 - Amino acid derived prodrugs of propofol, compositions and uses thereof - Google Patents
Amino acid derived prodrugs of propofol, compositions and uses thereof Download PDFInfo
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- WO2005021024A1 WO2005021024A1 PCT/US2004/002537 US2004002537W WO2005021024A1 WO 2005021024 A1 WO2005021024 A1 WO 2005021024A1 US 2004002537 W US2004002537 W US 2004002537W WO 2005021024 A1 WO2005021024 A1 WO 2005021024A1
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- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C329/02—Monothiocarbonic acids; Derivatives thereof
- C07C329/04—Esters of monothiocarbonic acids
- C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
Definitions
- the present invention provides propofol prodrugs, methods of making propofol prodrugs, pharmaceutical compositions of propofol prodrugs and methods of using propofol prodrugs and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post-chemotherapy or post-operative surgery nausea and vomiting.
- Propofol (2,6-diisopropylphenol), (1), is a low molecular weight phenol that is widely used as an intravenous sedative-hypnotic agent in the induction and maintenance of anesthesia and/or sedation in mammals.
- the advantages of propofol as an anesthetic include rapid onset of anesthesia, rapid clearance, and minimal side effects (Langley et al, Drugs 1988, 35, 334-372).
- Propofol may mediate hypnotic effects through interaction with the GAB A A receptor complex, a hetero-oligomeric ligand-gated chloride ion channel (Peduto et al, Anesthesiology 1991, 75, 1000-1009.).
- Propofol is rapidly metabolized in mammals with the drug being eliminated predominantly as glucuronidated and sulfated conjugates of propofol and 4-hydroxypropofol (Langley et al, Drugs 1988, 35, 334-372). Propofol clearance exceeds liver blood flow, which indicates that extrahepatic tissues contribute to the overall metabolism ofthe drug.
- Human intestinal mucosa glucuronidates propofol in vitro and oral dosing studies in rats indicate that approximately 90% ofthe administered drug undergoes first pass metabolism, with extraction by the intestinal mucosa accounting for the bulk of this presystemic elimination (Raoof et al., Pharm. Res. 1996, 13, 891-895).
- propofol is administered by injection or intravenous infusion and oral administration has not been considered therapeutically effective.
- Propofol has a broad range of biological and medical applications, which are evident at sub-anesthetic doses and include treatment and/or prevention of intractable migraine headache pain (Krusz et al, Headache 2000, 40, 224-230; Krusz, International Publication No. WO 00/54588).
- Propofol when used to maintain anesthesia, causes a lower incidence of post-operative nausea and vomiting ("PONV") when compared to common inhalation anesthetic agents and numerous controlled clinical studies support the anti-emetic activity of propofol (Tramer et al, Br. J. Anaesth.
- Nausea, retching and/or vomiting induced by a variety of chemotherapeutic agents has been controlled by low-dose propofol infusion in patients refractory to prophylaxis with conventional anti-emetic drugs (e.g., serotonin antagonists and corticosteroids).
- chemotherapeutic agents e.g., cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate, anthracycline drugs, etc.
- conventional anti-emetic drugs e.g., serotonin antagonists and corticosteroids
- Propofol has also been used to treat patients with refractory status epilepticus (Brown et al, Pharmacother.
- neurodegenerative diseases which may be treated or prevented with anti-oxidants include, but are not limited to, Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis ("ALS"), multiple sclerosis (“MS”), Pick disease, inflammatory diseases and diseases caused by inflammatory mediators such as tumor necrosis factor (TNF) and IL-1.
- ALS amyotrophic lateral sclerosis
- MS multiple sclerosis
- TNF tumor necrosis factor
- IL-1 tumor necrosis factor
- a significant problem with the formulation and use of propofol is poor water solubility. Accordingly, propofol must be specially formulated in aqueous media using solubilizers or emulsifiers (Briggs et al, Anaesthesia 1982, 37, 1099-1101).
- an oil-in- water emulsion (the emulsifier is the lecithin mixture Intralipid®), is used to formulate propofol (Picard et al, Anesth. Analg. 2000, 90, 963-969).
- the oil-in-water emulsion formulation causes discomfort and pain at the site of injection.
- One potential solution to the poor water solubility of propofol which avoids the use of additives, solubilizers or emulsifiers and the attendant injection site pain, is a water-soluble, stable propofol prodrug that is converted to propofol in vivo.
- propofol prodrugs methods of making propofol prodrugs, pharmaceutical compositions of propofol prodrugs and methods of using propofol prodrugs to treat or prevent diseases or disorders such as migraine headache pain, neurodegenerative disorders and post-chemotherapy or post-operative surgery nausea and vomiting which satisfies the above need.
- prodrugs of propofol and pharmaceutical compositions thereof are orally administered.
- prodrugs of propofol are translocated across the gastrointestinal mucosa via interaction with transporter proteins expressed within enterocytes lining the gastrointestinal tract.
- a compound of structural Formula (I) is provided:
- X is selected from the group consisting of a bond, -CH 2 -, -NR 11 -, -O- and-S-; m is 1 or 2; n is O or 1; R 1 is selected from the group consisting of hydrogen, [R 5 NH(CHR 4 ) p C(O)]-, R 6 -, R 6 C(O)- and R 6 OC(O ; R 2 is -OR 7 or -[NR 8 (CHR 9 ) q C(O)OR 7 ]; p and q are independently 1 or 2; R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
- compositions are provided.
- the pharmaceutical compositions disclosed herein generally comprise one or more compounds of Formulae (I) - (XVIII), and a pharmaceutically acceptable vehicle such as a diluent, carrier, excipient or adjuvant.
- the choice of diluent, carrier, excipient and adjuvant will depend upon, among other factors, the desired mode of administration.
- the mode of administration is oral.
- methods for treating various diseases or disorders generally comprise administering one or more compounds of Formulae (I) - (XVIII) in order to achieve a therapeutically effective concentration of propofol in the blood and/or tissue of a patient.
- the methods are useful for treating or preventing diseases or disorders including, but not limited to, migraine headache pain, post-chemotherapy or post-operative surgery nausea and vomiting and neurodegenerative disorders (e.g., epilepsy, Friedrich's disease, Parkinson's disease,
- the methods generally involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of one or more compounds of Formulae (I) - (XVIII), or pharmaceutical composition containing one or more compounds of Formulae (I) — (XVIII).
- a therapeutically effective amount of one or more compounds of Formulae (I) - (XVIII) or pharmaceutical composition containing one or more compounds of Formulae (I) — (XVIII).
- methods for inducing and/or maintaining anesthesia or sedation in a mammal are provided.
- the methods generally involve administering to a patient in need of such anesthesia or sedation induction and/or maintenance a therapeutically effective amount of one or more compounds of Formulae (I) - (XVIII), or pharmaceutical composition containing one or more compounds of Formulae (I) - (XVHI).
- Alkyl by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
- Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), cycloprop-1-en-l-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop- 1 -en- 1 -yl, but-2-en- 1
- alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used.
- an alkyl group comprises from 1 to 20 carbon atoms, more preferably, from 1 to 10 carbon atoms, even more preferably, 1 to 6 carbon atoms.
- C 1-6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.
- alkanyl by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
- Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl),
- alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
- the group may be in either the cis or trans conformation about the double bond(s).
- Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl; cycloprop-2-en-l-yl ; butenyls such as but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop- 1 -en- 1-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
- Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
- Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop- 1 -yn- 1 -yl, prop-2-yn- 1 -yl, etc. ; butynyls such as but- 1 -yn- 1 -yl, but- 1 -yn-3 -yl, but-3-yn-l-yl, etc.; and the like.
- Acyl by itself or as part of another substituent refers to a radical -C(O)R 30 , where R 30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein. Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
- Alkoxy by itself or as part of another substituent refers to a radical -OR where R 31 represents an alkyl or cycloalkyl group as defined herein.
- alkoxycarbonyl by itself or as part of another substituent, refers to a radical -C(O)OR 31 where R 31 is as defined above.
- Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
- Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, ⁇ s-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
- an aryl group comprises from 6 to 20 carbon atoms, more preferably, from 6 to 12 carbon atoms.
- “Arylallcyl” by itself or as part of another substituent refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group.
- Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used.
- an arylalkyl group is (C 6 -C 30 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety ofthe arylalkyl group is (C1-C 10 ) and the aryl moiety is (C 6 -C 20 ), more preferably, an arylalkyl group is (C 6 -C 2 o) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety ofthe arylalkyl group is (C ⁇ -C 8 ) and the aryl moiety is (C 6 -C 12 ).
- Carbamoyl by itself or as part of another substituent refers to the radical -C(O)N(R 32 )R 33 where R 32 and R 33 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl, as defined herein.
- Compounds refer to compounds encompassed by the generic formulae disclosed herein and include any specific compounds within those formulae whose structure is disclosed herein. The compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, • the chemical structure is determinative ofthe identity ofthe compound.
- the compounds may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, when stereochemistry at chiral centers is not specified, the chemical structures depicted herein encompass all possible configurations at those chiral centers including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomericaliy pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
- the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds.
- the compounds also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, and 18 O.
- Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, the hydrated, solvated and N-oxide forms are within the scope ofthe present invention.
- Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.
- the cycloalkyl group is (C 3 -C ⁇ 0 ) cycloalkyl, more preferably, (C 3 -C 7 ) cycloalkyl.
- Cycloheteroalkyl by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
- Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
- Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like.
- Heteroalkyl, Heteroalkanvk Heteroalkenyl and Heteroalkynyl by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more ofthe carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups.
- R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 and R 41 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
- Heteroaryl by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
- Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine,
- the heteroaryl group is from 5-20 membered heteroaryl, more preferably from 5-10 membered heteroaryl.
- Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
- Heteroarylalkyl by itself or as part of another substituent refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl group.
- heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety ofthe heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl, more preferably, 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.
- Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system.
- parent aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more ofthe rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc.
- Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
- Parent Heteroaromatic Ring System refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more ofthe rings are aromatic and one or more ofthe rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc.
- Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadia
- “Pharmaceutical composition” refers to at least one compound of Formulae (I) or (II) and a pharmaceutically acceptable vehicle, with which the compound is administered to a patient.
- “Pharmaceutically acceptable salt” refers to a salt of a compound of Formulae (I) or (II), which possesses the desired pharmacological activity ofthe parent compound.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, cam
- “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of Formulae (I) or (II) is administered.
- "Patient” includes humans.
- the terms “human” and “patient” are used interchangeably herein.
- “PEPTl” refers to an oligopeptide transporter protein that normally absorbs dipeptides and tripeptides (and related structures) in certain tissues, such as the intestine (Adibi, S. A., Gastroenterology 1997, 113, 332-340; Leibach et al, Ann. Rev. Nutr. 1996,
- Preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one ofthe clinical symptoms ofthe disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms ofthe disease).
- Prodrug refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. A hydroxyl containing drug may be converted to, for example, to an ester, carbonate, acyloxyalkyl or a sulfonate prodrug, which may be hydrolyzed in vivo to provide the hydroxyl compound.
- Prodrugs for drugs which functional groups different than those listed above are well known to the skilled artisan.
- “Promoiety” refers to a form of protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
- Protecting group refers to a grouping of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity ofthe functional group. Examples of protecting groups can be found in Green et al, “Protective Groups in Organic Chemistry", (Wiley, 2 nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic
- amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBz”), tert-butoxycarbonyl ("Boc”), trimethylsilyl ("TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC”), nitro-veratryloxycarbonyl
- hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
- “Substituted” refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s).
- Transported by the PEPT1 transporter refers to the translocation of a molecule across a membrane of a cell expressing the PEPT1 transporter. The translocation occurs through interaction with the transporter and is energized by cotransport of H + ions across the membrane.
- Treating” or “treatment” of any disease or disorder refers to one or more ofthe following: (1) ameliorating the disease or disorder (i.e., arresting or reducing the development ofthe disease or at least one ofthe clinical symptoms thereof); (2) ameliorating at least one physical parameter, which may not be discernible by the patient; (3) inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both; and (4) delaying the onset ofthe disease or disorder.
- “Therapeutically effective amount” means the amount of a compound or composition that, when administered to a patient, is sufficient to effect the desired therapy.
- the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., ofthe patient to be treated. Reference will now be made in detail to certain preferred compounds and methods of making and administering these compounds. The invention is not limited to those preferred compounds and methods but rather is defined by the claim(s) issuing herefrom.
- a first class of propofol prodrugs include compounds of structural Formula (I):
- X is selected from the group consisting of a bond, -CH 2 -, -NR 11 -, -O- and -S-; m is 1 or 2; n is 0 or 1 ; R 1 is selected from the group consisting of hydrogen, [R 5 NH(CHR 4 ) p C(O)]- 5 R 6 -, R 6 C(O)- and R 6 OC(O)-; R 2 is -OR 7 or -[NR 8 (CHR 9 ) q C(O)OR 7 ]; p and q are independently 1 or 2; R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cyclohetero
- a compound of Formula (I) is derived from ⁇ -amino acids (e.g., [H 2 N(CHR 4 )C(O)OH] and/or [HNR 8 (CHR 9 )C(O)OH]) including, but not limited to, the 20 genetically encoded amino acids and the non-coded amino acids such as, for example, 2,3-diaminobutyric acid, 2,4-diaminobutyric acid, hydroxylysine, homoserine, homoarginine, homotyrosine, homocysteine, homophenylalanine, citrulline, sarcosine, orthinine, N-methylleucine, kynurenine, penicillamine, 4-aminophenylalanine, 3-(2-naphthyl)alamne, 3-(l-naphthyl)alanine, methionine sulfone, methionine sulfoxide, t-
- n is 1 and R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl.
- R 3 is hydrogen, alkyl or substituted alkyl, more preferably, R 3 is hydrogen or C ⁇ -4 alkyl, even more preferably, R 3 is hydrogen or methyl.
- n is 1 and R 3 is hydrogen, aryl or substituted aryl.
- R 3 is hydrogen, phenyl or substituted phenyl.
- n is 1 and R 3 is hydrogen, arylalkyl or substituted arylalkyl.
- R 3 is hydrogen, benzyl or substituted benzyl.
- R 1 is hydrogen or [R 5 NH(CHR 4 ) p C(O)]-, where p is 1.
- R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 4 and R 5 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 1 is
- R 5 [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 4 is hydrogen, alkanyl or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen, and R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen, and R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl,
- R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1 and R 4 and R 5 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 4 and R 5 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, R 5 is R 6 -, R 6 C(O)- or R 6 OC(O)- and R 6 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl or heteroarylalkyl.
- R 6 is C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 1 is hydrogen or [R 5 NH(CHR 4 ) p C(O)]-, where p is 2.
- R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, when R 4 and R 5 are attached to adjacent atoms then R 4 and R 5 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R is [R 5 NH(CHR 4 ) p C(O)]-, p is 2 and R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 4 is hydrogen, C 1-4 alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 2, R 5 is hydrogen and R 4 is hydrogen, C M alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R is -OR and R is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R is hydrogen, C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl. Preferably, R 7 is hydrogen, C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 8 is hydrogen and R 9 is s hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 7 hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, more preferably, R 7 is hydrogen, C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R 8 is hydrogen and R 9 is hydrogen, alkanyl or cycloalkanyl.
- R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 7 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R 8 is hydrogen and R 9 is substituted alkanyl.
- R 9 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 7 is hydrogen, C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R 8 is hydrogen and R 9 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 9 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- R 7 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl and R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R and R together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- R 7 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 2 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl and R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 7 is hydrogen, C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 8 is hydrogen and R 9 is hydrogen, C 1-4 alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- m is 1, n is 0, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen, R 2 is -OR 7 , R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl and R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R is hydrogen, C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R is hydrogen.
- m is 1, n is 0, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 2 is -OH to provide a compound of Formula (III):
- R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 4 is hydrogen, alkanyl, or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 ,
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl,
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe
- ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- m is 2, n is 0, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen, R 2 is -OR 7 , R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl and R 7 is hydrogen, alkyl, 5 aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R 7 is hydrogen, C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 2, n is 0, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 2 is -OH to provide a l o compound of Formula (IV) :
- R is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 4 is hydrogen, alkanyl or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , 20 -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl. 5
- the ⁇ -carbon of the N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- m is 1, n is 0, X is -O-, R 1 is [R 5 NH(CHR 4 ) p C(O)K p is 1, R 5 is hydrogen, R 2 is -OR 7 , R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl and R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R 7 is hydrogen, C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 1, n is 0, X is -O-, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 2 is -OH to provide a compound of Formula (V):
- R 4 is hydrogen, alkanyl or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- m is 1, n is 0, X is -S-, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen, R 2 is -OR 7 , R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl and R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R 7 is hydrogen, C ⁇ -4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 1, n is 0, X is -S-, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 2 is -OH to provide a compound of Formula (VI):
- R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 4 is hydrogen, alkanyl, or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-mdolylmethyl.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- m is 1, n is 1, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1 , R 5 is hydrogen, R 2 is -OR 7 , R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl, R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl and R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted
- R is hydrogen, C ⁇ _ alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. More preferably, R is hydrogen or methyl.
- R 7 is hydrogen, C ⁇ -4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R is hydrogen.
- m is 1, n is 1, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 2 is -OH to provide a compound of Formula (VII):
- R is hydrogen or methyl and R is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 4 is hydrogen, alkanyl, or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- R 3 is hydrogen.
- m is 2, n is 1, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1 , R 5 is hydrogen, R 2 is -OR 7 , R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl, R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl and R 7 is hydrogen, alkyl,
- R 3 is hydrogen, C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 3 is hydrogen or methyl.
- R 7 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 2, n is 1, X is a bond, R 1 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 2 is -OH to provide a compound of Formula (VIII) :
- R 3 is hydrogen or methyl and R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 4 is hydrogen, alkanyl or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- the ⁇ -carbon ofthe the ⁇ -carbon ofthe
- N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- R is hydrogen.
- m is 1, n is 0, X is a bond, R 1 is selected from the group consisting of hydrogen, R 6 -, R 6 C(O)- and R 6 OC(O)-, R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 6 is alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R 7 is alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R 8 is hydrogen or alkyl, R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or
- R 1 is hydrogen.
- R is C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 7 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 1, n is 0, X is a bond, R 1 is hydrogen, R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R 8 is hydrogen or alkyl, R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R and R together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R is hydrogen, CM alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 1, n is 0, X is a bond, R 1 is hydrogen, R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1 and R 7 is hydrogen to provide a compound of Formula (IX):
- R 8 is hydrogen or methyl and R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 9 is hydrogen, alkanyl or cycloalkanyl.
- R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 9 is substituted alkanyl.
- R 9 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 ,
- R 9 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 9 is phenyl, benzyl,
- R and R together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- R 8 is hydrogen.
- m is 2, n is 0, X is a bond, R 1 is hydrogen, R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1, R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R is hydrogen or alkyl, R is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl or optionally, R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 7 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 2, n is 0, X is a bond, R 1 is hydrogen, R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1 and R 7 is hydrogen to provide a compound of Formula (X):
- R 8 is hydrogen or methyl and R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 9 is hydrogen, alkanyl or cycloalkanyl.
- R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R is substituted alkanyl.
- R 9 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 9 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 9 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- R and R together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- R 3 is hydrogen.
- R 8 is hydrogen.
- m is 1, n is 1, X is a bond, R 1 is hydrogen, R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1,
- R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl
- R 7 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl or heteroarylalkyl
- R 8 is hydrogen or methyl
- R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted
- R is hydrogen, C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. More preferably, R 3 is hydrogen or methyl.
- R 7 is hydrogen, CM alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. More preferably, R 7 is hydrogen.
- m is 1, n is 1, X is a bond, R 1 is hydrogen, R 2 is -[NR 8 (CHR 9 ) q C(O)OR 7 ], q is 1 and R 7 is hydrogen to provide a compound of Formula (XI):
- R 3 is hydrogen or methyl
- R 8 is hydrogen or methyl
- R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R and R together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 9 is hydrogen, alkanyl or cycloalkanyl.
- R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 9 is substituted alkanyl.
- R 9 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or
- R 9 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 9 is phenyl, benzyl,
- R and R together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon of the N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- R is hydrogen.
- R 8 is hydrogen.
- m is 1, n is 0, X is a bond, R 1 is hydrogen, R 2 is -OR 7 and R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R 7 is hydrogen, C ⁇ - alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 1, n is 0, X is a bond, R 1 is hydrogen, R 2 is -OR 7 and R 7 is hydrogen to provide a compound of Formula (XII):
- a compound of Formula (XII) the ⁇ -carbon ofthe amino acid residue is ofthe L-configuration. In another embodiment of a compound of Formula (XII), the ⁇ -carbon ofthe amino acid residue is ofthe D-configuration.
- m 2 is -OR 7 and R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R 7 is hydrogen, C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 2, n is 0, X is a bond, R 1 is hydrogen, R 2 is -OR 7 and R 7 is hydrogen to provide a compound of Formula (XIII):
- X is a bond
- R 1 is hydrogen
- R 2 is -OR 7
- R 7 is hydrogen to provide a compound of Formula (XIII):
- the ⁇ -carbon ofthe amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe amino acid residue is ofthe D-configuration.
- m is 1, n is 1, X is a bond, R 1 is hydrogen, R 2 is -OR 7 , R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl and R is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R 3 is hydrogen, C ⁇ -4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R is hydrogen or methyl.
- R 7 is hydrogen, C ⁇ -4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 1
- n is 1
- X is a bond
- R 1 is hydrogen
- R 2 is -OR 7
- R 7 is hydrogen to provide a compound of Formula (XIV):
- R 3 is hydrogen or methyl.
- the ⁇ -carbon ofthe amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe amino acid residue is ofthe D-configuration.
- m is 2, n is 1, X is a bond, R 1 is hydrogen, R 2 is -OR 7 , R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl and R 7 is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
- R 3 is hydrogen, C 1-4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 3 is hydrogen or methyl.
- R 7 is hydrogen, C ⁇ -4 alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 7 is hydrogen.
- m is 2, n is 1, X is a bond, R 1 is hydrogen, R 2 is -OR 7 and R 7 is hydrogen to provide a compound of Formula (XV):
- R 3 is hydrogen or methyl.
- the ⁇ -carbon ofthe amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe amino acid residue is ofthe D-configuration.
- Another class of propofol prodrugs include compounds of structural Formula (II):
- R 10 is hydrogen or [R 5 NH(CHR 4 ) p C(O)]-; n is O or 1; p and q are independently 1 or 2; R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl; each R 4 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, substituted arylalkyl
- a compound of Formula (II) is derived from ⁇ -amino acids (e.g. , [H 2 N(CHR 4 )C(O)OH] and/or [HNR 8 (CHR 9 )C(O)OH]) including, but not limited to, the 20 genetically encoded amino acids and the non-coded amino acids 2,3-diaminobutyric acid, 2,4-diaminobutyric acid, hydroxylysine, homoserine, homoarginine, homotyrosme, homocysteine, homophenylalanine, citrulline, sarcosine, orthinine, N-methylleucine, kynurenine, pemcillamine, 4-aminophenylalanine, 3-(2-naphthyl)alanine, 3-(l-naphthyl)alanine, methionine sulfone, methionine sulfoxide, t-butylalan
- n is 1 and R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl.
- n is 1 and R is hydrogen, alkyl or substituted alkyl.
- R is hydrogen or CM alkyl.
- n is 1 and R 3 is hydrogen, aryl or substituted aryl.
- R 3 is hydrogen, phenyl or substituted phenyl.
- n is 1 and R 3 is hydrogen, arylalkyl or substituted arylalkyl.
- R 3 is hydrogen, benzyl or substituted benzyl.
- R is
- R 5 NH(CHR 4 ) p C(O)]-, p is 1 and R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 4 and R 5 together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 10 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 4 is hydrogen, alkanyl or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 10 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 10 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 5 is hydrogen and R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- R 10 is
- R 5 NH(CHR 4 ) p C(O)]-, p is 1 and R 4 and R 5 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 4 and R 5 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- R 10 is
- R 5 NH(CHR 4 ) p C(O)]-, p is 1, R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl or substituted heteroarylalkyl, R 5 is R 6 -, R 6 C(O)- or R 6 OC(O)-, and R 6 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl or heteroarylalkyl.
- R 6 is selected from the group consisting of C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- R 10 is [R 5 NH(CHR 4 ) p C(O)]-, p is 2 and each R 4 is independently hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- each R 4 is independently hydrogen, C 1-4 alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl or substituted benzyl. More preferably, R 10 is [R 5 NH(CHR 4 ) p C(O)]-, p is 2, R 5 is hydrogen, and each R 4 is independently hydrogen, C 1- alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl or substituted benzyl.
- q is 1, R 8 is hydrogen or methyl and R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.
- R 8 is hydrogen or methyl and R 9 is hydrogen, alkanyl or cycloalkanyl.
- R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- q is 1
- R 8 is hydrogen or methyl
- R 9 is substituted alkanyl.
- R 9 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H,
- R 8 is hydrogen or methyl and R 9 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 9 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolyhnethyl.
- q is 1, and R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- R 8 is hydrogen or methyl and each R 9 is independently hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl. More preferably, R is hydrogen and each R is independently hydrogen, CM alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl or substituted benzyl. In still another embodiment of a compound of Formula (II), n is 0, q is 1, R 10 is
- R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl
- R is hydrogen or methyl and R is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R is hydrogen and R is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH CONH 2 ,
- R 4 is hydrogen, alkanyl or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R is hydrogen and R is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl, or optionally, R 8 and R 9 together with the
- R is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 8 is hydrogen and R 9 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded, form an azetidine, pyrrolidine or piperidine ring.
- R 9 is selected from the group consisting of hydrogen, methyl,
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- R 8 is hydrogen and R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl or optionally, R and R together with the atoms to which they are bonded, form an azetidine, pyrrolidine or piperidine ring.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- n is 1, q is 1, R 10 is hydrogen, R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl, R 8 is hydrogen, R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R is hydrogen, CM alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 3 is hydrogen or methyl.
- n is 1
- q is 1
- R 10 is hydrogen, to provide a compound of Formula (XVII):
- R 3 is hydrogen or methyl
- R 8 is hydrogen or methyl
- R 9 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 8 is hydrogen.
- R is hydrogen, alkanyl or cycloalkanyl.
- R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 9 is substituted alkanyl.
- R 9 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 or -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
- R 9 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 9 is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl.
- R 8 and R 9 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- the ⁇ -carbon ofthe amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe amino acid residue is ofthe D-configuration.
- R 3 is hydrogen.
- n is 1
- q is 1
- R 10 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1
- R 3 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl or heteroaryl
- R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl
- R is hydrogen, R is hydrogen or methyl
- R is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, aryl, substituted aryl, aryl
- R 3 is hydrogen, C 1- alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, more preferably, R 3 is hydrogen or methyl.
- R 8 is hydrogen and R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl or optionally, R 8 and R 9 together with the
- n is 1
- q is 1
- R 10 is [R 5 NH(CHR 4 ) p C(O)]-, p is 1, and R 5 is hydrogen to provide a compound of Formula (XVIII):
- R 3 is hydrogen or methyl
- R 4 is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl
- R is hydrogen or methyl
- R is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
- R 4 is hydrogen, alkanyl or cycloalkanyl.
- R 4 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.
- R 8 is hydrogen and R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 C0 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH,
- R 4 is substituted alkanyl.
- R 4 is -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H,
- R 8 is hydrogen and R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH 3 ,
- R 4 is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.
- R 4 is phenyl, benzyl,
- R 8 is hydrogen and R 9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl, or optionally, R 8 and R 9 together with the atoms to which they are bonded form an azetidine, pyrrolidine or piperidine ring.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe N-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe L-configuration.
- the ⁇ -carbon ofthe C-terminal amino acid residue is ofthe D-configuration.
- the ⁇ -carbons of both the N- and C-terminal amino acid residues are ofthe L-configuration.
- R is hydrogen.
- Compounds of structural Formulae (I) - (XVIII) may be administered orally and transported across cells (i.e., enterocytes) lining the lumen ofthe gastrointestinal tract. While not wishing to be bound by any particular transport mechanism, some ofthe compounds of structural Formulae (I) - (XVIII) may be substrates for the proton-coupled intestinal peptide transport system ("PEPT1") (Leibach et al, Annu. Rev. Nutr.
- PEPT1 may act as a vehicle for their effective uptake across the apical membrane ofthe gastric mucosa.
- Methods for determining whether compounds of Formulae (I) - (XVIII) serve as substrates for the PEPT1 transporter are disclosed in Example 131 herein (see Section 5).
- In vitro systems which use cells engineered to heterologously express the transport system, or cell-lines that endogenously express the transporter (e.g.
- Caco-2 cells may be used to assay transport of compounds of Formulae (I) - (XVIII) by PEPT1 transporter.
- Standard methods for evaluating the enzymatic conversion of propofol prodrug compounds to propofol in vitro are disclosed in Example 132 herein.
- Oral administration of propofol prodrug compounds to rats and monkeys is described in Examples 134 and 135 respectively.
- Compound (2) is a protected aspartic or glutamic acid residue, where the protecting groups Pg 1 and Pg 2 are removable under orthogonal conditions.
- protecting groups for the nitrogen atom include tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz) and
- 9-fluorenylmethyloxycarbonyl (Fmoc) moieties while those for the carboxyl group include tert-butyl, benzyl and 9-fluorenylmethyl esters.
- Nitrogen protected amino acid residues may be conveniently activated for coupling via conversion to their NHS esters, as illustrated by the preparation of compounds (7) and (8).
- compound (22) may be prepared by first generating the haloalkyl (or thioalkyl) propofol ether (24), then displacing the leaving group X 2 with the carboxylate anion of dipeptide (19), as shown in Scheme 7.
- the compounds of Formulae (I) - (XVIII), as described herein, may be used to treat and/or prevent migraine in patients.
- the methods comprise administering to a patient a therapeutically effective amount of a compound of Formulae (I) - (XVIII) to treat and/or prevent migraine.
- a therapeutically effective amount of the compound is administered to a patient suffering from a migraine headache.
- a therapeutically effective amount ofthe compound is administered to a patient at risk of developing a migraine.
- the compounds are administered orally to treat and/or prevent migraine.
- the compounds are administered parenterally
- the compounds are administered in amounts of between about 10 mg to about 4 g to treat or prevent migraine.
- the compounds of Formulae (I) - (XVIII) may also be used as anti-emetics and can be administered to patients at risk of vomiting and/or who are nauseous.
- the compounds may be administered to patients that are being concurrently treated with various chemotherapy agents and/or surgical procedures, which induce nausea, in order to treat and/or prevent nausea and vomiting.
- a therapeutically effective amount ofthe compound is administered to a patient to treat and/or prevent nausea and vomiting.
- the compounds are administered orally to treat and/or prevent nausea or vomiting.
- the compounds are administered parenterally (e.g., via inhalation or injection to treat and/or prevent nausea or vomiting.
- the compounds are administered in amounts of between about 10 mg to about 4 g to treat and/or prevent nausea or vomiting.
- the compounds of Formulae (I) - (XVIII) may also be used as hypnotic agents to induce and/or maintain general anesthesia and/or as a sedative.
- a therapeutically effective amount ofthe compound is administered to a patient to induce hypnosis, anesthesia and/or sedation.
- the compounds are administered intravenously when used as a general anesthetic, hi another embodiment, the compounds are administered by inhalation.
- the compounds may be formulated by methods used to formulate propofol, which are well l ⁇ iown in the art.
- compounds of Formulae (I) - (XVIII) that are water soluble may be formulated as an injectable aqueous solution, which contains significantly less emulsifiers or solubilizers than used in aqueous formulations of propofol, thereby avoiding discomfort at the site of injection.
- the compounds are administered orally in amounts of about 10 mg to 4 g daily when used as a sedative (e.g., for the treatment of anxiety conditions).
- the compounds may also be administered by inhalation, intravenously or intramuscularly when used as a sedative.
- the compounds of Formulae (I) - (XVIII) may be administered in similar amounts and in the same schedule as described in the art for propofol.
- dosage levels ofthe compounds of Formulae (I) - (XVIII) for producing general anesthesia, maintaining anesthesia and producing a sedative effect are as described in the art for propofol.
- the compounds of Formulae (I) - (XVIII) may also be used to inhibit oxidation in biological materials.
- the methods involve contacting the biological material with an effective amount ofthe compound.
- a therapeutically effective amount ofthe compound is administered to a patient suffering from a pathological condition treated by inhibition of oxidation.
- a therapeutically effective amount ofthe compound is administered to a patient at risk of developing a disease as a result of exposure to oxidative stress.
- the compounds may find particular use in preventing and/or treating oxidation in disorders ofthe central nervous system that involve an inflammatory component.
- the compounds of Formulae (I) - (XVIII) may be used to treat and/or prevent neurodegenerative conditions ofthe nervous system, which include, but are not limited to, Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Pick disease.
- a therapeutically effective amount of a compound e.g.
- the compounds of Formulae (I) - (XVIII) may also be used to treat and/or prevent trauma to the central nervous system such as, for example, skull fracture and its resulting edema, concussion, contusion, brain hemorrhages, shearing lesions, subdural and epidural hematoma, and spinal cord injury (e.g., mechanical injury due to compression or flexion of the spinal cord).
- trauma to the central nervous system such as, for example, skull fracture and its resulting edema, concussion, contusion, brain hemorrhages, shearing lesions, subdural and epidural hematoma, and spinal cord injury (e.g., mechanical injury due to compression or flexion of the spinal cord).
- a compound is parenterally admimstered by intravenous injection or injection directly into the central nervous system (i.e., intrathecally ("IT") or into the brain) to treat and/or prevent traumatic conditions ofthe central nervous system.
- a therapeutically effective amount of a compound e.g., between about 25 mg to about 500 mg TV or IM and between about 5 mg to about 100 mg IT
- the compounds of Formulae (I) - (XVIII) may also be used as anti-convulsives to treat and/or prevent seizures (e.g., epileptic seizures).
- Methods for treating and/or preventing convulsions comprise administering a therapeutically effective amount of a compound to a patient in need of such treatment.
- the compounds are admimstered orally to treat and/or prevent convulsions.
- the compounds are parenterally administered to treat and/or prevent convulsions.
- the compounds are administered in amounts of between about 10 mg to about 4 g daily to treat and/or prevent convulsions.
- compounds and/or pharmaceutical compositions of Formulae (I) - (XVIII) may be administered or applied singly, or in combination with other agents.
- compositions may also be administered or applied singly, or in combination with other pharmaceutically active agents, including other compounds of Formulae (I) - (XVIII).
- other pharmaceutically active agents including other compounds of Formulae (I) - (XVIII).
- Provided herein are methods of treatment and prophylaxis by administering to a patient a therapeutically effective amount of a composition or compound of Formulae (I) -
- the patient may be an animal, is more preferably, a mammal and even more preferably, a human.
- the compounds of Formulae (I) - (XVIII) and/or pharmaceutical compositions thereof are preferably admimstered orally.
- the compounds and/or pharmaceutical compositions thereof may also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local.
- Various delivery systems are known, (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) that can be used to administer a compound and/or pharmaceutical composition.
- Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin.
- administration can be by direct injection at the site (or former site) of cancer or arthritis.
- the compounds and/or pharmaceutical compositions thereof may be delivered via sustained release systems, preferably oral sustained release systems, hi one embodiment, a pump may be used (Langer, supra; Sefton, 1987, CRC Grit RefBiomed Eng. 14:201; Saudek et al, 1989, N Engl JMed. 321:574).
- polymeric materials can be used (see “Medical Applications of Controlled Release,” Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); “Controlled Drug Bioavailability,” Drug Product Design and Performance, Smolen and Ball
- polymeric materials are used for oral sustained release delivery.
- Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred, hydroxypropylmethylcellulose).
- Other preferred cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod.
- enteric-coated preparations can be used for oral sustained release administration.
- Preferred coating materials include polymers with a pH-dependent solubility (i.e., pH-controlled release), polymers with a slow or pH-dependent rate of swelling, dissolution or erosion (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release) and polymers that form firm layers that are destroyed by an increase in pressure (i.e., pressure-controlled release).
- osmotic delivery systems are used for oral sustained release administration (Verma et al, DrugDev. Ind. Pharm. 2000, 26:695-708).
- OROSTM osmotic devices are used for oral sustained release delivery devices (Theeuwes et al, United States Patent No. 3,845,770; Theeuwes et al, United States Patent No. 3,916,899).
- a compound may be conveniently delivered to the lung by a number of different devices.
- a Metered Dose Inhaler which utilizes canisters that contain a suitable low boiling propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotefrafluoroethane, carbon dioxide or other suitable gas may be used to deliver compounds directly to the lung.
- a Dry Powder Inhaler (“DPI)” device may be used to administer a compound to the lung (See, e.g., Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting 1999, 40, 397).
- DPI devices typically use a mechanism such as a burst of gas to create a cloud of dry powder inside a container, which may then be inhaled by the patient and are well known in the art and may be purchased from a number of commercial sources.
- MDDPI multiple dose DPI
- capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound and a suitable powder base such as lactose or starch for these systems.
- a liquid spray device supplied, for example, by Aradigm Corporation, Hayward, CA.
- Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be directly inhaled into the lung.
- a nebulizer device is used to deliver a compound to the lung. Nebulizers create aerosols from liquid drug formulations by using, for example, ultrasonic energy to form fine particles that may be readily inhaled (e.g., Verschoyle et al, British J.
- an electrohydrodynamic (“EHD”) aerosol device is used to deliver a compound to the lung.
- EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see e.g., Noakes et al, United States Patent No. 4,765,539; Coffee, United States Patent No. 4,962,885; Coffee, International Publication No., WO 94/12285; Coffee, International Publication No., WO 94/14543; Coffee,
- the electrochemical properties of a compound may be important parameters to optimize when delivering the compound to the lung with an EHD aerosol device, and such optimization is routinely performed by one of skill in the art. EHD aerosol devices may more efficiently deliver drugs to the lung than existing pulmonary delivery technologies. Other methods of intra-pulmonary delivery of a compound will be known to the skilled artisan.
- the compounds of Formulae (I) - (XVTII) and/or compositions containing such compounds preferably provide therapeutic or prophylactic levels of propofol upon in vivo administration to a patient.
- the promoiety or promoieties ofthe compounds may be cleaved either chemically and/or enzymatically.
- One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue of a mammal may enzymatically cleave the promoiety or promoieties ofthe administered compounds.
- the promoiety or promoieties of the compounds may be cleaved prior to absorption by the gastrointestinal tract (e.g., within the stomach or intestinal lumen) and/or after absorption by the gastrointestinal tract (e.g., in intestinal tissue, blood, liver or other suitable tissue of a mammal).
- propofol remains conjugated to a promoiety during transit across the intestinal mucosal barrier to provide protection from presystemic metabolism.
- the compounds are essentially not metabolized to propofol within enterocytes, but are metabolized to the parent drug within the systemic circulation. Cleavage of the promoiety or promoieties ofthe compounds after abso ⁇ tion by the gastrointestinal tract may allow these prodrugs to be absorbed into the systemic circulation either by active transport, passive diffusion or by a mixture of both active and passive processes.
- the compounds are actively absorbed through interaction with the intestinal peptide transporter PEPT1.
- the compounds and/or pharmaceutical compositions containing compounds of Formulae (I) - (XVIII) are preferably administered as sustained release systems.
- the compounds and/or pharmaceutical compositions are delivered by oral sustained release administration.
- the compounds and/or pharmaceutical compositions are administered twice per day (more preferably, once per day).
- compositions contain a therapeutically effective amount of one or more compounds of Formulae (I) - (XVIII), preferably, in purified form, together with a suitable amount of a pharmaceutically acceptable vehicle, so as to provide the form for proper administration to a patient.
- the compounds and pharmaceutically acceptable vehicles are preferably sterile.
- Water is a preferred vehicle when a compound is administered intravenously.
- Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
- Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
- excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
- the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
- compositions comprising a compound of Formulae (I) or (II) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- the present pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
- the pharmaceutically acceptable vehicle is a capsule (see e.g., Grosswald et al, United States Patent No. 5,698,155).
- compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
- Orally administered pharmaceutical compositions may contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin, flavoring agents such as peppermint, oil of wmtergreen, or cherry coloring agents and preserving agents, to provide a pharmaceutically palatable preparation.
- the pharmaceutical compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time.
- Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds and pharmaceutical compositions.
- fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
- a time delay material such as glycerol monostearate or glycerol stearate may also be used.
- Oral pharmaceutical compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.
- suitable carriers, excipients or diluents include water, saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at between about 5 mM to about 50 mM), etc.
- a compound of Formulae (I) - (XVIII) may also be formulated in rectal or vaginal pharmaceutical compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
- a compound of Formulae (I) - (XVIII) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- a compound may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
- ion exchange resins for example, as a sparingly soluble derivatives
- sparingly soluble salt for example, as a sparingly soluble salt.
- a compound of Formulae (I) - (XVIII) is acidic, it may be included in any of the above-described formulations as the free acid, a pharmaceutically acceptable salt, a solvate, hydrate or N-oxide.
- Pharmaceutically acceptable salts substantially retain the activity ofthe free acid, may be prepared by reaction with bases and tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form.
- Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include a compound with a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier is a liquid such as alcohol, water, polyethylene glycol or a perfluorocarbon.
- another material may be added to alter the aerosol properties ofthe solution or suspension ofthe compounds.
- this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid.
- the compounds of Formulae I) — (XVIII) can be used in combination therapy with at least one other therapeutic agent.
- the compound and the other therapeutic agent(s) can act additively or, more preferably, synergistically.
- a composition comprising a propofol prodrug compound is administered concurrently with the administration of another therapeutic agent, such as for example, another sedative, hypnotic agent or anesthetic agent (e.g., propofol), which can be part of the same composition as the propofol prodrug compound or a different composition
- another therapeutic agent such as, for example, another sedative, hypnotic agent or anesthetic agent, (e.g., propofol).
- H-AspfOPropofoD-OBzl (102) Compound (101) was treated with 30% TFA (30 mL) in dichloromethane (70 mL) for 30 min and the solvent removed in vacuo to afford the title compound, which was used in subsequent reactions without further purification. MS (ESI) m/z 385.85 (M+H + ). Boc-Asp(OPropofo ⁇ )-OH (103) To a flask containing 500 mg of 10% Pd-C was added a solution of compound (101) in methanol under nitrogen. The resulting mixture was degassed three times, after which hydrogen was introduced via a balloon apparatus. The suspended mixture was allowed to stir vigorously for 4 h.
- Boc-Glu(OPropofol)-OBzl (104) To a homogeneous solution of Boc-Glu-OBzl (7.20 g, 0.213 mol), DMAP (0.261 g, 0.021 mol) and propofol (3.76 mL, 0.20 mol) in tetrahydrofuran (40 mL) at room temperature was added dicyclohexylcarbodiimide (5.72 g, 0.278 mol). After stirring for 4 h, the dicyclohexylurea was filtered off and the solution was diluted with ether (250 mL).
- Triethylamine (5 mL) was added and after stirring for 6 h, the solution was extracted with ethyl acetate (200 mL), washed with 10% citric acid (2x50 mL), saturated sodium bicarbonate (2x50 mL) and brine (2x 50 mL). The organic layer was dried over
- the resin was filtered and washed with DMF (3 x 50 mL), methanol (3 x 50 mL), and dichloromethane (3 x 50 mL).
- a 20% v/v piperidine/DMF solution (50 mL) was then added to the resin and after shaking for 1 h at room temperature, the resin was filtered, washed with DMF (3 x 50 mL), methanol (3 x 50 mL), and dichloromethane (3 x 50 mL), then allowed to dry in a desiccators over 24 h.
- the title resin was obtained and carried through subsequent steps.
- Triethylamine (5 mL) was added and after stirring for 6 h the solution was extracted with ethyl acetate (100 mL), washed with 10% citric acid (2x25 mL), saturated sodium bicarbonate (2x25 mL) and brine (2x25 mL). The organic layer was dried over ⁇ a 2 SO and then concentrated in vacuo. The crude compound was purified by chromatography on silica gel (Biotage), eluting with a gradient of hexane to 10% EtOAc/hexane) then the eluant concentrated in vacuo.
- the isoleucine-loaded resin 500 mg, loading 1.3 mmol/g) and compound (103) (1.3 mmol) was suspended in DMF (8 mL) and diisopropylethylamme (0.68 mL, 3.9 mmol) and O-(lH-Benzotriazol-l-yl) NNN',N'-tetramethyhrronium hexafluorophosphate (493 mg, 1.3 mmol) was added. The reaction mixture was shaken for 12 h after which the resin was filtered and rinsed with DMF (3 x 15 mL), methanol (3 x 15 mL), and dichloromethane (3 x 15 mL). The resin was then soaked in 75% TFA (11 mL) in CH 2 C1 2 (4 mL) for 6 h. The resin was washed with
- Glu(O-+3u)-O-Trityl resin for Isoleucine-O-Trityl resin provided the title compound (131). MS (ESI) m/z 423.28 (M+H 4 ).
- the alanine-loaded resin (1.5 g, loading 0.5 mmol/g) and compound (106) (1.4 mmol) was suspended in DMF (15 mL) then diisopropylethylamme (0.73 mL, 4.2 mmol) and O-(lH-Benzotriazol-l-yl) N,NN',N'-teframethyluronium hexafluorophosphate (531 mg, 1.4 mmol) was added. The reaction mixture was shaken for 12 h after which the resin was filtered and rinsed with DMF (3 x 15 mL), methanol (3 x 15 mL), and dichloromethane (3 x 15 mL).
- Val-O-Trityl resin for Ala-O-Trityl resin provided the title compound (150).
- Boc-Asn(Trt)-OH for Boc-Val-OH provided the crude product.
- the residue was treated with 90% TFA (45 mL) in dichloromethane (4.5 mL) and 1% triisopropylsilane (0.5 mL) for 4 h.
- the resulting residue was purified by preparative LC/MS and treated with one molar equivalent of 1 N HC1 aqueous solution to afford the title compound (153).
- EXAMPLE 131 In Vitro Compound Transport Assays: Analysis of Electrogenic Transport in PEPTl-Expressing e « ⁇ p «,s Qocytes Transport-induced currents were also measured in Xenopus oocytes transfected with rat and human PEPT1 as described in PCT Application WOO 1/20331. Briefly: RNA preparation: Rat and human PEPT1 transporter cDNAs were subcloned into a modified pGEM plasmid that contains 5' and 3' untranslated sequences from the Xenopus ⁇ -actin gene. These sequences increase RNA stability and protein expression.
- Plasmid cDNA was linearized and used as template for in vitro transcription (Epicentre Technologies transcription kit, 4:1 methylated on-methylated GTP).
- Xenopus oocyte isolation Xenopus laevis frogs were anesthetized by immersion in Tricaine (1.5 g/mL in deionized water) for 15 min. Oocytes were removed and digested in frog ringer solution (90 mM NaCl, 2 mM KC1, 1 mM MgCl 2 , 10 mM NaHEPES, pH 7.45, no CaCl 2 ) with 1 mg/mL collagenase (Worthington Type 3) for 80-100 min with shaking. The oocytes were washed 6 times, and the buffer changed to frog ringer solution containing
- Electrodes (2-4 m ⁇ ) were microfabricated using a Sutter Instrument puller and filled with 3M KC1. The bath was directly grounded (transporter currents were less than 0.3 ⁇ A). Bath flow was controlled by an automated perfusion system (ALA Scientific Instruments, solenoid valves).
- oocytes were clamped at -60 to -90 mV, and continuous current measurements acquired using PowerLab Software and an ADInstruments digitizer. Current signals were lowpass filtered at 20 Hz and acquired at 4-8 Hz. All bath and drug-containing solutions were frog ringers solution containing CaCl 2 . Drugs were applied for 10-30 seconds until the induced current reached a new steady-state level, followed by a control solution until baseline currents returned to levels that preceded drug application. The difference current (baseline subtracted from peak current during drug application) reflected the net movement of charge resulting from electrogenic transport and was directly proportional to transport rate.
- EXAMPLE 132 Standard Methods for Determination of Enzymatic Cleavage of Prodrugs in Vitro
- Tissues were obtained from commercial sources (e.g., Pel-Freez Biologicals, Rogers, AR, or GenTest Co ⁇ oration, Woburn, MA). Experimental conditions used for the in vitro studies are described in Table 1 below. Each preparation was incubated with test compound at 37°C for one hour. Aliquots (50 ⁇ L) were removed at 0, 30, and 60 min and quenched with 0.1 % trifluoroacetic acid in acetonitrile.
- Pancreatin Stability Stability studies were conducted by incubating conjugate (5 ⁇ M) with 1 % (w/v) pancreatin (Sigma, P-1625, from porcine pancreas) in 0.025 M Tris buffer containing 0.5 M NaCl (pH 7.5) at 37 °C for 60 min. The reaction was stopped by addition of 2 volumes of methanol. After centrifugation at 14,000 rpm for 10 min, the supernatant was removed and analyzed by LC/MS/MS.
- Caco-2 Homogenate S9 Stability Caco-2 cells were grown for 21 days prior to harvesting.
- Step A Administration Protocol Propofol was administered as an intravenous bolus injection or by oral gavage to groups of four to six adult male Sprague-Dawley rats (weight approx 250 g) as solutions in PEG400, at doses of 10 mg per kg body weight (IV.) or 25 mg per kg body weight (oral). Animals were fasted overnight before the study and for 4 hours post-dosing. Blood samples (1.0 mL) were obtained via a jugular vein cannula at intervals over 24 hours after oral dosing. Blood was quenched immediately using acetonitrile with 1% formic acid and then was frozen at -80°C until analyzed.
- Step A Administration Protocol Test compounds were administered by oral gavage or as an intravenous bolus injection to groups of four to six adult male Sprague-Dawley rats (weight approx 250 g) as solutions in PEG400 at a dose of 25 mg-equivalents of propofol per kg body weight. Animals were fasted overnight before the study and for 4 hours post-dosing. Blood samples (1.0 L) were obtained via a jugular vein cannula at intervals over 24 hours after oral dosing. Blood was quenched immediately using acetonitrile with 1% formic acid and then was frozen at -80°C until analyzed.
- Step B LC/MS/MS Analysis Concentrations of propofol in whole blood were determined using an API 4000
- the mobile phases were 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B).
- the gradient condition was: 5% B for 1 min, increasing to 90% B in 2.5 min and maintained for 2 min. 10 ⁇ L of sample was injected.
- Each ofthe compounds (107), (122), (124) and (250) showed substantial oral bioavailabilities as propofol (F > 50%) illustrating that actively transported prodrugs can afford dramatic enhancements (> 200- fold) in oral bioavailability of propofol.
- Step A Administration Protocol Test compounds were administered by oral gavage or as an intravenous bolus injection to groups of two to four adult male Cynomologous (Macaca fascicularis) monkeys (weight approx 5 kg) as solutions in water or PEG400 at a dose of 25 mg-equivalents of propofol per kg body weight. Animals were fasted overnight before the study and for 4 hours post-dosing. Blood samples (1.0 mL) were obtained via the femoral vein at intervals over 24 hours after oral dosing. Blood was quenched immediately using acetonitrile with
- Step B LC/MS/MS Analysis Concentrations of propofol in whole blood were determined using an API 4000
- Oral bioavailability (F) ofthe prodrugs as propofol in monkeys were determined by comparison ofthe areas under the propofol concentration versus time curves (AUC) following oral administration ofthe prodrugs with the AUC measured following intravenous administration of propofol itself on a dose-normalized basis.
- the compounds (174), (213) and (250) had oral bioavailabilities as propofol > 10%, while (140), (146) and (208) had oral bioavailabilities as propofol > 40%, illustrating that actively transported prodrugs can afford significant enhancements in oral bioavailability of propofol.
Abstract
Description
Claims
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JP2006508638A JP2007521250A (en) | 2003-01-28 | 2004-01-28 | Prodrugs derivatized with amino acids of propofol, compositions thereof and uses thereof |
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EP04706490A EP1587527A4 (en) | 2003-01-28 | 2004-01-28 | Amino acid derived prodrugs of propofol, compositions and uses thereof |
AU2004268492A AU2004268492C1 (en) | 2003-01-28 | 2004-01-28 | Amino acid derived prodrugs of propofol, compositions and uses thereof |
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CA002510677A CA2510677A1 (en) | 2003-01-28 | 2004-01-28 | Amino acid derived prodrugs of propofol, compositions and uses thereof |
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- 2004-01-28 CN CNA2004800029678A patent/CN1744908A/en active Pending
- 2004-01-28 EP EP04706490A patent/EP1587527A4/en not_active Withdrawn
- 2004-01-28 US US10/766,990 patent/US7220875B2/en not_active Expired - Fee Related
- 2004-01-28 WO PCT/US2004/002537 patent/WO2005021024A1/en active Search and Examination
- 2004-01-28 CN CNA200710193342XA patent/CN101255123A/en active Pending
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- 2004-01-28 CA CA002510677A patent/CA2510677A1/en not_active Abandoned
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WO2012175642A1 (en) * | 2011-06-21 | 2012-12-27 | Centre National De La Recherche Scientifique (Cnrs) | Peptide prodrugs |
FR2976944A1 (en) * | 2011-06-21 | 2012-12-28 | Centre Nat Rech Scient | PEPTIDE PRODUCTS |
Also Published As
Publication number | Publication date |
---|---|
EP1587527A1 (en) | 2005-10-26 |
US7220875B2 (en) | 2007-05-22 |
MXPA05007792A (en) | 2006-01-31 |
CA2510677A1 (en) | 2005-03-10 |
AU2004268492A1 (en) | 2005-03-10 |
JP2007521250A (en) | 2007-08-02 |
AU2004268492B2 (en) | 2008-07-31 |
ZA200504940B (en) | 2006-09-27 |
KR20060055438A (en) | 2006-05-23 |
NZ540699A (en) | 2007-06-29 |
NO20053972L (en) | 2005-08-25 |
EP1587527A4 (en) | 2009-10-21 |
US20050004381A1 (en) | 2005-01-06 |
CN101255123A (en) | 2008-09-03 |
CN1744908A (en) | 2006-03-08 |
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