WO2010067233A1 - 1,2,4 triazolo[4,3-a][1,5] benzodiazépin-5(6h)-ones utilisées comme agonistes du récepteur de la cholécystokinine-1 (cck-1r) - Google Patents

1,2,4 triazolo[4,3-a][1,5] benzodiazépin-5(6h)-ones utilisées comme agonistes du récepteur de la cholécystokinine-1 (cck-1r) Download PDF

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Publication number
WO2010067233A1
WO2010067233A1 PCT/IB2009/055222 IB2009055222W WO2010067233A1 WO 2010067233 A1 WO2010067233 A1 WO 2010067233A1 IB 2009055222 W IB2009055222 W IB 2009055222W WO 2010067233 A1 WO2010067233 A1 WO 2010067233A1
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compound
phenyl
benzodiazepin
triazolo
indazol
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PCT/IB2009/055222
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English (en)
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Kimberly O'keefe Cameron
David Austen Perry
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Pfizer Inc.
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Publication of WO2010067233A1 publication Critical patent/WO2010067233A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • This invention relates to compounds of Formula (I), pharmaceutical compositions comprising the compounds, either alone or in combination with other pharmaceutical agents, methods of use of the compounds and combinations, and intermediates and methods useful in the preparation of the compounds.
  • the compounds of Formula (I) are agonists of the cholesystokinin-1 (CCK-1 ) receptor (CCK-1 R) and are therefore useful, for example, for weight management and the treatment of obesity, type 2 diabetes, gallstones and obesity-related disorders.
  • Obesity is a major public health concern because of its increasing prevalence and associated health risks that include co-morbidities such as dyslipidemia, hypertension, hyperglycemia, insulin resistance, type 2 diabetes, coronary heart disease and heart failure (collectively referred to as Metabolic Syndrome). Obesity and its co-morbidities may affect a person's quality of life through limited mobility and decreased physical endurance as well as through social, academic and job discrimination.
  • BMI body mass index
  • Overweight is typically defined as a BMI of 25 to 29.9 kg/m 2
  • obesity is typically defined as a BMI of 30 kg/m 2 or higher.
  • Cholecystokinin is a brain-gut peptide that acts as a gastrointestinal hormone, neurotransmitter and neuromodulator in the central and the peripheral nervous systems. Cholecystokinin is a peptide that exists in multiple active forms of varying lengths (e.g. CCK-58; CCK-39; CCK-33; CCK-8; and CCK-4), with different forms predominating in different species. Cholecystokinin-58 is the major molecular form in man, dog and cat but not in pig, cattle or rat intestine. See, e.g., G.A. Eberlien, V.E. Eysselein and H. Goebell, 1988, Peptides 9, pp. 993-998. CCK's peripheral effects, where the O-sulfated octapeptide CCK-8S is believed to be the predominant form, are centered on its role as a gastrointestinal satiety factor.
  • CCK central nervous system
  • CCK-1 and CCK-2 receptor subtypes belong to the seven transmembrane G-protein-coupled superfamily of receptors.
  • the CCK-1 receptor is located predominately in the periphery, including pancreatic acinar cells, pyloric sphincter, gall bladder, and vagal afferents, where it mediates pancreatic exocrine secretion, gastric emptying and gall bladder contraction, and transmits post-prandial satiety signals to the CNS.
  • the CCK-1 receptor is found in discrete regions within the CNS, including the nucleus tractus solatarius, area postrema, and the dorsal medial hypothalamus.
  • the CCK-2 receptor is located predominately in the CNS, and is less predominant in the periphery.
  • CCK and CCK receptor agonists inhibit gastric emptying and increase satiety in a variety of species, including humans, resulting in a reduction of food intake (see, e.g., T. H.
  • CCK-1 R agonism stimulates gallbladder contraction, pancreatic enzyme secretions and intestinal blood flow, and affects intestinal motor activity (See Rehfeld, J. F. Best, Practice and Res. Clin. Endocrin. and Metab. 2004, 18, 569-586).
  • CCK-1 agonists therefore, are useful in the treatment of obesity and associated co- -A-
  • Agonists of CCK-1 R are also useful in the treatment of type 2 diabetes. It has been reported that iv administration of CCK-8 to both healthy subjects and subjects with type 2 diabetes reduces plasma glucose levels and increases plasma insulin levels after meal ingestion without significantly affecting the postprandial levels of GIP, GLP-1 or glucagon (B. Ahren, J. Juul Hoist and S. Efendic, J. Clin. Endocr. Metab. 2000, 85(3), 1043-1048).
  • CCK-1 R agonists have been reported in the scientific journal and patent literature.
  • U.S. patent No. 5,798,353 discloses certain 3-acylamino-5-(polysubstituted phenyl)-1 ,4 benzodiazepin-2-ones as being CCK-1 R agonists useful in the treatment of obesity, type 2 diabetes and other disorders.
  • Certain 1 ,5-benzodiazepinones have been reported to be CCK-1 R agonists having anorectic activity in rodents (see, e.g., E. E. Sugg et al., (1998) Pharmaceutical Biotechnology 11 (Integration of Pharmaceutical Discovery and Development): 507-524).
  • the present invention relates to a compound of Formula (I)
  • X is CH or N
  • R 1 is selected from the group consisting of phenyl and a (C 3 -C 7 )cycloalkyl group; wherein the phenyl or cycloalkyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, -OH, -CF 3 , (Ci-C 3 )alkyl and (d-C 3 )alkoxy-;
  • R 2 is H, (Ci-C 3 )alkyl, benzyl, pyrimidyl, pyridyl, pyrazinyl or (R 6 )(R 7 )NC(O)CH 2 - in which R 6 and R 7 are independently selected from the group consisting of H and (C 1 -C 3 )alkyl; each R 3 is independently H or F; R 4 is H or methyl; and
  • R 5 is selected from the group consisting of (C ⁇ C 3 )alkyl, -CH 2 CH 2 OCH 3 , tetrahydrofuranyl and -(CH 2 ) n R 8 in which n is an integer from 0 to 2 and
  • R 8 is selected from the group consisting of phenyl, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy- and halo-substituted (Ci-C 3 )alkyl; pyridyl, which is optionally substituted with 1 to 3 independently selected (Ci-C 3 )alkyl groups; and cyclohexyl, which is optionally substituted with 1 or 2 hydroxyl groups; or a pharmaceutically acceptable salt thereof.
  • X is CH, and R 1 -R 5 are as defined above or below generally and preferably. In a further, preferred aspect, X is N, and R 1 -R 5 are as defined above or below generally and preferably.
  • R 1 is preferably selected from the group consisting of phenyl, cyclopentyl and cyclohexyl each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, -OH, -CF 3 , -CH 3 and - OCH 3 . More preferably, R 1 is phenyl or cyclohexyl, wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, -OH, -CF 3 , -CH 3 and -OCH 3 .
  • R 1 is unsubstituted phenyl or unsubstituted cyclohexyl; most preferably, unsubstituted phenyl.
  • R 2 is preferably selected from the group consisting of H, -CH 3 , 2-pyrimidyl and -CH 2 C(O)N(R 6 XR 7 ), in which R 6 and R 7 are independently selected from the group consisting of H and (CrC 3 )alkyl.
  • each of R 6 and R 7 is independently selected from the group consisting of (Ci-C 3 )alkyl.
  • R 6 and R 7 are -CH 3 and the other of R 6 and R 7 is selected from the group consisting (Ci-C 3 )alkyl, for example -CH 2 CH 2 CH 3 .
  • R 2 is selected from the group consisting of H, -CH 3 , and 2-pyrimidyl. More preferably, R 2 is H or -CH 3 ; most preferably, H.
  • R 3 is preferably H.
  • R 4 is preferably H.
  • R 1 is unsubstituted cyclohexyl or, preferably, unsubstituted phenyl;
  • R 2 is -CH 3 or preferably, H;
  • each of R 3 and R 4 is H;
  • R 5 is as defined above and below, generally and preferably.
  • R 5 is -(CH 2 ) n R 8
  • n is preferably O or 1 ; more preferably, 1
  • R 5 is selected from the group consisting Of -C 2 H 5 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 and -(CH 2 ) n R 8 in which R 8 is selected from the group consisting of phenyl, which is optionally substituted with 1 to 3, preferably 1 or 2, substituents independently selected from the group consisting of F, Cl, (CrC 3 )alkyl, (CrC 3 )alkoxy- and F-substituted(CrC 3 )alkyl such as -CHF 2 or, preferably, -CF 3 ; pyridyl, which is optionally substituted with 1 to 3, preferably 1 or 2, substituents independently selected from the group consisting of (Ci-C 3 )alkyl; and cyclohexy
  • R 8 is selected from the group consisting of phenyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, -CH 3 , -OCH 3 and -CF 3 ; pyridyl, which is optionally substituted with 1 or 2 independently selected (Ci-C 3 )alkyl groups; and cyclohexyl, which is optionally substituted with a hydroxyl group.
  • R 5 is selected from the group consisting Of -C 2 H 5 , -CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 and -(CH 2 ) n R 8 in which R 8 is selected from the group consisting of phenyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, -CH 3 , -OCH 3 and -CF 3 ; pyridyl, which is optionally substituted with 1 or 2 methyl groups; and cyclohexyl, which is optionally substituted with a hydroxyl group.
  • R 8 is a substituted phenyl group, the substituent(s) are preferably located at the 3- and/or 5-position, more preferably at the 3- and 5-positions.
  • R 8 When R 8 is pyridyl, it may be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; preferably, pyridin-2-yl or pyridin-4-yl; more preferably, pyridin-2-yl. If the pyridyl is substituted, it is preferably 4-su bstituted-py rid i n-2-y 1 , 6-substituted-pyridin-2-yl or 4, 6- disubstituted-pyridin-2-yl.
  • R 8 is a substituted cyclohexyl group, it is preferably mono substituted and the substituent is preferably located at the 1 -position.
  • X and R 1 , R 2 , R 3 and R 4 are as defined above, generally and preferably, and R 5 is selected from the group consisting Of -C 2 H 5 , -CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 , cyclohexylmethyl, benzyl, 3- methylbenzyl, 3,5-dimethylbenzyl and (4,6-dimethylpyridin-2yl)methyl; more preferably, from the group consisting Of -C 2 H 5 , -CH 2 CH 2 OCH 3 , benzyl, 3,5- dimethylbenzyl and (4,6-dimethylpyridin-2yl)methyl; more preferably, from the group consisting Of -C 2 H 5 , -CH 2 CH 2 OCH 3 , benzyl and 3,5-dimethylbenzyl; still more preferably, from the group consisting of -C 2 H 5 , -CH 2 CH 2 OCH 3 and 3,5- dimethylbenzyl;
  • the carbon atom designated "4" in Formula (I) has the "(S)" configuration.
  • the spatial orientation of R 5 in Formula (I) is as shown in the partial formula
  • a preferred subgenus of the invention as defined above relates to a compound of Formula (II)
  • R 5 in Formula (II) is preferably selected from the group consisting Of -C 2 H 5 ; -CH 2 CH 2 CH 3 ; -CH 2 CH 2 OCH 3 ; tetrahydrofuran-2-yl; phenyl, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, -CH 3 , -OCH 3 and CF 3 ; benzyl, in which the phenyl moiety is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, -CH 3 , -OCH 3 and CF 3 ; pyridin-2-yl, which is optionally substituted with 1 to 3 methyl groups; pyridin-2-ylmethyl, in which the pyridinyl moiety is optionally substituted with 1 to 3 methyl groups; cyclohexyl, which is optionally substituted with a hydroxy group; and cyclohexylmethyl, in which the
  • R 5 is selected from the group consisting of -C 2 H 5 ; -CH 2 CH 2 CH 3 ; -CH(CH 3 ) 2 ; -CH 2 CH 2 OCH 3 ; benzyl, in which the phenyl moiety is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, -CH 3 , -OCH 3 and CF 3 ; pyridin-2-ylmethyl, in which the pyridyl moiety is optionally substituted with 1 to 3 methyl groups; and cyclohexylmethyl.
  • R 5 is selected from the group consisting of -C 2 H 5 ; -CH 2 CH 2 OCH 3 ; benzyl, in which the phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, -CH 3 , -OCH 3 and CF 3 ; pyridin-2-ylmethyl, in which the pyridyl moiety is optionally substituted with 1 or 2 methyl groups; and cyclohexylmethyl.
  • R 5 is selected from the group consisting Of -C 2 H 5 , -CH 2 CH 2 OCH 3 , cyclohexylmethyl, benzyl, 3-methylbenzyl, 3,5- dimethylbenzyl and (4,6-dimethylpyridin-2yl)methyl.
  • the carbon designated "4" in Formula (II) has the “(S)" configuration.
  • the preferred stereochemical embodiments with respect to the chiral carbon atom of the 2-substituted piperidinyl moiety are (S) when R 5 is - C 2 H 5 , and (R) when R 5 is 3,5-dimethylbenzyl.
  • Preferred compounds of the present invention include: 6- ⁇ 2-[2-(cyclohexylmethyl)piperidin-1 -yl]-2-oxoethyl ⁇ -4-(1 H-indol-3-ylmethyl)-1 - phenyl-4H-[1 ,2,4]triazolo[4,3-a][1 ,5]benzodiazepin-5(6H)-one,
  • a subset of such compounds of particular interest includes:
  • a further subset of particular interest includes:
  • the present invention also relates to salts of the compounds of the present invention.
  • the compounds of the present invention, and intermediates that are basic in nature, are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such compounds are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions.
  • Certain of the intermediates are acidic in nature and are capable of forming salts with various bases. Sodium and potassium salts are preferred.
  • the compounds of the present invention may exist in both solvated and unsolvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when the solvent is water.
  • Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • a pharmaceutical composition is provided which comprises a compound of the present invention.
  • the composition also comprises at least one additional pharmaceutical agent, which is preferably an anti-obesity agent or an anti-diabetes (type 2) agent.
  • the additional pharmaceutical agent may also be an agent useful in the treatment of any of the co-morbidities of the primary indication for the composition.
  • the composition preferably comprises a therapeutically effective amount of a compound of the present invention, or a therapeutically effective amount of a combination of a compound of the present invention and an additional pharmaceutical agent.
  • the composition also preferably comprises a pharmaceutically acceptable excipient, diluent or carrier.
  • Also provided is a method of treating a disease, condition or disorder that is responsive to the agonistic modulation of the CCK-1 receptor in animals which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt.
  • the compound of the present invention may be used alone or in combination with at least one additional pharmaceutical agent, preferably an agent that is also useful in the treatment of the disease, condition or disorder being treated or a co-morbidity thereof.
  • Diseases, conditions or disorders that are responsive to the agonistic modulation of the CCK-1 receptor in animals include obesity, overweight, type 2 diabetes, cholecystitis and cholelithiasis. Co-morbidities of such diseases, conditions or disorders would likely be incidentally improved.
  • a method of treating obesity in an animal which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt.
  • the compound of the present invention may be used alone or in combination with one or more additional pharmaceutical agents, preferably an anti-obesity agent.
  • a method of weight management in an animal which comprises administering to the animal a weight-managing amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt.
  • the compound of the present invention may be used alone or in combination with one or more additional pharmaceutical agents, preferably an anti-obesity agent.
  • the present invention also provides a method of reducing food intake in an animal which comprises administering to the animal a food-intake-reducing amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt.
  • the compound of the present invention may be used alone or in combination with one or more additional pharmaceutical agents, preferably an anti-obesity agent.
  • a method of treating type 2 diabetes in an animal which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt.
  • the compound of the present invention may be used alone or in combination one or more additional pharmaceutical agents, preferably an anti- diabetes (type 2) agent or an anti-obesity agent.
  • kits for use by a consumer in the treatment of obesity comprises (a) a suitable dosage form comprising a compound of the present invention, and (b) instructions describing a method of using the dosage form to treat or prevent obesity.
  • the invention also relates to combining separate pharmaceutical compositions in kit form.
  • kits comprising: (a) a first pharmaceutical composition comprising a compound of the present invention, (b) a second pharmaceutical composition comprising a second compound useful for the treatment of obesity or type 2 diabetes, the prevention of cholecystitis or cholelithiasis or the treatment of a co-morbidity of obesity; and (c) a container for containing the first and second compositions.
  • the kit will also comprise directions for the administration of the separate components.
  • the kit form is especially advantageous when the separate components are preferably administered in different dosage forms or at different dosing intervals.
  • Blister packs are widely used in the pharmaceutical industry for the packaging of unit dosage forms (tablets, capsules and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via the opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the kit, e.g., as follows: "First Week, Monday, Tuesday, etc....; Second Week, Monday, Tuesday, etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a compound of the present invention may consist of one tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules, and vice versa.
  • the memory aid should reflect this.
  • alkyl means a straight- or branched-chain hydrocarbon radical of the general formula C n H 2n+I -
  • (CrC 3 )alkyl refers to a monovalent, straight- or branched-chain, saturated aliphatic group containing 1 to 3 carbon atoms, i.e., methyl, ethyl, n-propyl and /-propyl.
  • the alkyl portion of a group e.g., an alkoxy, acyl, alkylamino, dialkylamino, or alkylthio group, has the same meaning as above.
  • Halo-substituted alkyl refers to an alkyl group substituted with one or more, same or different halogen atoms (e.g., -CH 2 CI, -CHF 2 , -CF 3 , -C 2 F 5 , and the like).
  • halogen atoms e.g., -CH 2 CI, -CHF 2 , -CF 3 , -C 2 F 5 , and the like.
  • F-substituted alkyl mean the alkyl group is substituted with one or more fluorine atoms.
  • halo means F, Cl, Br or I.
  • halo will be F, Cl or Br; more preferably, F or Cl.
  • solvate refers to a molecular complex of a compound with one or more solvent molecules.
  • the solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to a solvate in which the solvent molecule is water.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. For example, an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, /-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent on a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent that blocks or protects the carboxy functionality such as an ester group.
  • Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(t ⁇ methylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, New York, 2007.
  • phrases "pharmaceutically acceptable” means that the substance or composition is compatible chemically and/or toxicologically with the other ingredients comprising a formulation, and/or the animal being treated therewith.
  • terapéuticaally effective is intended to qualify an amount of an agent for use in the therapy of a disease, condition, or disorder which (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • treating means treating, “treat”, and “treatment” embrace both preventative, i.e. prophylactic, and palliative treatment.
  • animal means humans as well as all other warm-blooded members of the animal kingdom possessed of a homeostatic mechanism, including mammals (e.g., companion animals, zoo animals and food-source animals) and birds.
  • mammals e.g., companion animals, zoo animals and food-source animals
  • companion animals are canines (e.g., dogs), felines (e.g., cats) and horses; some examples of food-source animals are pigs, cows, sheep, poultry and the like.
  • the animal is a mammal. More preferably, the mammal is a human or a companion animal. Most preferably, the animal is a human.
  • compounds of the present invention means the compounds of Formula (I) and Formula (II), as defined above generally and preferably (including all embodiments), pharmaceutically acceptable salts of the compounds, and hydrates or solvates of the compounds and salts, as well as all stereoisomers, atropisomers, tautomers and isotopically labeled compounds of the present invention.
  • the compounds of the present invention may be made by processes described herein or by other processes within the skill of a person having ordinary skill in the medicinal chemistry art, including processes analogous to those described in the art for producing compounds that are similar or analogous to the present compounds or have substituents that are similar to or the same as those of the present compounds (see, for example, US 7,265,104).
  • Scheme 1 illustrates one method of preparation of compounds of Formula (I) in which R 2 is other than -CH 2 C(O)N(R 6 )(R 7 ) and R 4 is H may be prepared.
  • Scheme 1 Compound (SM) may be prepared as described in Preparation 4(A) or 4(B) of
  • Compound (SM) is N-alkylated with a haloacetic acid fe/t-butyl ester such as fe/t-butyl 2-bromoacetate in the presence of a base such as sodium hexamethyldisilazide, lithium hexamethyldisilazide or sodium hydride, in an inert solvent such as DMF, NMP or THF, at a temperature of about -20 0 C to about 70 0 C to give compound (A).
  • a base such as sodium hexamethyldisilazide, lithium hexamethyldisilazide or sodium hydride
  • Compound (A) is then alkylated on the C-4 carbon with an alkylating agent (B) in which R 2 is other than H or -CH 2 C(O)N(R 6 )(R 7 ) and L is a leaving group, e.g., Cl, Br, I, OTs or OMs. If it is desired that R 2 be H in the final product compound (I), it will be necessary to use a protecting group such as Boc for R 2 in compound (B), then remove it in a later step.
  • R 2 is -CH 2 C(O)N(R 6 XR 7 ) is described in Scheme 8.
  • the alkylation reaction is conducted in the presence of a suitable base such as sodium te/t-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide or sodium hydride and an inert solvent, such as DMF, NMP or THF, at a temperature in the range of about -60 0 C to about 70 0 C, to give the corresponding compound of Formula (C).
  • a suitable base such as sodium te/t-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide or sodium hydride and an inert solvent, such as DMF, NMP or THF, at a temperature in the range of about -60 0 C to about 70 0 C, to give the corresponding compound of Formula (C).
  • a suitable base such as sodium te/t-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide or sodium
  • the t-butyl ester protecting group in the t-butoxycarbonylmethyl moiety in compound (C) may be removed by treatment of compound (C) with an acid such as hydrochloric acid in a polar solvent such as methanol, dioxane, THF or diethyl ether, or by treatment with TFA, by itself or in a solution of dichloromethane or chloroform, or with 85% aqueous phosphoric acid in dichloromethane to afford compound (D).
  • an acid such as hydrochloric acid in a polar solvent such as methanol, dioxane, THF or diethyl ether
  • R 2 is the protecting group Boc in compound (C)
  • the treatment with hydrochloric acid effects the selective removal of the t-butyl ester protecting group in the t-butoxycarbonylmethyl moiety, sparing the R 2 Boc group, to give the corresponding compound (D) (R 2 is Boc)
  • the use of TFA or aqueous phosphoric acid will effect removal of both the t-butyl ester protecting group in the t- butoxycarbonylmethyl moiety and the R 2 Boc group to give the carboxylic acid (D) in which R 2 is H.
  • Use of TFA in dichloromethane is the preferred method to convert compound (C) into compound (D).
  • Compound (D) may be converted into the corresponding acid chloride (E) by conventional means.
  • treatment of free acid (D) with thionyl chloride at a temperature in the range of room temperature to 100 0 C, preferably room temperature, or with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF at a temperature in the range of 0 0 C to room temperature affords the corresponding acid chloride (E).
  • Subsequent conversion to the compound of Formula (I) is effected by the treatment of compound (E) with compound (O) in a solvent such as dichloromethane or THF in the presence of an amine base such as triethylamine, pyridine or, preferably, diisopropylethylamine (Hunig's base), at a temperature in the range of about 0 0 C to room temperature.
  • a solvent such as dichloromethane or THF
  • an amine base such as triethylamine, pyridine or, preferably, diisopropylethylamine (Hunig's base)
  • the 2-substituted piperidines (O) may be prepared as described in Scheme 5 or 6, or may be obtained commercially from a number of sources including MicroChemistry Building Bocks (Moscow, Russia), AKos Screening Library (Basel, Switzerland), BioBlocks Products (San Diego, California, USA), Aurora Screening Library (Graz, Austria), ACB Blocks Stock (Moscow, Russia), Ambintar Stock Screening Collection (Paris, France), Aldrich (Milwaukee, Wl, USA), NetChem Product List (New Brunswick, NJ, USA), ChemBridge Building Block Library (San Diego, CA, USA) and ASDI Biosciences (Newark, DE, USA).
  • Scheme 2 describes an alternative method for preparing compound (C) where X is CH and each of R 2 and R 4 is H.
  • Compound (A) is condensed with aldehyde (F), wherein X is CH and R 2 is H, in an organic solvent such as toluene or xylene(s), in the presence of a base such as piperidine, at a temperature in the range of room temperature to 150 0 C, to give the corresponding alpha-beta unsaturated intermediate (G), which is reduced under standard conditions (e.g. Zn-AcOH; H 2 , Pd-C) to afford the corresponding compound (C) in which R 4 is H.
  • G alpha-beta unsaturated intermediate
  • C in which R 4 is H.
  • Scheme 3 illustrates an alternative method for the preparation of compounds of Formula (I), from compound (D) by amide coupling procedures.
  • Racemic compound (D) is coupled with the appropriate 2-substituted racemic piperidine (O) to give the corresponding amide adduct (I) as a mixture of four diastereomers.
  • the reaction is conducted in the presence of a coupling agent such as PyBOP, HBTU, T 3 P, CDMT, EDCI, HATU or EEDQ and an amine base such as triethylamine, ⁇ /-methylmorpholine or diisopropylethylamine in a solvent such as DMF, NMP, THF, DMA, dichloromethane or chloroform.
  • a coupling agent such as PyBOP, HBTU, T 3 P, CDMT, EDCI, HATU or EEDQ
  • an amine base such as triethylamine, ⁇ /-methylmorpholine or diisopropylethylamine in a solvent such as DMF, NMP, THF, DMA, dichloromethane or chloroform.
  • R 2 is an alkyl group.
  • HBTU pyrimidyl, pyridyl or pyrazinyl group.
  • Compound (D) may be resolved into its enantiomers (Da) and (Db) by reverse phase high performance liquid chromatography utilizing columns containing a chiral support. Coupling of (Da) or (Db) with the appropriate 2-substituted racemic piperidine (O) affords the corresponding adduct (Ia) or (Ib) as a mixture of two diastereomers, which may be separated further into its individual isomers, preferably by reverse phase high pressure chromatography utilizing columns containing a chiral support. Compound (I) may likewise be separated into (Ia) and (Ib).
  • Compound (C) in which R 4 is H is methylated on the C-4 carbon by treatment with CH 3 L wherein L is a leaving group such as Cl, Br, I, OTs or OMs, in the presence of a base such as sodium te/t-butoxide, lithium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide or sodium hydride, in an inert solvent such as DMF, NMP or THF, at a temperature in the range of about -20 0 C to about 70 0 C to afford compound (C) in which R 4 is methyl.
  • L is an iodine atom
  • the reaction is conducted in DMF in the presence of lithium te/t-butoxide.
  • Scheme 5 describes the preparation and resolution of certain 2-substituted piperidines (N), which constitute a subgenus of the compound (O) genus.
  • Compound (N) in which R is an alkyl, cycloalkyl or an optionally substituted phenyl group may be prepared by the method described in European J. Org. Chem. 2004, /7, 3623.
  • R-Br to a slurry of magnesium turnings in an ethereal solvent such as diethylether or THF is added R-Br to form a Grignard reagent, which is treated with the 2-pyridine-carboxaldehyde (H) to give compound (J).
  • Resolution of racemic (N) into its enantiomers (Na) and (Nb) is effected by reverse phase high performance liquid chromatography using a column with a chiral support where the R substituent contains a UV-absorbing chromophore, such as a phenyl group, which allows for ready detection of the separated enantiomers.
  • the R substituent does not contain a suitable chromophore it will be necessary to reversibly add one to the molecule, as described, for example, in Scheme 6.
  • the racemic (J) is converted into a chiral salt with a chiral acid such as mandelic acid, tartaric acid or camphor sulfonic acid and subjected to a classical resolution by selective crystallization (J. Org. Chem. 1971 , 36, 3648) to give one diastereomer, which upon neutralization affords one enantiomer (Na) or (Nb).
  • a chiral acid such as mandelic acid, tartaric acid or camphor sulfonic acid
  • Scheme 6 describes a method of preparing compound (O) and resolving it into enantiomers (Oa) and (Ob).
  • Compound (O) is prepared by hydrogenation of the corresponding 2- substituted pyridine compound (M) under 1-50 psig of hydrogen in the presence of a catalyst such as platinum oxide (Adam's catalyst), platinum on carbon, palladium on carbon or palladium hydroxide and a protic acid such as hydrochloric, sulfuric or acetic acid in a polar protic solvent such as methanol, ethanol or water.
  • a catalyst such as platinum oxide (Adam's catalyst), platinum on carbon, palladium on carbon or palladium hydroxide and a protic acid such as hydrochloric, sulfuric or acetic acid in a polar protic solvent such as methanol, ethanol or water.
  • a preferred method involves the use of Adam's catalyst in methanol and hydrochloric acid under 50 psig of hydrogen.
  • Compound (O) is resolved into its enantiomers (Oa) and (Ob) as follows: If the R 5 moiety in compound (O) contains a UV-absorbing chromophore, for detection purposes, the compound may be directly resolved into its enantiomers by chiral chromatography. Otherwise, a chromophore such as a Cbz group is added to the molecule, and the adduct is subjected to chiral chromatography.
  • DMAP Dynamic Metal Metal-Memiconductor
  • the reaction may also be conducted under two- phase Schotten-Baumann conditions using benzyl chloroformate and an aqueous solution of an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate or sodium or potassium hydrogen carbonate and an organic solvent such as acetonitrile, THF, ethyl acetate or dichloromethane.
  • an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate or sodium or potassium hydrogen carbonate
  • organic solvent such as acetonitrile, THF, ethyl acetate or dichloromethane.
  • benzyl chloroformate with triethylamine and DMAP in dichloromethane is preferred.
  • Other common methods for the introduction of a Cbz group are known (e.g., Peter G. M. Wuts and T. W. Greene, "Protective Groups in Organic Synthesis", Fourth Edition, John Wiley & Son
  • Compound (P) is then resolved into its enantiomers (Pa) and (Pb) by reverse phase high performance liquid chromatography on a chiral support.
  • the Cbz group is removed by hydrogenation under 1-50 psig of hydrogen, in the presence of a catalyst such as 10% palladium of carbon, or palladium black in a solvent such as methanol, ethanol or THF to give enantiomers (Oa) and (Ob).
  • a catalyst such as 10% palladium of carbon
  • a solvent such as methanol, ethanol or THF
  • the use of 10% palladium on carbon in ethanol under 45 psig of hydrogen is preferred.
  • Scheme 7 describes the early addition of the 2-substituted piperidine moiety in the reaction sequence with subsequent addition of the indolylmethyl/indazolylmethyl moiety.
  • R 2 is other than -CH 2 C(O)N(R 6 )(R 7 ) and R 4 is preferably H.
  • Compound (O) is treated with a haloacetyl halide such as bromoacetyl bromide (as illustrated above) or chloroacetyl chloride in the presence of an amine base such as triethylamine or diisopropylethylamine in dichloromethane or chloroform to give compound (Q).
  • a haloacetyl halide such as bromoacetyl bromide (as illustrated above) or chloroacetyl chloride in the presence of an amine base such as triethylamine or diisopropylethylamine in dichloromethane or chloroform
  • reaction may be conducted under two-phase Schotten-Baumann conditions (Bioorganic Chemistry, 2006, 34, 248 at 253) using bromoacetyl bromide and an aqueous solution of an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate and sodium or potassium hydrogen carbonate and an organic solvent such as acetonitrile, THF, ethyl acetate or dichloromethane.
  • Compound (SM) where R 4 is H, may be prepared as described in Preparation 4(A) or 4(B) of US 7,265,104 or by methods analogous thereto. While R 4 may be methyl, yields in the process are generally higher if the indazolylmethyl/indolylmethyl group is introduced into the molecule prior to the R 4 methyl group.
  • Compound (R) may be prepared from compounds (Q) and (SM) in the presence of a base such as sodium t-butoxide, sodium hexamethyldisilazide, sodium hydride or DBU and an inert solvent such as DMF, NMP, THF or 2- methyltetrahydrofuran at a temperature in the range of about -20 0 C to about 70 0 C to afford the N-alkylated product (R).
  • a base such as sodium t-butoxide, sodium hexamethyldisilazide, sodium hydride or DBU
  • an inert solvent such as DMF, NMP, THF or 2- methyltetrahydrofuran
  • the reaction may also be conducted under two- phase Schotten-Baumann conditions using an aqueous solution of an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate and sodium or potassium hydrogen carbonate and an organic solvent such as acetonitrile, THF, ethyl acetate or dichloromethane.
  • Compound (R) is alkylated on the C-4 carbon using a suitable electrophile such as compound (V) in which R 2 is a Boc group to give compound (I).
  • suitable electrophiles include compounds corresponding to compound (V) in which the mesylate leaving group is replaced with a different leaving group such as Cl, Br, I or OTs.
  • the preferred leaving group is OMs.
  • Boc group in (I) may be removed to give the corresponding compound in which R 2 is H by treatment with HCI in methanol, diethylether or 1 ,4-dioxane, or with TFA in dichloromethane.
  • Scheme 8 describes the preparation of compounds of Formula (I) in which R 2 is -CH 2 C(O)N(R 6 XR 7 ).
  • Compound (W) may be prepared by the N-alkylation of compound (SM) with a benzyl 2-haloacetate in the manner described in scheme 7 for the analogous alkylation of (SM) with compound (Q)
  • Compound (W) is then C-alkylated at C-4 by treatment with compound (EE) in the presence of a base such as sodium hexamethyldisilazide or sodium hydride and an inert solvent, such as DMF, NMP, THF or 2-methyltetrahydrofuran, at a temperature in the range of about -20 0 C to about 70 0 C, to afford the monoalkylated product (X).
  • a base such as sodium hexamethyldisilazide or sodium hydride
  • an inert solvent such as DMF, NMP, THF or 2-methyltetrahydrofuran
  • Compound (Y) is coupled with the amine (R 6 )(R 7 )NH under standard amide coupling conditions to give the corresponding amide adduct (Z).
  • Suitable coupling agents and reaction conditions are as described for the conversion of (D) into (I) in Scheme 3 above.
  • Hydrogenolysis of the benzyl ester (Z) in the presence of a catalytic amount of 5-10% palladium on carbon in a solvent such as ethanol, methanol, THF or ethyl acetate affords the free acid compound (D), which is converted into (I) by amide coupling with the appropriate 2-substituted piperidine compound (O) as described in Scheme 3.
  • the preferred coupling reagent for this transformation is HBTU.
  • Compound (EE) may be prepared from compound (CC) by N-alkylation with a haloacetic acid t-butyl ester in the presence of a base such as potassium or sodium carbonate in a polar aprotic solvent such as acetone, DMF or acetonitrile to give compound compound (DD), which is treated with a halogenating agent such as NBS, NCS or NIS in the presence of a catalytic amount of radical initiator such as AIBN in solvent such as carbon tetrachloride to give compound (EE).
  • a catalytic amount of potassium iodide may be added to the reaction mixture to facilitate the reaction.
  • Compound (FF) may be used to make compound (B) where R 2 is other than H or -CH 2 C(O)N(R 6 )(R 7 ).
  • Compound (FF) is treated with an appropriate R-halide in the presence of a base such as sodium hydride, sodium hexamethyldisilylazide or butyllithium in a solvent such as DMF, NMP or THF to give compound (GG).
  • a base such as sodium hydride, sodium hexamethyldisilylazide or butyllithium
  • a solvent such as DMF, NMP or THF
  • Compound (B) may be prepared from compound (HH) by the use of conventional halogenation procedures.
  • compound (HH) is heated in thionyl chloride, or allowed to react with methanesulfonyl chloride in the presence of about 1.1-1.6 equivalents of an amine base such as triethylamine, pyridine or ⁇ /, ⁇ /-diisopropylethylamine in DMF or dichloromethane. Higher equivalents of the amine base may lead to the formation of compound (B) where L is OMs.
  • the use of methanesulfonyl chloride is preferred for producing (B) where L is Cl.
  • Representative pharmaceutically acceptable acid addition salts of the present compounds include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, pamoate, palmitate, malonate, stearate, laurate, malate, borate, hexafluorophosphate, naphthylate, glucoheptonate, lactobionate and laurylsulfonate salts and the like.
  • Salts formed with bases include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as ammonium, quaternary ammonium, and 1 ° , 2 or 3 ° amine-derived cations including, but not limited to, ammonium, tetramethylammonium and tetraethylammonium and cations derived from methylamine, ethylamine, dimethylamine, trimethylamine, triethylamine, and the like. See, e.g., Berge, et al., J. Pharm. ScL, 66, 1-19 (1977).
  • the compounds of the present invention and certain intermediates contain one or more asymmetric or chiral centers such as the R 2 -bearing carbon atom and the R 4 -bearing carbon atom, and such compounds therefore exist in different stereoisomeric forms, as enantiomers and diasteroisomers.
  • Diastereomeric mixtures may be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers may be separated by use of a chiral HPLC column. They may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • any geometric isomers and atropisomers.of the compounds of the present invention form a part of the present invention.
  • a number of the compounds of the present invention and intermediates therefor exhibit tautomerism and therefore may exist in different tautomeric forms under certain conditions.
  • the term "tautomer” or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety where the hydrogen may migrate between the ring nitrogens.
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons. All such tautomeric forms (e.g., all keto-enol and imine-enamine forms) are within the scope of the invention.
  • the depiction of any particular tautomeric form in any of the structural formulas herein is not intended to be limiting with respect to that form, but is meant to be representative of the entire tautomeric set.
  • the compounds of the present invention and intermediates may exist in unsolvated as well as solvated forms with solvents such as water, ethanol, isopropanol and the like, and both solvated and unsolvated forms are included within the scope of the invention.
  • Solvates for use in the methods aspect of the invention should be with pharmaceutically acceptable solvents.
  • the present invention also embraces isotopically labeled compounds which are identical to the compounds of Formula (I) or intermediates therefore but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the intermediates or compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F, 123 1, 125 I and 36 CI, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts, hydrates and solvates thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 0, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy
  • lsotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of the present invention are CCK-1 agonists and are therefore useful for treating diseases, conditions and/or disorders that are responsive to the agonistic modulation or activation of the CCK-1 receptor.
  • diseases, conditions and disorders include obesity as well as non-obese overweight conditions and normal weight conditions where weight control or management is desired in order to prevent an obese or overweight condition from developing or to just maintain an optimum, healthy weight.
  • Other conditions responsive to the agonistic modulation or activation of the CCK-1 receptor include cholescystitis, cholelithiasis, gout and gall bladder disease.
  • the compounds of the present invention are also useful in treating or preventing co-morbidities of obesity such as dyslipidemia, hypertension, hyperglycemia, insulin resistance, type 2 diabetes, coronary heart disease and heart failure.
  • present compounds are useful in the treatment of any condition in which it is desirable to lose weight or to reduce food intake.
  • the present invention provides methods of treatment or prevention of such diseases, conditions and/or disorders responsive to the agonistic modulation of the CCK-1 receptor in an animal which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound of Formula (I) or Formula (II).
  • the present compounds will generally be administered in the form of a pharmaceutical composition.
  • the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) or Formula (II) in admixture with a pharmaceutically acceptable excipient, diluent or carrier, as well as methods of use of such compositions in the treatment of diseases, conditions and/or disorders that are responsive to the agonistic modulation of the CCK-1 receptor in an animal, or co- morbities thereof, which comprise administering such pharmaceutical composition to an animal in need of such treatment.
  • the compounds of the present invention may be administered to a patient at dosage levels in the range of about 0.1 mg to about 3,000 mg per day.
  • the dosage for a human will generally be in the range of about 0.01 mg to about 500 mg per day; more frequently, from about 0.01 mg to about 300 mg per day; preferably, from about 0.01 mg to about 200 mg or 250 mg per day; more preferably, from about 0.01 mg to about 75 mg or 100 mg per day; typically from about 0.01 mg to about 50 mg or 60 mg per day.
  • the specific dosage and dosage range that can be used depends on a number of factors, including the age and weight of the patient, the mode of administration, the severity of the disease, condition and/or disorder being treated, and the pharmacological activity of the compound being administered.
  • the determination of dosage ranges and optimal dosages for a particular patient is well within the ordinary skill in the art.
  • the compounds of this invention may be used in combination with other pharmaceutical agents (sometimes referred to herein as a "combination") for the treatment of the diseases, conditions and/or disorders mentioned herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided by the present invention.
  • Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.
  • Suitable anti-obesity agents include cannabinoid-1 (CB-1 ) antagonists (such as rimonabant), 11 ⁇ -hydroxy steroid dehydrogenase-1 (11 ⁇ -HSD type 1 ) inhibitors, stearoyl-CoA desaturase-1 (SCD-1 ) inhibitors, melanocortin 4 receptor (MCR-4) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (e.g., bromocriptine), GPR119 agonists, a melanocyte-stimulating hormone (MSH) and functional analogs thereof (such as those discussed in U.S.
  • CBD-1 cannabinoid-1
  • 11 ⁇ -HSD type 1 11 ⁇ -hydroxy steroid dehydrogenase-1
  • SCD-1 stearoyl-CoA desaturase-1
  • MCR-4 melan
  • anorectic agents e.g., bombesin receptor subtype 3 agonists
  • neuropeptide-Y (NPY) Y1 or Y5 receptor antagonists e.g., neuropeptide-Y (NPY) Y1 or Y5 receptor antagonists
  • NPY Y2 receptor agonists e.g., peptide YY3-36 (PYY3-36) and functional analogs thereof, thyromimetic agents, dehydroepiandrosterone and functional analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 (GLP-1 ) receptor agonists, ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc.,
  • AgRP human agouti-related protein
  • ghrelin receptor antagonists and inverse agonists histamine 3 receptor antagonists and inverse agonists
  • neuromedin U (NMU) receptor agonists e.g., those disclosed in WO 2007/109135
  • MTP/ApoB secretion inhibitors e.g., gut-selective MTP inhibitors, such as dirlotapide
  • T-type calcium channel blockers such as zonisamide
  • opioid receptor antagonists such as those discussed in WO 03/101963 and WO 2004/026305), and the like.
  • Preferred anti-obesity agents for use in the combination aspects of the present invention include CB-1 antagonists (e.g., rimonabant, taranabant, surinabant, otenabant, SLV319 (CAS No. 464213-10-3) and AVE1625 (CAS No. 358970-97-5)); gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No.
  • CB-1 antagonists e.g., rimonabant, taranabant, surinabant, otenabant, SLV319 (CAS No. 464213-10-3) and AVE1625 (CAS No. 358970-97-5)
  • gut-selective MTP inhibitors e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and
  • 5HT2c receptor agonists e.g., lorcaserin
  • MCR-4 agonists e.g., compounds described in US 6,818,658
  • lipase inhibitors e.g., Cetilistat
  • PYY3-36 variants thereof and pegylated PYY3-36 and variants (e.g., those described in US Publication 2006/0178501 )
  • opioid receptor antagonists e.g., naltrexone
  • oleoyl-estrone CAS No.
  • TM30338 obinepitide
  • pramlintide Symlin®
  • tesofensine NS2330
  • leptin and leptin receptor agonists liraglutide, bromocriptine, orlistat, exenatide (Byetta®)
  • AOD-9604 CAS No. 221231-10-3
  • sibutramine a compound of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • Suitable anti-diabetic agents for use in the combination aspects of the present invention include acetyl-CoA carboxylase-1 (ACC-1 ) inhibitors, acetyl-CoA carboxylase-2 (ACC-2) inhibitors, nonselective acetyl-CoA carboxylase (ACC-1/2) inhibitors, GPR119 agonists, phosphodiesterase (PDE)-I O inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas (e.g., acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimepiride, glipentide, glipizide, gliquidone, glisolamide, glisoxepide, glyburide/glibenclamide, glyclopyramide, tolazamide and tolbutamide), meglitinides (e.g., mitiglini
  • SIRT-1 inhibitors e.g., reservatrol
  • DPP-IV dipeptidyl peptidease IV
  • IGF-IV inhibitors e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin
  • insulin secreatagogues fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, insulin, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, sodium-glucose co- transporter (SGLT) inhibitors especially SGLT2 inhobitors, modulators of GPR40, modulators of GPR120, and glucokinase activators.
  • Preferred anti-diabetic agents are metformin and DPP-IV inhibitors.
  • Preferred anti-diabetic agents for use in the combination aspects of the present invention include metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, trodusquemine, reservatrol, hyrtiosal extract, sitaglipt
  • the compounds of this invention may also be used in combination with other pharmaceutical agents (e.g., LDL-cholesterol lowering agents, triglyceride lowering agents) for the treatment of the disease/conditions mentioned herein.
  • the present compounds may be used in combination with an HMG-CoA reductase inhibitor (such as atorvastatin, simvastatin, fluvastatin, pravastatin, cerivastatin, rosuvastatin or pitavastatin), an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, a squalene synthetase/epoxidase/cyclase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor (such as ezetimibe), niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor (such as avasimibe CS-505 (Sankyo) and eflucimibe), a bile acid reup
  • Nimotop ® ' Norvasc ® or Plendil ® or an angiotensin converting enzyme (ACE) inhibitor such as Accupril ® , Altace ® , Captopril ® , Lotensin ® , Mavik ® , Monopril ® , Prinivil ® , Univasc ® , Vasotec ® or Zestril ® ), an antibiotic, and anti-inflammatory agents such as aspirin or, preferably, a selective cyclooxygenase-2 (Cox-2) inhibitor such as
  • the dosage of the additional pharmaceutical agent is generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired.
  • the dosage range of the additional pharmaceutical agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day.
  • some variability in the general dosage range may also be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered and the like.
  • the determination of dosage ranges and optimal dosages for a particular patient is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
  • a compound of the present invention or a combination is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition.
  • the compound of the present invention and the other pharmaceutical agent(s) may be administered either separately or in a pharmaceutical composition comprising both. It is generally preferred that such administration be oral.
  • a combination of a compound of the present invention and at least one other pharmaceutical agent When a combination of a compound of the present invention and at least one other pharmaceutical agent are administered together, such administration may be sequential in time or simultaneous. Simultaneous administration of drug combinations is generally preferred.
  • a compound of the present invention and the additional pharmaceutical agent may be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous.
  • the administration of each may be by the same or by different methods.
  • a compound of the present invention or a combination can be administered to a patient separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular or subcutaneous), intracisternal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray or lotion), buccal or nasal dosage form (e.g., spray, drops or inhalant).
  • parenteral e.g., intravenous, intramuscular or subcutaneous
  • intracisternal e.g., intravaginal, intraperitoneal
  • topical e.g., powder, ointment, cream, spray or lotion
  • buccal or nasal dosage form e.g., spray, drops or inhalant
  • the compounds of the invention or combinations will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compound of the invention or combination may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release dosage forms depending on the desired route of administration and the specificity of release profile, commensurate with therapeutic needs.
  • the pharmaceutical compositions comprise a compound the invention or a combination in an amount generally in the range of from about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, usually in the range of about 1%, 2% or 3% to about 50%, 60% or 70%, more frequently in the range of about 1%, 2% or 3% to less than 50% such as about 25%, 30% or 35%.
  • Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known to those skilled in this art. For examples, see Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore MD, 20 th ed. 2000.
  • compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers or diluents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, triglycerides including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • a preferred carrier is Miglyol ® brand caprylic/capric acid ester with glycerine or propylene glycol (e.g., Miglyol ® 812, Miglyol ® 829, Miglyol ® 840) available from Condea Vista Co., Cranford, NJ.
  • Miglyol ® 812, Miglyol ® 829, Miglyol ® 840 available from Condea Vista Co., Cranford, NJ.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions for parenteral injection may also contain excipients such as preserving, wetting, emulsifying, and dispersing agents.
  • compositions can be accomplished with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, chews, lozenges, pills, powders, and multiparticulate preparations (granules).
  • a compound of the present invention or a combination is admixed with at least one inert excipient, diluent or carrier.
  • Suitable excipients, diluents or carriers include materials such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders (e.g., microcrystalline cellulose (available as AvicelTM from FMC Corp.) starches, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, calcium hydrogen phosphate, dextrin, alpha-cyclodextrin, beta-cyclodextrin, polyethylene glycol, medium chain fatty acids, titanium oxide, magnesium oxide, aluminum oxide and the like); (b) binders (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinylpyrrolidone, sucrose,
  • Solid compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients, diluents or carriers as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, and granules may be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the compound of the present invention and/or the additional pharmaceutical agent in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug may also be in micro-encapsulated form, if appropriate, with one or more of the above- mentioned excipients, diluents or carriers.
  • the active agent will typically comprise less than 50% (by weight) of the formulation, for example less than about 10% such as 5% or 2.5% by weight.
  • the predominant portion of the formulation comprises excipients, diluents or carriers such as fillers, disintegrants, lubricants and, optionally, flavors.
  • the composition of these excipients is well known in the art.
  • the fillers/diluents will comprise mixtures of two or more of the following components: microcrystalline cellulose, mannitol, lactose (any/all types), starch, and di-calcium phosphate.
  • the excipient, diluent or carrier mixtures typically comprise less than about 98% of the formulation and preferably less than about 95%, for example about 93.5%.
  • Preferred disintegrants include Ac-di-solTM, ExplotabTM, starch and sodium lauryl sulphate.
  • a disintegrant When present a disintegrant will usually comprise less than about 10% of the formulation or less than about 5%, for example about 3%.
  • a lubricant When present a lubricant will usually comprise less than about 5% of the formulation or less than about 3%, for example about 1%.
  • a preferred lubricant is magnesium stearate.
  • Tablets may be manufactured by standard tabletting processes, for example, direct compression or a wet, dry or melt granulation, melt congealing process and extrusion.
  • the tablet cores may be mono or multi-layer(s) and can be coated with appropriate overcoats known in the art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert excipients, diluents or carriers commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), Miglyol ® (available from CONDEA Vista Co., Cranford, NJ.) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters, such as for example, eth
  • composition may also include wetting, emulsifying and/or suspending agents and sweetening, flavoring and/or perfuming agents.
  • Oral liquid forms of the compounds of the invention or combinations include solutions, wherein the active compound is fully dissolved.
  • solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the invention show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils and glyceryl- and glyceride- based systems.
  • Glyceryl- and glyceride- based systems may include, for example, the following branded products (and corresponding generic products): CaptexTM 355 EP (glyceryl tricaprylate/caprate, from Abitec, Columbus OH), CrodamolTM GTC/C (medium chain triglyceride, from Croda, Cowick Hall, UK) or LabrafacTM CC (medium chain triglyides, from Gattefosse), CaptexTM 500P (glyceryl triacetate i.e.
  • medium chain (about C 8 to Ci 0 ) triglyceride oils are the medium chain (about C 8 to Ci 0 ) triglyceride oils. These solvents frequently make up the predominant portion of the composition, i.e., greater than about 50%, usually greater than about 80%, for example about 95%, 97% or 99%.
  • Other excipients, diluents or carriers may also be included with the solvents principally as taste-mask agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers, solubilizers and the like.
  • Suspensions in addition to the compound of the present invention or the combination, may further comprise excipients, diluents or carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • suspending agents e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound of the present invention or a combination with suitable non-irritating excipients, diluents or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity thereby releasing the active component(s).
  • suitable non-irritating excipients, diluents or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity thereby releasing the active component(s).
  • Dosage forms for topical administration of the compounds of the present invention or combinations include ointments, creams, lotions, powders and sprays.
  • the drugs are admixed with a pharmaceutically acceptable excipient, diluent or carrier, and any preservatives, buffers, or propellants that may be required or desired.
  • a pharmaceutically acceptable excipient e.g., diluent or carrier
  • any preservatives, buffers, or propellants that may be required or desired.
  • liquid compositions in solubilizing, non-aqueous solvents such as the medium chain triglyceride oils discussed above are a preferred dosage form.
  • Solid amorphous dispersions, including dispersions formed by a spray-drying process, are also a preferred dosage form for poorly soluble compounds of the invention.
  • solid amorphous dispersion is meant a solid material in which at least a portion of the poorly soluble compound is in the amorphous form and dispersed in a water- soluble polymer.
  • amorphous is meant that the poorly soluble compound is not crystalline.
  • crystalline is meant that the compound exhibits long-range order in three dimensions of at least 100 repeat units in each dimension.
  • Amorphous material may be characterized by techniques known in the art such as powder x-ray diffraction (PXRD) crystallography, solid state NMR, or thermal techniques such as differential scanning calorimetry (DSC).
  • At least a major portion (i.e., at least about 60 wt%) of the poorly soluble compound in the solid amorphous dispersion is amorphous.
  • the compound can exist within the solid amorphous dispersion in relatively pure amorphous domains or regions, as a solid solution of the compound homogeneously distributed throughout the polymer or any combination of these states or those states that lie intermediate between them.
  • the solid amorphous dispersion is substantially homogeneous so that the amorphous compound is dispersed as homogeneously as possible throughout the polymer.
  • substantially homogeneous means that the fraction of the compound that is present in relatively pure amorphous domains or regions within the solid amorphous dispersion is relatively small, on the order of less than about 20 wt%, and preferably less than about 10 wt% of the total amount of drug.
  • Water-soluble polymers suitable for use in the solid amorphous dispersions should be inert, in the sense that they do not chemically react with the poorly soluble compound in an adverse manner, are pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pHs (e.g. 1-8).
  • the polymer can be neutral or ionizable, and should have an aqueous-solubility of at least 0.1 mg/ml_ over at least a portion of the pH range of 1-8.
  • Water-soluble polymers suitable for use with the present invention may be cellulosic or non-cellulosic. The polymers may be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.
  • Exemplary water-soluble polymers include hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxy methyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO/PPO, also known as poloxamers), and mixtures thereof.
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • HPMC hydroxypropyl methyl cellulose
  • HPMCP hydroxypropyl methyl cellulose phthalate
  • CMEC carboxy methyl ethyl cellulose
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • PVP polyvin
  • Especially preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, poloxamers, and mixtures thereof. Most preferred is HPMCAS. See European Patent Application Publication No. 0 901 786 A2, the disclosure of which is incorporated herein by reference.
  • the solid amorphous dispersions may be prepared according to any process for forming solid amorphous dispersions that results in at least a major portion (at least 60%) of the poorly soluble compound being in the amorphous state.
  • Such processes include mechanical, thermal and solvent processes.
  • Exemplary mechanical processes include milling and extrusion; melt processes including high temperature fusion, solvent-modified fusion and melt-congeal processes; and solvent processes including non-solvent precipitation, spray coating and spray drying.
  • the solid amorphous dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0 901 786 A2.
  • a solvent such as acetone or methanol
  • the solid amorphous dispersions may be prepared to contain up to about 99 wt% of the compound, e.g., 1 wt%, 5 wt%, 10 wt%, 25 wt%, 50 wt%, 75 wt%, 95 wt%, or 98 wt% as desired.
  • the solid dispersion may be used as the dosage form itself or it may serve as a manufacturing-use-product (MUP) in the preparation of other dosage forms such as capsules, tablets, solutions or suspensions.
  • An example of an aqueous suspension is an aqueous suspension of a 1 :1 (w/w) compound/HPMCAS-HF spray-dried dispersion containing 2.5 mg/ml_ of compound in 2% polysorbate-80.
  • Solid dispersions for use in a tablet or capsule will generally be mixed with other excipients or adjuvants typically found in such dosage forms.
  • an exemplary filler for capsules contains a 2:1 (w/w) compound/HPMCAS-MF spray-dried dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g., Avicel (R0 -102) (15.8%), sodium starch (7%), sodium lauryl sulfate (2%) and magnesium stearate (1%).
  • the HPMCAS polymers are available in low, medium and high grades as Aqoat (R) -LF, Aqoat (R) -MF and Aqoat (R) -HF respectively from Shin-Etsu Chemical Co., LTD, Tokyo, Japan. The higher MF and HF grades are generally preferred.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the following paragraphs describe exemplary formulations, dosages, etc. useful for non-human animals.
  • the administration of the compounds of the present invention and combinations of the compounds of the present invention with anti- obesity agents can be effected orally or non-orally.
  • An amount of a compound of the present invention or combination of a compound of the present invention with an anti-obesity agent is administered such that an effective dose is received.
  • a daily dose that is administered orally to an animal is between about 0.01 and about 1 ,000 mg/kg of body weight, e.g., between about 0.01 and about 300 mg/kg or between about 0.01 and about 100 mg/kg or between about 0.01 and about 50 mg/kg, or between about 0.01 and about 25 mg/kg, or about 0.01 and about 10 mg/kg or about 0.01 and about 5 mg/kg of body weight.
  • a compound of the present invention can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply.
  • the compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).
  • a compound of the present invention can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate.
  • a premix or concentrate of the compound in an excipient, diluent or carrier is more commonly employed for the inclusion of the agent in the feed.
  • Suitable excipients, diluents or carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds.
  • a particularly effective excipient, diluent or carrier is the respective animal feed itself; that is, a small portion of such feed.
  • the carrier facilitates uniform distribution of the compound in the finished feed with which the premix is blended.
  • the compound is thoroughly blended into the premix and, subsequently, the feed.
  • the compound may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier.
  • a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like
  • the proportions of compound in the concentrate are capable of wide variation since the amount of the compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.
  • High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements, which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound of the present invention.
  • the mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity. If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the compound across the top of the dressed feed.
  • Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing a compound of the present invention with a sufficient amount of animal feed to provide from about 10 "3 to about 500 ppm of the compound in the feed or water.
  • the preferred medicated swine, cattle, sheep and goat feed generally contain from about 1 to about 400 grams of a compound of the present invention (or combination) per ton of feed, the optimum amount for these animals usually being about 50 to about 300 grams per ton of feed.
  • the preferred poultry and domestic pet feeds usually contain about 1 to about 400 grams and preferably about 10 to about 400 grams of a compound of the present invention (or combination) per ton of feed.
  • the compounds of the present invention may be administered top an animal parenterally.
  • Pellets or standard injectable solutions or suspensions are useful for parenteral administration.
  • parenteral administration involves injection of a sufficient amount of a compound of the present invention (or combination) to provide the animal with about 0.01 to about 20 mg/kg/day of body weight of the drug.
  • the preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from about 0.05 to about 10 mg/kg/day of body weight of drug.
  • the compounds of the present invention may be prepared in the form of a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean meat to fat ratio is sought.
  • Pellets containing an effective amount of a compound of the present invention, pharmaceutical composition, or combination may be prepared by admixing a compound of the present invention or combination with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, may be added to improve the pelleting process.
  • pellets may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired.
  • implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.
  • the compounds of the present invention may also be administered orally to non-human animals, for example companion animals such as dogs, cats and horses, and food-source animals, in the same dosage forms as used for humans, for example tablets, capsules, solutions, suspensions, pastes, powders etc.
  • Paste Formulations may be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
  • the present invention has several advantageous veterinary features.
  • the instant invention provides the means by which this may be accomplished.
  • utilization of the method of the present invention yields leaner animals that command higher sale prices from the meat industry.
  • starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd.
  • NMR spectra were recorded on a Varian UnityTM 400 (available from Varian Inc., Palo Alto, CA) at room temperature at 400 and 500 MHz 1 H, respectively. Chemical shifts are expressed in parts per million ( ⁇ ) relative to residual solvent as an internal reference. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet; v br s, very broad singlet; br m, broad multiplet. In some cases only representative 1 H NMR peaks are given.
  • Mass spectra were recorded by direct flow analysis using positive and negative atmospheric pressure chemical ionization (APcI) scan modes. A Waters APcl/MS model ZMD mass spectrometer equipped with Gilson 215 liquid handling system was used to carry out the experiments
  • Mass spectrometry analysis was also obtained by RP-HPLC gradient method for chromatographic separation. Molecular weight identification was recorded by positive and negative electrospray ionization (ESI) scan modes.
  • ESI electrospray ionization
  • Enantiomer 1 (100% ee) [(4S)-4-(1 H-indazol-3- ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-6H-[1 ,2,4]triazolo[4,3-a][1 ,5]benzodiazepin-6- yl]acetic acid eluted at 10.4 min, and enantiomer 2 [(4f?)-4-(1 H-indazol-3-ylmethyl)- 5-OXO-1 -phenyl-4,5-dihydro-6H-[1 , 2, 4]triazolo[4,3-a][1 ,5]benzodiazepin-6-yl]acetic acid (96.3 % ee) eluted at 15.2 min as measured on a Chiralpak AD-H analytical HPLC column.
  • the reaction mixture was stirred for 2 h at room temperature and concentrated under reduced pressure to remove the THF.
  • the residue was mixed with ethyl acetate and washed twice with water followed by brine.
  • the organic layer was dried with MgSO 4 , filtered and concentrated to give a yellow foam which was dissolved in dichloromethane (5 mL) with sonication. While this solution was stirred, diethyl ether (30 mL) was added causing a precipitate to form.
  • the solids were collected by filtration and dried under vacuum to give the product as a white solid (1.46 g, 41%).
  • 2-(3,5-Dimethylbenzyl)piperidine was prepared in the manner described in European J. Org. Chem. 2004, 17, 3623.
  • the mixture was filtered, concentrated and neutralized with a 10% aqueous solution of sodium hydroxide, then extracted with ethyl acetate.
  • f?-2-(3,5-dimethyl-benzyl)- piperidine was also prepared by the following method.
  • 2-(3,5- dimethyl-benzyl)-piperidine (Preparation 10) (57.0 g, 280 mmol) in 2-propanol (700 ml.) and water (35.0 ml.) was added 5,5-dimethyl-2-oxo-4-phenyl-5- [1 ,3,2]dioxaphosphinan-2-ol [commonly known as (+)-phencyphos, Syncom BV, Groningen, Netherlands (34.0 g, 140.0 mmol)].
  • the resulting slurry was heated to reflux, and the resulting solution was cooled slowly to 10 0 C at a rate of 5 °C/h.
  • the resulting slurry was filtered, and the filter cake was washed with 2-propanol (2 x 150 ml.) and dried at 50 0 C under high vacuum to afford 44.2 g of a white solid salt that was neutralized by partitioning between dichloromethane (500 ml.) and 1 N NaOH (400 ml_).
  • the organic layer was washed with water (100 ml.) and concentrated by vacuum distillation to afford the title compound as a colorless oil that partially solidified upon standing [24.5 g, 43% (50% max expected), 92% ee].
  • the reaction mixture was diluted with toluene (1 L) and washed twice with aqueous sodium chloride (2x 1.5L, 10 wt%).
  • the organic layer was heated to 55 0 C and was slowly charged with MTBE (8L) with stirring while maintaining the pot temperature above 50 0 C.
  • the resulting solution was cooled to 18 0 C over 12 h, and the precipitated solids were collected by filtration, washed with MTBE (2x 300 mL), and dried at 60 0 C under vacuum for 12 h to afford the title compound as an off-white crystalline solid (290.2 g, 77%).
  • reaction mixture was stirred at 0 0 C for 10 min followed by the slow addition of a solution of iodomethane (0.47 ml_, 7.5 mmol) in THF (2 ml_).
  • the reaction was allowed to warm to room temperature while stirring for 3 h.
  • the reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic extracts were washed sequentially with water and brine and were dried over MgSO 4 .
  • the resulting mixture was allowed to warm to room temperature with stirring for 15 h.
  • the reaction was poured into water and was extracted twice with a 4:1 solution of MTBE and ethyl acetate.
  • the extracts were combined and were washed sequentially with water and brine and were concentrated under reduced pressure to half volume. Hexanes were added, and the mixture was concentrated to half volume.
  • the mixture was filtered to give the product as a cream-colored solid (12.2 g, 80%).
  • This compound was prepared using a procedure analogous to that described in Example 12 except that enantiomer 2 of 2-benzyl-piperidine (Preparation 5) and [4- (1 H-indazol-3-ylmethyl)-5-oxo-1 -phenyl-4,5-dihydro-6H-[1 ,2,4]triazolo[4,3- a][1 ,5]benzodiazepin-6-yl]acetyl chloride were used as the starting materials. The product was isolated as a mixture of diastereomers.
  • the title compound was prepared using a procedure analogous to Example 12 except that 2-(3-methoxybenzyl)piperidine and [4-(1 H-indazol-3-ylmethyl)-5-oxo-1- phenyl-4,5-dihydro-6H-[1 ,2,4]triazolo[4,3-a][1 ,5]benzodiazepin-6-yl]acetyl chloride were used as the starting materials. The product was isolated as a mixture of diastereomers.
  • This compound was also isolated from the product obtained by the method described in Example 18 by preparative, chiral HPLC on a Chiralcel AS-H column (4.6 cm x 25 cm) eluting with carbon dioxide/methanol (70:30, 2.5 mL/min).
  • the desired product elutes as the second peak with a retention time of 4.1 min as measured on a Chiralpak AD-H analytical HPLC column.
  • This material was further purified by flash chromatography (33 - 100% ethyl acetate in heptane) to give the product which, after heating in acetonitrile, forms crystalline material upon cooling to room temperature.
  • the organic solution was concentrated to afford an oil that was added to a freshly prepared solution of anhydrous HCI in ethanol (prepared in advance by slow addition of acetyl chloride (415 g) to anhydrous ethanol (4.0 L). The mixture was heated at reflux for 3 h, then was distilled to a minimum volume under vacuum to afford an oil that was redissolved in ethyl acetate (2.0 L). The resulting solution was washed with an aqueous solution of sodium carbonate (0.3 M, 2 portions of 2 L) followed by an aqueous solution of sodium chloride (10 wt%, 2 L). The organic layer was concentrated under vacuum to afford a residue that was crystallized from acetonitrile (500 mL) to afford the title compound as a white crystalline solid (189.2 g, 55%).
  • the reaction mixture was stirred at 50 0 C for 18 h.
  • the reaction mixture was diluted with ethyl acetate and water.
  • a saturated aqueous solution of sodium bicarbonate was added.
  • the organic layer was separated, washed with water and dried over Na 2 SO 4 .
  • the mixture was filtered, and the filtrate concentrated under reduced pressure.
  • the residue was purified by flash chromatography (0 - 100% ethyl acetate in heptane) to afford the title compound as a mixture of diastereomers (32 mg, 30%).
  • the title compound was prepared using a procedure analogous to that described in Example 19 except that 2(S)-ethylpiperidine (J. Org. Chem. 1971 , 36, 3648) and racemic [4-(1 H-indazol-3-yl-methyl)-5-oxo-1 -phenyl-4,5-dihydro-6H-[1 ,2,4]- triazolo[4,3-a][1 ,5]benzodiazepin-6-yl]acetic acid (Preparation 2) were used as the starting materials. The product was isolated as a mixture of diastereomers.
  • the title compound was prepared using a procedure analogous to that described in Example 19 except that 2-[3-(trifluoromethyl)benzyl]piperidine was used as the starting material.
  • the product was isolated as a mixture of diastereomers.
  • the diastereomers were resolved by reverse-phase, preparative HPLC on a chiral column (Chiralcel O D-H column (4.6 cm x 25 cm) eluting with CO 2 / methanol (75:25, 2.5 ml_/min) to provide the desired product as the second eluting compound.
  • reaction mixture was partitioned between ethyl acetate and a saturated aqueous aqueous solution of sodium bicarbonate.
  • the organic layer was separated and washed sequentially with water followed by brine and dried over MgSO 4 .
  • the mixture was filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by flash chromatography (heptane/ethyl acetate gradient) to give the title compound in the form of a white foam as a mixture of diastereomers (532 mg, 90%).
  • the diastereomers were resolved by reverse phase preparative HPLC on a chiral column (Chiralcel OD-H column (4.6 cm x 25 cm) and eluted using CO 2 / methanol (75:25, 2.5 mL/min) to isolate the desired product as the second eluting compound.
  • the resulting mixture was agitated on a titer plate shaker at 50 0 C for 18 h.
  • Dichloromethane, water and a saturated aqueous solution of sodium bicarbonate were added, and the layers were separated.
  • the organic extracts were washed with water.
  • the original aqueous layer was extracted twice with dichloromethane. All of the organic extracts were combined and dried over MgSO 4 , filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by flash chromatography (20 to 100% ethyl acetate in heptane) to afford the title compound as a mixture of diastereomers (13 mg, 49%).
  • the title compound was prepared by a procedure analogous to that described in Example 31 using 2-isopropylpiperidine (10.6 mg, 0.083 mmol) in place of 2- benzylpiperidine.
  • the product was isolated in the form of a solid (50 mg, 92%) as a mixture of diastereomers.
  • reaction mixture was heated to 50 0 C for 15 h.
  • the reaction mixture was purified directly by preparative HPLC (column: 5 micron, C-18, XBridge 30.0x100.0 mm. Gradient (0.1% formic acid modifier): 5% - 95% acetonitrile in water over 8 min) to give the product (27 mg, 26%) in the form of a white solid as a mixture of diastereomers.
  • Example 34 The compounds of Examples 34 - 36 (Table 2) were prepared using procedures analogous to those described in Example 33.
  • the 2-substituted piperidine starting materials are available commercially, prepared in a manner analogous to the methods described herein for other intermediates, or prepared using procedures known to those of average skill in the art.
  • the reaction mixture was shaken at 50 0 C for 18 h.
  • the reaction was diluted with ethyl acetate and water.
  • the organic layer was separated, transferred to a pre-weighed vial and concentrated in a Genevac over night.
  • the residue was purified by preparative HPLC (Phenomenex, Gemini 5 micron, C18 110A, AXIA Packed Column; 50 x 21.2 mm) using a 15 - 100% gradient of acetonitrile in water (both containing 0.1% formic acid) for 8 min to afford the title compound in the form of a solid as a mixture of diastereomers.
  • the reaction mixture was agitated for 24 h on a shaker and was concentrated under reduced pressure to dryness.
  • Dichloroethane (2.0 ml.) was added followed by a 1 N aqueous solution of sodium hydroxide (2.0 ml_).
  • the vial was vortexed, and the bottom solvent layer was removed from the biphasic mixture.
  • the aqueous layer was again extracted with dichloroethane (2.0 ml_).
  • the combined organic extracts were transferred to a drying cartridge which was eluted with 1.0 ml. of dichloroethane.
  • the collected solution was concentrated, and the resulting material was purified by reverse-phase, preparative HPLC (see below) to provide the final compound as a mixture of diastereomers.
  • Examples 48 - 62 The compounds of Examples 48 - 62 (Table 5) were prepared using the general method described below:
  • Solvent A 0.1% trifluoroacetic acid/ water.
  • Solvent B acetonitrile. Volume of injection: 0.5 ⁇ l_ crude sample and 15 ⁇ l_ purified sample. Gradient: 5% B to 95% B in A over 6 min at 1.6 ml_/min.
  • the reaction mixture was heated at 50 0 C overnight and was quenched with a saturated aqueous solution of sodium bicarbonate solution.
  • the mixture was extracted with ethyl acetate two times.
  • the combined organic extracts were washed sequentially with water followed by brine and dried over magnesium sulfate.
  • the mixture was filtered, and the filtrate was concentrated to give the title compound (50 mg) as a mixture of diastereomers.
  • Example 6 The compounds of Examples 66 - 70 (Table 6) were prepared by a procedure analogous to that described in Example 65 using appropriately substituted starting materials/intermediates which are available commercially, prepared in a manner analogous to the methods described above for other intermediates, or prepared using procedures known to those of average skill in the art. Table 6
  • CCK Cholecystokinin
  • Cell membranes were prepared from one T-75 flask of cells by pelleting cells at 1000Xg at 4 0 C for 5 min and resuspending in 1 ml homogenization buffer (1 mM EDTA, 1 mM EGTA, 1 mM sodium bicarbonate pH 7.4, 100 ⁇ g/ml benzamidine, 100 ⁇ g /ml bacitracin, 5 ⁇ g/ml leupeptin, 5 ⁇ g/ml aprotinin). After sitting on ice for 10 min, the cells were homogenized with a Dounce homogenizer. The nuclei and unlysed cells were removed by centrifugation at 1000Xg at 4 0 C for 10 min.
  • the supernatant was transferred to new tube and then spun at 25,00Og at 4 0 C for 20 min.
  • the pellet was resuspended in 5 ml binding buffer (20 mM HEPES, pH 7.4, 5 mM MgCI 2 , 118 mM NaCI, 5 mM KCI, 1 mM EGTA, 100 ⁇ g/ml benzamidine, 100 ⁇ g /ml bacitracin, 5 ⁇ g/ml leupeptin, 5 ⁇ g/ml aprotinin).
  • the protein concentration was determined using the BCA Protein Determination Assay kit (Pierce).
  • the binding assay was performed in a 96 well format using 5 ⁇ g (rat CCK-1 receptors) or 3 ⁇ g (human CCK-1 and CCK-2 receptors) of membranes in 200 ⁇ l of binding buffer (25mM Hepes, 5mM MgCI 2 5mM KCL, pH 7.4) per well. Unlabelled CCK-8 (Sigma) or compounds were diluted in binding buffer and 2 ⁇ l of each were added to the assay plate so that their final concentration range was 10 ⁇ M to 0.01 nM. [ 125 l]-CCK-2 (Amersham) was diluted to 0.75 nM in binding buffer and 20 ⁇ l added to each well (final concentration is 75 pM).
  • the assay plates were incubated at at RT for 90 min with gentle shaking. Nonspecific counts were removed using a Packard Filtermat Harvester (Packard 96-well Unifilter plate with GF/C membrane) and washed with cold wash buffer (20 mM HEPES, 5 mM MgCI 2 , 118 mM NaCI, pH 7.4). After drying, the plates were counted by the Trilux 1450 Microbeta from Wallac after addition of 3OuL Ready Safe Liquid Scintillation Cocktail (Beckman Coulter). Data were analyzed using Pfizer proprietary data analysis software. IC 50 values may also be determined using commercially available software such as GraphPad Prism software.
  • EC50 values were determined using Pfizer proprietary data analysis software. EC 50 values may also be determined using commercially available software such as GraphPad Prism software.

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Abstract

L'invention concerne des agonistes CCK-1R de formule (I), dans laquelle R1-R5 et X sont tels que définis dans le descriptif, des compositions pharmaceutiques contenant ces composés ainsi que des méthodes d'utilisation de ces composés et de ces compositions. Lesdits composés sont utiles dans le traitement de l'obésité, du diabète de type 2 et de maladies associées.
PCT/IB2009/055222 2008-12-08 2009-11-20 1,2,4 triazolo[4,3-a][1,5] benzodiazépin-5(6h)-ones utilisées comme agonistes du récepteur de la cholécystokinine-1 (cck-1r) WO2010067233A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2014013505A2 (fr) * 2012-07-20 2014-01-23 Hetero Research Foundation Vildagliptine amorphe
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014013505A2 (fr) * 2012-07-20 2014-01-23 Hetero Research Foundation Vildagliptine amorphe
WO2014013505A3 (fr) * 2012-07-20 2014-03-20 Hetero Research Foundation Vildagliptine amorphe
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

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