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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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• • A—HUMAN NECESSITIES
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  • A61P3/04—Anorexiants; Antiobesity agents
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  • A61P3/00—Drugs for disorders of the metabolism
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to ⁇ 3 adrenergic receptor agonists and uses thereof to treat diseases, conditions and/or disorders modulated by ⁇ 3 adrenergic receptor agonists.
• the disease diabetes mellitus is characterized by metabolic defects in the production and utilization of carbohydrates that result in the failure to maintain appropriate blood sugar levels.
• the results of these defects include, inter alia, elevated blood glucose or hyperglycemia.
• Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels.
• Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
• Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) is the result of an absolute deficiency of insulin, the hormone that regulates carbohydrate utilization.
• Type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM)
• NIDDM non-insulin-dependent diabetes mellitus
• the compounds of the invention effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
• Obesity constitutes a major health risk that leads to mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia.
• Most than 50% of the adult population is overweight, and almost 25% of the population is considered to be obese.
• the incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan.
• obesity is a devastating disease which can also wreak havoc on an individual's mental health and self-esteem, which can ultimately affect a person's ability to interact socially with others.
• the compounds, pharmaceutical compositions, and combinations of the present invention also reduce body weight, or decrease weight gain, when administered to a mammal, including a human subject.
• the ability of the compounds to affect weight gain is due to activation of ⁇ 3 adrenergic receptors that stimulate the metabolism of adipose tissue.
• ⁇ -Adrenergic agents have been generally classified into ⁇ i, ⁇ 2 , and ⁇ 3 receptor-specific subtypes.
• Agonists of ⁇ -receptors promote the activation of adenyl cyclase.
• Activation of ⁇ i receptors invokes an increase in heart rate while activation of ⁇ 2 receptors induces smooth muscle tissue relaxation that produces a drop in blood pressure and the onset of skeletal muscle tremors.
• ⁇ 3 receptors Activation of ⁇ 3 receptors is known to stimulate lipolysis (e.g., the breakdown of adipose tissue triglycehdes into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the loss of fat mass. Accordingly, compounds that stimulate ⁇ 3 receptors are therefore useful as anti-obesity agents, and can be further used to increase the content of lean meat in edible animals. In addition, compounds that are ⁇ 3 receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is presently unknown.
• ⁇ 3 adrenergic receptors were believed to be located predominantly in adipose tissue, however, such ⁇ 3 receptors are now known to be present in such diverse tissues as the intestine, (J. Gin. Invest.. 91 , 344 (1993)) and the brain (Eur. J. Pharm.. 219, 193 (1992)). Stimulation of ⁇ 3 receptors has also been demonstrated to induce relaxation of smooth muscle in the colon, trachea, and bronchi. See, for example, Life Sciences. 44, 1411 (1989). Br. J. Pharm.. 112. 55 (1994), and Br. J. Pharmacol., 110. 1311 (1993). Furthermore, stimulation of ⁇ 3 receptors has also been found to induce relaxation of histamine-contracted guinea pig ileum. See, for example, J. Pharm. Exp. Then, 260, 1 , 192 (1992).
• the ⁇ 3 receptor is also expressed in the human prostate (J. Clin. Invest., 91 , 344 (1993). Because stimulation of the ⁇ 3 receptor causes relaxation of smooth muscles that have been shown to express the ⁇ 3 receptor, i.e. intestinal smooth muscle, one of ordinary skill in the art would also predict relaxation of prostate smooth muscle. Therefore, ⁇ 3 agonists are useful in the treatment or prevention of prostate disease.
• U.S. Patent No. 5,977,124 discloses certain ⁇ 3 adrenergic receptor agonists that may be used in the treatment of, inter alia, hypoglycemia and obesity.
• U.S. Patent No. 5,776,983 discloses certain catecholamines as ⁇ 3 - agonists.
• U.S. Patent No. 5,030,640 discloses certain ⁇ -heterocyclic ethanol amino alkyl indoles that may be used as growth promoters, bronchodilators, anti- depressants, and anti-obesity agents.
• U.S. Patent No. 5,019,578 discloses certain ⁇ -heterocyclic ethanolamines that may be used as growth promoters.
• U.S. Patent No. 4,478,849 discloses pharmaceutical compositions comprising certain ethanolamine derivatives and methods of using such compositions in the treatment of obesity and/or hyperglycaemia.
• U.S. Patent No. 4,358,455 discloses certain heterocyclic compounds that may be used for treating glaucoma and cardiovascular disease.
• U.S. Patent No. 5,393,779 discloses certain 2- hydroxyphenethyl amines that may be used as anti-obesity and hypoglycemic agents, as well as, other related utilities.
• U.S. Patent No. 5,153,210 discloses certain heterocyclic compounds that may be used as anti-obesity and anti-hyperglycaemic agents.
• U.S. Patent No. 6,251 ,925 discloses biaryl compounds that may be used for the treatment of diseases susceptible to amelioration by administration of an atypical beta-adrenoceptor agonist.
• U.S. Publication No. 2002-0052392A1 (PCT Publication No. WO 02/32897) discloses certain heterocyclic ⁇ 3 -adrenergic receptor agonists that may be used in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders, and in increasing the content of lean meat in edible animals.
• the present invention provides ⁇ 3 -adrenergic receptor agonists of structural Formula (I) wherein
• Ar is phenyl, a 5- or 6-membere aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from O, S, or N, a benzene ring fused to a (C 3 -C 8 )cycloalkyl, a benzene ring fused to a 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O, S, or N, or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O, S, or N fused to a 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O, S, or N (preferably, Ar is phenyl or pyridyl, more preferably pyridyl);
• R 1 and R 2 are each independently hydrogen, hydroxy, halogen, cyano, nitro, -NR 1a R 2a , -NR 1a S0 2 R 2a , -OR 1a , -S0 2 R 2a , -CF 3 , (C 3 -C 8 )cycloalkyl, phenyl, -NR 1a COR 2a , -C0R 2a , or (CrC 6 )alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, nitro, halogen, and cyano, where R 1a and R 2a are each independently hydrogen, (C 3 -C 8 )cycloalkyl, phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, (CrC 6 )alkyl, and (d-C 6 )alkoxy, or (C C 6 )alkyl optionally substituted with 1 to 3 substituents selected from
• R 3 and R 4 are each, independently, hydrogen, or (C-i-C ⁇ Jalkyl optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, (CrC 6 )alkoxy, and fluoro;
• R 5 is hydrogen, (CrC 6 )alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, (CrC ⁇ Jalkoxy, and fluoro;
• R 6 and R 7 are each independently hydrogen, halogen, or (C C 6 )alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, (C- ⁇ -C 6 )alkoxy, and fluoro;
• R 8 is -CONR 1b R 2b , -SOR 1b , -S0 2 R 1b , -S0 2 NR 1b R 2b , -NR 1b S0 2 R 2b , or - C0 2 R 1b (preferably, R 8 is is -CONR 1b R 2b );
• R 9 is hydrogen, (CrC 6 )alkoxy, or (C-i-C ⁇ Jalkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, and (CrC 6 )alkoxy;
• X is -0-, -NH-, -NR 1a -, -CH 2 -, -CH 2 CH 2 - or -CH 2 0- (preferably, X is -0-);
• m is O or 1 ;
• HET is an aromatic heterocyclic ring selected from the group consisting of imidazole, oxazole, pyrazole, and thiazole (preferably, HET is oxazole or pyrazole, more preferably oxazole); a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug.
• Ar is pyridyl (more preferably, 3- pyridyl); R 3 , R 4 , R 5 , and R 6 are hydrogen; R 7 and R 9 are each independently hydrogen, fluoro, or (C C 6 )alkyl; R 8 is -CONR 1b R 2b (where R 1b and R 2b are are each independently selected from hydrogen, (C 3 -C 6 )cycloalkyl, or (C C 6 )alkyl optionally substituted one or more fluoro, or R 1b and R 2b taken together with the nitrogen to which they are attached form a 4- to 6-membered non-aromatic heterocyclic ring optionally containing one additional heteroatom selected from O and N, more preferably R 1b and R 2b are are each independently selected from hydrogen or (CrC 6 )alkyl, most preferably R 1b and R 2b are are each independently selected from hydrogen or methyl); X is -O- and m is 1
• Preferred compounds of Formula (IA) include: 2-[4-(4- ⁇ 2-[2(R)-hydroxy- 2-(6-methyl-pyridin-3-yl)-ethylamino]-ethoxy ⁇ -phenyl)-oxazol-2-yl]-N,N- dimethyl-acetamide; 2-(4- ⁇ 4-[2-(2(R)-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]- phenyl ⁇ -oxazol-2-yl)-N,N-dimethyl-acetamide; N,N-diethyl-2-(4- ⁇ 4-[2-(2(R)- hydroxy-2-pyhdin-3-yl-ethylamino)-ethoxy]-phenyl ⁇ -oxazol-2-yl)-acetamide; 2-[4- (4- ⁇ 2-[2-(6-chloro-pyridin-3-yl)-2(R)-hydroxy-ethyla
• More preferred compounds of Formula (IA) include: 2-[4-(4- ⁇ 2-[2(R)- hydroxy-2-(6-methyl-pyridin-3-yl)-ethylamino]-ethoxy ⁇ -phenyl)-oxazol-2-yl]-N,N- dimethyl-acetamide; 2-(4- ⁇ 4-[2-(2(R)-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]- phenyl ⁇ -oxazol-2-yl)-N,N-dimethyl-acetamide; N,N-diethyl-2-(4- ⁇ 4-[2-(2(R)- hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl ⁇ -oxazol-2-yl)-acetamide; 2-[4- (4- ⁇ 2-[2(R)-hydroxy-2-(6-methyl-pyridin-3-yl)-ethylamin
• R 1 is hydrogen, hydroxy, halogen, (C C ⁇ Jalkyl, or (d- C ⁇ jalkoxy (preferably, R 1 is hydrogen, halogen or (C C 6 )alkyl);
• R 3 and R 4 are hydrogen;
• R 5 , R 6 , R 7 and R 9 are each independently hydrogen or (CrC 6 )alkyl optionally substituted with one or more fluoro substituents (preferably, R 5 , R 6 , R 7 and R 9 are all hydrogen);
• R 8 is -CONR 1b R 2b , where R 1b and R 2b are each independently selected from hydrogen, (C 3 -C 6 )cycloalkyl or (C ⁇ -C 6 )alkyl optionally substituted one or more fluoro, or R 1a and R 1b taken together with the nitrogen to which they are attached form a 4- to 6-membered non-aromatic heterocyclic ring optionally containing one additional heteroatom selected from O or N (preferably, R 1a and R
• Preferred compounds include 2-[4-(4- ⁇ 2-[2(R)-hydroxy-2-(6-methyl- pyridin-3-yl)-ethylamino]-ethoxy ⁇ -phenyl)-oxazol-2-yl]-N,N-dimethyl-acetamide; and 2-[4-(4- ⁇ 2-[2(R)-hydroxy-2-(6-methyl-pyridin-3-yl)-ethylamino]-ethoxy ⁇ - phenyl)-oxazol-2-yl]-N-methyl-acetamide; or a pharmaceutically acceptable salt thereof, a solvate or hydrate of the compound or the salt.
• Ar is pyridyl (more preferably, 3- pyridyl); R 3 , R 4 , R 5 , and R 6 are hydrogen; R 7 and R 9 are each independently hydrogen, fluoro, or (C C 6 )alkyl; R 8 is -CONR 1b R 2b (where R 1b and R 2b are are each independently selected from hydrogen, (C 3 -C 6 )cycloalkyl, or (C- ⁇ -C 6 )alkyl optionally substituted one or more fluoro, or R 1b and R 2b taken together with the nitrogen to which they are attached form a 4- to 6-membered non-aromatic heterocyclic ring optionally containing one additional heteroatom selected from O and N, more preferably R 1b and R 2b are are each independently selected from hydrogen or (C- ⁇ -C 6 )alkyl, most preferably R 1b and R 2b are are each independently selected from hydrogen or methyl); X is -O-
• Preferred compounds of Formula (IB) include: 2-(3- ⁇ 4-[2-(2(R)-hydroxy-2- pyridin-3-yl-ethylamino)-ethoxy]-phenyl ⁇ -pyrazol-1-yl)-N,N-dimethyl-acetamide; N-ethyl-2-(3- ⁇ 4-[2-(2(R)-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl ⁇ - pyrazol-1-yl)-N-methyl-acetamide; 2-(3- ⁇ 4-[2-(2(R)-hydroxy-2-pyridin-3-yl- ethylamino)-ethoxy]-phenyl ⁇ -pyrazol-1 -yl)-1 -morpholin-4-yl-ethanone; 2-(3- ⁇ 4-[2- (2(R)-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-pheny
• a pharmaceutical composition which comprises (1 ) a compound of the present invention, and (2) a pharmaceutically acceptable excipient, diluent, or carrier.
• the pharmaceutical composition may further comprise an additional pharmaceutical agent.
• a preferred pharmaceutical agent is an anti-obesity agent selected from the group consisting of an apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, a MCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor (e.g., sibutramine), a sympathomimetic agent, a cannabinoid receptor antagonist (e.g., rimonabant (SR-141.716A)), a dopamine agonist (e.g., bromocriptine), a melanocyte-stimulating hormone receptor analog, a 5HT2c agonist, a melanin concentrating hormone antagonist, leptin
• anorectic agent e.g., a bombesin agonist
• a Neuropeptide-Y antagonist e.g., a thyromimetic agent, a dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor (e.g., AxokineTM), a human agouti- related protein (AGRP), a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.
• an anorectic agent e.g., a bombesin agonist
• a Neuropeptide-Y antagonist e.g., a thyromimetic agent, a dehydroepiandrosterone or an analog thereof
• a glucocorticoid receptor agonist or antagonist e.g
• a method for treating a disease, condition or disorder modulated by a ⁇ 3 adrenergic receptor agonist in animals that includes the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof).
• Diseases, conditions, and/or disorders modulated by ⁇ 3 adrenergic agonists include weight loss (e.g., increased energy expenditure), obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, Crohn's disease, proctitis, asthma, intestinal motility disorder, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, fatty liver, and airway inflammatory disorder.
• the compounds of the present invention may be used in the manufacture of a medicament for treating a disease, condition or disorder which is modulated by a ⁇ 3 adrenergic receptor antagonist.
• Compounds of the present invention may be administered in combination with at least one additional pharmaceutical agent described hereinbelow.
• Preferred pharmaceutical agents include anti-obesity agents (described above).
• the combination therapy may be administered as (a) a single pharmaceutical composition which comprises a compound of the present invention, at least one additional pharmaceutical agent described above and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described above and a pharmaceutically acceptable excipient, diluent, or carrier.
• the pharmaceutical compositions may be administered simultaneously or sequentially and in any order.
• a pharmaceutical kit for use by a consumer to treat diseases, conditions and/or disorders modulated by ⁇ 3 adrenergic receptor agonists in an animal.
• the kit 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 diseases linked to the modulation of the ⁇ 3 adrenergic receptor.
• a pharmaceutical kit comprising: a) a first dosage form comprising (i) a compound of the present invention and (ii) a pharmaceutically acceptable carrier, excipient or diluent; b) a second dosage form comprising (i) an additional pharmaceutical agent described above, and (ii) a pharmaceutically acceptable carrier, excipient or diluent; and c) a container.
• R' is hydrogen or an amino-protecting group
• R 5 is hydrogen, (CrC ⁇ Jalkyl optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, (CrC 6 )alkoxy, and fluoro;
• R 8 is -CONR 1b R 2 , -SOR b , -S0 2 R 1b , -S0 2 NR 1b R 2b , -NR 1b S0 2 R 2b , or -C0 2 R 1b , where R 1b and R 2b are each independently hydrogen, amino, amino(CrC 6 )alkyl, aminoaryl, (C-i-C ⁇ Jalkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, (CrC 6 )alkoxy, fluoro, amino, (CrC ⁇ Jalkylamino, and acyl, (C 3 -C 8 )cycloalkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, alkyl, (C-i-C ⁇ Jalkoxy, hydroxy, amino, aminoalkyl-, acyl, and amido, a 3- to 8-membered aromatic or non-aromatic hetero
• alkyl refers to a hydrocarbon radical of the general formula C n H 2n + ⁇ .
• the alkane radical may be straight or branched.
• (Ci-C ⁇ jalkyl” refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, / ' - propyl, ⁇ -butyl, / ' -butyl, s-butyl, f-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).
• the alkane radical may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls) selected from the group of substituents listed below in the definition for "substituted.”
• substituents generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls
• substituents generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls
• substituents such as perchloro or perfluoroalkyls
• halo-substituted alkyl refers to an alkyl group substituted with one or more halogen atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, and the like).
• cycloalkyl refers to nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiro-fused ring.
• cycloalkyl includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, and the like.
• the cycloalkyl ring is a 3 to 8 membered ring.
• the cycloalkyl may be optionally substituted with one of more substituents (typically, one to three substituents) selected from the group of substituents listed below in the definition for "substituted.”
• the cycloalkyl group may be attached to the chemical entity or moiety by any one of the carbon atoms within the carbocyclic ring system.
• a cycloalkyl fused to a benzene ring refers to groups such as indanyl.
• non-aromatic heterocyclic ring refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiro-fused ring.
• Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, and the like.
• the heterocycle is 3 to 8 membered ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen.
• the non-aromatic heterocyclic groups may be optionally substituted with one of more substituents (typically, one to three substituents) selected from the group of substituents listed below in the definition for "substituted.”
• a heterocyclic ring that is fused to an aryl group includes groups such as 2,3- dihydrobenzofuranyl, 2,3-dihydroindolyl, 2,3-dihydrobenzothiophenyl, 2,3- dihydrobenzothiazolyl, etc.
• the heterocyclic group may be attached to the chemical entity or moiety by any one of the atoms within the heterocyclic ring system.
• aryl refers to aromatic moieties having single (e.g., phenyl) or fused ring system (e.g., naphthalene, anthracene, phenanthrene, etc.). Unless indicated otherwise, the aryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) selected from the group of substituents listed below in the definition for "substituted.” Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.) The aryl group may be attached to the chemical entity or moiety by any one of the carbon atoms within the aromatic ring system.
• Preferred aryl substituents are halogens (F, Cl, Br or I, preferably F or CI), (C ⁇ -C 4 )alkoxy, (C r C 4 )alkyl, halo-substituted(C C 4 )alkyl (e.g., CH 2 F, CHF 2 and CF 3 ) and cyano.
• An aryl group fused to a cycloalkyl group includes groups such as indanyl.
• the aryl portion (i.e., aromatic moiety) of an aroyl or aroyloxy i.e., (aryl)-C(O)-O-
• aromatic heterocyclic ring or “heteroaryl” refers to aromatic moieties containing at least one heteratom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within the aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, oxadiazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, etc.).
• heteratom e.g., oxygen, sulfur, nitrogen or combinations thereof
• aromatic ring system e.g., pyrrolyl, pyridyl, pyrazolyl
• the heteroaromatic moiety may consist of a single or fused ring system.
• a typical single heteroaryl ring is a 5- to 6-membered ring containing one to three heteroatoms selected from oxygen, sulfur and nitrogen and a typical fused heteroaryl ring system is a 9- to 10-membered ring system containing one to four heteroatoms selected from oxygen, sulfur and nitrogen.
• the heteroaryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) selected from the group of substituents listed below in the definition for "substituted.”
• the heteroaryl group may be attached to the chemical entity or moiety by any one of the atoms within the aromatic ring system (e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, or pyrid-6- yl).
• the heteroaryl portion (i.e., heteroaromatic moiety) of a heteroaroyi i.e., (heteroaryl )-C(0)-0-
• acyl refers to alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups.
• acyl includes groups such as (d- C ⁇ jalkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, f-butylacetyl, etc.), (C 3 -C 6 )cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), a
• alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions above. Unless indicated otherwise, the acyl group may be unsubstituted or optionally substituted with one of more substituents (typically, one to three substituents) selected from the group of substituents listed below in the definition for "substituted.”
• substituted specifically envisions and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament. Those skilled in the art will also appreciate that certain substitutions may be inherently unstable and therefore do not form a part of this invention.
• Suitable substituents for any of the groups defined above include (CrC 6 )alkyl, partially or fully saturated (C 3 - C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, aryl, heteroaryl, partially or fully saturated 3- to 6- membered heterocycle, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (C C 6 )alkoxy, aryloxy, sulfhydryl (mercapto), (C C 6 )alkylthio, arylthio, amino, mono- or di-(C C 6 )alkyl amino, quaternary ammonium salts, amino(C C 6 )alkoxy, aminocarboxylate (i.e., -NH-C(0)-0-(C C 6 )alkyl), N-(C C 6 )alkylaminocarboxylate, hydroxy(C ⁇ -C 6 )alky
• substituted combinations such as "substituted aryl(C ⁇ -C 6 )alkyl" either the aryl or the alkyl group may be substituted, or both the aryl and the alkyl groups may be substituted with one or more substituents (typically, one to three substituents except in the case of perhalo substitutions).
• An aryl substituted carbocyclic or heterocyclic group may be a fused ring (e.g., indanyl, dihydrobenzofuranyl, dihydroindolyl, etc.).
• a cycloalkyl substituted carbocyclic or heterocyclic group may be a spiro-fused ring.
• solvate refers to a molecular complex of a compound of the present invention with one or more solvent molecules.
• 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 the complex where 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.
• 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, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
• a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
• Suitable protecting groups include acetyl and silyl.
• a "carboxy- protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
• Common carboxy-protecting groups include -CH 2 CH 2 S0 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxy- methyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
• protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991.
• terapéuticaally effective amount means an amount of a compound of the present invention that (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.
• animal refers to humans (male and female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
• animal refers to food-source animals such as cows, pigs, sheep and poultry.
• phrases "pharmaceutically acceptable” indicates 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.
• a ⁇ 3 adrenergic receptor or “modulation of a ⁇ 3 adrenergic receptor” refers to the activation or deactivation of ⁇ 3 adrenergic receptors.
• a ⁇ 3 adrenergic receptor ligand may act as an agonist, partial agonist, inverse agonist, antagonist, partial antagonist, and the like.
• agonist refers to both full and partial agonists.
• treating embrace both preventative, i.e., prophylactic, and palliative treatment.
• compounds of the present invention refer to compounds of Formula (I), (IA), (IA-1 ), and (IB) prodrugs thereof, pharmaceutically acceptable salts of the compounds, and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds.
• compounds of the present invention refer to compounds of Formula (I), (IA), (IA-1 ), and (IB) prodrugs thereof, pharmaceutically acceptable salts of the compounds, and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds.
• the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by ⁇ 3 adrenergic receptor agonists.
• Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
• the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
• reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
• Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
• Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
• specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
• many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
• Suitable amino-protecting groups include acetyl, trifluoroacetyl, f-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
• NH-Pg amino-protecting groups
• BOC f-butoxycarbonyl
• CBz benzyloxycarbonyl
• Fmoc 9-fluorenylmethyleneoxycarbonyl
• an ⁇ -bromoketone (1a) is cyclocondensed with an appropriately substituted amide to provide oxazole (1b).
• the cyclocondensation is typically conducted at elevated temperature in a polar protic or aprotic solvent (e.g., dimethylformamide or N-methylpyrrolidine).
• a polar protic or aprotic solvent e.g., dimethylformamide or N-methylpyrrolidine.
• the ⁇ -bromoketone (1a) starting material may be prepared by conventional methods, for example, according to those methods disclosed in Scheme 2 below for the conversion of a protected acetophenone derivative (2b) to ⁇ -bromoketone (2c).
• the intermediate oxazole (1 b) is then demethylated, preferably with methanesulfonic acid/methionine under standard conditions to provide phenol (1c), which is then functionalized with methanesulfonic acid 2-phenoxycarbonylamino-ethyl ester in the presence of a weak base (e.g., potassium carbonate) in an aprotic solvent (e.g., dimethylsulfoxide) to afford the protected amine (1d).
• a weak base e.g., potassium carbonate
• an aprotic solvent e.g., dimethylsulfoxide
• oxirane derivative a compound of the present invention where HET is oxazole.
• the oxirane intermediates may be prepared according to methods well-known to those skilled in the art, such as those described in U.S. Patent Nos. 5,541 ,197; 5,561 ,142; 5,705,515; and 6,037,362, all of which are incorporated herein by reference. Certain oxirane derivatives are also commercially available.
• This reaction is typically performed with stirring at room temperature (or at elevated temperature if required) in the presence of a dehydrating reagent (e.g., a stoichiometric amount of a diazocarboxyl compound, e.g., 1 ,1'-(azodicarbonyl)- dipiperidine (ADDP), and a phosphine, e.g., triphenylphosphine).
• a dehydrating reagent e.g., a stoichiometric amount of a diazocarboxyl compound, e.g., 1 ,1'-(azodicarbonyl)- dipiperidine (ADDP), and a phosphine, e.g., triphenylphosphine.
• the condensation reaction may be carried out in any reaction-inert solvent (e.g., tetrahydrofuran, dimethylformamide, a hydrocarbon, or halogenated hydrocarbon solvent).
• the bromination is performed according to conventional methods, preferably by the reaction of (2a) with tetrabutylammonium tribromide (TBA ' Br 3 ).
• TSA ' Br 3 tetrabutylammonium tribromide
• Compound (2b) is cyclocondensed with an appropriately substituted amide to afford the protected oxazole (1d) which is then deprotected to afford the amine (1e).
• deprotection may be accomplished using conventional deprotection methods. For example, when Pg is a benzyl group, then the benzyl group may be removed by treating with methanesulfonic acid, or various other deprotecting agents using standard conditions well-known to those skilled in the art.
• the deprotection is performed by hydrogenolysis in the presence of a suitable metal catalyst (e.g., palladium on carbon) in an inert solvent.
• a suitable metal catalyst e.g., palladium on carbon
• Amine (1e) is then coupled with an appropriately substituted oxirane derivative (Q) to provide compounds of the present invention where HET is an oxazole.
• the protected amine (2b) is heated with N,N- dimethylformamide diethyl acetal to afford the protected amine (3a).
• the reaction between the protected amine (2b) and N,N-dimethylformamide diethylacetal is achieved by simply combining both reactants together neat and heating the resulting mixture for an extended period of time, generally for about twenty-four to about forty-eight hours.
• the resulting product is then precipitated by the addition of a non-polar solvent (e.g., hexanes).
• a non-polar solvent e.g., hexanes
• the subsequent cyclocondensation of (3a) with hydrazine hydrate is preferably achieved by combining the reactants in a polar protic solvent (e.g., ethanol) and heating the mixture for about twelve to about twenty-four hours.
• a polar protic solvent e.g., ethanol
• the resulting pyrazole (3b) is then N-alkylated with ethyl bromoacetate, preferably in the presence of a base (e.g., sodium ethoxide) in a polar protic solvent (e.g., ethanol) to provide acetate (3c).
• a base e.g., sodium ethoxide
• a polar protic solvent e.g., ethanol
• the commercially available pyrazolo-anisole derivative (4a) is N-alkylated with ethyl bromoacetate to provide acetate (4b), which is then saponified with base (e.g., sodium hydroxide) in an aqueous solvent system (e.g., aqueous tetrahydrofuran) to provide acid (4c).
• base e.g., sodium hydroxide
• aqueous solvent system e.g., aqueous tetrahydrofuran
• Amide (4d) is then prepared by reacting acid (4c) with an appropriately substituted amine, preferably in an inert solvent (e.g., 1 ,2-dichloroethane) in the presence of benzotriazole-1 -yl-oxy-fr/s-pyrrolidino-phosphonium hexafluroide (PyBop).
• an inert solvent e.g. 1 ,2-dichloroethane
• benzotriazole-1 -yl-oxy-fr/s-pyrrolidino-phosphonium hexafluroide PyBop
• the oxazole and pyrazole residues disclosed contain substitutents that are limited to an R 8 moiety.
• Methods for preparing other heterocyclic congeners comprising R 7 and/or R 9 moieties is outlined in Scheme 5 below.
• the methylene linking group interposed between the HET and R 8 groups of the intermediate compound (5a) depicted in Scheme 5 contains at least one acidic hydrogen atom which may be displaced and substituted with an R 7 and/or R 9 group(s).
• Pg represents a conventional O-protecting group, (e.g., methyl, benzyl, tetrahydropyranyl, and the like) and HET is as defined above.
• HET denotes an oxazole, pyrazole, or thiazole heterocyclic moiety.
• the NH functional group of such residue should be appropriately protected using conventional protection schemes described earlier.
• the active methylene group of compound (5a) is deprotonated with a suitable base and the resulting anion(s) treated with an appropriate reagent containing a leaving group (e.g., R 7 -L and/or R 9 -L, wherein R 7 and R 9 are as defined above, except that R 7 and R 9 are neither hydrogen nor halogen) to afford the functionalized, protected phenol derivative (5b).
• a leaving group e.g., R 7 -L and/or R 9 -L, wherein R 7 and R 9 are as defined above, except that R 7 and R 9 are neither hydrogen nor halogen
• Suitable leaving groups include halogen (preferably bromo, or iodo), triflate, and the like.
• the deprotonation is normally accomplished with a strong base (e.g., lithium diisopropylamide, sodium hydride, lithium carbonate, lithium bis(trimethylsilyl)amide, and the like) in a reaction-inert solvent (e.g., tetrahydrofuran or ether).
• a strong base e.g., lithium diisopropylamide, sodium hydride, lithium carbonate, lithium bis(trimethylsilyl)amide, and the like
• a reaction-inert solvent e.g., tetrahydrofuran or ether
• the deprotonation is accomplished with lithium bis(trimethylsilyl)amide in tetrahydrofuran.
• the exact stoichiometric amounts of base and R 7 -L and/or R 9 -L employed will dictate whether compound (5b) is further functionalized to form compound (5c).
• the protected phenol derivative(s) (5b) and/or (5c) may then be deprotected according to conventional methods well-known to those skilled in the art, including those methods disclosed above. Functionalization, followed by coupling with a substituted oxirane derivative (Q) according to the methods disclosed above in Schemes 1 through 4 provides a compound of the present invention.
• the compounds of the present invention may be isolated and used per se or in the form of its pharmaceutically acceptable salt, solvate and/or hydrate.
• salts refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound, N- oxide, or prodrug with a suitable organic or inorganic acid and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
• alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
• non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., Berge, et al., J. Pharm. Sci Cincinnati 66, 1-19 (1977).
• prodrug means a compound that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
• a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
• a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (d- C 8 )alkyl, (C 2 -C ⁇ 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthal
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (CrC 6 )alkanoyloxymethyl, 1- ((CrC 6 )aIkanoyloxy)ethyl, 1 -methyl-1 -((CrC 6 )alkanoyloxy)ethyl, (d- C 6 )alkoxycarbonyloxymethyl, N-(CrC 6 )alkoxycarbonylaminomethyl, succinoyl, (CrC ⁇ Jalkanoyl, ⁇ -amino(CrC 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ - aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , P(0)(0(C Ce)alkyl
• a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (d-C ⁇ o)alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl-natural ⁇ - aminoacyl, -C(OH)C(0)OY' wherein Y' is H, (C ⁇ -C 6 )alkyl or benzyl, -C(OY 0 )Y ⁇ wherein Y 0 is (d-C 4 ) alkyl and Yi is (C C 6 )alkyl, carboxy(C ⁇ -C 6 )alkyl, amino(d- C 4 )alkyl or mono-N- or di-N,N-(
• the compounds of the present invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention.
• the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention. Both the single positional isomers and mixture of positional isomers resulting from the N- oxidation of the pyrimidine and pyrazine rings are also within the scope of the present invention.
• Diastereomeric mixtures can 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 can 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
• converting e.g., hydrolyzing
• some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
• the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. It is also possible that the compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all of the tautomeric forms of the imidazole and pyrazole moieties are included in the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
• the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, 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 compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 123 l, and 36 CI, respectively.
• Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier 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.
• Isotopically 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 hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• Compounds of the present invention are useful for treating diseases, conditions and/or disorders modulated by ⁇ 3 adrenergic receptor agonists; therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
• a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
• Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
• the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
• GRAS solvents recognized by persons skilled in the art as safe
• safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
• Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
• the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
• buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
• the formulations may be prepared using conventional dissolution and mixing procedures.
• the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
• a suitable solvent in the presence of one or more of the excipients described above.
• the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
• the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
• 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 present invention further provides a method of treating diseases, conditions and/or disorders modulated by ⁇ 3 adrenergic receptor agonists in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier.
• ⁇ 3 adrenergic agonists have indicated that the following diseases, disorders and/or conditions are modulated by ⁇ 3 adrenergic agonists: weight loss (e.g., increased energy expenditure), obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, Crohn's disease, proctitis, asthma, intestinal motility disorder, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, fatty liver, and airway inflammatory disorder.
• weight loss e.g., increased energy expenditure
• obesity e.g., increased energy expenditure
• diabetes irritable bowel syndrome
• inflammatory bowel disease e.ophagitis
• duodenitis esophagitis
• Crohn's disease e.g., proctitis
• asthma intestinal motility disorder
• ulcer e.g., gastritis
• hypercholesterolemia e.g.,
• the compounds of the present invention described herein are useful in treating diseases, conditions, or disorders that are modulated by ⁇ 3 adrenergic receptor agonists. Consequently, the compounds of the present invention (including the compositions and processes used therein) may be used in the manufacture of a medicament for the therapeutic applications described herein.
• the compounds of the present invention can be administered to a patient at dosage levels in the range of from about 0.7 mg to about 7,000 mg per day.
• dosage levels in the range of from about 0.7 mg to about 7,000 mg per day.
• a dosage in the range of from about 0.01 mg to about 100 mg per kilogram body weight is typically sufficient.
• some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like.
• the determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
• the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.
• Suitable pharmaceutical agents include anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (e.g., sibutramine), sympathomimetic agents, cannabinoid receptor antagonists (e.g., rimonabant (SR-141.716A)), dopamine agonists (e.g., bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein),
• anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-
• anorectic agents e.g., a bombesin agonist
• Neuropeptide-Y antagonists thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like.
• anorectic agents e.g., a bombesin agonist
• Neuropeptide-Y antagonists e.g., thyromimetic agents, dehydroepiandrosterone or an analog thereof
• anti-obesity agents including the preferred agents set forth hereinbelow, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
• anti-obesity agents selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine.
• compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
• anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; and orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. All of the above recited U.S. patents are incorporated herein by reference.
• antihypertensive agents include antihypertensive agents; antidepressants; insulin and insulin analogs (e.g., LysPro insulin); GLP- 1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH 2 ; sulfonylureas and analogs thereof: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide ® , glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; ⁇ 2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166; glitazones: ciglitazone, Actos ® (pioglitazone), englit
• the dosage of the additional pharmaceutical agent will also be 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 an anti-obesity 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 of a compound of the present invention and at least one additional pharmaceutical agent 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 at least one other pharmaceutical agent may be administered either separately or in the pharmaceutical composition comprising both. It is generally preferred that such administration be oral. However, if the subject being treated is unable to swallow, or oral administration is otherwise impaired or undesirable, parenteral or transdermal administration may be appropriate.
• parenteral or transdermal administration may be appropriate.
• parenteral or transdermal administration may be appropriate.
• when a combination of a compound of the present invention and at least one other pharmaceutical agent are administered together such administration can be sequential in time or simultaneous with the simultaneous method being generally preferred.
• a compound of the present invention and the additional pharmaceutical agent can 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. When a compound of the present invention and the additional pharmaceutical agent are administered sequentially, the administration of each can be by the same or by different methods.
• a compound of the present invention or a combination of a compound of the present invention and at least one additional pharmaceutical agent is preferably administered in the form of a pharmaceutical composition.
• 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, (for example, intravenous, intramuscular, or subcutaneous) intracistemal, intravaginal, intraperitoneal, intravesical, local (for example, powder, ointment or drop), or buccal, or nasal, dosage form.
• 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, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
• 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 may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microorganism contamination of the 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, powders, and granules.
• a compound of the present invention or a combination is admixed with at least one inert customary pharmaceutical excipient (or carrier) such as sodium citrate or dicalcium phosphate or
• fillers or extenders e.g., starches, lactose, sucrose, mannitol, silicic acid and the like
• binders e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like
• humectants e.g., glycerol and the like
• disintegrating agents e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate and the like
• solution retarders e.g., paraffin and the like
• paraffin and the like e.g., paraffin and
• compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients 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 can 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 can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage form may contain inert diluents 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), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
• inert diluents commonly used in the art, such as water or other solvent
• composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Suspensions in addition to the compound of the present invention or the combination, may further comprise 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 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 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 and combinations of the compounds of the present invention with anti- obesity agents may comprise ointments, powders, sprays and inhalants.
• the drugs are admixed under sterile condition with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.
• Ophthalmic formulations, eye ointments, powders, and solutions are also intended to be included within the scope of the present invention.
• 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 (e.g., by injection).
• 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, preferably between about 0.01 and about 300 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 a carrier is more commonly employed for the inclusion of the agent in the feed.
• Suitable 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 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.
• 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 prepared in the form of a paste or 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.
• 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.
• Paste formulations can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
• Pellets containing an effective amount of a compound of the present invention, pharmaceutical composition, or combination can 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, can be added to improve the pelleting process.
• a diluent such as carbowax, carnuba wax, and the like
• a lubricant such as magnesium or calcium stearate
• more than one pellet 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 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.
• a p-Methoxybromoacetophenone (3.0 g, 13 mmol) and methyl malonate monoamide (23 g, 196 mmol) were combined in a round-bottomed flask and heated to about 130 ° C for 90 minutes. The reaction mixture was then allowed to cool to room temperature, and the resulting orange solid was partitioned between ethyl acetate and water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuo.
• Benzyl [2-(4-acetyl-phenoxy)-ethyl]-carbamate ⁇ a (10.2 g, 32.5 mmol) was dissolved in dichloromethane (100 ml) and methanol (50 ml), and tetrabutylammonium tribromide (15.7 g, 32.5 mmol) was added in one portion.
• the reaction mixture was stirred for about 16 hours, and was then quenched with water.
• the aqueous phase was extracted with ethyl acetate, and then washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium bisulfite.
• Methoxy malonamide (10.6 g, 90.6 mmol) and benzyl [2-(4-bromoacetyl- phenoxy)-ethyl]-carbamate ⁇ 2b (2.37 g, 6.04 mmol) were combined in a round- bottomed flask and heated to 130 C for about 90 minutes. The reaction mixture was then allowed to cool to room temperature, and the resulting orange solid was partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnresium sulfate, filtered, and concentrated in vacuo.
• Ethyl hydrazinoacetate hydrochloride (1.91 g, 12.3 mmol) and 3- dimethylamino-1-(4-methoxy-phenyl)-prop-2-en-1-one I -5a (2.53 g, 12.3 mmol) were dissolved in ethanol (40 ml). Potassium carbonate (1.70 g, 12.3 mmol) was added to this solution, and the resulting mixture was heated to 80 °C for about 16 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The crude paste was suspended in water (50 ml), and the pH was adjusted to 9.
• [5-(4-Methoxy-phenyl)-pyrazol-1-yl]-acetic acid ethyl ester l-5b (2.50 g, 9.60 mmol) was dissolved in tetrahydrofuran (30 ml) and methanol (30 ml). To this mixture, LiOH (902 mg, 38.4 mmol), and water (30 ml) were added. The mixture was stirred for about 15 minutes, and was then partitioned between ethyl acetate and water. The pH was adjusted to 3, and the aqueous phase was extracted with ethyl acetate.
• Example 1 illustrates the preparation of compounds of the present invention where Ar is a pyridyl group.
• Table I lists compounds that were prepared using the general procedures described above for the preparation of compounds 1-1A, 1-1 B and 1-1C with the appropriate starting materials.
• Example 2 illustrates the preparation of compounds of the present invention where Ar is a phenyl group.
• Table II below lists compounds having the following general structure that were prepared using the general procedures described above for the preparation of compound 2-1A with the appropriate starting materials.
• Example 3 illustrates the preparation of compounds of the present invention where HET is a pyrazole.
• BIOLOGICAL ASSAYS The utility of the compounds of the present invention, in the practice of the methods of the instant invention, can be evidenced by activity in at least one of the protocols described in detail below.
• ⁇ 3 receptor agonist activity and selectivity over ⁇ i and ⁇ 2 adrenergic receptors may be determined by measurement of cyclic adenosine monophosphate (cAMP) accumulation in Chinese hamster ovary cells.
• cAMP cyclic adenosine monophosphate
• Chinese hamster ovary cells uniquely transfected with the cDNA for the human ⁇ i, ⁇ 2 , or ⁇ 3 adrenergic receptor are grown to confluence in Ham's F12 media (Gibco BRL, Life Technologies, Inc., Grand Island, NY) containing 10% fetal bovine serum, 500 mg/ml geneticin, 100 U/ml penicillin, 100 mg/ml streptomycin, and 250 ng/ml fungizone according to the procedure described in American Type Culture Catalog of Cell Lines and Hybridomas, Seventh Edition, 1992, p. 36, ATCC CCL 61 CHO-K1.
• Compounds are prepared as 25 mM stock solutions in DMSO (0.1% DMSO final concentration), diluted in Ham's F12 media and added to the cells at 10 "10 to 10 "5 M along with 10 "5 M isobutylmethylxanthine to inhibit phosphodiesterase activity. The media and cells are then incubated for sixty minutes at 37 ° C. At the end of the incubation period, the media is aspirated and the cells lysed in 0.01 N HCI. The cellular content of cAMP is then determined by radioimmunoassay (RIA) using a kit from New England Nuclear (Burlington, MA).
• RIA radioimmunoassay
• Example 1-1 H A range of EC 5 o values from 13 ⁇ M to 155 ⁇ M were observed for the compounds listed in Examples 1 , 2 and 3 (Example 1-1 A through Example 3- 1 K). As a specific example, the compound of Example 3-1 H had an EC 50 of 88 ⁇ M. Example 3-1 H was chosen for illustrative purposes only and does not imply that the compound of Example 3-1 H is a preferred compound. Assay 2
• GPCRs G protein-coupled receptors exhibit at least two agonist affinity states.
• High affinity agonist binding to GPCRs requires the association or coupling of the receptor with the GDP-bound heterotrimeric G protein complex.
• the low affinity agonist binding site is indicative of the uncoupled receptor state.
• the high affinity agonist binding site can be converted to the low affinity site by addition of GTP or its analogs.
• G proteins display high affinity for GDP.
• G proteins display high affinity for GTP.
• Two affinity states for agonists can be detected in radioligand competetion binding assays.
• a two-site fit is generally observed for agonists for many GPCRs and can be calculated using commercially available software.
• the high affinity site (K i ) corresponds to the G protein-coupled state and, in the case of ⁇ 3 -adrenergic receptors correlates well with the functional ED 50 for stimulation of cAMP accumulation.
• radioligand binding assay In order to identify compounds that attenuate the binding of [ 125 l]cyanopindolol (ICYP) to ⁇ 3 adrenergic receptors, the following radioligand binding assay can be used.
• ICYP 03 Adrenergic Receptor Competition Binding Assay
• the specific activity of [ 125 I]ICYP is 2000 Ci/mmole. ICYP undergoes catastrophic decay upon radiolysis. Therefore, the specific activity always remains at 2000 Ci/mmole, but the concentration will decrease over time. The final concentration of ICYP is 250 pM. Therefore, a 2.5 nM (10 x) stock needs to be made. [ 125 I]CYP can be obtained from New England Nuclear, Boston, MA.
• Competitors Up to four compounds can be tested in thirteen competition curves in a 96 well format. An example for a single compound is outlined below. [Comp 1]
• the next compound would begin in F 3,4. Two pairs of totals and nonspecific binding are added to the plates. Wells E 3,4 and G 7,8 are for total cpm bound. Wells D 3,4 and H 7,8 are for 100 ⁇ M pindolol to determine non-specific binding.
• each well in order add: 20 ⁇ l buffer to "total" wells; 20 ⁇ l 1 mM pindolol to pindolol wells; 20 ⁇ l of each concentration of compound to the appropriate wells; 20 ⁇ l of 2.5 nM ICYP to all wells; and 160 ⁇ l membranes diluted to 15 ⁇ g/160 ⁇ l.
• Binding Buffer 50 mM Hepes/10 mM MgCI 2 , pH 7.4 (prepared from 10 x stock solution) and 0.2 % BSA (fraction V)
• Protease inhibitors prepared as 100 x stock solution: 100 ⁇ g/ml bacitracin; 100 ⁇ g/ml benzamidine; 5 ⁇ g/ml aprotin; and 5 ⁇ g/ml leupeptin.
• Wash Buffer 50 nM Hepes/10 mM MgCI 2 , pH 7.4, ice cold (prepared from 10 x stock solution)
• thermogenesis As will be well known to one of ordinary skill in the art, during increased energy expenditure, animals generally consume increased amounts of oxygen.
• metabolic fuels such as, for example, glucose and fatty acids
• thermogenesis an effect commonly referred to in the art as thermogenesis.
• the measurement of oxygen consumption in animals, including humans and companion animals is an indirect measure of thermogenesis, and indirect calorimetry may be commonly used in animals, e.g., humans, by one of ordinary skill in the art, to measure such energy expenditures.
• thermogenic response The ability of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, to generate a thermogenic response may be demonstrated according to the following protocol using male Sprague-Dawley rats (Charles River, Wilmington, MA).
• Whole animal oxygen consumption may be measured using an open circuit, indirect calorimeter (Oxymax TM , Columbus Instruments, Columbus, OH).
• the gas sensors are calibrated with nitrogen gas and gas mixture (0.5% carbon dioxide, 20.5% oxygen, 79% nitrogen; Abco Industrial Supplies, Waterford, CT) before each experiment.
• Male Sprague-Dawley rats (300 - 380 g body weight) are placed in sealed chambers (43 x 43 x 10 cm) of the calorimeter and the chambers placed in activity monitors. Air flow rate through the chambers is set at 1.6 - 1.7 l/min.
• the calorimeter software calculates the oxygen consumption (ml/kg/hour) based on the flow rate of air through the chambers and the difference in oxygen content at inlet and outlet ports.
• the activity monitors have fifteen infrared light beams spaced one inch apart on each axis; ambulatory activity is recorded when two consecutive beams are broken (repeated interruptions of the same beam are not registered) and the results are recorded as counts. Basal oxygen consumption and ambulatory activity are measured every ten minutes for two and one-half to three hours. At the end of the basal period, the chambers are opened and the test compound (0.01 - 20 mg/kg, prepared in water, 0.5% methyl cellulose, or other suitable vehicle) or an equivalent amount of vehicle is administered by oral gavage.
• Oxygen consumption and ambulatory activity are measured every ten minutes for an additional two to six hours post-dosing. Percent change in oxygen consumption is calculated by averaging the post-dosing values and dividing by basal oxygen consumption (average of the pre-dosing values except the first hour). Oxygen consumption values obtained during time periods where ambulatory activity exceeds 100 counts are excluded from the calculation. Thus, the values represent % change in resting oxygen consumption.
• the compounds of the present invention may be tested for hypoglycemic activity accoprding to the following procedure, and as an aid in determining dosages when compared to other test compounds and standards.
• mice Five to eight-week old C57 BL/6J-ob/ob mice (Jackson Laboratory, Bar Harbor, ME) are housed five animals per cage at an ambient temperature of 66 ° C under standard animal care practices. After a one week acclimation period, the animals are weighed and 25 microliters of blood is collected via an occular bleed prior to any treatment. The blood sample is immediately diluted 1 :5 with saline containing 2% sodium heparin, in tubes held on ice. Blood samples are centrifuged for two minutes to remove red blood cells and the supernatant is analyzed for glucose concentration using a clinical autoanalyzer (Abbott Spectrum ® CCx; Abbott Laboratories, Abbott Park, IL).
• mice Animals are then regrouped, in groups of five animals per cage, such that the mean glucose values of the groups are similar.
• the mice are then dosed once or twice daily for five days with test compound (0.01 - 20 mg/kg), with a positive control such as englitazone or ciglitazone (50 mg/kg p.o.) (U.S. Pat. No. 4,467,902; Sohda et al., Chem. Pharm. Bull., 32, 4460-4465, (1984)), or with vehicle. All compounds are administered by oral gavage in a vehicle consisting of 0.5% w/v methyl cellulose, or with other suitable vehicle. On Day 5, the animals are weighed again and bled (via the occular route) for blood glucose levels as described hereinabove. Plasma glucose is then calculated by the equation:
• the animals dosed with vehicle maintain substantially unchanged hyperglycemic glucose levels (e.g. 300 mg/dl), while positive control animals have depressed glucose levels (e.g. 130 mg/dl).
• the glucose lowering activity of test compounds is expressed in terms of % glucose normalization. For example, a glucose level which is the same as the positive control is expressed as 100%.
• In vivo selectivity for ⁇ i and ⁇ 2 receptors may be determined by measurements of heart rate, blood pressure, and plasma potassium concentration gathered on conscious catheterized rats (male, Sprague-Dawley, 300-400 g body weight).
• rats are anesthetized with pentobarbital (50-60 mg/kg i.p.) and the left carotid artery is cannulated with PE50 tubing.
• the catheter is tunneled subcutaneously, exteriorized at the back of the neck, filled with a solution of polyvinylpyrrolidone in heparinzied saline, flame sealed, and taped. Experiments are performed seven days after surgery.
• the catheters are untaped and flushed with saline. After at least thirty minutes, basal values for heart rate and blood pressure are measured by attaching the catheter to a pressure transducer, the results recorded on a Grass Model 7 polygraph (Grass Medical Instruments, Quincy, MA), and a basal blood sample (0.5 ml) is obtained from the arterial catheter. After obtaining basal values, the test compound or vehicle is administered by oral gavage and blood pressure (measure of ⁇ 2 activity) and heart rate (measure of ⁇ i activity) measurements are taken at 15, 30, 45, and 60 minutes, and blood samples for potassium determination ( ⁇ 2 ) are obtained at 30 and 60 minutes.
• Isoproterenol a non-selective ⁇ -agonist
• Plasma potassium is determined by flame spectrophotometry. To determine changes, basal values are subtracted from the average of the post-dosing values.
• the compounds of Formula (I) have the effect of reducing intestinal motility and thus have utility in aiding in the treatment of various gastrointestinal disorders such as irritable bowel syndrome, peptic ulceration, esophagitis, gastritis, duodenitis (including that induced by Helicobacter pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's Disease and proctitis), and gastrointestinal ulcerations.
• irritable bowel syndrome peptic ulceration, esophagitis, gastritis, duodenitis (including that induced by Helicobacter pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's Disease and proctitis), and gastrointestinal ulcerations.
• peptic ulceration including that induced by Helicobacter pylori
• intestinal ulcerations including inflammatory bowel disease, ulcerative colitis, Crohn's Disease and proctitis
• gastrointestinal ulcerations including that induced by Helicobacter py
• In vivo activity of the compounds of Formula (I) for the treatment or prevention of intestinal motility disorders can be determined according to the following procedures. Eighteen-hour fasted male Sprague-Dawley derived (CD) rats (175 - 225 g) are dosed with 0.01 - 20 mg/kg p.o. of test compound or vehicle (distilled water). Thirty minutes after administration of test compound, the rats are orally dosed with 0.25 ml of a solution of sodium chromate in 0.9% saline containing about 20,000 cpm of 51 Cr (specific activity 350 mCi/mg Cr).
• the rats are sacrificed, the gastroesophageal, pyloric, and ileocecal junctions are then ligated, and the stomachs and small intestines are removed.
• the small intestines are then divided into ten equal lengths, and the stomach and each length of intestine assayed for radioactivity with a gamma counter.
• Gastric emptying rate may then be determined for each rat by comparing the amount of radioactivity in the intestine relative to the total in the intestine plus stomach.
• the geometric center of the distribution of the radioactive marker is then used as a measure of the overall transit rate through the stomach and intestine.
• Sprague-Dawley rats (175 - 225 g) may be anesthetized with methoxyflurane. A small abdominal incision is then made, and the pylorus ligated. Immediately after the ligation, a solution of the test compound or vehicle (distilled water) is injected into the proximal duodenum. The doses of test compound used should be 0.01 - 20 mg/kg body weight. The incisions are then closed and the rats allowed to recover from the anesthesia. Two hours after the ligation, the rats are sacrificed and the gastric fluid collected and cleared by centrifugation.
• Total volume of secretion is determined by weight, and acidity is determined by titration to pH 7.0 with 0.1 N sodium hydroxide using an automatic titrator. The data from two experiments are then pooled. A group of rats treated with 10 mg/kg of of the anti-secretory histamine H 2 -receptor antagonist cimetidine may be included as a positive control. Statistical evaluations can be made using Student's t-test.
• In vitro activity for relaxation of contracted ileum from isolated guinea pig ileum is determined according to the following procedures. Fresh, isolated segments of guinea pig ileum (about 1.5 cm in length) are mounted in tissue baths containing Tyrode's physiological salt solution at about 30 ° C and aerated continuously with oxygen:carbon dioxide (95%:5%). Tissues are then equilibrated for 60 - 90 minutes under 4.0 gm tension in order to achieve stable baselines. Histamine is then added to the baths and in a cumulative fashion in concentrations ranging from 1 nM to 10 mM. The maximum tension generated after each addition of histamine is recorded on a Grass Physiograph (Grass Medical Instruments, Quincy, MA).
• the tissues are then washed with several changes of Tyrode's solution, basal tension is readjusted to 4.0 gm, and a stable baseline is then again obtained.
• Each tissue is then exposed to a single concentration of a test compound (1 nM - 10mM) or vehicle and, after a thirty minute equilibration period, the histamine dose response curve is then repeated. Results from multiple experiments are standardized (0-100%) to the maximum response of the control tissues and plotted as percent maximum tension vs. the log of the histamine concentration in the absence and presence of the test compound.
• Assay 7 Protection Against Gastric Ulceration Food (but not water) is withheld from female Sprague-Dawley rats (Charles River, Wilmington, MA) weighing 70 - 120 g. Access is then permitted to food for ninety minutes. A single dose of test compound is then administered p.o. (0.01-20 mg/kg in a dosing volume of 1 ml/100 g), and indomethacin (Sigma Chemical Co., St. Louis, MO) (60 mg/kg, 1 ml/100 g body weight) is then injected subcutaneously. Control rats receive the subcutaneous injection of indomethacin and oral administration of vehicle (0.5% methyl cellulose in distilled water) for the ⁇ -adrenoceptor agonist.
• indomethacin Sigma Chemical Co., St. Louis, MO
• the animals are then allowed continued access to food but water is withdrawn.
• the animals are then sacrificed by cervical dislocation six hours after dosing with indomethacin.
• the stomach are then removed, opened along the greater curvature and washed in 0.9% saline.
• An assessment of gastric damage is carried out by an observer who is unaware of the dosing regimen.
• a transparent plastic grid divided into 1 mm 2 sections is placed over the antrum and the area of macroscopic damage assessed as the total area of visible lesions in mm 2 . This value is then expressed as a percentage of the total antral area.
• mice are administered reserpine (2.5 mg/kg i.p. dissolved in 1% citric acid). Their rectal temperatures are measured three and one-half hours later. The mice are then divided into different groups so as to obtain the same mean rectal temperature in each group. One-half hour later, (i.e., four hours after reserpine administration), the mice are given the vehicle or test compound. Rectal temperature is measured again ninety minutes later (i.e., five hours and thirty minutes after reserpine administration) (Bourin, et al., The Value of the Reserpine Test in Psychopharmacology, Arzneim. Forsch., 33, 1173, (1983)).
• mice One-half hour after the mice are placed in individual cages, their rectal temperatures are recorded. The animals are allocated so as to obtain the same mean rectal temperature in each group.
• Apomorphine (16 mg/kg s.c.) is given thirty minutes after the test compound or vehicle. Rectal temperature is then measured again thirty minutes after the apomorphine treatment (Puech, et al., Antagonism of Hypothermia and Behavioral Response to Apomorphine; A Simple, Rapid, and Discriminating Test for Screening Anti-Depressants and Neuroleptics, Psychopharmacology, 75, 84, (1981 )).
• Avoidance training is initiated 48 hours (Day 3) after inescapable shock in automated two-way shuttle boxes (60 x 21 x 30 cm) with Plexiglass ® walls and a floor consisting of stainless-steel rods spaced 1.0 cm apart in order to evaluate escape deficits.
• Each shuttle box is divided into two chambers of equal size by a stainless-steel partition with a gate providing access to the adjacent compartment through a 7 x 7 cm space.
• Shuttle box sessions are performed for three consecutive days (Days 3, 4, and 5). The animals are placed individually in the shuttle box and allowed to habituate to the environment for five minutes (for the first session only) and then subjected to thirty trials.
• the intertrial interval should be thirty seconds.
• a light signal, used as a conditioned stimulus is presented during the first three seconds of each trial. Crossing the gate into the other compartment of the box during this "conditioned stimulus only" period (referred to as avoidance response) allows rats to avoid shocks.
• a period with conditioned stimulus plus foot-shock (0.8 mA) may be presented if an avoidance response does not occur. Crossing the gate into the other compartment during this conditioned stimulus plus shock period is referred to as an escape response. Absence of escape response during the three-second duration conditioned stimulus plus shock is considered to be an escape failure.
• In vitro activity of the compounds of Formula (I) for the treatment of airway inflammatory disorders may be determined by measurement of guinea pig bronchial ring relaxation according to the following procedure.
• Guniea pig bronchial rings are obtained from tri-colored guinea pigs of either sex (250 - 350 g), anesthized with urethane (1.25 g/kg) and suspended under an initial tension of 2.0 g in Krebs solution at 37 ° C gassed with 95% oxygen:5% carbon dioxide. After about one hour of equilibration, the guinea pig bronchial rings are contracted with acetylcholine (10 "3 M), relaxed to maximal relaxation with theophylline (10 "3 M), and then allowed to equilibrate for a further sixty minutes while they are washed with Krebs solution every fifteen minutes.
• the composition of the Krebs solution is (mM):NaCI 118.0, FCI 5.4, CaCI 2 , 2.5, KHP0 4 1.2, MgS0 4 1.2, NaHC0 3 25.0, and glucose 11.7.
• Prostate Disease Ventral prostates of male Sprague-Dawley rats 300 - 400 g anesthetized with diethyl ether are quickly excised and placed in oxygenated Krebs solution. While maintained at room temperature in this buffer, adherent fatty and connective tissues are removed. The prostates are then suspended in 10 ml organ baths containing Krebs solution warmed to 37°C and aerated with a mixture of 95% oxygen and 5% carbon dioxide.
• the composition of the Krebs solution is 118.4 mM NaCI, 4.7 mM KCI, 1.2 mM MgS0 4 , 2.5 mM CaCI 2 , 11.1 mM dextrose, 25.0 mM NaHC0 3 and 1.2 mM KH 2 P0 4 , dissolved in distilled and demineralized water.
• the tissues are attached to isometric force-displacement transducers and isometric contraction is recorded under a loading tension of 0.5g. Equilibration is undertaken for one or two hours before the addition of test compounds. Submaximal contractions are first elicited by repeated concentrations of 1 x 10 "6 M phenylephrine until constant responses are obtained.
• a concentration-response curve to cumulate concentrations of phenylephrine or acetylcholine (10 9 to lO /l) is determined.
• a concentration response curve to phenylephrine or acetylcholine is determined in the presence of the compounds.
• Prostatic tissue specimens are obtained from patients with symptomatic BPH, who are undergoing open prostatectomy. Isolated human prostatic tissue is cut into five to eight strips (3mm wide, 3mm thick and 15mm long in each strip). The strips are mounted vertically in organ baths containing 20 ml Krebs- Henseleit solution of the following composition (mM): NaCI 112, KCI 5.9, MgCI 2 1.2, CaCI 2 2, NaHC0 3 25, NaHP0 4 1.2, glucose 11.5. The medium is maintained at 37°C and at pH 7.4, and is equilibrated with a gas mixture consisting of 95% oxygen and 5% carbon dioxide. A resting tension of 0.5g is applied and the responses are recorded isometrically through a force- displacement transducer. The preparations are equilibrated for ninety minutes before starting the experiments.
• mM mM
• Concentration-response curves for phenylephrine or acetylcholine (10 "9 to 1 ⁇ 1) are determined by adding the compound directly to the bathing media in a cumulative fashion.
• the prostate strips are incubated in the presence of compound (1 or 10 ⁇ M) for thirty minutes before and then phenylephrine or acetylcholine are added to the medium in a cumulative fashion to obtain to the concentration-response curve in the presence of the compound.
• Compounds of the Formula (I) lower triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in combating medical conditions wherein such lowering (and raising) is thought to be beneficial.
• the compounds of Formula (I) can be used in the treatment of hypertriglyceridaemia, hypercholesterolemia, and conditions of low HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
• Activity of compounds of Formula (I) for dyslipidemia can be determined according to the following procedure.
• vehicle 0.5% w/v methyl cellulose/distilled water, water, or other suitable vehicle
• Plasma concentrations of free fatty acids and triglyceride are determined using a clinical autoanalyzer (Abbott Spectrum ® CCx; Abbott Laboratories, Abbott Park, IL).
• Decrease in Body Fat Activity of compounds of the present invention for decrease in body fat can be determined according to the following procedure.
• C57BL/6J ob/ob mice male, 30-40 g body weight, Jackson Lab, Bar Harbor, ME
• Body weight of each mouse is measured daily and food intake per cage determined by weighing the amount of food left in the trough.
• mice are weighed and then sacrificed by cervical dislocation.
• the epididymal fat pads from each mouse are excised and weighed.
• the fat versus body weight ratio is determined for each mouse using the absolute body weights and the fat pad weights.
• a reduction in fat pad weight is indicative of a reduction in total body fat.

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