Title of Invention

"BICYCLIC PIPERIDINE DERIVATIVES"

Abstract

BICYCLIC PIPERIDINE DERIVATIVES Certain novel bicyclic N-acylated piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

Full Text

FIELD OF THE INVENTION The present invention relates to bicyclic piperidine derivatives, their synthesis, and their use as melanocortin receptor (MC-R) agonists. More particularly, the compounds of the present invention are selective agonists of the melanocortin-4 receptor (MC-4R) and are thereby useful for the treatment of disorders responsive to the activation of MC-4R, such as obesity, diabetes, male sexual dysfunction, and female sexual dysfunction. BACKGROUND OF THE INVENTION Obesity, which can be defined as a body weight more than 20% above the ideal body weight, is a major health concern in Western societies. It is estimated that about 97 million adults in the United States are overweight or obese. Obesity is the result of a positive energy balance, as a consequence of increased ratio of caloric intake to energy expenditure. Epidemiological studies have shown that increasing degrees of overweight and obesity are important predictors of decreased life expectancy. Obesity causes or exacerbates many health problems, both independently and in association with other diseases. The medical problems associated with obesity, which can be serious and life-threatening, include hypertension; type 2 diabetes mellitus; elevated plasma insulin concentrations; insulin resistance; dyslipidemias; hyperlipidemia; endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory complications, such as obstructive sleep apnea; cholelithiasis; gallstones; arterioscelerosis; heart disease; abnormal heart rhythms; and heart arrythmias (Kopelman, P.G., Nature 404, 635-643 (2000)). Obesity is further associated with premature death and with a significant increase in mortality and morbidity from stroke, myocardial infarction, congestive heart failure, coronary heart disease, and sudden death. In the vast majority of obese individuals, the cause of the excess adiposity is not immediately apparent. A currently accepted working hypothesis is that obesity is the result of a maladaptation of the innate metabolic response to environmental challenges such as unlimited availability of low cost/energy dense foods and sedentariness (Hill et al., Science 1998; 280:1371). The study of energy intake in free living humans has met with only limited success and definitive experimental evidence that hyperphagia causes most forms of human obesity is lacking. Following the discovery of leptin, the interest in the neurohormonal regulation of food intake has regained momentum. However, while much knowledge has been gained on the regulation of food intake in rodents and other animal species, the understanding of the neurophysiology of feeding behavior in humans remains extremely limited. Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake. Several lines of evidence support the notion that the G-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R) family, several of which are expressed in the brain, are the targets of POMC derived peptides involved in the control of food intake and metabolism. A specific single MC-R that may be targeted for the control of obesity has not yet been identified, although evidence has been presented that MC-4R signalling is important in mediating feed behavior (S.Q. Giraudo et al., "Feeding effects of hypothalamic injection of melanocortin-4 receptor ligands," Brain Research. 80: 302-306 (1998)). Evidence for the involvement of MC-R's in obesity includes: i) the agouti (Avy) mouse which ectopically expresses an antagonist of the MC-IR, MC-3R and -4R is obese, indicating that blocking the action of these three MC-R's can lead to hyperphagia and metabolic disorders; ii) MC-4R knockout mice (D. Huszar et al., Cell. 88: 131-141 (1997)) recapitulate the phenotype of the agouti mouse and these mice are obese; iii) the cyclic heptapeptide MT-n (a non-selective MC-IR, -3R, -4R, and -5R agonist) injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4R antagonist; MC-IR and -5R agonist) reverses this effect and can induce hyperphagia; iv) chronic intraperitoneal treatment of Zucker fatty rats with an cc-NDP-MSH derivative (HP228) has been reported to activate MC-IR, -3R, -4R, and -5R and to attenuate food intake and body weight gain over a 12-week period (I. Corcos et al., "HP228 is a potent agonist of melanocortin receptor-4 and significantly attenuates obesity and diabetes in Zucker fatty rats," Society for Neuroscience Abstracts, 23: 673 (1997)). Five distinct MC-R's have thus far been identified, and these are expressed in different tissues. MC-IR was initially characterized by dominant gain of function mutations at the Extension locus, affecting coat color by controlling phaeomelanin to eumelanin conversion through control of tyrosinase. MC-IR is mainly expressed in melanocytes. MC-2R is expressed in the adrenal gland and represents the ACTH receptor. MC-3R is expressed in the brain, gut, and placenta and may be involved in the control of food intake and thermogenesis. MC-4R is uniquely expressed in the brain, and its inactivation was shown to cause obesity (A. Kask, et al., "Selective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats," Biochem. Biophys. Res. Commun.. 245: 90-93 (1998)). MC-5R is expressed in many tissues, including white fat, placenta and exocrine glands. A low level of expression is also observed in the brain. MC-5R knockout mice reveal reduced sebaceous gland lipid production (Chen et al., Cell 91: 789-798 (1997)). Weight loss drugs that are currently used to treat obesity have limited efficacy and significant side effects. Studies of the weight loss medications orlistat (Davidson, M.H. et al. (1999) JAMA 281:235-42), dexfenfluramine (Guy Grand, B. et al. (1989) Lancet 2:1142-5), sibutramine (Bray, G. A. et al. (1999) Obes. Res. &:189-98) and phentermine (Douglas, A. et al. (1983) Int. J. Obes. 7:591-5) have demonstrated a limited weight loss of about 5%-10% of body weight for drug compared to placebo. The side effects of these drugs and anti-obesity agents further limit their use. Dexfenfluramine was withdrawn from the market because of suspected heart valvulopathy; orlistat is limited by gastrointestinal side effects; the use of topiramate is limited by central nervous system effects; and the use of sibutramine is limited by its cardiovascular side effects which have led to reports of deaths and its withdrawal from the market in Italy. There is a need for a weight loss treatment with enhanced efficacy and fewer undesirable side effects. The instant invention addresses this problem by providing melanocortin receptor (MC-R) agonists, and in particular selective agonists of the melanocortin-4 receptor (MC-4R), useful in the treatment and prevention of obesity and obesity-related disorders, including diabetes. Melanocortin receptor involvement in male and female sexual dysfunction has also been reported. Erectile dysfunction denotes the medical condition of inability to achieve penile erection sufficient for successful sexual intercourse. The term "impotence" is oftentimes employed to describe this prevalent condition. Approximately 140 million men worldwide, and, according to a National Institutes of Health study, about 30 million American men suffer from impotency or erectile dysfunction. It has been estimated that the latter number could rise to 47 million men by the year 2000. Erectile dysfunction can arise from either organic or psychogenic causes, with about 20% of such cases being purely psychogenic in origin. Erectile dysfunction increases from 40% at age 40, to 67% at age 75, with over 75% occurring in men over the age of 50. In spite of the frequent occurrence of this condition, only a small number of patients have received treatment because existing treatment alternatives, such as injection therapies, penile prosthesis implantation, and vacuum pumps, have been uniformly disagreeable [for a discussion, see "ABC of sexual health - erectile dysfunction," Brit. Med. J. 318: 387-390 (1999)]. Only more recently have more viable treatment modalities become available, in particular orally active agents, such as sildenafil citrate, marketed by Pfizer under the brand name of Viagra®. (See "Emerging pharmacological therapies for erectile dysfunction," Exp. Opin. Ther. Patents 9: 1689-1696 (1999)). Sildenafil is a selective inhibitor of type V phosphodiesterase (PDE-V), a cyclic-GMP-specific phosphodiesterase isozyme [see R.B. Moreland et al.. "Sildenafil: A Novel Inhibitor of Phosphodiesterase Type 5 in Human Corpus Cavernosum Smooth Muscle Cells," Life Sci., 62: 309-318 (1998)]. Prior to the introduction of Viagra on the market, less than 10% of patients suffering from erectile dysfunction received treatment. Sildenafil is also being evaluated in the clinic for the treatment of female sexual dysfunction. The regulatory approval of Viagra® for the oral treatment of erectile dysfunction has invigorated efforts to discover even more effective methods to treat erectile dysfunction. Several additional selective PDE-V inhibitors are in clinical trials. UK-114542 is a sildenafil backup from Pfizer with supposedly improved properties. Tadalafil or IC-351 (ICOS Corp.) is claimed to have greater selectivity for PDE-V over PDE-VI than sildenafil. Other PDE-V inhibitors include vardenafil from Bayer, M-54033 and M-5401S from Mochida Pharmaceutical Co., and E-4010 from Eisai Co., Ltd. Other pharmacological approaches to the treatment of erectile dysfunction have been described [see, e.g., "Latest Findings on the Diagnosis and Treatment of Erectile Dysfunction," Drug News & Perspectives. 9: 572-575 (1996); "Oral Pharmacotherapy in Erectile Dysfunction." Current Opinion in Urology. 7: 349-353 (1997)]. A product under clinical development by Zonagen is an oral formulation of the alpha-adrenoceptor antagonist phentolamine mesylate under the brand name of Vasomax®. Vasomax® is also being evaluated for the treatment of female sexual dysfunction. Drugs to treat erectile dysfunction act either peripherally or centrally. They are also classified according to whether they "initiate" a sexual response or "facilitate" a sexual response to prior stimulation [for a discussion, see "A Therapeutic Taxonomy of Treatments for Erectile Dysfunction: An Evolutionary Imperative," Int. J. Impotence Res.. 9: 115-121 (1997)]. While sildenafH and phentolamine act peripherally and are considered to be "enhancers" or "facilitators" of the sexual response to erotic stimulation, sildenafil appears to be efficacious in both mild organic and psychogenic erectile dysfunction. Sildenafil has an onset of action of 30-60 minutes after an oral dose with the effect lasting about 4 hours, whereas phentolamine requires 5-30 minutes for onset with a duration of 2 hours. Although sildenafil is effective in a majority of patients, it takes a relatively long time for the compound to show the desired effects. The faster-acting phentolamine appears to be less effective and to have a shorter duration of action than sildenafil. Oral sildenafil is effective in about 70% of men who take it, whereas an adequate response with phentolamine is observed in only 35-40% of p'atients. Both compounds require erotic stimulation for efficacy. Since sildenafil indirectly increases blood flow in the systemic circulation by enhancing the smooth muscle relaxation effects of nitric oxide, it is contraindicated for patients with unstable heart conditions or cardiovascular disease, in particular patients taking nitrates, such as nitroglycerin, to treat angina. Other adverse effects associated with the clinical use of sildenafil include headache, flushing, dyspepsia, and "abnormal vision," the latter the result of inhibition of the type VI phosphodiesterase isozyme (PDE-VI), a cyclic-GMP-specific phosphodiesterase that is concentrated in the retina. "Abnormal vision" is defined as a mild and transient "bluish" tinge to vision, but also an increased sensitivity to light or blurred vision. Synthetic melanocortin receptor agonists (melanotropic peptides) have been found to initiate erections in men with psychogenic erectile dysfunction [See H. Wessells et_al., "Synthetic Melanotropic Peptide Initiates Erections in Men With Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study," J. Urol. 160: 389-393 (1998); Fifteenth American Peptide Symposium. June 14-19, 1997 (Nashville TN)]. Activation of melanocortin receptors of the brain appears to cause normal stimulation of sexual arousal. In the above study, the centrally acting a-melanocyte-stimulating hormone analog, melanotan-II (MT-ff), exhibited a 75% response rate, similar to results obtained with apomorphine, when injected intramuscularly or subcutaneously to males with psychogenic erectile dysfunction. MT-H is a synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2, v/hich contains the 4-10 melanocortin receptor binding region common to cc-MSH and adrenocorticotropin, but with a lactam bridge. It is a non-selective MC-1R, -3R, -4R, and -5R agonist (Dorr et al., Life Sciences. Vol. 58,1777-1784, 1996). MT-H (also referred to as PT-14) (Erectide®) is presently in clinical development by Palatin Technologies, Inc. and TheraTech, Inc. as a non-penile subcutaneous injection formulation. It is considered to be an "initiator" of the sexual response. The time to onset of erection with this drug is relatively short (10-20 minutes) with a duration of action approximately 2.5 hours. Adverse reactions observed with MT-II include nausea, flushing, loss of appetite, stretching, and yawning and may be the result of activation of MC-1R, MC-2R, MC-3R, and/or MC-5R. MT-II must be administered parenterally, such as by subcutaneous, intravenous, or intramuscular route, since it is not absorbed into the systemic circulation when given by the oral route. MT-II's erectogenic properties apparently are not limited to cases of psychogenic erectile dysfunction in that men with a variety of organic risk factors developed penile erections upon subcutaneous injection of the compound; moreover, the level of sexual desire was significantly higher after MT-II administration than after placebo [see H. Wessells, "Effect of an Alpha-Melanocyte Stimulating Hormone Analog on Penile Erection and Sexual Desire in Men with Organic Erectile Dysfunction." Urology. 56: 641-646 (2000)]. Compositions of melanotropic peptides and methods for the treatment of psychogenic erectile dysfunction are disclosed in U.S. Patent No. 5,576,290, assigned to Competitive Technologies. Methods of stimulating sexual response in females using melanotropic peptides have been disclosed in U.S. Patent No. 6,051,555. Spiropiperidine, piperidine and piperazine derivatives have been disclosed in WO 99/64002 (16 December 1999); WO 00/74679 (14 December 2000); WO 01/70708 (27 September 2001); WO 01/70337 (27 September 2001); WO 01/91752 (6 December 2001); WO 02/059095 (1 August 2002); WO 02/059107(1 August 2002); WO 02/059108(1 August 2002); WO 02/059117(1 August 2002); WO 02/068387 (6 September 2002); WO 02/068388 (6 September 2002); WO 03/007949 (30 January 2003); and WO 03/009847 (6 February 2003) as agonists of the melanocortin receptor(s) and particularly as selective agonists of the MC-4R receptor and thereby useful for the treatment of diseases and disorders, such as obesity, diabetes, and sexual dysfunction, including erectile dysfunction and female sexual dysfunction. Because of the unresolved deficiencies of the various pharmacological agents discussed above, there is a continuing need in the medical arts for improved methods and compositions to treat individuals suffering from psychogenic and/or organic sexual dysfunction. Such methods should have wider applicability, enhanced convenience and ease of compliance, short onset of action, reasonably long duration of action, and minimal side effects with few contraindications, as compared to agents now available. It is therefore an object of the present invention to provide bicyclic piperidine derivatives which are melanocortin receptor agonists and thereby useful to treat obesity, diabetes, male sexual dysfunction, and female sexual dysfunction. It is another object of the present invention to provide bicyclic piperidine derivatives which are selective agonists of the melanocortin-4 (MC-4R) receptor. It is another object of the present invention to provide pharmaceutical compositions comprising the melanocortin receptor agonists of the present invention with a pharmaceutically acceptable carrier. It is another object of the present invention to provide methods for the treatment or prevention of disorders, diseases, or conditions responsive to the activation of the melanocortin-4 receptor in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. It is another object of the present invention to provide methods for the treatment or prevention of obesity, diabetes mellitus, male sexual dysfunction, and female sexual dysfunction by administering the compounds and pharmaceutical compositions of the present invention to a mammal in need thereof. It is another object of the present invention to provide methods for the treatment of erectile dysfunction by administering the compounds and pharmaceutical compositions of the present invention to a mammal in need thereof. These and other objects will become readily apparent from the detailed description that follows. SUMMARY OF THE INVENTION The present invention relates to novel bicyclic N-acylated piperidines of structural formula I: (Formula Removed) These bicyclic piperidine derivatives are effective as melanocortin receptor agonists and are particularly effective as selective melanocortin-4 receptor (MC-4R) agonists. They are therefore useful for the treatment and/or prevention of disorders responsive to the activation of MC-4R, such as obesity, diabetes as well as male and female sexual dysfunction, and in particular, male erectile dysfunction. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier. The present invention also relates to methods for the treatment or prevention of disorders, diseases, or conditions responsive to the activation of the melanocortin-4 receptor in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The present invention also relates to methods for the treatment or prevention of obesity, diabetes mellitus, male sexual dysfunction, and female sexual dysfunction by administering the compounds and pharmaceutical compositions of the present invention. The present invention also relates to methods for treating erectile dysfunction by administering the compounds and pharmaceutical compositions of the present invention. The present invention also relates to methods for treating erectile dysfunction by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to treat the condition. The present invention also relates to methods for treating or preventing obesity by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to prevent or treat the condition. The present invention also relates to methods for treating or preventing diabetes by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent known to be useful to prevent or treat the condition. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to bicyclic N-acylated piperidine derivatives useful as melanocortin receptor agonists, in particular, as selective MC-4R agonists. Compounds of the present invention are described by structural formula I: (Formula Removed) or a pharmaceutically acceptable salt thereof; wherein X and Y are independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) C2-6 alkenyl, (4) -(CH2)nC3-8 cycloalkyl, (5) -(CH2)n-phenyl, (6) -(CH2)n-naphthyl, (7) -(CH2)n-heteroaryl, (8) -(CH2)nC2-8 heterocycloalkyl, (9) -(CH2)nON, (10) -(CH2)nCON(R5)2, (11) -(CH2)nC02R5, (12) -(CH2)nCOR5, (13) -(CH2)nNR5C(0)R5, (14) -(CH2)nNR5c02R5, (15) -(CH2)nNR5C(0)N(R5)2 (16) -(CH2)nNR5s02R5, (17) -(CH2)nS(0)pR5, (18) -(CH2)nS02N(R5)2, (19) -(CH2)nOR5, (20) -(CH2)nOC(0)R5, (21) -(CH2)nOC(0)OR5, (22) -(CH2)nOC(0)N(R5)2, (23) -(CH2)nN(R5)2, and (24) -(CH2)nNR5S02N(R5)2, wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CHo) are unsubstituted or substituted with one to three groups independently selected from R3 and oxo; Rl is selected from the group consisting of (1) hydrogen, (2) amidino, (3) C1-4 alkyliminoyl, (4) C1-10 alkyl, (5) -(CH2)n-C3-7 cycloalkyi, (6) -(CH2)n-phenyl, (7) -(CH2)n-naphthyl, and (8) -(CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyi are unsubstituted or substituted with one to three groups independently selected from R3 and oxo; R2 is selected from the group consisting of (1) C1-6 alkyl, (2) phenyl, (3) naphthyl, and (4) heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl is unsubstituted or substituted with one to three groups independently selected from R3 and oxo; each R3 is independently selected from the group consisting of (1) C1-8 alkyl, (2) -(CH2)n-phenyl, (3) -(CH2)n-naphthyl, (4) -(CH2)n-heteroaryl, (5) -(CH2)nC2-8 heterocycloalkyl, (6) -(CH2)nC3-7 cycloalkyi, (7) halogen, (8) OR4, (9) -(CH2)nN(R4)2, (10) -(CH2)nCsN, (11) -(CH2)nC02R4, (12) N02, (13) -(CH2)nNR4sO2R4 (14) -(CH2)nS02N(R4)2, (15) -(CH2)nS(0)pR4 (16) -(CH2)nNR4C(0)N(R4)2, (17) -(CH2)nC(0)N(R4)2, (18) -(CH2)nNR4C(0)R4, (19) -(CH2)nNR4CO2R4, (20) -(CH2)nNR4C(0)-heteroaryl, (21) -(CH2)nC(0)NR4N(R4)2, (22) -(CH2)nC(0)MR4NR4C(0)R4, (23) 0(CH2)nC(0)N(R4)2, (24) CF3, (25) -CH2CF3, (26) OCF3, and (27) OCH2CF3, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4alkyl, trifluoromethyl, and C1-4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C1-4alkyl, trifluoromethyl, and C1-4 alkoxy, or wherein two R3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R4 is independently selected from the group consisting of (1) hydrogen, (2) C1-6 alkyl, (3) -(CH2)n-phenyl, (4) -(CH2)n-heteroaryl, (5) -(CH2)n-naphthyl, (6) -(CH2)nC2-8 heterocycloalkyl, (7) -(CH2)nC3-7 cycloalkyl, and (8) -(CH2)nC3-7 bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, cycloalkyl, bicycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from halogen, I / We Claim: 1. A bicyclic N-acylated piperidine compounds of structural formula 1 : (Formula Removed) or a pharmaceutically acceptable salt thereof; wherein X and Y are independently selected from the group consisting of (1) hydrogen, (2) C1-8alkyl, (3) C2-6 alkenyl, (4) -(CH2)nC3-8 cycloalkyl, (5) -(CH2)n-phenyl, (6) -(CH2)n-naphthyl, (7) -(CH2)n-heteroaryl, (8) -(CH2)nC2-8 heterocycloalkyl, (9) -(CH2)nC-N, (10) -(CH2)nCON(R5R5), (11) -(CH2)nCO2R5, (12) -(CH2)nCOR5, (13) -(CH2)nNR5C(O)R5, (14) -(CH2)nNR5CO2R5, (15) -(CH2)nNR5c(O)N(R5)2, (16) -(CH2)nNR5SO2R5, (17) -(CH2)nS(O)pR5, (18) -(CH2)nSO2N(R5)(R5), (19) -(CH2)nOR5, (20) -(CH2)nOC(O)R5, (21) -(CH2)nOC(O)OR5, (22) -(CH2)nOC(O)N(R5)2, (23) -(CH2)nN(R5)(R5), and (24) -(CH2)nNR5SO2N(R5)(R5); wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from R3 and oxo; R1 is selected from the group consisting of (1) hydrogen, (2) amidino, (3) C1-4 alkyliminoyl, (4) Ci-io alkyl, (5) -(CH2)n-C3-7 cycloalkyl, (6) -(CH2)n-phenyl, (7) -(CH2)n-naphthyl, and (8) -(CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and (CH2) are unsubstituted or substituted with one to three groups independently selected from R3 and oxo; R2 is selected from the group consisting of (1) C1-6 alkyl, (2) phenyl, (3) naphthyl, and (4) heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl is unsubstituted or substituted with one to three groups independently selected from R3 and oxo; each R3 is independently selected from the group consisting of (1) C1-8 alkyl, (2) -(CH2)n-phenyl, (3) -(CH2)n-naphthyl, (4) -(CH2)n-heteroaryl, (5) -(CH2)nC2-8 heterocycloalkyl, (6) -(CH2)nC3-7 cycloalkyl, (7) halogen, (8) OR4, (9) -(CH2)nN(R4)2, (10) -(CH2)nC-N, (11) -(CH2)nCO2R4, (12) NO2, (13) -(CH2)nNR4SO2R4 (14) -(CH2)nSO2N(R4)2, (15) -(CH2)nS(O)pR4, (16) -(CH2)nNR4C(O)N(R4)2, (17) -(CH2)nC(O)N(R4)2, (18) -(CH2)nNR4C(O)R4, (19) -(CH2)nNR4CO2R4, (20) -(CH2)nNR4C(O)-heteroaryl, (21) -(CH2)nC(O)NR4N(R4)2, (22) -(CH2)nC(O)NR4NR4c(O)R4, (23) O(CH2)nC(O)N(R4)2, (24) CF3, (25) CH2CF3, (26) OCF3, and (27) OCH2CF3, wherein phenyl, naphthyl, and heteroaryi are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy, or wherein two R3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R4 is independently selected from the group consisting of (1) hydrogen. (2) C1-6alkyl, (3) -(CH2)n-phenyl, (4) -(CH2)n-heteroaryl, (5) -(CH2)n-naphthyl, (6) -(CH2)nC2-8 heterocycloalkyl, (7) -(CH2)nC3-7 cycloalkyl, and (8) -(CH2)nC3-7 bicycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, cycloalkyl, bicycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from halogen, C1-4 alkyl, hydroxy, and C1-4 alkoxy, or two R4 groups together with the atom to which they are attached form a 4- to 8- membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and-NC1-4 alkyl; each R5 is independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) -(CH2)n-phenyl, (4) -(CH2)n-naphthyl, (5) -(CH2)n-heteroaryl, and (6) -(CH2)nC3-7 cycloalkyl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, (CH2) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3 and oxo, or wherein two R5 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and -NC 1-4 alkyl; each R6 is independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) -(CH2)nC3-6 cycloalkyl, (4) -(CH2)n-aryl, (5) hydroxy, (6) halogen, and (7) amino; each R7 is independently selected from the group consisting of (1) hydrogen, (2) C1-8alkyl, (3) -(CH2)nC3-6 cycloalkyl, (4) -(CH2)n-aryl, (5) hydroxy, (6) halogen, and (7) amino; r is 1 or 2; s is 0, 1, or 2; t is 1,2, or 3; n is 0, 1 or 2; and p is 0, 1, or 2. 2. The compound as claimed in Claim 1 wherein R1 is selected from the group consisting of hydrogen, C1-6 alkyl, -(CH2)0-lC3-6 cycloalkyl, and -(CH2)0-1-phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and (CH2) are optionally substituted with one to three groups independently selected from R3 and oxo. 3. The compound as claimed in Claim 1 wherein R2 is phenyl or thienyl, optionally substituted with one to three groups independently selected from R3; Wherein X is selected from the group consisting of (1) hydrogen, (2) -(CH2)n-phenyl, (3) -(CH2)n-naphthyl, (4) -(CH2)n-heteroaryl, (5) -(CH2)nC3-8 cycloalkyl, and (6) -(CH2)nC2-8 heterocycloalkyl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R3, and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R3 and oxo. 4. The compound as claimed in Claim 3 wherein R2 is phenyl optionally substituted with one to three groups independently selected from R3- 5. The compound as claimed in Claim 3 wherein X is selected from the group consisting of (1) hydrogen, (2) -(CH2)0-1-phenyl, (3) -(CH2)o-l-heteroaryl, (4) -(CH2)0-l-C2-8 heterocycloalkyl, and (5) -(CH2)0-l-C3-8 cycloalkyl, wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R3, and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R3 and oxo. 6. The compound as claimed in Claim 1 wherein Y is selected from the group consisting of (1) C1-6 alkyl, (2) -(CH2)n-phenyl, (3) -(CH2)n-naphthyl, (4) -(CH2)n-heteroaryl, (5) -(CH2)n-C3-8 cycloalkyl, (6) -(CH2)n-C2-8 heterocycloalkyl, (7) -(CH2)nC(O)N(R5)2, (8) -(CH2)nCO2R5, (9) -(CH2)nS(O)pR5, (10) -(CH2)nOR5, (11) -(CH2)nNR5C(O)R5, and (12) -(CH2)nNR5SO2R5, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl, heterocycloalkyl and (CH2) are optionally substituted with one to three groups independently selected from R3 and oxo. 7. The compound as claimed in Claim 6 wherein Y is selected from the group consisting of (1) C1.6 alkyl, (2) -(CH2)0-1-phenyl, (3) -(CH2)0-l-heteroaryl, (4) -(CH2)o-l-C3-8cycloalkyl, (5) -(CH2)0-l-C2-8 heterocycloalkyl, (6) -(CH2)0-1NHC(O)R5, (7) -(CH2)0-1CO2R5, (8) -(CH2)0-1C(O)N(R5)2, and (9) -(CH2)0-lS(O)pR5, wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R3 and oxo. 8. The compound as claimed in Claim 3 wherein R6 and R7 are hydrogen. 9. The compound as claimed in Claim 1 wherein r is 1 and s is 1. 10. The compound as claimed in Claim 1 wherein r is 2 and s is 1. 11. The compound as claimed in Claim 1, selected from the group consisting of: (Formula Removed) (3S,4R)-3-[(3-{2-[l-(acetylamino)propyl]-4-chlorophenyl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-l-tert- butyl-4-(2,4-difluorophenyl)pyrrolidine (Formula Removed) N-(tert-butyl)-8-{[(3S,4R)-l-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-cyclohexyl-8- azabicyclo[3.2.1 ]octane-3-carboxamide (Formula Removed) (3R,4R)-l-tert-butyl-3-({3-cyclohexyl-3-[(methylthio) methyl]-8-azabicyclo[3.2.1 ]oct-8-yl}carbonyl)-4- (2,4-difluorophenyl) pyrrolidine (Formula Removed) (3R,4R)-l-tert-butyl-3-({3-cyclohexyl-3-[(methylsulfinyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl}carbonyl)- 4-(2,4-difluorophenyl)pyrrolidine (Formula Removed) (3R,4R)-l-tert-butyl-3-({3-cyclohexyl-3-[(methylsulfonyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl}carbonyl)- 4-(2,4-difluorophenyl)pyramiding (Formula Removed) (3R,4R)-4-[(3-{2-[l -(acetylamino)propyl]-4-chlorophenyl}-8-azabicyclo[3.2.1 ]oct-8-yl)carbonyl]-l -tert- butyl-3-(2,4-difluorophenyl)piperidine (Formula Removed) (3R,4R)-l-tert-butyl-4-({3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8-aza-bicyclo[3.2.1]oct-8-yl}carbonyl)-3-(2,4-difluorophenyl)piperidine or a pharmaceutically acceptable salt thereof. 12. The compound as claimed in Claim 11 wherein the pharmaceutical ly acceptable salt thereof is the hydrochloride salt. 13. The compound as claimed in Claim 11 wherein the pharmaceutically acceptable salt thereof is the trifluoroacetic acid salt. 14. The compound as claimed in Claim 1 which is: (Formula Removed) wherein; Y is hydrogen; X is -(CH2)n-phenyl, where n = 0 and phenyl is di-substituted with R3, where R3 is chloro and - (CH2)nNR4C(O)R4 Where n = 1, R4 is hydrogen and -CH3; and where (CH2) is substituted with C2 alkyl Rl is C4 alkyl R2 is phenyl which is di-substituted with R3 where both R3 are fluoro. t is 2, r is 1, and s is 1 15. The compound as claimed in Claim 1 which is: (Formula Removed) wherein; Y is hydrogen; X is - (CH2) n-phenyl, where n = 0 and phenyl is di-substituted with R3, where R3 is chloro and -(CH2)nNR4C (O) R4 Where n = 1, R4 is hydrogen and -CH2; and where (CH2) is substituted with C2 alkyl Rl is C4 alkyl R2 is phenyl which is di-substituted with R3 where both R3 are fluoro. t is 2, r is 2, and s is 1 16. The compound as claimed in Claim 1 which is: (Formula Removed) wherein; Y is hydrogen; X is - (CH2) n-phenyl, where n = 0 and phenyl is di-substituted with R3, where R3 is - (CH2) n-C6 cycloalkyl where n = 0, and -(CH2)nC(O)N(R4)2 where n = 0 and R4 is hydrogen and C4 alkyl. Rl is C4 alkyl R2 is phenyl which is di-substituted with R3 where both R3 are fluoro. t is 2, r is 2, and s is 1 17. A pharmaceutical composition comprising a compound of structural formula 1 as claimed in claim land pharmaceutically acceptable carrier; wherein the said pharmaceutical composition optionally comprising a second active ingredient selected from the group consisting of an insulin sensitizer, an insulin mimetic, a sulfonylurea, an α-glucosidase inhibitor, and a HMG-CoA reductase inhibitor.

Documents:

4095-DELNP-2005-Abstract-(03-03-2008).pdf

4095-DELNP-2005-Abstract-(13-01-2009).pdf

4095-DELNP-2005-Abstract-(19-12-2008).pdf

4095-delnp-2005-abstract.pdf

4095-delnp-2005-assignment.pdf

4095-DELNP-2005-Claims-(03-03-2008).pdf

4095-DELNP-2005-Claims-(09-01-2009).pdf

4095-DELNP-2005-Claims-(13-01-2009).pdf

4095-DELNP-2005-Claims-(19-12-2008).pdf

4095-delnp-2005-claims.pdf

4095-delnp-2005-complete specification (granted).pdf

4095-DELNP-2005-Correspondence-Others-(03-03-2008).pdf

4095-DELNP-2005-Correspondence-Others-(09-01-2009).pdf

4095-DELNP-2005-Correspondence-Others-(13-01-2009).pdf

4095-DELNP-2005-Correspondence-Others-(19-12-2008).pdf

4095-DELNP-2005-Correspondence-Others-(29-09-2008).pdf

4095-DELNP-2005-Correspondence-Others-21-05-2008.pdf

4095-delnp-2005-correspondence-others.pdf

4095-delnp-2005-description (complete)-03-03-2008.pdf

4095-delnp-2005-description (complete).pdf

4095-DELNP-2005-Form-1-(03-03-2008).pdf

4095-delnp-2005-form-1.pdf

4095-delnp-2005-form-18.pdf

4095-DELNP-2005-Form-2-(03-03-2008).pdf

4095-DELNP-2005-Form-2-(09-01-2009).pdf

4095-delnp-2005-form-2.pdf

4095-DELNP-2005-Form-3-(03-03-2008).pdf

4095-delnp-2005-form-3.pdf

4095-delnp-2005-form-5.pdf

4095-DELNP-2005-GPA-(19-12-2008).pdf

4095-DELNP-2005-Others-Document-(03-03-2008).pdf

4095-DELNP-2005-Others-Document-(09-01-2009).pdf

4095-delnp-2005-pct-210.pdf

4095-delnp-2005-pct-220.pdf

4095-delnp-2005-pct-237.pdf

4095-DELNP-2005-PCT-304-(19-12-2008).pdf