Bicyclic piperidine derivatives as melanocortin-4 receptor agonists

专利摘要:

公开号:AU2004226452A1
申请号:U2004226452
申请日:2004-03-22
公开日:2004-10-14
发明作者:Liangqin Guo；Ravi P Nargund；Zhixiong Ye
申请人:Merck and Co Inc；
IPC主号:A61P3-04

专利说明:
WO 2004/087159 PCT/US2004/008711 TITLE OF THE INVENTION BICYCLIC PIPERIDINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR AGONISTS 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 arrythnias (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.
WO 2004/087159 PCT/US2004/008711 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-1R, 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-II (a non-selective MC-1R, -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-1R and -5R agonist) reverses this effect and can induce hyperphagia; iv) chronic intraperitoneal treatment of Zucker fatty rats with an c-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -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-1R 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-1R 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, -2- WO 2004/087159 PCT/US2004/008711 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 -3- WO 2004/087159 PCT/US2004/008711 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-54018 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 sildenafil 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 patients. 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 -4- WO 2004/087159 PCT/US2004/008711 appears to cause normal stimulation of sexual arousal. In the above study, the centrally acting c melanocyte-stimulating hormone analog, melanotan-I (MT-Il), exhibited a 75% response rate, similar to results obtained with apomorphine, when injected intramuscularly or subcutaneously to males with psychogenic erectile dysfunction. MT-1I is a synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe Arg-Trp-Lys]-NH2, which contains the 4-10 melanocortin receptor binding region common to a-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-II (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 -5- WO 2004/087159 PCT/US2004/008711 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: X R6 R7
R
1 y) o
R
2 O R (I) -6- WO 2004/087159 PCT/US2004/008711 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: X R 6
R
7
R
1 N o R (1) -7- WO 2004/087159 PCT/US2004/008711 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) C 2 -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(R 5 )2, (11) -(CH2)nCO2R 5 , (12) -(CH2)nCOR 5 , (13) -(CH2)nNR 5
C(O)R
5 , (14) -(CH2)nNR 5 CO2R 5 , (15) -(CH2)nNR 5
C(O)N(R
5 )2, (16) -(CH2)nNR 5 SO2R 5 , (17) -(CH2)nS(O)pR 5 , (18) -(CH2)nSO2N(R 5 )2, (19) -(CH2)nOR 5 , (20) -(CH2)nOC(O)R 5 , (21) -(CH2)nOC(O)OR 5 , (22) -(CH2)nOC(O)N(R 5 )2, (23) -(CH2)nN(R 5 )2, and (24) -(CH2)nNR 5 SO2N(R 5 )2, wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R1 is selected from the group consisting of (1) hydrogen, (2) amidino, -8- WO 2004/087159 PCT/US2004/008711 (3) C 1 4 alkyliminoyl, (4) CI-10 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 R 3 , and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;
R
2 is selected from the group consisting of (1) CI-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 R 3 , and wherein alkyl is unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; each R 3 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) OR 4 , (9) -(CH2)nN(R 4 )2, (10) -(CH2)nC=-N, (11) -(CH2)nCO2R 4 , (12) NO2, (13) -(CH2)nNR 4 SO2R 4 (14) -(CH2)nSO2N(R 4 )2, (15) -(CH2)nS(O)pR 4 , -9- WO 2004/087159 PCT/US2004/008711 (16) -(CH2)nNR 4
C(O)N(R
4 )2, (17) -(CH2)nC(O)N(R 4 )2, (18) -(CH2)nNR 4
C(O)R
4 , (19) -(CH2)nNR 4
CO
2
R
4 , (20) -(CH2)nNR 4 C(O)-heteroaryl, (21) -(CH2)nC(O)NR 4
N(R
4 )2, (22) -(CH2)nC(O)NR 4
NR
4
C(O)R
4 , (23) O(CH2)nC(O)N(R 4 )2, (24) CF3, (25) -CH 2
CF
3 , (26) OCF3, and (27) OCH2CF3, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 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 R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R 4 is independently selected from the group consisting of (1) hydrogen, (2) C1-6 alkyl, (3) -(CH2)n-phenyl, (4) -(CH12)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 R 4 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 R 5 is independently selected from the group consisting of -10- WO 2004/087159 PCT/US2004/008711 (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 R 3 , and wherein alkyl, (CH2) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein two R 5 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;
R
6 and R 7 are each 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; r is 1 or 2; s is 0, 1, or 2; tis 1,2,or3; nis 0, 1 or 2; and pis 0, 1, or2. In one embodiment of the compounds of structural formula I, R1 is selected from the group consisting of hydrogen, C1-6 alkyl, -(CH 2 )0-1C3-6 cycloalkyl, and -(CH2)0-1-phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo. In a second embodiment of the compounds of structural formula I, R 2 is phenyl or thienyl optionally substituted with one to three groups independently selected from R 3 . In a class of this embodiment, R 2 is phenyl optionally substituted with one to three groups independently selected from
R
3 . -11 - WO 2004/087159 PCT/US2004/008711 In a third embodiment of the compounds of structural formula I, R 3 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) -(CH 2 )nC 2 -8 heterocycloalkyl, (6) -(CH2)nC3-7 cycloalkyl, (7) halogen, wherein phenyl, naphthyl, and heteroaryl 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 R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group. In a fourth embodiment of the compounds of structural formula I, 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 R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo. In a class of this embodiment, X is selected from the group consisting of hydrogen, -(CH2)0-1-phenyl, -(CH2)0 1-heteroaryl, -(CH 2
)
0
-
1
C
2
-
8 heterocycloalkyl, and -(CH2)0-1C 3 -8 cycloalkyl, wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and whereincycloalkyl, heterocycloalkyl, and CH2 are optionally substituted with one to three groups independently selected from R 3 and oxo. In a subclass of this class, X is selected from the group consisting of hydrogen and -(CH2)0-1-C3-8 cycloalkyl, wherein cycloalkyl and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo. In a subclass of this subclass, X is selected from the group consisting of hydrogen and cyclohexyl, wherein cyclohexyl is optionally substituted with one to three groups independently selected from R 3 and oxo. - 12- WO 2004/087159 PCT/US2004/008711 In a fifth embodiment of the compounds of structural formula I, Y is selected from the group consisting of C1-6 alkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)n-C3-8 cycloalkyl, -(CH2)nC2-8 heterocycloalkyl, -(CH2)nC(O)N(R 5 )2, -(CH 2 )nCO2R 5 , -(CH2)nS(O)pR 5 , (CH2)nOR 5 , -(CH2)nNR 5
C(O)R
5 , and -(CH2)nNR 5 SO2R 5 , wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo. In a class of this embodiment, Y is selected from the group consisting of Cl-6 alkyl, -(CH2)0-1-phenyl, -(CH2)0-1-heteroaryl, -(CH2)n-C3-8 cycloalkyl, -(CH2)0-1C2-8 -heterocycloalkyl, -(CH2)0o-lNHC(O)R 5 , -(CH 2 )0- 1 CO2R 5 , -(CH 2 )0-lC(0)N(R 5 )2, and -(CH2)0 1S(O)pR 5 , wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo. In a subclass of this class, Y is selected from the group consisting of -(CH2)0-1-phenyl, -(CH 2
)
0
-NHC(O)R
5 , -(CH2)0 1C(O)N(R 5 )2, and -(CH2)0-1S(O)pRS, wherein (CH2) is optionally substituted with one to three groups independently selected from R 3 and oxo. In yet a further embodiment of compounds of structural formula I, r is 1. In a class of this embodiment, r is 1 and s is 1. In yet a further embodiment of compounds of structural formula I, r is 2. In a class of this embodiment, r is 2 and s is 1. In yet another embodiment of the compounds of structural formula I, t is 2. In a further embodiment of the compounds of the present invention, there are provided compounds of structural formula IIa or lfIb of the indicated relative stereochemical configurations having the trans orientation of the R 2 and bridged piperidine carbonyl substituents:
XR
6 7
R
1 R 7 R t N or N N- N N N' 2O R2 0 R2 0 (la) (Jlb) or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of (1) hydrogen, (2) -(CH2)n-phenyl, (3) -(CH2)n-naphthyl, -13- WO 2004/087159 PCT/US2004/008711 (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 R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo; Y is selected from the group consisting of 0 0 0 0 OH 3
OCH
3 v ,Et O1CH3 01OCH 3 0 0 0 O 0 OCH O ' S'CH3 kO O'CH 3 0 CH 3 0 0 0 H~~O O 'C<eKO, NOH NH O OH 0 0 0 0 CH 3 0
NCH
3 Et N CH3 N N N t N O-H 3 N H H H H H 0 0 0 0 0 0 N -- CH 3 N SCH 3 HH
YINH
2 ~ 0 00 r-ZN 0 O, O, N H 0 0 -HN N- OH HN
N
CH 3 H H - 14- WO 2004/087159 PCT/US2004/00871 1 N0 C NH0 0 0 H, NH OH 3 CH NHCH C H 3 < -1H H 3 NH OH c ~~ 01 l N H O 3 NH- ,/ H N _SCH3 I-zl 3HX 0 0 00 0OH 3 . 0l CH 0) CO 0 ICH 0 Hs KX
OH
3 -i .L s~ N NN
,-
7 0 H N S -OHr N~ Np. </i -CH 2 HC-K}H §iKCH2 KY sS Sr COH 3 S N-N HO N ,N~ QH ,NOH K H 3 0 --/1 S .3J"S CH S OH 2 N NCH 3 NN N> N CO K/Ni~~o</ 30/CC 2 /i~H2 </Nyi H 0 '+0J Cj-HO 0 A/ N-1 N -iI N OH 3 HON H H H HN F- N 0 HOC r- H 2 N O N - -<H H -0 N- N-0 /2-e ', 3I - ~N '>N H N HN- N 40
CO
3 H - 15 - WO 2004/087159 PCT/US2004100871 1
H
2 C ,N N ~4N'~ N H 2 0 Nf N 0 N p! N-i -a_ HN-NH H 2 0-/ 'CH, HN-NKOH3 N H2- -N-CH 2
(O)CH
3 -()(H) -(O)M-t-BU
-CH
2
SCH(CH
3
)
2
-CH
2
S(OH)CH
2
(CH
3
)
2 f-CH 2
S(O)
2
CH(CH
3
)
2 f-C(O)NHCH 2
CH
2
N(CH
3
)
2 ' -C(O)CH(CH 3
)
2 -CHMNCOtBu
~-CH
2
SCH
3 t-CH 2 S(0)CH3 -CHAS() 2
CH
3 t-CH 2
N(CH
3 )C(0)t-Bu t-CH 2 N(iPr)C0Me -CH 2 NAPr)S0 2 Me I-CH(Et)NHC(0)Me t~CH(Me)NHC(0)Me -CH 2 NHC(0)Me j-CO)N HC(Me) 2
CH
2 OMe -C(0)NHCMe 2
CH
2 0H f-CH 2
CH
2 C(Me) 2 0H N NH , N N-OH 3 N_0
H
2 .. H 2 C .,N H 2 C .. H 2 C,. Ni1 N )N N 2 p0 2 0 0 0 0 HCN H 2 C,. H 2 C.. N H2C...N NMe 02 0- :NH 00 0 Ko - 16 - WO 2004/087159 PCT/US2004/008711
-CH
2
CH
2 NEt 2
-CH
2 CONEt 2 ~Me N'KN H2CH 2 C H 2 C N OO
H
2 C 'CH,
NH
2 O O and NkN N-N N-N H N
'CH
3
CH
2 CF HC wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R1 is hydrogen, amidino, C1-4 alkylimninoyl, C1-6 alkyl, C5-6 cycloalkyl, -(CH2)0-1 phenyl, -(CH2)0-1 heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;
R
2 is phenyl or thienyl optionally substituted with one to three groups independently selected from R 3 ; each R 3 is independently selected from the group consisting of (1) C1-8 alkyl, (2) -(CH2)n-heteroaryl, (3) -(CH2)nC2-8 heterocycloalkyl, (4) halogen, (5) OR 4 , (6) -(CH2)nN(R 4 )2, (7) -(CH2)nC-N, (8) -(CH2)nCO2R 4 , (9) -(CH2)nNR 4 SO2R 4 (10) -(CH2)nSO2N(R 4 )2, (11) -(CH2)nS(O)pR 4 , (12) -(CH2)nNR 4
C(O)N(R
4 )2, (13) -(CH2)nC(O)N(R 4 )2, (14) -(CH2)nNR 4
C(O)R
4 , - 17- WO 2004/087159 PCT/US2004/008711 (15) -(CH2)nNR 4 CO2R 4 , (16) -(CH2)nNR 4 C(O)-heteroaryl, (17) -(CH2)nC(O)NR 4
N(R
4 )2, (18) -(CH2)nC(O)NR 4
NR
4
C(O)R
4 , (19) O(CH2)nC(O)N(R 4 )2, (20) CF3, (21) CH2CF3, (22) OCF3, and (23) OCH2CF 3 ; wherein phenyl, naphthyl, and heteroaryl 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 C 1 4 alkoxy, or wherein two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R 4 is independently selected from the group consisting of (1) hydrogen, (2) Cl-8 alkyl, (3) phenyl, (4) heteroaryl, (5) -(CH2)nC2-8 heterocycloalkyl, and (6) C3-6 cycloalkyl; 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 R 4 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 R 5 is independently selected from the group consisting of (1) hydrogen, (2) CI-8 alkyl, (3) -(CH2)n-phenyl, (4) -(CH2)n-naphthyl, (5) -(CH2)n-heteroaryl, and -18- WO 2004/087159 PCT/US2004/008711 (6) -(CH2)nC 3
-
7 cycloalkyl; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, (CH2) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein two R 5 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 -NC1- 4 alkyl;
R
6 and R 7 are each independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) -(CH2)n C3-6 cycloalkyl, (4) -(CH2)n-aryl, (5) hydroxy, (6) halogen, and (7) amino; r is 1 or 2; sis 0, 1 or2; tis 1,2, or3; n is 0, 1, or 2; and pis 0, 1, or 2. In another embodiment, Y is selected from the group consisting of
-CH
2
SCH
3 , I-CH 2
S(O)CH
3 , -CH 2
S(O)
2
CH
3 , -CH(Et)NHC(O)Me,
I-CH
2
CH
2 NEt 2 , -CH 2 CONEt 2 , 2< 0 NN NIN O H O H H NN O S OH ,and N -19- WO 2004/087159 PCT/US2004/008711 wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo. In yet a further embodiment of the compounds of the present invention, there are provided compounds of structural formula IIIa or IIIb of the indicated relative stereochemical configurations having the trans orientation of the phenyl and piperidine carbonyl substituents:
XR
6 7 R 1 X R 6 R7 R ( ) ( r b) or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of (1) hydrogen, (2) -(CH2)0-1-phenyl, (3) -(CH2)0-1-naphthyl, (4) -(CH2)0-1-heteroaryl, (5) -(CH2)0-1 C3-8 cycloalkyl, and (6) -(CH 2
)
0 -1C2-8 heterocycloalkyl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo; Y is selected from the group consisting of - 20 - WO 2004/087159 PCT/US2004/008711 t-CH 2
SCH
3 , -CH 2
S(O)CH
3 , -jCH 2
S(O)
2
CH
3 , -CH(Et)NHC(O)Me,
-CH
2
CH
2 NEt 2 , -CH 2 CONEt 2 , O H 0 H H N"N N 0 O o OH ,and /,-_N wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R1 is hydrogen, C1-4 alkyl, or -(CH2)0-1 phenyl; each R 3 is independently selected from the group consisting of (1) C1-8 alkyl, (2) -(CH2)0-1-heteroaryl, (3) -(CH2)0-1C2-8 heterocycloalkyl, (4) halogen, (5) OR 4 , (6) -(CH2)0-1N(R 4 )2, (7) -(CH2)0-1C-N, (8) -(CH2)0-CO2R 4 , (9) -(CH2)0-1NR 4 SO2R 4 (10) -(CH2)0- 1 SO2N(R 4 )2, (11) -(CH2)0- 1 S(O)0-3R 4 , (12) -(CH2)0-1NR 4
C(O)N(R
4 )2, (13) -(CH2)0-1C(O)N(R 4 )2, (14) -(CH2)0-INR 4
C(O)R
4 , (15) -(CH2)0-1NR 4 CO2R 4 , (16) -(CH2)0-1NR 4 C(O)-heteroaryl, (17) -(CH2)0-1C(O)NR 4
N(R
4 )2, -21 - WO 2004/087159 PCT/US2004/008711 (18) -(CH 2
)
0 - C(O)NR 4
NR
4
C(O)R
4 , (19) O(CH 2
)
0 - C(O)N(R 4 )2, (20) CF3, (21) CH2CF 3 , (22) OCF3, and (23) OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1 4 alkyl, trifluoromethyl, and C 1 -4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C 1 -4 alkyl, trifluoromethyl, and C1-4 alkoxy, or wherein two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R 4 is independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) phenyl, (4) heteroaryl, (5) -(CH2)0-1C 2 -8 heterocycloalkyl, and (6) C 3 -6 cycloalkyl; 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
C
1
-
4 alkoxy, or two R 4 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 R 5 is independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) -(CH2)0-1-phenyl, (4) -(CH2)0-1-naphthyl, (5) -(CH2)0-1-heteroaryl, and (6) -(CH2)0-1 C3-7 cycloalkyl; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, (CH 2 ) and cycloalkyl are unsubstituted or substituted -22- WO 2004/087159 PCT/US2004/008711 with one to three groups independently selected from R 3 and oxo, or wherein two R 5 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 14 alkyl;
R
6 and R 7 are each independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) -(CH2)0-1 C3-6 cycloalkyl, (4) -(CH2)0-1-aryl, (5) hydroxy, (6) halogen, and (7) amino; t is 1, 2, or 3; ris 1 or 2; and sis 0, 1 or2. Illustrative but nonlimiting examples of compounds of the present invention that are useful as melanocortin-4 receptor agonists are the following: GI HLY O N N N 'N N N ANf /Y8 0 F 0 F F F - 23 N 0 F 0 F -23- WO 2004/087159 PCT/US2004/008711 CI S N 0 N /11 N N O F 0 F F F CI Cl 0N' 0 Ni" N N ,and H F 0 F F F H N N OoN 0 F F or a pharmaceutically acceptable salt thereof. The compounds of structural formula I are effective as melanocortin receptor agonists and are particularly effective as selective agonists of MC-4R. 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/or female sexual dysfunction, in particular, erectile dysfunction, and further in particular, male erectile dysfunction. Another aspect of the present invention provides a method for the treatment or prevention of obesity or diabetes in a mammal in need thereof which comprises administering to said mammal a therapeutically or prophylactically effective amount of a compound of structural formula I. Another aspect of the present invention provides a method for the treatment or prevention of male or female sexual dysfunction including erectile dysfunction which comprises administering to a mammal in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound of structural formula I. -24 - WO 2004/087159 PCT/US2004/008711 Another aspect of the present invention provides a pharmaceutical composition comprising a compound of structural formula I and a pharmaceutically acceptable carrier. Another aspect of the present invention provides a method for the treatment or prevention of male or female sexual dysfunction including erectile dysfunction which comprises administering to a mammal in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound of structural formula I in combination with a therapeutically effective amount of another agent known to be useful for the treatment of these conditions. Yet another aspect of the present invention provides a method for the treatment or prevention of obesity which comprises administering to a mammal in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound of structural formula I in combination with a therapeutically effective amount of another agent known to be useful for the treatment of this condition. Yet another aspect of the present invention relates to the use of a compound of formula I for the manufacture of a medicament useful for the treatment or prevention, or suppression of a disease mediated by the melanocortin-4 receptor in a mammal in need thereof. Yet another aspect of the present invention relates to the use of a compound of formula I for the manufacture of a medicament useful for the treatment or prevention, or suppression of a disease mediated by the melanocortin-4 receptor, wherein the disease is selected from the group consisting of obesity, diabetes, male sexual dysfunction and female sexual dysfunction in a mammal in need thereof. Yet another aspect of the present invention relates to the use of a compound of formula I for the manufacture of a medicament useful for the treatment or prevention, or suppression of male erectile dysfunction in a mammal in need thereof. Yet another aspect of the present invention relates to the use of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent selected from the group consisting of an insulin sensitizer, an insulin mimetic, a sulfonylurea, an c-glucosidase inhibitor, a HMG-CoA reductase inhibitor, a serotonergic agent, a 33-adrenoreceptor agonist, a neuropeptide Y1 antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5 antagonist, a pancreatic lipase inhibitor, a cannabinoid CB 1 receptor antagonist or inverse agonist, a melanin-concentrating hormone receptor antagonist, a bombesin receptor subtype 3 agonist, and a ghrelin receptor antagonist, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment, control, or prevention of diabetes or obesity in a mammal in need of such treatment. Yet another aspect of the present invention relates to the use of a therapeutically effective amount of a compound of formula I, and pharmaceutically acceptable salts and esters thereof, and a therapeutically effective amount of an agent selected from the group consisting of an insulin - 25 - WO 2004/087159 PCT/US2004/008711 sensitizer, an insulin mimetic, a sulfonylurea, an -glucosidase inhibitor, a IIHMG-CoA reductase inhibitor, a serotonergic agent, a (3-adrenoreceptor agonist, a neuropeptide Y1 antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5 antagonist, a pancreatic lipase inhibitor, a cannabinoid CB 1 receptor antagonist or inverse agonist, a melanin-concentrating hormone receptor antagonist, a bombesin receptor subtype 3 agonist, and a ghrelin receptor antagonist, and pharmaceutically acceptable salts and esters thereof, for the manufacture of a medicament for treatment or prevention of diabetes or obesity which comprises an effective amount of a compound of formula I and an effective amount of the agent, together or separately. Yet another aspect of the present invention relates to the use of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent selected from the group consisting of: a type V cyclic-GMP selective phosphodiesterase inhibitor, an a2-adrenergic receptor antagonist, and a dopaminergic agent, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment, control, or prevention of erectile dysfunction in a mammal in need of such treatment. Yet another aspect of the present invention relates to the use of a therapeutically effective amount of a compound of formula I, and pharmaceutically acceptable salts and esters thereof; and a therapeutically effective amount of an agent selected from the group consisting of a type V cyclic GMP-selective phosphodiesterase inhibitor, an a2-adrenergic receptor antagonist, and a dopaminergic agent, and pharmaceutically acceptable salts and esters thereof; for the manufacture of a medicament for treatment or prevention of erectile dysfunction which comprises an effective amount of a compound of formula I and an effective amount of the agent, together or separately. Melanocortin receptor agonist compounds can be provided in kit. Such a kit typically contains an active compound in dosage forms for administration. A dosage form contains a sufficient amount of active compound such that a beneficial effect can be obtained when administered to a patient during regular intervals, such as 1 to 6 times a day, during the course of 1 or more days. Preferably, a kit contains instructions indicating the use of the dosage form for weight reduction (e.g., to treat obesity or overweight) or sexual dysfunction, and the amount of dosage form to be taken over a specified time period. Throughout the instant application, the following terms have the indicated meanings: The term "alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains of the designated length which may be in a straight or branched configuration, or combinations thereof. The term alkyl also includes methylene groups which are designated as (CH2). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, 1 methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2 dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3 - 26 - WO 2004/087159 PCT/US2004/008711 methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethyl butyl, 1,2 dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethyl butyl, n-heptyl, 1 methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 4-ethylpentyl, 1-propylbutyl, 2-propylbutyl, 3-propylbutyl, 1,1-dimethylpentyl, 1,2 dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl. 2,4 dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 4,4-dimethylpentyl, 1-methyl-1-ethylbutyl, 1 methyl-2-ethylbutyl, 2-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1 diethylpropyl, n-octyl, n-nonyl, and the like. The term "alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. The term "alkynyr'l" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "C1-4 alkyliminoyl" means C1-3alkylC(=NH)-. The term "aryl" includes mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl and naphthyl. The term "heteroaryl" includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Examples thereof include, but are not limited to, pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl, triazinyl, tetrazolyl, thiadiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, benzoxazolyl, and the like. In one embodiment of the present invention, heteroaryl is selected from the group consisting of pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl, triazinyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxathiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, and benzoxazolyl. In a class of this embodiment, heteroaryl is selected from the group consisting of pyridinyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, and pyrazinyl. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, quinazoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine, thienopyridine, benzisodiazole, triazolopyrimidine, and 5,6,7,8-tetrahydroquinoline. - 27 - WO 2004/087159 PCT/US2004/008711 The term "cycloalkyl" includes mono- or bicyclic non-aromatic rings containing only carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The term "heterocycloalkyl" is intended to include non-aromatic heterocycles containing one to four heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyls include, but are not limited to, azetidine, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, 1-thia-4-aza-cyclohexane. Substitution on the heterocycloalkyl ring includes substitution on carbon and/or nitrogen atoms of the heterocycloalkyl ring. Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus for example, NR 4
R
4 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like. The term "subject" means a mammal. One embodiment of the term "mammal" is a "human," said human being either male or female. The instant compounds are also useful for treating or preventing obesity and obesity related disorders in cats and dogs. As such, the term "mammal" includes companion animals such as cats and dogs. The term "mammal in need thereof" refers to a mammal who is in need of treatment or prophylaxis as determined by a researcher, veterinarian, medical doctor or other clinician. The term "composition," as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By a melanocortin receptor "agonist" is meant an endogenous or drug substance or compound that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor. By a melanocortin receptor "antagonist" is meant a drug or a compound that opposes the melanocortin receptor-associated responses normally induced by another bioactive agent. The "agonistic" properties of the compounds of the present invention were measured in the functional assay described below. The functional assay discriminates a melanocortin receptor agonist from a melanocortin receptor antagonist. By "binding affinity" is meant the ability of a compound/drug to bind to its biological target, in the the present instance, the ability of a compound of structural formula I to bind to a melanocortin receptor. Binding affinities for the compounds of the present invention were measured in the binding assay described below and are expressed as IC50's. - 28 - WO 2004/087159 PCT/US2004/008711 "Efficacy" describes the relative intensity with which agonists vary in the response they produce even when they occupy the same number of receptors and with the same affinity. Efficacy is the property that enables drugs to produce responses. Properties of compounds/drugs can be categorized into two groups, those which cause them to associate with the receptors (binding affinity) and those that produce a stimulus (efficacy). The term "efficacy" is used to characterize the level of maximal responses induced by agonists. Not all agonists of a receptor are capable of inducing identical levels of maximal responses. Maximal response depends on the efficiency of receptor coupling, that is, from the cascade of events, which, from the binding of the drug to the receptor, leads to the desired biological effect. The functional activities expressed as EC50's and the "agonist efficacy" for the compounds of the present invention at a particular concentration were measured in the functional assay described below. Optical Isomers - Diastereomers - Geometric Isomers - Tautomers Compounds of structural formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of structural formula I. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist as tautomers such as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed within the compounds of structural formula I. Compounds of structural formula I may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer of a compound of the general formula I, IIa, lIb, lIa, and IlIb may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. Salts The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. -29 - WO 2004/087159 PCT/US2004/008711 Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N' dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p toluenesulfonic acid, trifluoroacetic acid, and the like. Particularly preferred are citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts, such as the hydrochloride salts. Utility Compounds of formula I are melanocortin receptor agonists and as such are useful in the treatment, control or prevention of diseases, disorders or conditions responsive to the activation of one or more of the melanocortin receptors including, but are not limited to, MC-1, MC-2, MC-3, MC-4, or MC 5. Such diseases, disorders or conditions include, but are not limited to, obesity, diabetes mellitus, hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, depression, anxiety, compulsion, neuroses, insomnialsleep disorder, substance abuse, pain, male and female sexual dysfunction, fever, inflammation, immunemodulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer's disease. Some compounds encompassed by formula I show highly selective affinity for the melanocortin-4 receptor (MC-4R) relative to MC-1R, MC-2R, MC-3R, and MC-5R, which makes them especially useful in the prevention and treatment of obesity, as well as male and/or female sexual dysfunction, including erectile dysfunction. The compositions of the present invention are useful for the treatment or prevention of disorders associated with excessive food intake, such as obesity and obesity-related disorders. The obesity herein may be due to any cause, whether genetic or environmental. -30- WO 2004/087159 PCT/US2004/008711 The obesity-related disorders herein are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating, binge eating, and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g. children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer. The compositions of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy. The term "metabolic syndrome", also known as syndrome X, is defined in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATP-III). E.S. Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined as having metabolic syndrome if the person has three or more of the following symptoms: abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and high fasting plasma glucose. The criteria for these are defined in ATP-1I. The term "diabetes," as used herein, includes both insulin-dependent diabetes mellitus (i.e., IDDM, also known as type I diabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type II diabetes). Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes (i.e., non-insulin-dependent diabetes mellitus), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese. The compositions of the present invention are useful for treating both Type I and Type II diabetes. The compositions are especially effective for treating Type II diabetes. The compounds or combinations of the present invention are also useful for treating and/or preventing gestational diabetes mellitus. Treatment of diabetes mellitus refers to the administration of a compound or combination of the present invention to treat diabetes. One outcome of treatment may be decreasing the -31 - WO 2004/087159 PCT/US2004/008711 glucose level in a subject with elevated glucose levels. Another outcome of treatment may be improving glycemic control. Another outcome of treatment may be decreasing insulin levels in a subject with elevated insulin levels. Another outcome of treatment may be decreasing plasma triglycerides in a subject with elevated plasma triglycerides. Another outcome of treatment may be lowering LDL cholesterol in a subject with high LDL cholesterol levels. Another outcome of treatment may be increasing HDL cholesterol in a subject with low HDL cholesterol levels. Another outcome may be decreasing the LDL/HDL ratio in a subject in need thereof. Another outcome of treatment may be increasing insulin sensivity. Another outcome of treatment may be enhancing glucose tolerance in a subject with glucose intolerance. Another outcome of treatment may be decreasing insulin resistance in a subject with increased insulin resistance or elevated levels of insulin. Another outcome may be decreading triglycerides in a subject with elevated triglycerides. Yet another outcome may be improving LDL cholestrol, non-HDL cholesterol, triglyceride, HDL cholesterol or other lipid analyte profiles. Prevention of diabetes mellitus refers to the administration of a compound or combination of the present invention to prevent the onset of diabetes in a mammal at risk thereof. "Obesity" is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m 2 ). "Obesity" refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m 2 , or a condition whereby a subject with at least one co-morbidity has a BMI greater than or equal to 27 kg/m 2 . An "obese subject" is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m 2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m 2 . A "subject at risk of obesity" is an otherwise healthy subject with a BMI of 25 kg/m 2 to less than 30 kg/m 2 or a subject with at least one co morbidity with a BMI of 25 kg/m 2 to less than 27 kg/m 2 . The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in Asians. In Asian countries, including Japan, "obesity" refers to a condition whereby a subject with at least one obesity-induced or obesity-related co-morbidity, that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m 2 . In Asian countries, including Japan, an "obese subject" refers to a subject with at least one obesity-induced or obesity related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m 2 . In Asia-Pacific, a "subject at risk of obesity" is a subject with a BMI of greater than 23 kg/m 2 to less than 25 kg/m 2 . As used herein, the term "obesity" is meant to encompass all of the above definitions of obesity. Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, non-insulin dependent diabetes mellitus - type II (2), impaired glucose tolerance, impaired - 32 - WO 2004/087159 PCT/US2004/008711 fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility. In particular, co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions. Treatment of obesity and obesity-related disorders refers to the administration of the compounds or combinations of the present invention to reduce or maintain the body weight of an obese subject. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in subjects in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss. Prevention of obesity and obesity-related disorders refers to the administration of the compounds or combinations of the present invention to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis. "Male sexual dysfunction" includes impotence, loss of libido, and erectile dysfunction. - 33 - WO 2004/087159 PCT/US2004/008711 "Erectile dysfunction" is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm. An increase in erectile dysfunction and sexual dysfunction can have numerous underlying causes, including but not limited to (1) aging, (b) an underlying physical dysfunction, such as trauma, surgery, and peripheral vascular disease, and (3) side-effects resulting from drug treatment, depression, and other CNS disorders. Treatment of male sexual dysfunction refers to the administration of a compound or combination of the present invention to treat impotence and/or loss of libido, and/or erectile dysfunction in a male mammal in need thereof. One outcome of treatment may be a decrease in impotence. Another outcome of treatment may be an increase in libido. Yet another outcome of treatment may be a decrese in the magnitude or frequency of erectile dysfunction. Treatment of male sexual dysfunction refers to the administration of a compound or combination of the present invention to treat one or more of the symptoms of male sexual dysfunction in a male mammal in need thereof. One outcome of treatment may be increasing the ability to achieve an erection. Another outcome of treatment may be increasing the ability to maintain an erection. Another outcome of treatment may be reducing ejaculatory failure. Another outcome of treatment may be decreasing premature ejaculation. Yet another outcome of treatment may be increasing the ability to achieve an orgasm. Prevention of male sexual dysfunction and male erectile dysfunction refers to the administration of the compounds or combinations of the present invention to prevent the symptoms of sexual dysfunction and male erectile dysfunction in a male mammal at risk thereof. "Female sexual dysfunction" can be seen as resulting from multiple components including dysfunction in desire, sexual arousal, sexual receptivity, and orgasm related to disturbances in the clitoris, vagina, periurethral glans, and other trigger points of sexual function. In particular, anatomic and functional modification of such trigger points may diminish the orgasmic potential in breast cancer and gynecologic cancer patients. Treatment of female sexual dysfunction with an MC-4 receptor agonist can result in improved blood flow, improved lubrication, improved sensation, facilitation of reaching orgasm, reduction in the refractory period between orgasms, and improvements in arousal and desire. In a broader sense, "female sexual dysfunction" also incorporates sexual pain, premature labor, and dysmenorrhea. The terms "administration of" and or "administering" a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to a subject in need of treatment. -34- WO 2004/087159 PCT/US2004/008711 The administration of the compounds of the present invention in order to practice the present methods of therapy is carried out by administering a therapeutically effective amount of the compound to a subject in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors. The term "therapeutically effective amount" as used herein means the amount of the active compound that will elicit the biological or medical response in a tissue, system, subject, mammal, or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term "prophylactically effective amount" as used herein means the amount of the active compound that will elicit the biological or medical response in a tissue, system, subject, mammal, or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, to prevent the onset of the disorder in subjects as risk for obesity or the disorder. The therapeutically or prophylactically effective amount, or dosage, of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration, other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgement. Administration and Dose Rances Any suitable route of administration may be employed for providing a mammal, especially a human with an effective amount, or dosage, of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of Formula I are administered orally or topically. When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligrams per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. It may be necessary to use dosages outside these limits in some cases. When treating diabetes mellitus and/or hyperglycemia, as well as other diseases or disorders for which compounds of formula I are useful, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram -35 - WO 2004/087159 PCT/US2004/008711 to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. It may be necessary to use dosages outside these limits in some cases. For the treatment of sexual dysfunction compounds of the present invention are given in a dose range of 0.001 milligram to about 100 milligram per kilogram of body weight, preferably as a single dose orally or as a nasal spray. In the case where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 1500 mg of a compound of Formula I per day, preferably from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750, 1000, 1250, or 1500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. For use where a composition for intranasal administration is employed, intranasal formulations for intranasal administration comprising 0.001-10% by weight solutions or suspensions of the compounds of Formula I in an acceptable intranasal formulation may be used. For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 100 mg (preferably from 0.01 mg to about 50 mg, more preferably 0.1 mg to 10 mg) of a compound of Formula I per kg of body weight per day. This dosage regimen may be adjusted to provide the optimal therapeutic response. It may be necessary to use dosages outside these limits in some cases. For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used. The magnitude of prophylactic or therapeutic dosage of the compounds of the present invention will, of course, vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. It will also vary according to the age, weight and response of the individual patient. Such dosage may be ascertained readily by a person skilled in the art. Combination Therapy Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of - 36 - WO 2004/087159 PCT/US2004/008711 Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I for the treatment or prevention of obesity and/or diabetes, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) insulin sensitizers including (i) PPARy antagonists such as glitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY 300512, and the like), and compounds disclosed in WO97/10813, 97/27857, 97/28115, 97/28137, and 97/27847; (ii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics, such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and GLP-1 (7-36)-NH 2 ); (c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide; (d) c-glucosidase inhibitors, such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like; (e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bile acid absorbers/sequestrants, such as cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®, and the like, (ii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iii) proliferator-activater receptor cx agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and the like, and (acyl CoA:cholesterol acyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide, (v) anti oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; (f) PPARc agonists such as beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibric acid derivatives, such as Atromid®, Lopid® and Tricor@, and the like, and PPARca agonists as described in WO 97/36579 by Glaxo; (g) PPAR8 agonists, such as those disclosed in WO97/28149; and -37- WO 2004/087159 PCT/US2004/008711 (h) anti-obesity agents, such as (1) growth hormone secretagogues, growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686, CP 424,391, L-692,429 and L-163,255, and such as those disclosed in U.S. Patent Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos. 2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO 02/32888; (2) protein tyrosine phosphatase-lB (PTP-lB) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CB 1 receptor antagonists or inverse agonists, such as rimonabant (Sanofi Synthelabo), and SR-147778 (Sanofi Synthelabo), and those disclosed in U.S. Patent Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, and EPO Application No. EP-658546; (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) 13-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A, and such as those disclosed in U.S. Patent Application Nos. 5,705,515, and US 5,451,677 and PCT Patent Publications WO94/18161, WO95/29159, WO97/46556, WO98/04526 and WO98/32753, WO 01/74782, and WO 02/32897; (6) pancreatic lipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, and those disclosed in PCT Application No. WO 01/77094; (7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Patent No. 6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8) neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and those disclosed in U.S. Patent Nos. 6,140,354, 6,191,160, 6,313,298, 6,337,332, 6,329,395, 6,326,375, 6,335,345, and 6,340,683, European Patent Nos. EP-01010691, and EP-01044970, and PCT Patent Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; (9) melanin-concentrating hormone (MCH) receptor antagonists, such as those disclosed in WO 01/21577 and WO 01/21169; (10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, and WO 02/51809, and Japanese Patent Application No. JP 13226269; (11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; (12) orexin-1 receptor antagonists, such as SB -38 - WO 2004/087159 PCT/US2004/008711 334867-A, and those disclosed in PCT Patent Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838; (13) serotonin reuptake inhibitors such as fluoxetine, paroxetine, and sertraline, and those disclosed in U.S. Patent Application No. 6,365,633, and PCT Patent Application Nos. WO 01/27060 and WO 01/162341; (14) melanocortin agonists, such as Melanotan II or those described in WO 99/64002 and WO 00/74679; (15) other Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), and those disclosed in PCT Application Nos. WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, and WO 02/12178; (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R 1065, and those disclosed in U.S. Patent No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin -A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131, and those discribed in U.S. Patent No. 5,739,106; (21) GLP-1 agonists; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described and disclosed in PCT Application No. WO 02/15905, and O-[3-(1H-imidazol-4-yl)propanol]-carbamates (Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000)), piperidine-containing histamine H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32 (2001), benzophenone derivatives and related compounds (Sasse, A. et al., Arch. Pharm.(Weinheim) 334:45-52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem.. 43:3335-43 (2000)); (25) 03-hydroxy steroid dehydrogenase-1 inhibitors (03-HSD-1); 26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (29) ghrelin antagonists, such as those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives, such as those disclosed in U.S. Patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT International Publication Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, and WO 96/23520; (32) BRS3 (bombesin receptor subtype 3) agonists; (33) CNTF (Ciliary neurotrophic factors), such as GI 181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTF derivatives, such as axokine (Regeneron), and those disclosed in PCT Application Nos. WO 94/09134, WO 98/22128, and WO 99/43813; (35) monoamine reuptake inhibitors, such as those disclosed in PCT Application Nos. WO 01/27068, and WO 01/62341; (36) UCP-1 (uncoupling -39- WO 2004/087159 PCT/US2004/008711 protein-1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 napthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT Patent Application No. WO 99/00123; (37) thyroid hormone j agonists, such as KB-2611 (KaroBioBMS), and those disclosed in PCT Application No. WO 02/15845, and Japanese Patent Application No. JP 2000256190; (38) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP-IV) inhibitors, such as DPP-728, P 3298, TSL 225, valine pyrrolidide, TMC 2A/2B/2C, CD-26 inhibitors, FE 999011, P9310/K364, VIP 0177, NVPLAF237, DPP4, SDZ 274-444; and the compounds disclosed in EP 1258476, EP 1258480, and WO 03/000180; (45) fatty acid transporter inhibitors; (46) dicarboxylate transporter inhibitors; (47) glucose transporter inhibitors; (48) phosphate transporter inhibitors; (49) Metformin (Glucophage®); and (50) Topiramate (Topimax®); and (50) peptide YY, PYY 3-36, peptide YY analogs, and PYY agonists such as those disclosed in WO 03/026591, WO 03/057235, and WO 03/027637; and (51) cyclo-oxygenase-2 inhibitors such as rofecoxib, celecoxib, and arcoxia. Examples of other anti-obesity agents that can be employed in combination with a compound of Formula I are disclosed in "Patent focus on new anti-obesity agents," Exp. Opin. Ther. Patents, 10: 819-831 (2000); "Novel anti-obesity drugs," Exp. Opin. Invest. Drugs, 9:1317-1326 (2000); and "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity, Exp. Opin. Ther. Patents, 11:1677-1692 (2001). The role of neuropeptide Y in obesity is discussed in Exp. Opin. Invest. Drugs, 9:1327-1346 (2000). Cannabinoid receptor ligands are discussed in Exp. Opin. Invest. Drugs, 9:1553-1571 (2000). Examples of other active ingredients that may be combined with a compound of Formula I for the treatment or prevention of male or female sexual dysfunction, in particular, male erectile dysfunction, either administered separately or in the same pharmaceutical compositions, include, but are not limited to (a) type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitors, including sildenafil and (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351); (b) alpha-adrenergic receptor antagonists, including phentolamine and yohimbine or pharmaceutically acceptable salts thereof; (c) dopamine receptor agonists, such as apomorphine or pharmaceutically acceptable salts thereof; and (d) nitric oxide (NO) donors. The instant invention also includes administration of a single pharmaceutical dosage formulation which contains both the MC-4R agonist - 40 - WO 2004/087159 PCT/US2004/008711 in combination with a second active ingredient, as well as administration of each active agent in its own separate pharmaceutical dosage formulation. Where separate dosage formulations are used, the individual components of the composition can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e. sequentially prior to or subsequent to the administration of the other component of the composition. The instant invention is therefore to be understood to include all such regimes of simultaneous or alternating treatment, and the terms "administration" and "administering" are to be interpreted accordingly. Administration in these various ways are suitable for the present compositions as long as the beneficial pharmaceutical effect of the combination of the MC-4R agonist and the second active ingredient is realized by the patient at substantially the same time. Such beneficial effect is preferably achieved when the target blood level concentrations of each active ingredient are maintained at substantially the same time. It is preferred that the combination of the MC-4R agonist and the second active ingredient be co-administered concurrently on a once-a-day dosing schedule; however, varying dosing schedules, such as the MC-4R agonist once a day and the second active ingredient once, twice or more times per day, is also encompassed herein. A single oral dosage formulation comprised of both a MC-4R agonist and a second active ingredient is preferred. A single dosage formulation will provide convenience for the patient, which is an important consideration especially for patients with diabetes or obese patients who may be in need of multiple medications. The compounds in the combinations of the present invention may be administered separately, therefore the invention also relates to combining separate pharmaceutical compositions into a kit form. The kit, according to this invention, comprises two separate pharmaceutical compositions: a first unit dosage form comprising a prophylactically or therapeutically effective amount of the melanocortin-4 receptor agonist, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier or diluent in a first unit dosage form, and a second unit dosage form comprising a prophylactically or therapeutically effective amount of the second active ingredient or drug, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier or diluent in a second unit dosage form. In one embodiment, the kit further comprises a container. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days or time in the treatment schedule in which the dosages can be administered. -41- WO 2004/087159 PCT/US2004/008711 Pharmaceutical Compositions Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the typical oral dosage unit form, in which case solid pharmaceutical carriers are typically employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray. The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening -42- WO 2004/087159 PCT/US2004/008711 agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Preparation of Compounds of the Invention The compounds of structural formula I of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described in detail in PCT International Application Publications WO 02/068387 (6 September 2002), WO 02/068388 (6 September 2002), WO 02/067869 (6 September 2002), and WO 03/007949 (30 January 2003), which are incorporated by reference herein in their entirety, in conjunction with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described previously hereinabove. The free amine bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, and extraction of the liberated amine free base into an -43 - WO 2004/087159 PCT/US2004/008711 organic solvent followed by evaporation. The amine free base isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation, or crystallization. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electron spray ion-mass spectroscopy. The phrase "standard peptide coupling reaction conditions" means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in an inert solvent such as dichloromethane in the presence of a catalyst such as HOBT. The use of protecting groups for the amine and carboxylic acid functionalities to facilitate the desired reaction and minimize undesired reactions is well documented. Conditions required to remove protecting groups are found in standard textbooks such as Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY, 1991. CBZ and BOC are commonly used protecting groups in organic synthesis, and their removal conditions are known to those skilled in the art. For example, CBZ may be removed by catalytic hydrogenation in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as methanol or ethanol. In cases where catalytic hydrogenation is contraindicated due to the presence of other potentially reactive functionalities, removal of CBZ groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid or by treatment with a mixture of TFA and dimethylsulfide. Removal of BOC protecting groups is carried out with a strong acid, such as trifluoroacetic acid, hydrochloric acid, or hydrogen chloride gas, in a solvent such as methylene chloride, methanol, or ethyl acetate. Abbreviations Used in the Description of the Preparation of the Compounds of the Present Invention: AIBN azobisisobutyronitrile BOC (boc) t-butyloxycarbonyl BOP benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate Bu butyl calc. Calculated celite CeliteTM diatomaceous earth CBZ (Cbz) benzyloxycarbonyl CH2C12 methylene chloride CH30OH methanol DCM 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H pyran -44 - WO 2004/087159 PCT/US2004/008711 DIEA Diisopropylethylamine DMAP dimethylaminopyridine DMF N,N-dimethylformamide DPPA diphenylphosphoryl azide dppf 1, 1'-Bis(diphenylphosphino)ferrocene EDC 1-(3-dimethylaminopropyl)3-ethylcarbodiimide HCI Et3N triethyl amine ESI-MS electron spray ion-mass spectroscopy Et ethyl EtOAc ethyl acetate h hour or hours HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOAt 1-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole hydrate MC-xR melanocortin receptor (x being a number) Me methyl MS mass spectrum Ms Methanesulfonyl NMM N-methylmorpholine Otf (OTf) Trifluoromethanesulfonyl PG protecting group Ph phenyl Pr propyl PyBrop bromo-tris-pyrrolidino-phosphonium hexafluorophosphate r.t. room temperature t-bu tert-butyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin-layer chromatography. Reaction Scheme A illustrates the general method employed in the synthesis of the compounds of structural formula (I). As shown in reaction Scheme A, the compounds of structural -45 - WO 2004/087159 PCT/US2004/008711 formula (I) are derived by coupling a 4-substituted bridged piperidine intermediate of general formula 1 with an acid of general formula 2. The preparation of specific bridged piperidine intermediates of general formula 1 is provided in Schemes 1 and 2. The preparation of acids of general formula 2, including pyrrolidine acid 2A, and piperidine acids 2B and 2C, shown below,
R
1
R
1 R N N % H0 2 C R 2
HO
2 C R 2
HO
2 C R 2 2A 2B 2C is provided in Schemes E-I. All substituents in the Schemes are as defined above unless indicated otherwise. As illustrated in Scheme A, the amide bond coupling reaction of 1 to form compounds of formula (I) is conducted in an appropriate inert solvent such as dimethylformamide (DMF), methylene chloride or the like and may be performed with a variety of reagents suitable for amide coupling reactions such as O-(7-azabenzotriazol-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or benzotriazol-1 yloxytripyrrolidinephosphonium hexafluorophosphate (PyBOP). Preferred conditions for the amide bond coupling reaction shown in reaction Scheme A are known to those skilled in organic synthesis. Such modifications may include, but are not limited to, the use of basic reagents such as triethylamine (TEA) or N-methylmorpholine (NMM), or the addition of an additive such as 1-hydroxy-7 azabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt). Alternatively, 4-substituted bridged piperidines of formula 1 may be treated with an active ester or acid chloride derived from carboxylic acid of general formula 2 which also affords compounds of structural formula (I). The amide bond coupling shown in reaction Scheme A is usually conducted at temperatures between 0OC and room temperature, occasionally at elevated temperatures, and the coupling reaction is the synthesis and deprotected under acidic conditions, for instance using trifluoroacetic acid in a solvent like methylene chloride or hydrogen chloride in a solvent such as ethyl acetate at room temperature. -46 - WO 2004/087159 PCT/US2004/008711 Scheme A HT 2 RR2 N R RNs 2s R2 tr C0 2 H - r N0 X Y N X Y (i) Reaction Schemes B-J illustrate methods for the synthesis of the carboxylic acids of general formula A and B, that are utilized in the amide bond coupling reaction shown in reaction Scheme A. Reaction Scheme B illustrates a preferred method for the synthesis of compounds of general formula 2B wherein r is 2 and s is 1 such that the resulting heterocycle is a 3-aryl-4-piperidine carboxylic acid derivative 10. The synthesis of 10 begins with a commercially available P3-keto ester such as 3. Generally a protecting group interchange of an N-BOC group for the N-benzyl group is performed initially. Thus a. P-keto ester of formula 3 is subjected to debenzylation by hydrogenolysis using a palladium-on-carbon catalyst in a solvent system such as 1:1 ethanol-water under a hydrogen atmosphere. The resulting piperidone 4 is then protected as its tert-butyl carbamate using BOC anhydride in the presence of a base and a suitable solvent. For example, this can be accomplished in a two phase mixture of chloroform and aqueous sodium bicarbonate as shown. Incorporation of the 3-aryl substituent is then performed in two steps. First, the P3-keto ester group is converted to the corresponding vinyl triflate 6 using trifluoromethanesulfonic anhydride and an organic base like N,N diisopropylethylamine in an aprotic solvent such as methylene chloride. The resulting vinyl triflate 6 is then subjected to a palladium-catalyzed cross-coupling reaction with an aryl boronic acid (2) using a palladium (II) catalyst such as [ 1, 1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). Preferred conditions for this reaction are the use of a toluene-ethanol-aqueous sodium carbonate solvent system at an elevated temperature, for instance 50-100 0 C, for a period of 2-24 hours. The resulting aryl-substituted tetrahydropyridine derivative 8 can be reduced to a piperidine such as 9 using a variety of known techniques and the method chosen will determine the stereochemical outcome of the product. For instance, hydrogenation of 8 with a palladium on carbon catalyst in a solvent such as ethanol affords cis 3,4-disubstituted piperidines of general formula 9. Alternatively, a dissolving metal reduction using a metal, such as magnesium in methanol, reduces the double bond of 8 and produces a mixture of both cis and trais 3,4-disubstituted piperidines of formula 9. The resulting mixture of cis and trans diastereoisomers may be separated chromatographically or it may be subsequently epimerized to afford -47 - WO 2004/087159 PCT/US2004/008711 the pure trans isomer of 9 by treating the mixture with a base like sodium methoxide in methanol. Finally, hydrolysis of either the cis or trans 3-aryl-4-piperidine carboxylic ester 9 affords either a cis or trans 3-aryl4-piperidine carboxylic acid of general formula 10, corresponding to an acid of general formula 2B wherein r is 2 and s is 1. The cis or trans carboxylic acids of general formula 10 are produced as racemates and either may be resolved to afford enantiomerically pure compounds by methods known in organic synthesis. Preferred methods include resolution by crystallization of diastereoisomeric salts derived from acids 10 and a chiral amine base or the use of chiral stationary phase liquid chromatography columns. Scheme B N^ Ph H 2 , Pd/C NH (BOC) 2 0 EtOOO- HC ) EtOOC" * HI NaHCO 3 o ! 0EtOH-H 2 0 (1:1) CHCl/H 2 0O 3 4 BOC T20N'BOC Sdiisopropylethylamnine EtOOC EtOOC N 0 CH 2
CI
2 OT 5 6
R
3
R
3 RX/ 7 NBOC B(OH)2 EtOOc Mg Na 2
CO
3 , MeOH Pd(dppf),CI.CH 2 C1 2 (cat.) /.J~ R toluene/ethanol/water R 3
R
3 8 N'BOC N BOC c BOC EtOOC 1. Na, MeOH HO 2 C"' HO 2 C N or . Ra 2. aq. NaOH r-Ra o 9RR R R3s R 3 Ra 10 (trans) 10 (cis) Reaction Scheme C illustrates a preferred method for the synthesis of compounds of general formula 2C wherein r is 1 and s is 2, such that the resulting heterocycle is a 4-aryl-3-piperidine carboxylic acid derivative 17. The synthesis of 17 is similar to the one shown in reaction Scheme B, and may begin with either of the commercially available P-keto esters 11 or 12. Conversion of one of these starting materials to the N-BOC-protected piperidine 13 is performed as shown and the resulting -keto ester is subjected to the two-step arylation protocol previously described to yield 15. Reduction of the -48- WO 2004/087159 PCT/US2004/008711 double bond of 15 using conditions appropriate for obtaining either cis or trans 17 is followed by ester hydrolysis which affords either a cis or trans 4-aryl-3-piperidine-carboxylic acid of general formula 17 which corresponds to an acid of general formula 2C wherein r is 1 and s is 2. The cis or trans carboxylic acids of general formula 17 are produced as racemates and either may be resolved to afford enantiomerically pure compounds by methods known in organic synthesis. Preferred methods include resolution by crystallization of diastereoisomeric salts derived from the acids 17 and a chiral amine base or by the use of chiral stationary phase liquid chromatography columns. Ph Scheme C O J N' O N (BOO)20 SHol H2, Pd/C NH. (BOC) , HCI NaHCO 3
O
2 Et EtOH-H 2 0 C0o 2 EI (1:1)
CHCI
3
/H
2 0 11 12 Tf 2 0 O NBOC diisopropylethylamine TfO NBOC
CO
2 Et CH 2
CI
2
CO
2 Et 13 14
R
3
R
3 tQ -"-B(O H)2 t3_6, jM B(R NBOC Me Na2C0O 3 , R CO 2 Et MeOH Pd(dppf) 2 C1 2
.CH
2 Ci 2 (cat.) 15 toluene/ethanol/water R3 NBOC RN 1. Na, MeOH "I R0E-/ C0 2 H '4 CO 2 Et 2. aq. NaOH R 3
R
3 17 (trans) 16 or Rs INBOC
R
3 R 1 3 7 (cis) The synthesis of the N-BOC protected carboxylic acids of general formula 10 and 17 illustrated in reaction Schemes B and C are useful for the preparation of title compounds of structural formula I bearing a variety of R1 substituents as noted above. For the synthesis of certain title - 49 - WO 2004/087159 PCT/US2004/008711 compounds of structural formula I, for instance when it is desired that R1 be a tert-butyl group, it is preferable to incorporate that R1 substituent at an earlier stage of the synthesis. The synthesis of a 1 substituted-3-ketopiperidine-4-carboxylic ester (21) is shown in reaction Scheme D. A primary amine 18 bearing a desired R1 substituent like a tert-butyl group is reacted with ethyl 4-bromobutyrate at elevated temperature in the absence of a solvent to afford the N-substituted ethyl 4-aminobutyrate 19. The amino ester 19 is then alkylated a second time with ethyl bromoacetate in a high boiling inert solvent such as toluene and in the presence of a base such as powdered potassium carbonate. The resulting aminodiesters of general formula 20 are then cyclized using an intramolecular Dieckmann reaction to afford piperidines such as 21. The Dieckmann reaction is performed using a strong base such as potassium tert-butoxide or the like, in an aprotic solvent such as THF at temperatures between room temperature and the boiling point of the solvent. The resulting 1-substituted-3-ketopiperidine-4 carboxylic ester 21 corresponds to a compound of general formula 5 shown in reaction Scheme B, where the BOC group is replaced with the desired R1 substituent. The compounds of general formula 21 may then be converted to compounds of general formula 2 where the R1 substituent replaces the BOC group using the reaction sequence illustrated in reaction Scheme B. Scheme D R' Br_,-_,CO 2 Et H
H
2 NR 1__ D R1N Ns CO 2 Et 18 19 Br CO2Et EtO2
,CN'R
1 KO-t-BU, R 1 ECOt, Et CEtO toluene, heat 20 E 2 21
K
2 00 3 , 20 Et0 2 C- 21 When it is desirable to synthesize a compound of general formula 17 wherein the BOC group is replaced with a substituent group R1, a reaction sequence similar to the one illustrated in reaction Scheme C may be employed as shown in reaction Scheme E. An amine 18 bearing the desired RI substituent is first subjected to a Michael addition with excess ethyl acrylate in the presence of a solvent such as THF or ethanol. The resulting diester 22 is then converted to a 1-substituted-4 ketopiperidine-3-carboxylic ester 23 using an intramolecular Dieckmann reaction under conditions similar to those illustrated in reaction Scheme C. The substituted piperidine 23 corresponds to a compound of general formula 13 shown in reaction Scheme C, wherein the BOC group is replaced with the desired R1 substituent. The compounds of general formula 23 may then be converted to compounds of general formula 2 where the R1 substituent replaces the BOC group using the methodology illustrated in reaction Scheme C. -50- WO 2004/087159 PCT/US2004/008711 Scheme E
H
2 N R CO0 2 Et EtO2C N R 1 18 EtOH or THF 22
CO
2 Et K O-t-Bu, N.R THF oi 23
CO
2 Et Reaction Scheme F illustrates a strategy for the synthesis of compounds of general formula 2A when the values of r and s are selected such that the resulting heterocycle is a 3-aryl-4 pyrrolidine carboxylic acid derivative (29). The preferred method for the synthesis of compounds of general formula 29 involves the azomethine ylid 3+2 cycloaddition reaction of an azomethine ylid precursor of general formula 25 and a substituted cinnamic ester 24. The azomethine cycloaddition reaction of 24 and 25 affords the 3,4-disubstituted pyrrolidine 26, and the stereochemical relationship of the substituents on the newly formed pyrrolidine ring is determined by the stereochemistry of the double bond in the cinnamate ester 24. Thus the trans ester 24 affords a trans 3,4-disubstituted pyrrolidine of formula 26 as shown. The corresponding cis cinnamate ester affords a cis 3,4-disubstituted pyrrolidine of general formula 26. Cis or trans 3-arylpyrrolidine-4-carboxylic esters of general formula 26 may be resolved to afford enantiomerically pure compounds using a method such as resolution by crystallization of the diastereoisomeric salts derived from 26 and a chiral carboxylic acid, or directly by the use of chiral stationary phase liquid chromatography columns. Reaction Scheme F illustrates the case where a trans cimnnamic ester 24 is converted to a trans 3,4-disubstituted pyrrolidine 26 and its subsequent resolution affords the enantiomerically pure trans pyrrolidine esters 27 and 28. Finally, the esters of general formula 26 (or their pure enantiomers 27 and 28) are hydrolyzed to the corresponding amino acid hydrochlorides of general formula 29 as shown at the bottom of reaction Scheme F. Amino acids of general formula 29 are zwitterionic. Therefore it is in some cases difficult to achieve efficient separation and purification of these compounds from aqueous reactions or workups. In these cases it is preferred to effect the hydrolysis using a reagent such potassium trimethylsilanolate in diethyl ether. Under these conditions the potassium salt of the carboxylic acid is produced which affords an easily isolated precipitate in ether. The resulting salt is then converted to the corresponding amino acid hydrochloride by treatment with excess hydrogen chloride in a suitable solvent such as ethyl acetate. Alternatively, esters such as 26 may be converted directly to the amino acid hydrochlorides 29 under acidic hydrolysis conditions. The hydrolysis of the ester 26 is achieved by prolonged reaction with concentrated hydrochloric acid at an elevated temperature. For example, this -51- WO 2004/087159 PCT/US2004/008711 reaction may be conducted in 8 M hydrochloric acid at reflux overnight. The reaction mixture is then cooled and evaporated in vacuo to afford the amino acid hydrochloride 29. The amino acid hydrochlorides of general formula 29 correspond to an amino acid hydrochloride of general formula 2A wherein both r and s are I and may be employed directly in the amide bond coupling step illustrated in reaction Scheme A to produce the compounds of the present invention of structural formula I. Scheme F
RR
1 R N Me 3 Si N OMe MeO 0R325 0 MeO R R CF 3
CO
2 H, CH 2 1 2 - R 3 3 24 R 26 R 3
R
3 RI
R
1 pI N N separate MeO MeO, isomers OI O and O chiral HPLC 1 R jR R R 27 2 '
R
3 R 3
R
3 i3
R
1
R
1 N N *HCI
H
3 0 1) K OSiMe 3 , Et 2 0 HO HCI 2) HCI, EtOAc HO 0 " 0 R -or -aq.HCI - 3 26 R 3 3 29 R 3
R
3 Another preferred method for the synthesis of enantiomerically pure 3-arylpyrrolidine-4 carboxylic acid derivatives is illustrated in reaction Scheme G. In this synthetic method, a substituted cinnamic acid of general formula 29 is first derivatized with a chiral auxilliary such as (S)-(-)-4-benzyl-2 oxazolidinone (30). The acylation of chiral auxiliary 30 with cinnamic acids of formula 29 is performed by initial activation of the acid to afford a mixed anhydride. Typically acids of general formula 29 are reacted with an acid chloride such as pivaloyl chloride in the presence of a base such as triethylamine and in a suitable aprotic solvent such as THF. The intermediate cinnamyl-pivaloyl anhydride is converted to the product 31 by reaction with the oxazolidinone 30 in the presence of lithium chloride, an amine base such as triethylamine and in a solvent such as THF, and the reaction is conducted at temperatures between -20 0 C and room temperature for periods of 1-24 hours. Alternatively, the oxazolidinone 30 may be deprotonated with a strong base such as n-butyllithium in THF at low -52- WO 2004/087159 PCT/US2004/008711 temperatures such as -78 0 C and then reacted with a mixed anhydride obtained from acid 29 and an acid chloride like pivaloyl chloride as noted above. The cinnamyl oxazolidinone of general formula 31, which is produced by either of these methods, is then reacted with the azomethine ylid precursor 25 in a manner similar to that described in reaction Scheme F, and the products of the reaction are the substituted pyrrolidines of general formulas 33 and 34 as shown. The products 33 and 34 are diastereoisomers of each other and may therefore be separated by standard methods such as recrystallization or by liquid chromatography on a solid support such as silica gel. As discussed above, if the trans isomer of the cinnamic acid of general formula 29 is employed in the first step of reaction Scheme G, then a trans isomer of the substituted cinnamyl oxazolidinone 31 is produced. If such a trans cinnamyl oxazolidinone is then subjected to the azomethine ylid cycloaddition with an azomethine ylid precursor of formula 25, the products are the diastereoisomeric trans- disubstituted pyrrolidines related to 33 and 34. Scheme G 0 0 03 SR 1. pivaloyl chloride,O HO 3 EtsN, THF 3N R3 2. Et 3 N 0 Ph R3 29 Li~, ,Ik31 LiCI, O/NH 30 THF Ph
R
3
R
3 R' 25 0 0 R Me3Si, N OM_ O N separate isomers
CF
3
CO
2 H, N liquid chromatography CHC2l2 PR Ph
R
3
R
3
R
3
R
3 OOR OO R3 0c 0 0 O <N and N"" NR N R 33 Ph 34 Ph The azomethine ylid cycloaddition reactions shown in reaction Schemes F and G are generally conducted with the commercially available azomethine ylid precursor N-(methoxymethyl)-N (trimethylsilylmethyl)-benzylamine (25, R1 = -CH 2 Ph). When the R1 substituent in the title compounds of structural formula I is chosen to be a group other than benzyl, it is generally preferable to remove the - 53 - WO 2004/087159 PCT/US2004/008711 benzyl group from the substituted pyrrolidine compound at this point, and replace it with a more readily removed protecting group such as an N-BOC group. Reaction Scheme H illustrates this process with a generalized 3,4-disubstituted pyrrolidine of formula 32. The preferred method for removal of the N benzyl group from compounds of general formula 32 will depend upon the identity of the R 3 substituents. If these substituents are unaffected by hydrogenation conditions, then the N-benzyl group may be removed by hydrogenolysis using a palladium on carbon catalyst in a solvent such as ethanol and in the presence of hydrogen gas or a hydrogen donor such as formic acid. Occasionally it may be preferred that one of the substituents R 3 be a halogen or another substituent defined above which would be reactive under hydrogenation conditions. In these cases, the compound of general formula 32 is reacted with 1-chloroethyl chloroformate in an inert solvent such as toluene at temperatures between room temperature and 110 0 C (Olafson, R.A. et al. J. Org. Chem. 1984, 49, 2081). The toluene is then removed, and the residue is heated in methanol for a period of 15-60 minutes, and the product is the debenzylated pyrrolidine of general formula 35. The resulting pyrrolidine 35 is then protected as its tert butyl carbamate (36) using BOC anhydride in the presence of a base and a suitable solvent. For example, this can be accomplished in a two phase mixture of chloroform and aqueous sodium bicarbonate as shown in reaction Scheme H. The oxazolidinone chiral auxilliary is next hydrolyzed from the pyrrolidines of general formula 36 as shown at the bottom of reaction Scheme H. The hydrolysis reaction is accomplished using lithium hydroperoxide generated in situ from lithium hydroxide and 30% aqueous hydrogen peroxide. The reaction is typically conducted in a solvent system such as aqueous THF, and the reaction is performed at temperatures between 0 0 C and room temperature for a period of 1-6 hours. The resulting carboxylic acids of general formula 37 correspond to carboxylic acids of general formula 2 where both r and s are 1. Using the methodology presented in reaction Scheme A, the compounds of general formula 37 may then be converted to the compounds of the present invention of structural formula I. -54- WO 2004/087159 PCT/US2004/008711 Scheme H
R
3
R
3
R
3
R
3 r-R Pd/carbon, H 2 , EtOH o . R3 O N - O - O N 1. 1 -chloroethyl N chloroformate, toluene H Ph P 2. MeOH, heat Ph 32 R R 35 R R (BO)R, BOC (BOC)20 , 0 o 30% H 2 0 2 , HO NaHCO3 O-N LiOH o
CHCI
3
-H
2 0 BO c aq. THF Ph 36 R 3
R
3 36 37 As noted previously in the discussion of reaction Scheme D, it may occasionally be preferable to incorporate the R1 substituent into the substituted pyrrolidine of general formula 37 at an earlier stage of the synthesis, for instance when it is desired that R1 be a tert-butyl group. In such cases, it is possible to utilize an azomethine ylid precursor (2Q) bearing the desired R1 substituent in the cycloaddition reactions illustrated in reaction Schemes F and G. Reaction Scheme I illustrates the preparation of azomethine precursors of formula 25 starting with amines of general formula 18. Reaction of the amine of formula 18 with chloromethyltrimethylsilane at high temperature and in the absence of solvent affords the N-trimethylsilylmethyl-substituted amine of general formula 38. Subsequent reaction of 38 with aqueous formaldehyde in the presence of methanol and a base such as potassium carbonate then affords the generalized ylid precursor 25 which can be utilized in the cycloaddition reactions discussed above. Scheme I
R
1 MeSiCI ( 37% aqueous
H
2 N1 R formaldehyde RS ,9---N -)W- Me3Si _NvOM e heat Mesi N'H K 2 00 3 , MeOH MeSiN oMe 18 38 25 Compounds of general formula 1 wherein t = 1 or 3 may be prepared according to Schemes 1, 2 or 3 starting with the appropriate starting material. For example, to prepare compounds of general formula 1 in which t =3, pseudopelletierine may be substituted for compound 1-1 in Scheme 1. The following Intermediates and Examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any manner. -55- WO 2004/087159 PCT/US2004/008711 Intermediate 1-10 was prepared as described in Scheme J following the general procedure described in Scheme F to produce the compounds of the present invention of structural formula I. PREPARATION OF INTERMEDIATE 1 (3S.4R)-1-tert-buty1-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochloride salt (1-10) N HO . HCI 0 F F 1-10 StepA: Preparation of N-tert-butyl-N-(trimethylsilylmethvl)amine A mixture of tert-butylamine (18.0 mL, 171 mmol) and (chloromethyl)trimethylsilane (7.00 g, 57.1 rnmol) was heated in a thick-walled glass tube at 200'C overnight. After cooling to ambient temperature, the reaction mixture was poured into 1 N NaOH and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4), and the volatiles evaporated in vacuo. Distillation (atmospheric pressure; - 135oC) of the residual liquid gave the title compound as a colorless liquid. Step B: Preparation of N-tert-butyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine N-tert-Butyl-N-(trimethylsilylmethyl)amine from Step A (8.47 g, 53.1 mmol) was added dropwise, over approximately 30 minutes, via a pressure equalizing addition funnel to a stirred solution of aqueous formaldehyde (5.98 mnL of a 37 wt. % solution in water, 79.7 mmol) at O'C (ice cooling). After 45 minutes, methanol (6.45 mniL, 159.3 mmol) was added and the resulting solution was saturated with potassium carbonate. After stirring vigorously for approximately 5 h, the aqueous phase was removed. The organic phase was saturated with potassium carbonate and stirred overnight. The reaction mixture was poured into water and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4) and the volatiles evaporated in vacuo. Distillation (high vacuum; ~70oC) of the residual liquid afforded the title compound as a colorless liquid. - 56 - WO 2004/087159 PCT/US2004/008711 Ste C: Preparation of methyl (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3 carboxylate and methyl ( 3
S,
4 R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3 carboxylate Trifluoroacetic acid (116 IL, 1.51 mmol) was added to a solution of N-tert-butyl-N (methoxymethyl)-N-(trimethylsilylmethyl)amine from Step B (3.07 g, 15.1 mmol) and methyl (2E)-3 (2,4-difluorophenyl)prop-2-enoate (2.99 g, 15.1 mmol) in methylene chloride (60 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methlene chloride. The combined organic extracs were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by normal phase medium pressure liquid chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) gave the racemic title compound as a colorless liquid. The racemic titled compound was resolved into its enantiomeric components using preparative chiral high pressure liquid chromatography on CHIRALPAK AD Phase (5 % isopropanol/heptanes as eluent) to give in order of elution: methyl (3S,4R)-1 -tert-butyl-4-(2,4-difluorophenyl) pyrrolidine-3-carboxylate enantiomer of the titled compound as a colorless oil followed by the methyl (3R,4S)-1-tert-butyl-4-(2,4 difluorophenyl) pyrrolidine-3-carboxylate enantiomer of the title compound as a colorless oil. Step D: Preparation of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochloride salt (1-10) A mixture of the methyl (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl) pyrrolidine-3 carboxylate enantiomer of Step C (1.37 g, 4.61 mmol) and potassium trimethylsilanolate (0.68 g, 5.30 rmmol) in diethyl ether (23 mL) was stirred at room temperature overnight. A saturated solution of hydrogen chloride in ethyl acetate was then added, the volatiles were evaporated and the residual solid 1 10 was used without further purification in the preparation of Examples detailed below. Alternatively, (3S,4R)-l-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (1-10) may be prepared according to the procedure of Scheme I: Scheme I Step A Step B I- 1-2 1-3 - 57 - WO 2004/087159 PCT/US2004/008711 CN OH NC OH ' 1 N N. StepOC N Step D Nq 1-4 1-5 HO,C Step E N F F 1-10 Step A: A solution of (S)-2-methyl-CBS-oxazaborolidine (131 mL, 1 M in toluene), borane-N,N diethylaniline (46.36 L) in MTBE (10 L) was heated to 38-42 'C, then a solution of 2-chloro-2',4'-di fluoro-acetophenone I-1 (4891 g) in MTBE (16 L) was added over 10 hr. The homogeneous solution was stirred at 40 oC for one hour, then allowed to cooled to 18 'C and stirred overnight. Methanol (2.3 L) was added over 60 min, while maintaining the temperature at <20 oC with cooling. The reaction mixture was stirred 30 min, then 5.0 N aq HC1 (10 L) was added over 30 min, while maintaining the temperature at 22-25 oC with cooling. After stirring 30 min, the phases were separated, and the organic phase was washed with saturated aqueous NaC1, then concentrated in vacuo to obtain a solution of compound I-2. Step B: Compound I-2 in the MTBE solution from Step A (5040 g, 98 wt%, 25.67 mol) was diluted with methanol (5 L), then tert-butylamine (25 L) was added. The mixture was cooled to 25 'C, solid NaOH pellets (1048 g) were added, and the resulting reaction mixture was stirred and warmed to reflux. After 12-20 hr at reflux, the mixture was concentrated in vacuo to 1/3 volume, then water (5 L) and MTBE (20 L), were added. The phases were separated and the aqueous phase was re-extracted with MTBE (2 x 2 L). The combined extracts were washed with saturated aqueous NaC1 (1 L), and then concentrated in vacuo. Heptane (40 L) was added and the concentration was continued to bring the volume to 20 L. The mixture was heated to -90 "C to dissolve all solids, then allowed to cool to 22 'C to crystallize over 4 hr. The mixture was cooled to 0 oC, stirred 12-15 hr, then filtered. The resulting filtrate was washed with cold heptane (2 x 5 L), then dried in vacuo at 35 "C to obtain compound I-3. Step C: A mixture of compound I-3 (5.205 kg, 99.9%, 22.68 mol) and acrylonitrile (26.9 L, 408 mol) was heated to reflux (-77 oC) under nitrogen atmosphere. After heating for 20 h (-90% conversion), one equivalent each of ethanol (1.32 L, 22.68 mol) and formamide (0.9 L, 22.68 mol) was added and heating was continued for 12 h. After cooling to 22 'C, the solution was concentrated to 12 L -58- WO 2004/087159 PCT/US2004/008711 by distillation (80-90 torr at 20-22 C pot temperature), and the resulting residue was diluted with isopropyl acetate (22 L) and re-concentrated (55-75 torr and 22-27 'C pot temperature). This was repeated. Then the residue was diluted with isopropyl acetate to a total volume of 34 L, and the supernatant was filtered using a 10-15 ptm porosity filter. The filter cake was washed with isopropyl acetate, and the filtrate was diluted with a total of 24 L of isopropyl acetate. The combined filtrate (-54 L) was washed with a solution made up of water (31.2 L), acetic acid (52 mL, 4 mol%), and saturated brine (3.1 L), followed by a 12% aqueous NaCi wash (2 x 34 L). The organic layer was concentrated (15-45 torr and 5-29 oC) to ~15 L volume and flushed with 5 x 6 L n-heptane, during which time product crystallized. The slurry was diluted with n-heptane to a volume of 23 L and stirred at 0-5 'C for 1-3 days until a concentration of 10 g/18 L is achieved, then filtered and washed with cold (5 °C) n-heptane (14 L). The wet cake was dried in vacuo at 20 oC with a nitrogen sweep to afford compound I-4. Step D: A solution of compound I-4 (5.73 kg, 99.9%, 20.28 mol) in dry THF (31.3 L) was cooled to -20 oC, then chloro diethylphosphate (3.79 kg, 21.29 mol) was added. LiHMDS (1.35 M in THF solution; 31.5 L, 42.58 mol) was slowly added over 1.5 h while maintaining the reaction temperature at 15 'C. After stirring at -15 0 C for 2 h, the reaction mixture was quenched with water (50.6 L) at <15 OC and extracted with n-heptane (40.5 L) at 20 'C. The organic layer was washed with 10% aq NaCl solution (52 L), and extracted with 3 N HCI solution (40.6 L, 121.8 mol) with cooling to keep the temperature <35 'C. The aqueous layer (58 L) was adjusted to pH 11-12 with 50% aq NaOH (6.13 L, 116.1 mol) and extracted with n-heptane (54 L). The organic phase was washed once with 10% aq NaCl solution (26 L) and the resulting heptane solution containing compound I-5 was used in Step E. Step E: The solution of compound -5 (4.88 kg, 18.46 mol) in n-heptane (-65 L total) from the Step D was solvent-switched to ethanol (-20.6 L total). To this solution was added 50% aq NaOH (2.7 L, 51.15 mol) over 2 min with stirring. Upon addition of the NaOH, the temperature of the mixture rose from 16 to 34 oC. The mixture was then heated to reflux (78-80 °C) under nitrogen for 5-6 h. After cooling to 20 'C, the solution was diluted with ethanol (25.4 L) and methanol (40.6 L). The solution was then cooled to 12 'C; the pH was adjusted to apparent pH 6.8 with 96% H 2
SO
4 (1.42 L, 25.6 mol), while maintaining the temperature at -20 'C. The sodium sulfate slurry was filtered through a bed of Solka Floc® (5 kg) and anhydrous powder Na 2
SO
4 (4 kg), and washed with 1:1 EtOH:MeOH (20 L). The filtrate was filtered, concentrated and solvent-switched to a 2-propanol solution (~15 L volume). The resulting slurry was heated at reflux (~80 oC) for 2 h, then cooled to 16 'C. MTBE (30.4 L, 3 vol relative to IPA) was added to the mixture over 5 h. After stirring at 16-17 oC for 3 days, the resulting slurry was filtered and washed with 12 L 1:3 IPA:MTBE. The solids were dried in vacuo (150 torr) at 50 oC with a nitrogen sweep to give compound (1-10). -59- WO 2004/087159 PCT/US2004/008711 PREPARATION OF INTERMEDIATE 2 (3R,4R)-1-tert-butvyl-3-(2,4-difluorophenvl)piperidine-4-carboxylic acid (1-12) F F N ,,OH O 1-12 (3R,4R)-1-tert-butyl-3-(2,4-difluorophenyl)piperidine-4-carboxylic acid (1-12) is also be prepared from the appropriate starting materials following the general procedure described for the preparation of Intermediate 1. Alternatively, (3R,4R)-1-tert-butyl-3-(2,4-difluorophenyl)piperidine-4-carboxylic acid (1-12) may be prepared according to the procedure of Scheme J: Scheme J OH H HO F N StepA F N CN F F F _ CF 1-3 J-1 NC F,,% CON CONH2 Step B Step C F N J-2 J-3 Step D F CH Step E F 0 2 H F F N N J-4 1-12 - 60 - WO 2004/087159 PCT/US2004/008711 Step A: A mixture of compound -3 (24 g, 0.105 mol), 4-bromobutyronitrile (42 g, 0.28 mole, 2.7 eq) K 2 C0 3 (22 g, 0.16 mol, 1.52 eq) and DMF (70 mL) was heated at 50oC for 64 hr. The reaction was quenched into water (500 mL) and extracted with ether (2 x 250 rnL). The ether layer was extracted with IN HCl (2 x 125 mL), and the resulting aqueous layer was extracted with hexanes (2 x 100 mL). The aqueous layer was then made basic with 5N NaOH, and extracted with ether (2 x 250 mL). The organic layer was washed with brine, dried with Na 2
SO
4 , filtered and concentrated. The residue was chromatographed (silica, 9/1 hexanes/THF then 4:1 hexanes/THF) to give compound J-1 as a colorless oil. Step B: Compound J-1 (50 g, 0.169 mol) was dissolved in THF (500 mL) and the solution was cooled to -15 0 C. Diethyl chlorophosphonate (25 mL, 1.74 mol, 1.03 eq) was added, followed by the dropwise addition of IM LiHMDS in THF (350 mL, 2.07 eq). The LiHMDS was added over 100 minutes while maintaining a reaction temperature between -12 C and -15oC. The reaction was allowed to warm slowly to RT and aged overnight. The reaction was quenched with water and extracted twice with ether. The ether layer was washed with brine, dried with sodium sulfate, filtered and concentrated to give compound J-2. Step C: Compound J-2 was dissolved in ethanol (150 mL), 50% NaOH (24 mL) was added and the mixture was refluxed for 5 hours. The reaction was acidified with 12 N HC1 (60 mL) at which point it solidified. The mass was diluted with ethanol (50 mL) and methanol (200 mL), and filtered. The cake was washed with ethanol, and the filtrate was concentrated and flushed with isopropyl alcohol (500 mL). Additional isopropyl alcohol was added and the mixture concentrated to circa 300 mL. The slurry was filtered and the resulting cake was washed with isopropyl alcohol. The solid cakes were combined to give compound J-3. Step D: Compound J-3 was dissolved in methanol (iL) and saturated with HC1 gas. The solution was refluxed for 72 hr, then concentrated and partitioned between ether and saturated NaHCO 3 solution. The ether layer was dried with Na 2
SO
4 , filtered and concentrated to afford compound J-4. Additional compound J-4 was obtained from the filtrate above by similar treatment with HCl/MeOH followed by chromatography (silica 90/10/1 CH2Cl2/MeOHINH40H). Step E: Compound J-4 was dissolved in 6N HCI (300 mL) and the solution was refluxed for 3 hr. The solution was then concentrated and the resulting residue was dissolved in water and re-concentrated. The residue was then flushed with isopropyl alcohol (2 x 300 mL) and ethyl acetate (2 x 500 mL). The -61- WO 2004/087159 PCT/US2004/008711 resulting slurry was stirred at room temperature for 1 hr and filtered. The resulting solid was washed with ethyl acetate and dried to give compound 1-12. Scheme 1 ONN S Step A Step B Step C 0 H O OH 1-1 1-2 1-3 1-4 OTYO O O OTO0 Step D Step E Step F OH OH 1-5 1-6 1-7 H N N 0 1-8 1-9 F F/ H F ,,0 H Step I N O ON , OH N H O N 1-9 1-10 O 'i< 1-11 EXAMPLE 1 -62- WO 2004/087159 PCT/US2004/008711 N-(tert-butyl)-8-{ [(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-cyclohexyl-8 azabicyclo[3.2.1]octane-3-carboxamide (1-11) Step A: Preparation of ethyl 3-(methoxymethylene)-8-azabicyclo[3.2.1]octane-8-carboxylate (1 2) To a solution of NI-carbethoxy- 4-tropinone (1-1) (8.00 g, 40.6 mmol, Acros) and (methoxymethyl)tripheylphosphonium chloride (16.7 g, 48.7 mmol) in THF was added sodium bis(trimethylsilyl)amide (48.7 mL, 48.7 nrnol, 1.0 N in THF) at 0 oC. After stirring at room temperature overnight, the solvent was removed by rotary evaporation. The mixture was quenched with a saturated aqueous solution of NH4C1, extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-20% ethyl acetate/hexanes as eluent) afforded (1-2) as a colorless oil. Step B: Preparation of ethyl 3-formyl-8-azabicyclo[3.2.1loctane-8-carboxylate (1-3 Ethyl 3-(methoxymethylene)-8-azabicyclo[3.2.1]octane-8-carboxylate (1-2) (2.31 g, 10.3 mmol) was added to a mixture of an aqueous solution of HC1 (10.3 mnL, 61.5 mmol, 6.0 N in water) and tetrahydrofuran (40.0 mL) at room temperature. The mixture was stirred for 3 h and quenched with water, extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 and brine, dried over anhydrous MgSO4, concentrated to give (1-3) as colorless oil. Step C: Preparation of 8-(ethoxycarbonyl)-8-azabicyclo[3.2. 1]octane-3-carboxylic acid (1-4) A solution of ethyl 3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate (1-3) (1.84 g, 8.71 mmol) in t-BuOH (50.0 mL) was diluted with an aqueous 5% NaH2PO4 solution (35.3 mL, 14.8 mmol, 0.42 N in water). With vigorous stirring, an aqueous 1.0 M KMnO4 solution (52.3 mL, 52.3 mmol) was added at room temperature. The mixture was stirred for 10 minutes and quenched with a saturated aqueous solution of Na2SO3. The resulting pH of the mixture was adjusted to 3 with cold (0 'C) dilute HCI to dissolve the colloidal MnO2. The mixture was then extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous MgSO4, concentrated to give (1-4) as white solid. Step D: Preparation of 3-cyclohex-2-en-1-yl 8-ethyl 8-azabicyclo[3.2.1]octane 3,8-dicarboxylate (1-5) - 63 - WO 2004/087159 PCT/US2004/008711 To a solution of 8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-4) (1.88 g, 8.27 mmol) in dichloromethane (30.0 mL) was added 2-cyclohexen-1-ol (0.812 g, 8.27 mmol, Aldrich), EDC (2.38 g, 12.4 nnol), and DMAP (0.100 g). The mixture was stirred at room temperature overnight and quenched with EtOAc (200 mL). The organic solution was washed with a 5% aqueous HCI solution (100 mL), saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mnL), and dried over anhydrous MgSO4, and concentrated. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-5) as colorless oil. Step E: Preparation of 3-cyclohex-2-en-1-yl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3 carboxylic acid (1-6) To a solution of diisopropylamine (0.471 g, 4.65 mmol) in anhydrous THF (10.0 mL) was added n-BuLi (2.91 mL, 4.65 mnol, 1.6 N in THF) at 0 oC. The mixture was stirred at the temperature for 15 minutes and cooled to - 78 'C, followed by addition of a solution of 3-cyclohex-2-en 1-yl 8-ethyl 8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (-5) (1.30 g, 4.23 mmol) in THF (5.0 mL). After stirring at - 78 OC for 30 min, TMSCI (0.459 g, 4.23 mmol) was added and the resulting solution was stirred at - 78 'C for 1 h. The mixture was allowed to warm to room temperature and stirred at 80 'C overnight. After cooling to room temperature, 2 N aqueous solution of HCI (10 mL) was added to the mixture. The mixture was stirred continued for 5 minutes, then partitioned between Et 2 0 (50 mL) and 2 N HCI aqueous solution. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 10%-50% ethyl acetate/hexanes as eluent) afforded (1-6) as a white solid. Sep F Preparation of 3-cyclohexyl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-7) To a solution of 3-cyclohex-2-en-1-yl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3 carboxylic acid (-6) (1.86 g, 6.05 mmol) in MeOH (20.0 mL) was added PtO 2 (68.7 mg, 0.30 mmol) and the suspension was placed on a shaker under hydrogen atmosphere (50 psi) overnight. The solid was filtered out and rinsed with MeOH; the resulting solution was concentrated to give (1-7) as white solid. Ste G: Preparation of ethyl 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8 azabicyclof3.2. loctane-8-carboxylate (1-8) To a solution of 3-cyclohexyl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3 carboxylic acid (1-7) (1.50 g, 4.85 mmol) in CHC13 (60.0 mL) was slowly added oxalyl chloride (2.67 mL, 5.33 mmol, 2.0 N), followed by addition of DMF (3 drops) as a catalyst. After the bubbling ceased, the mixture was stirred for 30 min and the solvents were removed under vacuum. To the mixture was - 64 - WO 2004/087159 PCT/US2004/008711 added t-BuNH2 (5.32 g, 72.7 mmol) and the resulting suspension was warmed up to 80 oC overnight. The solvents were removed under vacuum; the reaction was quenched with 1 N HCI, and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-8) as a white solid. Step H: Preparation of 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8-azoniabicyclo[3.2. 1]octane iodide (1-9) To a solution of ethyl 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8 azabicyclo[3.2. 1]octane-8-carboxylate (1-8) (1.00 g, 2.74 mmol) in DCM (20.0 mL) was slowly added iodotrimethylsilane (2.20 g, 11.0 mmol). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the solid was washed with ether (2 x 5 mL) to give (1-9) as a yellow solid. Step I: Preparation of N-(tert-butyl)-8-{ [(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3 yllcarbonyl } -3-cyclohexvl-8-azabicycloF3.2.11 loctane-3-carboxamide (1-11) To a solution of (3R,4S)-1-tert-butyl-4-(2,4-difiuorophenyl) pyrrolidine-3-carboxylic acid (1-10) (0.150 g, 0.357 mmol) in dichloromethane (5.0 mL) was added 3-[(tert butylamino)carbonyl]-3-cyclohexyl-8-azoniabicyclo[3.2.1]octane iodide (1-9) (0.101 g, 0.357 mmol), O (7-azabenzotriazol- 1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphat (HATU, 0.163 g, 0.428 mmol), 1-hydroxyl-7-azabenzotriazole (HOAT, 0.058 g, 0.428 mmol), and NMM (0.108 g, 1.07 mmol). The mixture was stirred at room temperature overnight and concentrated. Purification of the resulting crude residue by high-pressure liquid chromatography (gradient elution, 15%-95% acetonitrilelwater as eluent), followed by the addition of 1 N HCI solution in ether afforded (1-11) as a white solid (mn/z (ES) 558 (MH+)). EXAMPLE 2 (3R,4R)-1-tert-butyl-4-( { 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8-aza-bicyclo[3.2.1]oct-8 Pl} carbonvl)-3-(2,4-difluorophenvyl)piperidinium chloride (1-13) - 65 - WO 2004/087159 PCT/US2004/008711 F F H HI F N F N H Step A ~N o OH N OHH 0 NIH 1-9 1-12 O 1-13 Step A: Preparation of (3R,4R)-1-tert-butyl-4-({ 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8 azabicyclo[3.2.1 oct-8-vyll} carbonyl)-3-(2,4-difluorophenyl)piperidinium chloride (1-13) To a solution of 3-[(tert-butylamino)carbonyl]-3-cyclohexyl-8 azoniabicyclo[3.2.1]octane iodide (1-9) (42.0 mg, 0.100 mmol) in dichloromethane (5.0 mL) was added (3R, 4 R)-1-tert-butyl-3-(2,4-difluorophenyl)piperidine-4-carboxylic acid (1-12) (35.7 mg, 0.120 mmol), HOBt (16.2 mg, 0.120 mmol), EDC (23.0 mg, 0.120 mmol), and DIEA (38.8 mg, 0.300 mmol). The mixture was stirred at room temperature overnight, quenched with a saturated aqueous solution of NaHCO3, and extracted with dichloromethane (3 x 20 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, and concentrated. Purification of the crude residue by high pressure liquid chromatography (gradient elution; 15%-95% acetonitrile/water as eluent) and addition of a solution of 1 N HCI solution in ether afforded (1-13) as a white solid (m/z (ES) 572 (MH)). Scheme 2 0 0 0 0 00 N Step A N Step B - I 0 OTf 0 B0 ) Step D 2-1 2-2 2-3 OH 0 OTf 0 Step C I CI CI 2-4 2-5 - 66 - WO 2004/087159 PCT/US2004/008711 OOOO OO N N N 0 Step E O Step F OH Step G I I CI Cl Cl Cl 2-6 2-7 2-8 O O H HI OO N N 0 HN' Step H HN cI CI 2-9 2-10 F F/ H HI N F N ©oo C+0 0_ N' 2-10 1-10 CI 2-11 EXAMPLE 3 (3S,4R)-3-[(3-{ 2-[ 1-(acetylamino)propyl]-4-chlorophenyl }-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1-tert butyl-4-(2,4-difluorophenyl)pyrrolidinium trifluoroacetate (2-11) Step A: Preparation of ethyl 3-{ [(trifluoromnethyl)sulfonyl]oxy } azabicyclo[3.2.1]oct-2-ene-8 carboxylate (2-2) - 67 - WO 2004/087159 PCT/US2004/008711 To a solution of N-carbethoxy- 4-tropinone (-1) (15.0 g, 76.1 mmol) in 150 mL anhydrous tetrahydrofuran at -78 oC was slowly added KN(TMS)2 (182 mL, 0.5 mL in toluene). The solution was stirred at - 78 oC for 30 minutes, and then a solution of N-phenyltrifluoromethane sulfonamide (32.6 g, 91.3 mmol) in 150 mL anhydrous tetrahydrofuran was added. The mixture was stirred at - 78 oC for 2 h and quenched with a saturated aqueous ammonium chloride (150 mL). After the removal of tetrahydrofuran under vacuum, the aqueous layer was then extracted with EtOAc (3 x 150 mL). The combined EtOAc layers were washed with 1N KOH (150 ml), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-30% ethyl acetate/hexanes as eluent) afforded (2-2) as a colorless oil. Step B: Preparation of ethyl 3-(4,4,5,5-tetramethyl-l1,3,2-dioxaborolan-2-yl)-8 azabicvclo[3.2.1]oct-2-ene-8-carboxvlate (2-3) A vigorously stirred suspension of the ethyl 3-{ [(trifluoromethyl) sulfonyl]oxy }-8 azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2-2) (24.0 g, 72.8 mmol), bis(pinacolato)diboron (20.4 g, 80.2 mmol), potassium acetate (21.5 g, 219 mmol), and [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (2.98 g of a 1:1 complex with methylene chloride, 3.64 mmol) in methyl sulfoxide (anhydrous, 500 mL) was degassed via three vacuum/nitrogen ingress cycles and then heated at 80 oC for approximately 15 h. After cooling to ambient temperature, the reaction mixture was poured into water/brine (1:1) mixture and filtered through Celite eluted with ethyl acetate. The filtrate was separated and the aqueous phase was re-extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (anhydrous MgSO4), filtered, and concentrated in vacuo. Purification of the crude residue by HPLC (gradient elution; 0%-20% ethyl acetate/hexane as eluent) furnished (2-3) as a white solid. Step C: Preparation of 4-chloro-2-propionylphenyl trifluoromethanesulfonate (2-5) To a solution of 5'-chloro-2'-hydroxypropiophenone (2-4) (14.0 g, 75.8 mmol) in methylene chloride (110 mL) was added dimethylaminopyridine (0.93 g, 7.58 mmol) and the solution was cooled to - 78 'C. Triethyl amine (12.5 mL, 89.5 rniol) was added followed by dropwise addition of trifluoromethane sulfonic anhydride (25.0 g, 88.7 mmol) over a period of 30 minutes (keeping the reaction temperature below - 70 oC, and stirred at - 78 'C for 3 h. The mixture was poured into ice cooled water, diluted with EtOAc; the layers were separated, and the aqueous layer was extracted with 2 x 100 mL EtOAc. Combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-10% ethyl acetate/hexanes as eluent) afforded (2-5) as a colorless oil. -68- WO 2004/087159 PCT/US2004/008711 Ste D: Preparation of ethyl 3-(4-chloro-2-propionylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-8 carboxylate (2-6) To a mixture of 4-chloro-2-propionylphenyl trifluoromethanesulfonate (2) (21.0 g, 66.3 mmol), absolute ethanol (120 mL), toluene (120 mL), and 2M aqueous solution of sodium carbonate (100 mL) was added ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene 8-carboxylate (2-3) (20.3 g, 66.3 mmol). The mixture was evacuated and flushed with nitrogen three times. After addition of tetrakis(triphenylphosphine)palladium(0) (7.69 g, 6.63 rmmol), the mixture was heated at 75 oC for 1 h and TLC showed no remaining trifluoromethanesulfonate. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (2-6) as a colorless oil. S Preparation of ethyl 3-(4-chloro-2-propionylphenyl)-8-azabicyclo[3.2.1]octane-8 carboxylate (2-7) A solution of ethyl 3-(4-chloro-2-propionylphenyl)-8-azabicyclo[3.2. 1]oct-2-ene-8 carboxylate (2-6) (1.50 g, 4.31 mmol, ) in 10 mL of ethanol and 10 mL acetic acid was shaken under hydrogen at 1 atmospheric pressure with platinum oxide (980 mg, 0.431 mmol, added in portions) for 60h at room temperature. Solid was filtered through a pad of Celite and rinsed with ethanol. The ethanol solution was concentrated to give (2-7) as colorless oil. eSte.F: Preparation of ethyl 3-[4-chloro-2-(1-hydroxypropyl)phenyl]-8-azabicyclo[3.2.1]octane 8-carboxylate (2-8) To a solution of (S) (-)-o,a-dephenyl-2-pyrrolidinemethanol (0.724 g, 2.86 mmol) in anhydrous tetrahydrofuran (25 mL) was added trimethylborate (0.446 g, 4.29 mmol) all at once and stirred at room temperature for I h. The borane dimethylsulfide complex (7.15 mL, 14.3 mmol, 2.0 M in THF) was added dropwise over a period of I h. The mixture was then cooled to 0 0 C with an ice-bath and a solution of ethyl 3-(4-chloro-2-propionylphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (2-7) (5.00 g, 14.9 mmol) in 15 mL of anhydrous tetrahydrofuran was added dropwise over a period of 3 h (keeping the reaction temperature below 4 °C). The reaction mixture was allowed to warm slowly up to room temperature and stirred overnight. After the reaction was complete, the mixture was added portionwise to a stirring mixture of 2 N HC1 (125 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue by flash - 69 - WO 2004/087159 PCT/US2004/008711 chromatography over silica gel (5% ethyl acetone/dichloromethane as eluent) afforded (2-8) as a colorless oil. Step G: Preparation of ethyl 3- {2-[1-(acetylamino)propyl]-4-chlorophenyl}-8 azabicyclo[3.2. l]octane-8-carboxylate (2-9) To a solution of ethyl 3-[4-chloro-2-(1-hydroxypropyl)phenyl]-8 azabicyclo[3.2.1]octane-8-carboxylate (2-8) (2.25 g, 6.39 mmol) in acetonitrile (100 mL) was added concentrated H2SO4 (5.11 mL, 95.9 rmmol) in 50 mL of acetonitrile. The mixture was stirred at 60 'C for 1 h, quenched with I N NaOH (200 mL), and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography over silica gel (a mixture of 9:1:0.1 methylenechloride:MeOH:30%NH4OH as eluent) afforded (2-9) as a white solid. Step H: Preparation of 3-{ 2-[ 1-(acetylamino)propyl]-4-chlorophenyl }-8 azoniabicyclo[3.2.1 ]octane iodide (2-10) To a solution of ethyl 3-{2-[1-(acetylamino)propyl]-4-chlorophenyl }-8 azabicyclo[3.2.1]octane-8-carboxylate (2-9) (0.200 g, 0.51 mmol) in DCM (5.0 mL) was added iodotrimethylsilane (0.360 mL, 2.55 mmol) slowly. The mixture was stirred at room temperature overnight. After the reaction was completed, the solvents were removed under vacuum and solid was washed with ether (2 x 5 mL) to give (2-10) as yellow solid. Step Preparation of (3S,4R)-3-[(3- { 2-[ l1-(acetylamino)propyl]-4-chlorophenyl } -8 azabicyclo[3.2.1]oct-8-yl)carbonyl]-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidinium trifluoroacetate (2-11) To a solution of (3R,4S)-l-tert-butyl-4-(2,4-difluorophenyl) pyrrolidine-3-carboxylic acid (1-10) (0.144 g, 0.508 mmol) in dichloromethane (10.0 mL) was added 3-{ 2-[1 (acetylamino)propyl]-4-chlorophenyl}-8-azoniabicyclo[3.2.1]octane iodide (2-10) (0.228 g, 0.508 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphat (HATU, 0.232 g, 0.610 mmol), 1-hydroxyl-7-azabenzotriazole (HOAT, 0.083 g, 0.610 mmol), and NMM (0.514 g, 5.08 mmol). The mixture was stirred at room temperature overnight, quenched with a saturated aqueous solution of NaHCO3, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue and separation of isomers by high-pressure liquid chromatography (15% to 95% acetonitrile/water as eluent) afforded (2 11) as a white solid (nm/z (ES) 586 (MIW)). -70- WO 2004/087159 PCT/US2004/008711 EXAMPLE 4 (3R,4R)-4-[(3-{ 2-[1-(acetylamino)propyl]-4-chlorophenyl }-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1-tert butyl-3-(2,4-difluorophenyl)piperidinium chloride (2-12) F F H HI N F N 2-10 1-12 4 Step A N O It". OH H N) CCI 2-10 1-12 CI 2-12 Ste A: Preparation of (3R,4R)-4-[(3-{ 2-[ 1-(acetylamino)propyl]-4-chlorophenyl }-8 azabicyclo[3.2. 1]oct-8-yl)carbonyl]-1-tert-butyl-3-(2,4-difluorophenyl)piperidinium chloride (2-12) To a solution of 3-{ 2-[ 1-(acetylamino)propyl]-4-chlorophenyl }-8 azoniabicyclo[3.2.1]octane iodide (2-10) (46.8 mg, 0.115 mmol) in dichloromethane (2.0 mL) was added (3R,4R)-1-tert-butyl-3-(2,4-difluorophenyl)piperidine-4-carboxylic acid (1-12) (34.0 mg, 0.115 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphat (HATU, 52.1 mg, 0.138 mmol), 1-hydroxyl-7-azabenzotriazole (HOAT, 19.0 mg, 0.138 mmol), and NMM (35.0 g, 0.345 mmol). The mixture was stirred at room temperature overnight and quenched with a saturated aqueous solution of NaHCO3, extracted with dichloromethane (3 x 20 mL). The extracts were washed with brine, and dried over anhydrous MgS04, and concentrated. Purification of the crude residue by prep-TLC (developed with 10% methanol/methylenechloride as mobile phase and separation of isomers by high pressure liquid chromatography (gradient elution; 15%-95% acetonitrile/water as eluent) and addition of a solution of 1 N HC1 solution in ether afforded (2-12) as a white solid (mn/z (ES) 600 (MH )). -71- WO 2004/087159 PCT/US2004/008711 Scheme 3 0 0 S OH HI Step A Step B Step C OH OH OH 1-7 3-1 3-2 >of- 0o~ Y 0 > >ONO OO OOO Step D Step E Step F OH . OMs S 3-3 3-4 3-5 F F/ H O NHCI Step G F / F N N 3-6 N *,,,OHS 1-10 3-7 EXAMPLE 5 Step A: Preparation of 3-carboxy-3-cyclohexyl-8-azoniabicyclor3.2.11 octane iodide (3-1) To a solution of 3-cyclohexyl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3 carboxylic acid (1-7) (2.50 g, 8.08 mmol) in 80 mL of chloroform was added iodotrimethylsilane (4.75 mL, 16.8 mmol) dropwise. The mixture was stirred at room temperature overnight and warmed up to 50 oC for additional two hours. After the reaction was completed, the volatiles were removed under vacuum to give (3-1) as a yellow solid. Step B: Preparation of 8-(tert-butoxycarbonyl)-3-cyclohexyl-8-azabicyclo[3.2.1]octane-3 carboxylic acid (3-2) - 72 - WO 2004/087159 PCT/US2004/008711 To a solution of 3-carboxy-3-cyclohexyl-8-azoniabicyclo[3.2. 1]octane iodide (3-1) (2.74 g, 8.08 mmol) in 30 mL of dioxane was added 30 mL of 1.2 N NaOH aqueous solution followed by addition of di(tert-butyl) dicarbonate (3.00 g, 13.7 mmol). The mixture was stirred at room temperature overnight and the volatiles were removed under vacuum. The residue was diluted with ethyl acetate (100 n) and quenched with 1 N HCI aqueous solution (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give (3-2) as a white solid. Step C: Preparation of tert-butyl 3-cyclohexyl-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8 carboxylate (3-3) To a solution of 8-(tert-butoxycarbonyl)-3-cyclohexyl-8-azabicyclo[3.2.1]octane-3 carboxylic acid (3-2) (1.47 g, 4.35 mmol) in 50 mL of anhydrous tetrahydrofuran was added borane methyl sulfide complex (8.70 mL, 17.4 mnimol, 2.0 M in tetrahydrofuran) dropwise at room temperature. The mixture was stirred at 50 oC for 48 hours and the volatiles were removed under vacuum. Purification of the crude residue by flash chromatography over silica gel (50% ethyl acetate/hexanes as eluent) afforded (3-3) as a white solid. Step D: Preparation of tert-butyl 3-cyclohexyl-3-{ [(methylsulfonyl)oxy] methyl}-8 azabicyclof3.2.1]octane-8-carboxylate (3-4) To a solution of tert-butyl 3-cyclohexyl-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8 carboxylate (3-3) (0.870 g, 2.69 mmol) in methylene chloride was added diisopropylamine (0.562 mL, 3.23 mmol), dimethylaminopyridine (32.5 mg, 0.269 mmol), and methanesulfonyl chloride (0.229 mL, 2.97 mmol). The mixture was stirred at room temperature for four hours and diluted with methylene chloride, washed with water, a saturated aquous solution of NaHCO3, and 1 N HCI aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated to give (3-4) as a colorless oil. Step E: Preparation of tert-butyl 3-cyclohexyl-3-[(imethylthio)methyl]-8-azabicyclo[3.2.1]octane 8-carboxylate (3-5) To a solution of tert-butyl 3-cyclohexyl-3-{ [(methylsulfonyl)oxy] methyl}-8 azabicyclo[3.2.1]octane-8-carboxylate (3-4) (1.01 g, 2.69 mmol) in 50 mL of DMF was added sodium thiomethoxide (0.943 g, 13.5 mmol). The mixture was stirred at 60 oC for 3 days. After cooling to room temperature, 200 mL of diethyl ether was added. The solid was filtered and the filtrates were washed with water three times. The organics were dried over anhydrous MgSO4, filtered, and concentrated to give (3-5) as a clear yellow oil. - 73 - WO 2004/087159 PCT/US2004/008711 Step F: Preparation of 3-cyclohexyl-3-[(methylthio)methyl]-8-azoniabicyclo[3.2.1]octane chloride (3-6) To a solution of 4.0 N HC1 in dioxane (20.0 mL) was added tert-butyl 3-cyclohexyl-3 [(methylthio)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (3-5) (0.870 g, 2.46 rnuol). The mixture was stirred at room temperature for three hours and the volatiles were removed under vacuum to give (3 6) as a pale solid. Step G: Preparation of (3R,4R)-1-tert-butyl-3-({ 3-cyclohexyl-3-[(methylthio) methyl]-8 azabicyclof3.2. ll1oct-8-yl }carbonyl)-4-(2.4-difluorophenvyl) pyrrolidinium chloride (3-7) To a solution of (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl) pyrrolidine-3-carboxylic acid (1-10) (0.170 g, 0.601 mmol) in dichloromethane (5.0 mL) was added 3-cyclohexyl-3 [(methylthio)methyl]-8-azoniabicyclo[3.2.1]octane chloride (3-6) (0.174 g, 0.601 mmol), 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.173 g, 0.901 mmol), 1-hydroxyl-7 azabenzotriazole (HOAT, 0.082 g, 0.603 mmol), and diisopropylethylamine (0.105 mL, 0.601 mmol). The mixture was stirred at room temperature overnight, diluted with methylene chloride, washed with water and a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue by preparative TLC (90% methylene chloride, 9% methanol, 1% of a 40% of NH40H aqueous soltion as eluent), followed by the addition of one equivalent HCI in ether to afford (3-7) as white solid (m/z (ES) 519 (MH+)). EXAMPLE 6 F F F/ F Step A N N N 0 II S SN 3-7 3-8 Step A: Preparation of (3R,4R)-1l-tert-butyl-3-( { 3-cyclohexyl-3-[(methylsulfinyl)methyl]-8 azabicyclor3.2.1loct-8-vl}carbonyl)-4-(2,4-difluorophenyl)pyrrolidinium chloride (3-8) To a solution of (3R,4R)-1-tert-butyl-3-({ 3-cyclohexyl-3-[(methylthio) methyl]-8 azabicyclo[3.2.1]oct-8-yl}carbonyl)-4-(2,4-difluorophenyl) pyrrolidinium chloride (3-7) (0.150 g, 0.270 -74 - WO 2004/087159 PCT/US2004/008711 mmol) in ethanol (6.0 mL) was added a solution of NalO4 (0.174 g, 0.813 mmol) in 6.0 mL of water. The mixture was stirred at room temperature for 50 min. The solid was filtered and filtrate was concentrated, diluted with methylene chloride, washed with a saturated aqueous solution of Na2SO3. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated, followed by the addition of one equivalent HC1 in ether to afford (3-8) as white solid (m/z (ES) 534 (MH+)). EXAMPLE 7 F F F F NN Step A O N N O0 0 0 3-8 3-9 Step A: Preparation of (3R,4R)-1-tert-butyl-3-({ 3-cyclohexyl-3-[(methylsulfonyl)methyl]-8 azabicyclo[3.2.11oct-8-vyl lcarbonyl)-4-(2,4-difluorophenyl)pyrrolidinium chloride (3-9) To a solution of (3R,4R)-1-tert-butyl-3-({ 3-cyclohexyl-3-[(methylsulfinyl)methyl]-8 azabicyclo[3.2.1]oct-8-yl}carbonyl)-4-(2,4-difluorophenyl)pyrrolidinium chloride (3-8) (50 mg, 0.090 mmol) in ethanol (2.0 mL) was added a solution of the oxone ® (276 mg, 0.451 mmol) in 2.0 mL of water. The mixture was stirred at room temperature for 40 min. The solid was filtered and filtrate was concentrated, diluted with methylene chloride dried over anhydrous Na2SO4, filtered, and concentrated, followed by the addition of one equivalent HCI in ether to afford (3-9) as white solid (nm/z (ES) 551 (MH+)). Using the appropriate starting materials and intermediates, including (3R,4S)-1-tert butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (1-10) for the peptide coupling reaction, and following procedures analogous to the procedure described for the preparation of Compound 2-11 (Example 3), the following compounds 8-1 and 9-1 may be prepared: - 75 - WO 2004/087159 PCT/US2004/008711 CI CI 0N 0 N H O30 8-1 9-1 F F BIOLOGICAL ASSAYS A. Binding Assay. The membrane binding assay was used to identify competitive inhibitors of 1251 NDP-alpha-MSH binding to cloned human MCRs expressed in mouse L- or Chinese hamster ovary (CHO)-cells. Cell lines expressing melanocortin receptors were grown in T-180 flasks containing selective medium of the composition: 1 L Dulbecco's modified Eagles Medium (DMEM) with 4.5 g L glucose, 25 mM Hepes, without sodium pyruvate, (Gibco/BRI); 100 ml 10% heat-inactivated fetal bovine serum (Sigma); 10 mL 10,000 unit/mL penicillin & 10,000 jig/mL streptomycin (Gibco/BRI); 10 ml 200 mM L-glutamine (Gibco/BR1); 1 mg/mL geneticin (G418) (Gibco/BRI). The cells were grown at 37 0 C with CO2 and humidity control until the desired cell density and cell number was obtained. The medium was poured off and 10 mls/monolayer of enzyme-free dissociation media (Specialty Media Inc.) was added. The cells were incubated at 37 0 C for 10 min or until cells sloughed off when flask was banged against hand. The cells were harvested into 200 mL centrifuge tubes and spun at 1000 rpm, 40 C, for 10 min. The supernatant was discarded and the cells were resuspended in 5 mls/monolayer membrane preparation buffer having the composition: 10 mM Tris pH 7.2-7.4; 4 pg/mL Leupeptin (Sigma); 10 tM Phosphoramidon (Boehringer Mannheim); 40 pig/mL Bacitracin (Sigma); 5 gg/mL Aprotinin (Sigma); 10 mM Pefabloc (Boehringer Mannheim). The cells were homogenized with motor-driven dounce (Talboy setting 40), using 10 strokes and the homogenate centrifuged at 6,000 rpm, 4 0 C, for 15 min. The pellets were resuspended in 0.2 mls/monolayer membrane prep buffer and aliquots were placed in tubes (500-1000 gL/tube) and quick frozen in liquid nitrogen and then stored at -80 0 C. Test compounds or unlabelled NDP-ac-MSH was added to 100 [tL of membrane binding buffer to a final concentration of 1 pM. The membrane binding buffer had the composition: 50 mM Tris pH 7.2; 2 mlv CaC12; 1 mM MgC12; 5 mM KCI; 0.2% BSA; 4 ptg/mL Leupeptin (SIGMA); 10 g 1 M -76- WO 2004/087159 PCT/US2004/008711 Phosphoramidon (Boehringer Mannheim); 40 gg/mL Bacitracin (SIGMA); 5 pg/mL Aprotinin (SIGMA); and 10 mM Pefabloc (Boehringer Mannheim). One hundred pL of membrane binding buffer containing 10-40 gg membrane protein was added, followed by 100 RtM 125I-NDP-a-MSH to final concentration of 100 pM. The resulting mixture was vortexed briefly and incubated for 90-120 min at room temp while shaking. The mixture was filtered with Packard Microplate 196 filter apparatus using Packard Unifilter 96-well GFIC filter with 0.1% polyethyleneimine (Sigma). The filter was washed (5 times with a total of 10 mL per well) with room temperature of filter wash having the composition: 50 mM Tris-HC1 pH 7.2 and 20 mM NaC1. The filter was dried, and the bottom sealed and 50 pL of Packard Microscint 20 was added to each well. The top was sealed and the radioactivity quantitated in a Packard Topcount Microplate Scintillation counter. B. Functional assay. Functional cell based assays were developed to discriminate melanocortin receptor agonists from antagonists. Cells (for example, CHO- or L-cells or other eukaryotic cells) expressing a human melanocortin receptor (see e.g. Yang-YK; Ollmann-MM; Wilson-BD; Dickinson-C; Yamada-T; Barsh GS; Gantz-I; Mol-Endocrinol. 1997 Mar; 11(3): 274-80) were dissociated from tissue culture flasks by rinsing with Ca and Mg free phosphate buffered saline (14190-136, Life Technologies, Gaithersburg, MD) and detached following 5 rmin incubation at 37 0 C with enzyme free dissociation buffer (S-014-B, Specialty Media, Lavellette, NJ). Cells were collected by centrifugation and resuspended in Earle's Balanced Salt Solution (14015-069, Life Technologies, Gaithersburg, MD) with additions of 10 mM HEPES pH 7.5, 5 mM MgCl2, 1 mM glutamine and 1 mg/ml bovine serum albumin. Cells were counted and diluted to 1 to 5 x 10 6 /mL. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was added to cells to 0.6 mM. Test compounds were diluted in dimethylsulfoxide (DMSO) (10-5 to 10-10 M)*and 0.1 volume of compound solution was added to 0.9 volumes of cell suspension; the final DMSO concentration was 1%. After room temperature incubation for 45 min, cells were lysed by incubation at 100 0 C for 5 min to release accumulated cAMP. cAMP was measured in an aliquot of the cell lysate with the Amersham (Arlington Heights, IL) cAMP detection assay (RPA556). The amount of cAMP production which resulted from an unknown compound was compared to that amount of cAMP produced in response to alpha-MSH which was defined as a 100 % agonist. The EC50 is defined as the compound concentration which results in half maximal stimulation, when compared to its own maximal level of stimulation. Antagonist assay: Antagonist activity was defined as the ability of a compound to block cAMP production in response to alpha-MSH. Solution of test compounds and suspension of receptor - 77 - WO 2004/087159 PCT/US2004/008711 containing cells were prepared and mixed as described above; the mixture was incubated for 15 min, and an EC50 dose (approximately 10 nM alpha-MSH) was added to the cells. The assay was terminated at 45 min and cAMP quantitated as above. Percent inhibition was determined by comparing the amount of cAIP produced in the presence to that produced in the absence of test compound. C. In vivo food intake models. 1) Overnight food intake. Sprague Dawley rats are injected intracerebroventricularly with a test compound in 400 nL of 50% propylene glycollartificial cerebrospinal fluid one hour prior to onset of dark cycle (12 hours). Food intake is determined using a computerized system in which each rat's food is placed on a computer monitored balance. Cumulative food intake for 16 h post compound administration is measured. 2) Food intake in diet induced obese mice. Male C57/B 16J mice maintained on a high fat diet (60% fat calories) for 6.5 months from 4 weeks of age are are dosed intraperitoneally with test compound. Food intake and body weight are measured over an eight day period. Biochemical parameters relating to obesity, including leptin, insulin, triglyceride, free fatty acid, cholesterol and serum glucose levels are determined. D. Rat Ex Copula Assay Sexually mature male Caesarian Derived Sprague Dawley (CD) rats (over 60 days old) are used with the suspensory ligament surgically removed to prevent retraction of the penis back into the penile sheath during the ex copula evaluations. Animals receive food and water ad lib and are kept on a normal light/dark cycle. Studies are conducted during the light cycle. 1) Conditioning to Supine Restraint for Ex Copula Reflex Tests. This conditioning takes - 4 days. Day 1, the animals are placed in a darkened restrainer and left for 15 - 30 minutes. Day 2, the animals are restrained in a supine position in the restrainer for 15 - 30 minutes. Day 3, the animals are restrained in the supine position with the penile sheath retracted for 15 - 30 minutes. Day 4, the animals are restrained in the supine position with the penile sheath retracted until penile responses are observed. Some animals require additional days of conditioning before they are completely acclimated to the procedures; non-responders are removed from further evaluation. After any handling or evaluation animals are given a treat to ensure positive reinforcement. 2) Ex Copula Reflex Tests. Rats are gently restrained in a supine position with their anterior torso placed inside a cylinder of adequate size to allow for normal head and paw grooming. For a 400-500 gram rat, the diameter of the cylinder is approximately 8 cm. The lower torso and hind limbs are restrained with a non-adhesive material (vetrap). An additional piece of vetrap with a hole in it, through which the glans penis will be passed, is fastened over the animal to maintain the preputial sheath -78- WO 2004/087159 PCT/US2004/008711 in a retracted position. Penile responses will be observed, typically termed ex copula genital reflex tests. Typically, a series of penile erections will occur spontaneously within a few minutes after sheath retraction. The types of normal reflexogenic erectile responses include elongation, engorgement, cup and flip. An elongation is classified as an extension of the penile body. Engorgement is a dilation of the glans penis. A cup is defined as an intense erection where the distal margin of the glans penis momentarily flares open to form a cup. A flip is a dorsiflexion of the penile body. Baseline and or vehicle evaluations are conducted to determine how and if an animal will respond. Some animals have a long duration until the first response while others are non-responders altogether. During this baseline evaluation latency to first response, number and type of responses are recorded. The testing time frame is 15 minutes after the first response. After a minimum of 1 day between evaluations, these same animals are administered the test compound at 20 mg/kg and evaluated for penile reflexes. All evaluations are videotaped and scored later. Data are collected and analyzed using paired 2 tailed t-tests to compared baseline and/or vehicle evaluations to drug treated evaluations for individual animals. Groups of a minimum of 4 animals are utilized to reduce variability. Positive reference controls are included in each study to assure the validity of the study. Animals can be dosed by a number of routes of administration depending on the nature of the study to be performed. The routes of administration includes intravenous (IV), intraperitoneal (IP), subcutaneous (SC) and intracerebral ventricular (ICV). E. Models of Female Sexual Dysfunction Rodent assays relevant to female sexual receptivity include the behavioral model of lordosis and direct observations of copulatory activity. There is also a urethrogenital reflex model in anesthetized spinally transected rats for measuring orgasm in both male and female rats. These and other established animal models of female sexual dysfunction are described in McKenna KE et al, A Model For The Study of Sexual Function In Anesthetized Male And Female Rats. Am. J. Physiol. (Regulatory Integrative Comp. Physiol 30): R1276-R1285, 1991; McKenna KE et al, Modulation By Peripheral Serotonin of The Threshold For Sexual Reflexes In Female Rats, Pharm. Bioch. Behav., 40:151-156, 1991; and Takahashi LK et al, Dual Estradiol Action In The Diencephalon And The Regulation Of Sociosexual Behavior In Female Golden Hamsters, Brain Res., 359:194-207, 1985. Representative compounds of the present invention were tested and found to bind to the melanocortin-4 receptor. These compounds were generally found to have IC50 values less than 10 tM. Representative compounds of the present invention were also tested in the functional assay and found generally to activate the melanocortin-4 receptor with EC50 values less than 5ftM. -79- WO 2004/087159 PCT/US2004/008711 EXAMPLES OF PHARMACEUTICAL COMPOSITIONS As a specific embodiment of an oral composition of a composition of the present invention, 15 mg of Example 3 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 ming to fill a size O hard gelatin capsule. As another specific embodiment of an oral composition of a compound of the present invention, 10 mg of Example 4 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gelatin capsule. As another specific embodiment of an oral composition of a compound of the present invention, 15 mg of Example 2 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gelatin capsule. While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable. - 80 -

权利要求:
Claims (36)
[1] 1. A compound of structural formula I: x R6 R 7 R Y N O R2 (1) 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)nC-N, (10) -(CH2)nCON(R 5 R5), (11) -(CH2)nCO2R 5 , (12) -(CH2)nCOR 5 , (13) -(CH2)nNR 5 C(O)R 5 , (14) -(CH2)nNR 5 CO2R 5 , (15) -(CH2)nNR 5 C(O)N(R 5 )2, (16) -(CH2)nNR 5 SO2R 5 , (17) -(CH2)nS(O)pR 5 , (18) -(CH2)nSO2N(R 5 )(R 5 ), (19) -(CH2)nOR 5 , (20) -(CH2)nOC(O)R 5 , (21) -(CH2)nOC(O)OR 5 , (22) -(CH2)nOC(O)N(R 5 )2, -81- WO 2004/087159 PCT/US2004/008711 (23) -(CH2)nN(R 5 )(R 5 ), and (24) -(CH2)nNR 5 SO2N(R 5 )(R 5 ); wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R1 is selected from the group consisting of (1) hydrogen, (2) amidino, (3) C1-4 alkyliminoyl, (4) C1-10 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 R 3 , and wherein alkyl, cycloalkyl and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R 2 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 R 3 , and wherein alkyl is unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; each R 3 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, - 82 - WO 2004/087159 PCT/US2004/008711 (7) halogen, (8) OR 4 , (9) -(CH2)nN(R 4 )2, (10) -(CH2)nC-N, (11) -(CH2)nCO2R 4 , (12) NO2, (13) -(CH2)nNR 4 SO2R 4 (14) -(CH2)nSO2N(R 4 )2, (15) -(CH2)nS(O)pR 4 , (16) -(CH2)nNR 4 C(O)N(R 4 )2, (17) -(CH2)nC(O)N(R 4 )2, (18) -(CH2)nNR 4 C(O)R 4 , (19) -(CH2)nNR 4 CO2R 4 , (20) -(CH2)nNR 4 C(O)-heteroaryl, (21) -(CH2)nC(O)NR 4 N(R 4 )2, (22) -(CH2)nC(O)NR 4 NR 4 C(O)R 4 , (23) O(CH2)nC(O)N(R 4 )2, (24) CF3, (25) CH2CF3, (26) OCF 3 , and (27) OCH2CF3, wherein phenyl, naphthyl, and heteroaryl 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 R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R 4 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-naphthlyl, (6) -(CH2)nC2-8 heterocycloalkyl, - 83 - WO 2004/087159 PCT/US2004/008711 (7) -(CH2)nC3- 7 cycloalkyl, and (8) -(CH2)nC3-7 bicycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, cycloalkyl, bicycloalkyl, and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from halogen, C1- 4 alkyl, hydroxy, and C1-4 alkoxy, or two R 4 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 -NCI-4 alkyl; each R 5 is independently selected from the group consisting of (1) hydrogen, (2) C 1-8 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 R 3 , and wherein alkyl, (CH2) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein two R 5 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 -NC1-4 alkyl; R 6 and R 7 are each 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; r is 1 or 2; sis 0,1,or2; t is 1, 2, or 3; n is 0, 1 or 2; and p is 0, 1, or 2. - 84- WO 2004/087159 PCT/US2004/008711
[2] 2. The compound of Claim 1 wherein R1 is selected from the group consisting of hydrogen, C1- 6 alkyl, -(CH2)0-1C3-6 cycloalkyl, and -(CH2)0-1-phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
[3] 3. The compound of Claim 1 wherein R 2 is phenyl or thienyl, optionally substituted with one to three groups independently selected from R 3 , and pharmaceutically acceptable salts thereof.
[4] 4. The compound of Claim 3 wherein R 2 is phenyl optionally substituted with one to three groups independently selected from R 3 , and pharmaceutically acceptable salts thereof.
[5] 5. The compound of Claim 3 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 R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
[6] 6. The compound of Claim 5 wherein X is selected from the group consisting of (1) hydrogen, (2) -(CH2)0-1-phenyl, (3) -(CH2)0-1-heteroaryl, (4) -(CH2)0-1-C2-8 heterocycloalkyl, and (5) -(CH2)0-1-C3-8 cycloalkyl, - 85- WO 2004/087159 PCT/US2004/008711 wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
[7] 7. The compound of 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(R 5 )2, (8) -(CH2)nCO2R 5 , (9) -(CH2)nS(O)pR 5 , (10) -(CH2)nOR 5 , (11) -(CH2)nNR5C(O)R5, and (12) -(CH2)nNR 5 SO2R 5 , wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
[8] 8. The compound of Claim 5 wherein Y is selected from the group consisting of (1) C1-6 alkyl, (2) -(CH2)0-1-phenyl, (3) -(CH2)0-1-heteroaryl, (4) -(CH2)0-1-C3-8 cycloalkyl, (5) -(CH2)0-1-C2-8 heterocycloalkyl, (6) -(CH 2 )0-INHC(O)R 5 , (7) -(CH2)0-1CO2R 5 , (8) -(CH2)0-1C(O)N(R 5 )2, and (9) -(CH2)O-1S(O)pR 5 , - 86- WO 2004/087159 PCT/US2004/008711 wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
[9] 9. The compound of Claim 5 wherein R 6 and R 7 are hydrogen.
[10] 10. The compound of Claim 1 wherein r is 1 and s is 1.
[11] 11. The compound of Claim 1 wherein r is 2 and s is 1.
[12] 12. The compound of Claim 1 of structural formula Ha or lIb of the indicated trans relative stereochemical configuration: X R R 7 7 R 1 X R6 7 R n. /.N r )sor N "rN) 0 R 2 0 R 2 (lla) (lib) or a pharmaceutically acceptable salt thereof; 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)n-C2-8 heterocycloalkyl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo; Y is selected from the group consisting of: - 87 - WO 2004/087159 PCT/US2004/008711 O 0 0 0 CH .oCH3, ,E tCH ' O CH 3 o H3 C "OJ H 3 , O O O KO CH3, po S'CH3, Op1O'OH3, O CH 3 O O O VkO- NCHa , OpO, N OH '<KOH, H O 0 O CH 3 0 N C H S ' NEt, N CH ON CH N Y' N NzOH3,X H H H H H O 0 O 0 YN"- H 3 '-"C H3H . NH 2 , O O 0 - IN 0 N ' 'NC H NS 'C H N 0, IS, H H O O H ' N OH H , H N CH3 N H N H O 0 IHb0 0 H 3 NH NHH 3 NCHH, ) CH OH 3 K 0 0 0 0 0 CH 0, 0 O HO N O O O -- O ,C C 00H HN OH 3 -88- WO 2004/087159 PCT/US200-I/00871 I NN 'j-CH 2 , CH - N oQ M S N> N K N> N OH 3 -C2 H 3 C / -CH 2 </ -- CH 2 </ OH1 s s C~~H 3 2j , N-~N N-.N N OH 2 /N CH 2 K' H0 'C-i s >'S SO 2 H 2 N N H 3 NN N> N OH 3 </~K -jCH 2 HK< 11-HC<H< K 0 H0 CH3 0' OH 3 </ H -- HC N N ~ N>" CH 2 C H H HOH L.N N~ OH 3 ,N CH 3 N ~ Nzz OH2 ----- zl - 3 N/ 0 H 3 0 zO H 2 N -< OH 2 .7 N N-OH2 H~2O N % NNN H 3 C, N Iz HN~ N 4 .C- 3 N 'N H3 N OH 2 OH 2 1 IN /~N N 0 N 0 H2CH 2 0 /2C HN, ,-NH N OH 2 HNN 'CH, N 2-o -NH-CO)OH 3 , -()(C32 -O)NH-t-Bu -89 - WO 2004/087159 PCT/US200-I/00871 I I-GH 2 SCH(CH 3 ) 2 , -CH 2 S(O)GH(CH ) 2 -CH 2 S(O) 2 CH(CH 3 ) 2 -C(O)NHCH 2 HANCH 3 ) -C(O)CH(CHB) 2 , -CH 2 NHCOtBu, .1-CH 2 SCH 3 , -CHAS()CH 3 , -I-CHASO) 2 CH 3 , j-CH 2 N(CH 3 )C(O)t-Bu, -CH 2 NiPr)COMe , -CHN(iPr)SO 2 Me, -CH(Et)NIHC(O)Me, - CH(Me)NHC(O)Me, -CH 2 NHC(O)Me, -VOC(O)NHC(Me) 2 CH 2 OMe, t-C(O)NHC(MVe) 2 CH 2 OH, - -CH 2 CH 2 C(Me) 2 OH, 0 / 0 /- ILN NH N N-CH 3 ,IkN 0 H2C.. N H2C N H2C NJ N2 0 0 0 00 H2C,,N" H 2 C, H 2 C... N6 H2CN W-Ne 0 2 S) 0S , -NH 0 0 H H 0 ' 0 - 90 - WO 2004/087159 PCT/US2004/008711 -CH 2 CH 2 NEt 2 , CH 2 CONEt 2 , {Me A H 2 CN H 2 C'N H 2 C ' N2 % N "N S0 0 0 H2 'CH NH 2 0 0 and N N-N N-N ,N 'CH 3 ' 'CH 2 CF 3 H 2 C. wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R 1 is hydrogen, amidino, C1-4 alkyliminoyl, C1-6 alkyl, C5-6 cycloalkyl, -(CH2)0-1 phenyl, -(CH2)0- 1 heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R 2 is phenyl or thienyl optionally substituted with one to three groups independently selected from R 3 ; each R 3 is independently selected from the group consisting of (1) C1-8 alkyl, (2) -(CH2)n-heteroaryl, (3) -(CH2)n-C2-8 heterocycloalkyl, (4) halogen, (5) OR 4 , (6) -(CH2)nN(R 4 )2, (7) -(CH2)nC-N, (8) -(CH2)nCO2R 4 , (9) -(CH2)nNR 4 SO2R 4 (10) -(CH2)nSO2N(R 4 )2, (11) -(CH2)nS(O)pR 4 , (12) -(CH2)nNR4C(O)N(R 4 )2, (13) -(CH2)nC(O)N(R 4 )2, -91 - WO 2004/087159 PCT/US2004/008711 (14) -(CH2)nNR 4 C(O)R 4 , (15) -(CH2)nNR 4 CO2R 4 , (16) -(CH2)nNR 4 C(O)-heteroaryl, (17) -(CH2)nC(O)NR 4 N(R 4 )2, (18) -(CH2)nC(O)NR 4 NR 4 C(O)R 4 , (19) O(CH2)nC(O)N(R 4 )2, (20) CF3, (21) CH2CF3, (22) OCF3, and (23) OCH2CF3, wherein phenyl, naphthyl, and heteroaryl 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, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, or wherein two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R 4 is independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) phenyl, (4) heteroaryl, (5) -(CH2)nC2-8 heterocycloalkyl, and (6) C3-6 cycloalkyl, 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 C 1 - 4 alkoxy, or two R 4 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 R 5 is independently selected from the group consisting of (1) hydrogen, (2) C 1 -8 alkyl, (3) -(CH2)n-phenyl, (4) -(CH2)n-naphthyl, -92 - WO 2004/087159 PCT/US2004/008711 (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 R 3 , and wherein alkyl, (CH2) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein two R 5 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 -NCI-4 alkyl; R 6 and R 7 are each 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; r is 1 or 2; sis O, 1 or2; tis 1, 2, or 3; n is 0, 1, or 2; and pis 0, 1, or 2.
[13] 13. The compound of Claim 1 of structural formula fia or HIb of the indicated trans relative stereochemical configuration: X R R7 R X R 6 R 7 R Y t N )' O r N )S t S - or 0 0 R 3 R 3 -. R 3 RR (ila) (1lib) or a pharmaceutically acceptable salt thereof; wherein - 93 - WO 2004/087159 PCT/US2004/008711 X is selected from the group consisting of (7) hydrogen, (8) -(CH2)0-1-phenyl, (9) -(CH2)0-1-naphthyl, (10) -(CH2)0-1-heteroaryl, (11) -(CH2)0-1 C3-8 cycloalkyl, and (12) -(CH2)0-1 C2-8 heterocycloalkyl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH2) are optionally substituted with one to three groups independently selected from R 3 and oxo; Y is selected from the group consisting of -CH 2 SCH3, -CH 2 S(O)CH 3 , -CH 2 S(O) 2 CH 3 , -CH(Et)NHC(O)Me, -CH 2 CH 2 NEt 2 , -CH 2 CONEt 2 , x 0 N, N H O H H o K N NN O , OH ,and N wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo; R1 is hydrogen, C1-4 alkyl, or -(CH 2 ) 0 - 1 phenyl; each R 3 is independently selected from the group consisting of (1) C1-8 alkyl, (2) -(CH2)0-1-heteroaryl, (3) -(CH2)0-1-C2-8 heterocycloalkyl, - 94 - WO 2004/087159 PCT/US2004/008711 (4) halogen, (5) OR 4 , (6) -(CH2)0-1N(R 4 )2, (7) -(CH2)0-1C-N, (8) -(CH2)0_1CO 2 R 4 , (9) -(CH2)0-1NR 4 SO2R 4 (10) -(CH 2 )0-ISO2N(R 4 ) 2 , (11) -(CH 2 )0-1S(O)0-3R 4 , (12) -(CH2)0-1NR 4 C(O)N(R 4 )2, (13) -(CH2)0-IC(O)N(R 4 )2, (14) -(CH 2 ) 0 -INR 4 C(O)R 4 , (15) -(CH2)0-1NR 4 CO2R 4 , (16) -(CH2)0-1NR 4 C(O)-heteroaryl, (17) -(CH2)0-1C(O)NR 4 N(R 4 )2, (18) -(CH 2 ) 0 -C(O)NR 4 NR 4 C(O)R 4 , (19) O(CH2)0-1C(O)N(R 4 )2, (20) CF3, (21) CH2CF3, (22) OCF3, and (23) OCH2CF3, wherein phenyl, naphthyl, and heteroaryl 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 (CH 2 ) 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 R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R 4 is independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) phenyl, (4) heteroaryl, (5) -(CH2)0-1C2-8 heterocycloalkyl, and (6) C3-6 cycloalkyl, - 95 - WO 2004/087159 PCT/US2004/008711 wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, cycloalkyl, bicycloalkyl, and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from halogen, C1-4 alkyl, hydroxy, and C1-4 alkoxy, or two R 4 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 R 5 is independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) -(CH2)0-1-phenyl, (4) -(CH2)0-1-naphthyl, (5) -(CH2)0-1-heteroaryl, and (6) -(CH2)0-1 C3-7 cycloalkyl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, (CH2) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein two R 5 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 -NC1-4 alkyl; R 6 and R 7 are each independently selected from the group consisting of (1) hydrogen, (2) C1-8 alkyl, (3) -(CH2)0-1 C3-6 cycloalkyl, (4) -(CH2)0-1-aryl, (5) hydroxy, (6) halogen, and (7) amino; tis 1, 2, or 3; r is 1 or 2; and s is 0, 1 or 2.
[14] 14. The compound of Claim 11 selected from the group consisting of: - 96 - WO 2004/087159 PCT/US2004/008711 CI HH 0 F 0 F FF SN N 0 F O F F F S N 0 N NN 0 F H 0 F N NI F F H N N 0 F F or a pharmaceutically acceptable salt thereof.
[15] 15. The compound of Claim 14 which is: - 97 - WO 2004/087159 PCT/US2004/008711 CI IL O N N HO F F or a pharmaceutically acceptable salt thereof.
[16] 16. The compound of Claim 14 which is: CI O N AN N 7 H 0 F F or a pharmaceutically acceptable salt thereof.
[17] 17. The compound of Claim 14 which is: H N N O O F F or a pharmaceutically acceptable salt thereof.
[18] 18. A method 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 which comprises administering to the mammal a therapeutically or prophylactically effective amount of a compound according to Claim 1. -98- WO 2004/087159 PCT/US2004/008711
[19] 19. A method for the treatment or prevention of obesity in a mammal in need thereof which comprises administering to the mammal a therapeutically or prophylactically effective amount of a compound according to Claim 1.
[20] 20. A method for the treatment or prevention of an obesity-related disorder selected from the group consisting of overeating, binge eating, and bulimia, hypertension, diabetes, elevated plasma insulin concentrations, insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, metabolic syndrome, insulin resistance syndrome, sexual and reproductive dysfunction, infertility, hypogonadism, hirsutism, obesity-related gastro-esophageal reflux, Pickwickian syndrome, cardiovascular disorders, inflammation, systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer, cardiac hypertrophy and left ventricular hypertrophy, in a mammal in need thereof which comprises administering to the mammal a therapeutically or prophylactically effective amount of a compound according to Claim 1.
[21] 21. A method for the treatment or prevention of diabetes mellitus in a mammal in need thereof comprising administering to the mammal a therapeutically or prophylactically effective amount of a compound according to Claim 1.
[22] 22. A method for the treatment or prevention of male or female sexual dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically or prophylactically effective amount of a compound according to Claim 1.
[23] 23. A method for the treatment or prevention of erectile dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically or prophylactically effective amount of a compound according to Claim 1.
[24] 24. A pharmaceutical composition which comprises a compound of Claim 1 and a pharmaceutically acceptable carrier.
[25] 25. The pharmaceutical composition of Claim 24 further - 99 - WO 2004/087159 PCT/US2004/008711 comprising a second active ingredient selected from the group consisting of an insulin sensitizer, an insulin mimetic, a sulfonylurea, an c-glucosidase inhibitor, and a HI MVIG-CoA reductase inhibitor.
[26] 26. A method of treating erectile dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of the composition of Claim 24.
[27] 27. A method of treating erectile dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1 in combination with a type V cyclic-GMP-selective phosphodiesterase inhibitor, an a2-adrenergic receptor antagonist, or a dopaminergic agent.
[28] 28. A method of treating diabetes in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of the composition of Claim 24.
[29] 29. A method of treating obesity in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of the composition of Claim 24.
[30] 30. A method of treating diabetes or obesity in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1 in combination with an insulin sensitizer, an insulin mimetic, a sulfonylurea, an c-glucosidase inhibitor, a HMG-CoA reductase inhibitor, a serotonergic agent, a 33-adrenoreceptor agonist, a neuropeptide Y1 antagonist, a neuropeptide Y5 antagonist, a pancreatic lipase inhibitor, a cannabinoid CB 1 receptor antagonist or inverse agonist, or a melanin-concentrating hormone receptor antagonist.
[31] 31. The compound of Claim 14 wherein the pharmaceutically acceptable salt thereof is the hydrochloride salt.
[32] 32. The compound of Claim 14 wherein the pharmaceutically acceptable salt thereof is the trifluoroacetic acid salt.
[33] 33. The use of a compound according to Claim 1 for the manufacture of a medicament useful for the treatment or prevention of a disease mediated by the melanocortin-4 receptor in a human subject in need thereof. - 100 - WO 2004/087159 PCT/US2004/008711
[34] 34. The use according to Claim 33 wherein the disease mediated by the melanocortin-4 receptor is selected from the group consisting of obesity, diabetes, male sexual dysfunction and female sexual dysfunction.
[35] 35. The use according to Claim 34 wherein the male sexual dysfunction is male erectile dysfunction.
[36] 36. The use of a compound according to Claim 1 for the manufacture of a medicament useful for the treatment or prevention of an obesity-related disorder selected from the group consisting of overeating, binge eating, and bulimia, hypertension, diabetes, elevated plasma insulin concentrations, insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, metabolic syndrome, insulin resistance syndrome, sexual and reproductive dysfunction, infertility, hypogonadism, hirsutism, obesity-related gastro-esophageal reflux, Pickwickian syndrome, cardiovascular disorders, inflammation, systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer, cardiac hypertrophy and left ventricular hypertrophy. - 101 -

类似技术:

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公开号 | 公开日 | 专利标题

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EP1610789B1|2010-07-21|Bicyclic piperidine derivatives as melanocortin-4 receptor agonists

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US7160886B2|2007-01-09|Acylated piperazine derivatives as melanocortin-4 receptor agonists

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US20100160306A1|2010-06-24|Acylated Piperidine Derivatives as Melanocortin-4 Receptor Agonists

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AU2006304305B2|2010-04-01|Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators

同族专利:

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公开号 | 公开日

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WO2004087159A1|2004-10-14|

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EP1610789B1|2010-07-21|

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AU2004226452B2|2008-07-24|

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EP1610789A4|2008-02-27|

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EP1610789A1|2006-01-04|

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US20060194780A1|2006-08-31|

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AT474577T|2010-08-15|

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US7276520B2|2007-10-02|

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DE602004028228D1|2010-09-02|

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CA2519939A1|2004-10-14|

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JP2006521359A|2006-09-21|

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CN1764458A|2006-04-26|

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法律状态:
2008-11-20| FGA| Letters patent sealed or granted (standard patent)|

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2010-01-21| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE PATENTEE NAME FROM MERCK & CO., INC. TO MERCK SHARP & DOHME CORP. |

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2011-10-20| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US45767903P| true| 2003-03-26|2003-03-26||

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US60/457,679||2003-03-26||

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PCT/US2004/008711|WO2004087159A1|2003-03-26|2004-03-22|Bicyclic piperidine derivatives as melanocortin-4 receptor agonists|

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