Field of the invention
This invention generally re1αtes to muscarinic receptor antagonists which are useful, among other uses for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. The invention also re1αtes to pharmaceutical compositions containing the compounds of the present invention and the methods of treating the diseases mediated through muscarinic receptors.
Background of the invention
Muscarinic receptors as members of the G Protein Coupled Receptors (GPCRs) are composed of a family of 5 receptor sub-types (Mi, M2, MI, M4 and MS) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor sub-types in the brain and other organs has been documented. For example, the MI subtype is located primarily in neuronal tissues such as cereberal cortex and autonomic ganglia, the M2 subtype is present mainly in the heart where it mediates cholinergically induced bradycardia, and the MB subtype is located predominantly on smooth muscle and salivary g1αnds (Nature, 323, p.411 (1986); Science, 237, p.527(1987)).
A review in Current Opinions in Chemical Biology, 3, p. 426 (1999), as well as in Trends in Pharmacological Sciences, 22, p. 409 (2001) by Eglen et. al., describes the biological potentials of modu1αting muscarinic receptor subtypes by ligands in different disease conditions, such as Alzheimer's Disease, pain, urinary disease condition, chronic obstructive pulmonary disease, and the like.
A review in J. Med. Chem., 43, p. 4333 (2000), by Felder et. al. describes therapeutic opportunities for muscarinic receptors in the central nervous system and e1αborates on muscarinic receptor structure and function, pharmacology and their therapeutic uses.
The pharmacological and medical aspects of the muscarinic c1αss of acetylcholine agonists and antagonists are presented in a review in Molecules, 6, p. 142 (2001).
Birdsall et. al. in Trends in Pharmacological Sciences, 22, p. 215 (2001) have also summarized the recent developments on the role of different muscarinic receptor subtypes using different muscarinic receptor of knock out mice.
Muscarinic agonists such as muscarine and pilocarpine and antagonists such as atropine have been known for over a century, but little progress has been made in the discovery of receptor subtype-selective compounds, making it difficult to assign specific functions to the
individual receptors. Although c1αssical muscarinic antagonists such as atropine are potent bronchodi1αtors, their clinical utility is limited due to high incidence of both peripheral and central adverse effects such as tachycardia, blurred vision, dryness of mouth, constipation, dementia, etc. Subsequent development of the quarterly derivatives of atropine such as ipratropium bromide are better tolerated than parenterally administered options, but most of these are not ideal anti-cholinergic bronchodi1αtors, due to 1αck of selectivity for muscarinic receptor sub-types, resulting in dose-limiting side-effects such as thirst, nausea, mydriasis and those associated with the heart such as tachycardia mediated by the Ma receptor.
Annual Review of Pharmacological Toxicol, 41, p. 691 (2001), describes the pharmacology of the lower urinary tract infections. Although anti-muscarinic agents such as oxybutynin and tolterodine that act non-selectively on muscarinic receptors have been used for many years to treat b1αdder hyperactivity, the clinical effectiveness of these agents has been limited due to the side effects such as dry mouth, blurred vision and constipation. Tolterodine is considered to be generally better tolerated than oxybutynin. (Steers et. al., in Curr. Opin. Invest. Drugs, 2, 268; Chappie et. al., in Urology, 55,, 33; Steers et al., Adult and Pediatric Urology, ed. Gillenwatteretal., pp 1220-1325, St. Louis, MO; Mosby. 3rd edition (1996)).
There remains a need for development of new highly selective muscarinic antagonists, which can interact with distinct subtypes, thus avoiding the occurrence of adverse effects.
Compounds having antagonistic activity against muscarinic receptors have been described in Japanese patent application 1αid Open Number 92921/1994 and 135958/1994; WO 93/16048; U.S. Patent No. 3,176,019; GB 940,540; EP 0325 571; WO 98/29402; EP 0801067; EP 0388054; WO 9109013; U.S. Patent No. 5,281,601. Also, U.S. Patent Nos. 6,174,900, 6,130,232 and 5,948,792; WO 97/45414 are re1αted to 1,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated, 1,4-disubstitued piperidine derivatives; WO 93/16018 and WO96/33973 are other references of interest. US Patent No. 5,397,800 discloses 1-azabicyclo[2.2.1]heptanes. US Patent No.5, 001,160 describes l-aryl-l-hydroxy-l-substituted-3-(4-substituted-l-piperazinyl)-2-propanones. WO 01/42213 describes 2-biphenyl-4-piperidinyl ureas. WO 01/42212 describes carbamate derivatives. WO 01/90081 describes amino alkyl 1αctam. WO 02/53564 describes novel quinuclidine derivatives. WO 02/00652 describes carbamates derived from ary1αlkyl amines. WO 02/06241 describes 1,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives.
A report in J. Med. Chem., 44, p. 984 (2002), describes cyclohexylmethyl piperidinyl triphenylpropioamide derivatives as selective MI antagonist discriminating against the other receptor subtypes.
Summary of the invention
In one aspect, azabicyclo derivatives are provided as muscarinic receptor antagonists which can be useful as safe and effective therapeutic or prophy1αctic agents for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems. Also provided are processes for the synthesis of such compounds.
In another aspect, pharmaceutical compositions containing such compounds are provided together with acceptable carriers, excipients or diluents which can be useful for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems.
The disclosure also includes within its scope prodrugs of such compounds. In general, such prodrugs will be functionalized derivatives of these compounds which are readily converted in vivo into the defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known to the artisan skilled in the art.
The enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds as well as metabolites having the same type of activity are also provided, as well as pharmaceutical compositions comprising such compounds, their prodrugs, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients.
Other aspects will be set forth in the description which follows, and in part will be apparent from the description or may be learnt by the practice of the invention. The aspects may be realized and obtained by means of the mechanisms and combinations pointed out in the appended c1αims.
In accordance with one aspect, there are provided compounds having the structure of
Formu1α I
(Formula Removed)
Formu1α I H and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters,
enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein RI and R2 are independently selected from C1-C6alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl or optionally substituted phenyl wherein optional substituent(s) is/are selected from C1-C3 alkyl, C1-C3 alkoxy or halogen;
R3 represents C1-C6 alkyl wherein 1-3 hydrogen atom(s) may be rep1αced by C5-C7 cycloalkyl, 1, 3-dioxo-l, 3-dihydro-isoindolyl or optionally substituted phenyl wherein the optional substituent(s) is/are selected from C1-C4 alkyl or halogen; Z represents oxygen orNR4 wherein R4 represents hydrogen or C1-C3 alkyl.
In accordance with a second aspect, there is provided a method for treatment or prophy1αxis of an animal or a human suffering from a disease or disorder of the respiratory, urinary and gastrointestinal systems, wherein the disease or disorder is mediated through muscarinic receptors.
In accordance with a third aspect, there is provided a method for treatment or prophy1αxis of an animal or a human suffering from a disease or disorder associated with muscarinic receptors, comprising administering to a patient in need thereof, an effective amount for muscarinic receptor antagonist compound as described above.
In accordance with a fourth aspect of the present invention, there is provided a method for treatment or prophy1αxis of an animal or a human suffering from a disease or disorder of the respiratory system such as bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, etc.; urinary system which induce such urinary disorders as urinary incontinence, lower urinary tract symptoms (LUTS), etc.; and gastrointestinal system such as irritable bowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compounds as described above, wherein the disease or disorder is associated with muscarinic receptors.
In accordance with a fifth aspect of the present invention, there are provided processes for preparing the compounds as described above.
Compounds described herein exhibit significant potency in terms of their activity, which was determined by in vitro receptor binding assays. The compounds are tested in vivo. Some of the compounds of the present invention were found to be potent muscarinic receptor antagonists with high affinity towards MI receptors. Therefore, pharmaceutical compositions for the possible treatment for diseases or disorders associated with muscarinic receptors are provided herein. In addition, such compounds can be administered orally or parenterally.
Detailed description of the invention
The compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, these compounds may be prepared by the following reaction sequences as shown in Schemes I and II:
(Formula Removed)Compounds of Formu1α VI may be prepared by the illustrative reaction sequence of Scheme I, which depicts condensing a compound of Formu1α II with a compound of Formu1α III wherein RI and R2 are independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl or optionally substituted phenyl wherein optional substituent(s) is/are selected from C1-C3 alkyl, C1-C3 alkoxy or halogen; R4 represents hydrogen or C1-C3 alkyl; P is any protecting group for an amino group, in the presence of N-methylmorpholine and 1-hydroxybenzotriazole and a condensing agent to give a protected compound of Formu1α IV, which on deprotection in the presence of a deprotecting agent in an organic solvent gives an unprotected intermediate of Formu1α V which is finally N-alky1αted or benzy1αted with a suitable alky1αting or benzy1αting agent L-R3 to give a compound of Formu1α VI wherein L is any leaving group and RI represents C1-C6 alkyl wherein 1-3 hydrogen atom(s) may be rep1αced by C5-C7 cycloalkyl, 1,3-dioxo-l, 3-dihydro-isoindolyl or optionally substituted phenyl wherein the optional substituent is/are selected from C1-C4 alkyl or halogen. P is any protecting group for an amino group for a compound of Formu1α III and is selected from benzyl and t-butyloxy carbonyl groups.
The reaction of a compound of Formu1α II with a compound of Formu1α III to give a compound of Formu1α IV can be carried out in the presence of a condensing agent, for example,
l-(3-dimethy1αminopropyl)-3-ethyl carbodiimide hydrochloride (EDC), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,3-dicyclohexylcarbodiimide (DCC).
The reaction of a compound of Formu1α II with a compound of Formu1α III to give a compound of Formu1α IV can be carried out in a solvent, for example, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene or chloroform, at a temperature ranging from about 0-140°C.
The deprotection of a compound of Formu1α IV to give a compound of Formu1α V can be carried out with a deprotecting agent, for example, pal1αdium on carbon and hydrogen, ammonium formate and pal1αdium on carbon, trifluoroacetic acid (TFA) or hydrochloric acid.
The deprotection of a compound of Formu1α IV to give a compound of Formu1α V can be carried out in an organic solvent, for example, methanol, ethanol, tetrahydrofuran or acetonitrile, at a temperature ranging from about 10-50°C.
The N-alky1αtion or benzy1αtion of a compound of Formu1α V to give a compound of Formu1α VI can be carried out with an alky1αting or benzy1αting agent, L-R3 wherein L is any leaving group, known in the art, for example, halogen, O-mestyl or O-tosyl group.
The N-alky1αtion or benzy1αtion of a compound of Formu1α V to give a compound of Formu1α VI can be carried out in an optional presence of potassium carbonate and potassium iodide in a suitable organic solvent, for example, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or acetonitrile, at a temperature ranging from about 25-100°C.
(Scheme Removed)
Compounds of Formu1α X may be prepared by the illustrative reaction sequences as shown in Scheme II, which depicts condensing a compound of Formu1α II with a compound of Formu1α VII wherein R1 and R2 are independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl or optionally substituted phenyl wherein optional substituent(s) is/are selected C1-C3 alkyl, C1-C3 alkoxy or halogen; P is any protecting group for an amino group, R' is any protecting group for a hydroxy group, in a condensing agent to give a compound of Formu1α VIII which on deprotection in the presence of deprotecting agent in an organic solvent gives an unprotected intermediate of Formu1α IX which is finally alky1αted or benzy1αted with suitable alky1αting or benzy1αting agent L-Ra to give a compound of Formu1α X wherein L is any leaving group and R3 represents C1-C6 alkyl wherein 1-3 hydrogen atom(s) may be rep1αced by C5-C7 cycloalkyl, 1, 3-dioxo-l, 3-dihydro-isoindolyl or optionally substituted phenyl wherein the optional substituent is/are selected from C1-C4 alkyl or halogen.
P is any protecting group for an amino group for a compound of Formu1α VII and is selected from benzyl and t-butyloxy carbonyl groups.
R' is any protecting group for a hydroxy group for a compound of Formu1α VII and is selected from p-toluene sulfonyl and methane sulfonyl groups.
The reaction of a compound of Formu1α II with a compound of Formu1α VII to give a compound of Formu1α VIII can be carried out in the presence of a condensing agent, for example, l,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) or l,4-diazabicyclo[2.2.2]octane (DABCO).
The reaction of a compound of Formu1α II with a compound of Formu1α VII to give a compound of Formu1α VIII can be carried out in a solvent, for example, benzene, toluene or xylene.
The deprotection of a compound of Formu1α VIII to give a compound of Formu1α IX can be carried out in the presence of a deprotecting agent, for example, pal1αdium on carbon and hydrogen gas or ammonium formate and pal1αdium on carbon.
The deprotection of a compound of Formu1α VIII to give a compound of Formu1α IX can be carried out in a solvent, for example, methanol or ethanol.
The N-alky1αtion or benzy1αtion of a compound of Formu1α IX to give a compound of Formu1α X can be carried out with an alky1αting or benzy1αting agent, L-R3 wherein L is any leaving group, known in the art, for example, halogen, O-mestyl or O-tosyl group.
The alky1αtion or benzy1αtion of a compound of Formu1α IX to give a compound of Formu1α X can be carried out with an alky1αting or benzy1αting agent, L-R3 in a solvent, for
example, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or acetonitrile, at temperatures ranging from about 25-100°C.
In the above scheme, where specific bases, condensing agents, protecting groups, deprotecting agents, N-alky1αting/benzy1αting agents, solvents, catalysts etc. are mentioned, it is to be understood that other bases, condensing agents, protecting groups, deprotecting agents, N-alky1αting/benzy1αting agents, solvents, catalysts etc. known to those skilled in the art may be used. Simi1αrly, the reaction temperature and duration may be adjusted according to the desired needs.
Suitable salts of the compounds represented by the Formu1α 1 were prepared so as to solubilize the compound in aqueous medium for biological evaluations. Examples of such salts include pharmacologically acceptable salts such as inorganic acid salts (e.g. hydrochloride, hydrobromide, sulphate, nitrate and phosphorate), organic acid salts (e.g. acetate, tartarate, citrate, fumarate, maleate, tolunesulphonate and methanesulphonate). When carboxyl group is included in the Formu1α I as a substituent, it may be an alkali metal salt (e.g. sodium, potassium, calcium, magnesium, and the like). These salts may be prepared by the usual prior art techniques, such as treating the compound with an equivalent amount of inorganic or organic acid or base in a suitable solvent.
Preferred compounds according to the invention and capable of being produced by Schemes I and II include:
Compound Chemical Name
No.
1. (2R, 2S) (1α, 5α, 6α)-N- {3-[4-(l,3-dioxo-l, 3-dihydro-isoindol-2-yl)-butyl]-3-
azabicyclo [3.1.0] hex-6-yl-methyl}-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide
2. (2R) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopent-1 -eny 1-2-pheny 1αcetam ide
3. (2R, 2S) (1α, 5α, 6α)-N-(3-Isopropyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-2-pheny1αcetamide
4. (2R, 2S) (1α, 5α, 6α)-N-(3-Diphenylmethyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-
hydroxy-2-cyclopentyl-2-pheny1αcetamide
5. (2R, 2S) (1α, 5α, 6α)-N-(3-sec-butyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyI-2-pheny1αcetamide
6. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
(3-pentyl)-2-pheny1αcetamide
7. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclohexyl-2-(4-methoxyphenyl) acetamide
8. (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-(N-
ethyl)-2-pheny1αcetamide
9. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-(N-ethyl)-2-pheny 1αcetam ide
10. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclohexyl-(N-ethyl)-2-pheny1αcetamide
11. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)- 2-hydroxy-2-
(3-pentyl)-(N-methyl)-2-pheny1αcetamide
12. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
(sec-butyl)-(N-methyl)-2-pheny1αcetamide
13. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
isopropyl-(N-methyl)-2-pheny1αcetamide
14. (2R, 2S) (1α, 5α, 6α)-N-[3-(4-tert-butyl-benzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-
hydroxy-2-cyclopentyl-2-pheny1αcetamide
15. (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclohex-2-enyl-2-pheny1αcetamide
16. (1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-
2,2-dipheny1αcetamide
17. (2R, 2S) (1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-
hydroxy-2-cyclopentyl-2-pheny1αcetamide
18. (2R, 2S) (1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-
hydroxy-2-cyclohexyl-2-pheny1αcetamide
19. (1α, 5α, 6α)-N-[3-(3-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yI-methyl]-2-hydroxy-
2,2-dipheny1αcetamide
20. (1α, 5α, 6α)-N-[3-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-
dipheny1αcetamide
21. (2R, 2S) (1α, 5α, 6α)-N-[3-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-
hydroxy-2-cyclohexyl-2-pheny1αcetamide
22. (2R, 2S) (1α, 5α, 6α)-N-[3-(2,4-difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-
hydroxy-2-cyclohexyl-2-pheny1αcetamide
23. (1α, 5α, 6α)-N-[3-(2,4-difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-
2,2-dipheny1αcetamide
24. (2R, 2S) (1α, 5α, 6α)-N-[3-(3-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-
hydroxy-2-cyclopentyl-2-pheny1αcetamide
25. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-
methylphenyl)-2-pheny1αcetamide
26. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-
methylphenyl)-(N-methyl)-2-pheny1αcetamide
27. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-
fluorophenyl)-2-pheny1αcetamide
28. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-
fluorophenyl)-2-phenyl acetic acid ester
29. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicycIo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-
fluorophenyl)-(N-methyl)-2-pheny1αcetamide
30. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-
methylphenyl)-2-pheny1αcetamide
31. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-
methylphenyl)-(N-methyl)-2-pheny1αcetamide
32. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-
methylphenyl)-2-phenyl acetic acid ester
33. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-2-(3-methylphenyl) acetic acid ester
34. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicydo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-2-(3-methylphenyl) acetic acid ester tartarate salt
35. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-2-(3-methylphenyl) acetamide

36. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-2-(3-methylphenyl) acetamide tartarate salt
37. (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2,2-di(4-
fluorophenyl)acetic acid ester
38. (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2,2-di(4-
fluorophenyl)-acetamide
39. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo [3.1.0] hex-6-yl-methy!)-2-hydroxy-2-
cyclobutyl-2-phenyl acetic acid ester
40. (2R, 2S) (1α, 5α, 6α)-N-(3-cyclohexylmethyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-
hydroxy-2-cyclopentyl-2-pheny1αcetamide
41. (2R) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-(N-methyl)-2-pheny1αcetamide
42. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
cyclopentyl-2-(4-methylphenyl) acetamide
43. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
phenyl-2-(4-methylphenyl) acetic acid ester
44. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
methyl-2-phenyl acetic acid ester
45. (2R, 2S) (1α, 5α, 6α)-N- (3-benzyl-3-azabicyclo [3.1.0] hex-6-yl-methyl)-2-hydroxy-2-
methyl-2-phenyl acetamide
46. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo [3.1.0] hex-6-yl-methyl)-2-hydroxy-2-
isopropyl-2-phenyl acetic acid ester
47. (1α, 5α, 6α)-N- (3-methyl-3-azabicyclo [3.1.0] hex-6-yl-methyl)-2-hydroxy-2-phenyl-
(N-methyl)-2-pheny1αcetamide
48. (1α, 5α, 6α)-N- (3-benzyl-3-azabicyclo [3.1.0] hex-6-yl-methyl)-2-hydroxy-2, 2-di (3-
methylphenyl) acetamide
49. (2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo [3.1.0] hex-6-yl-methyl)-2-hydroxy-2- (3-
pentyl)-2-phenyl acetic acid ester
50. (2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-
methyl-(N-methyl)-2-pheny1αcetamide
Because of their valuable pharmacological properties, compounds disclosed herein may be administered to an animal for treatment orally, or by parenteral route. The pharmaceutical
compositions containing such compounds are preferably produced and administered in dosage units, each unit containing a certain amount of at least one compound described herein and/or at least one physiologically acceptable addition salt thereof. The dosage may be varied over extremely wide limits as the compounds are effective at low dosage levels and re1αtively free of toxicity. The compounds may be administered in the low micromo1αr concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
Prodrugs of the compounds of Formu1α I are also provided. In general, such prodrugs will be functional derivatives of these compounds, which readily are converted in vivo into the defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known.
Enantiomers, diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts of these compounds as well as metabolites having the same type of activity are also provided, along with pharmaceutical compositions comprising the molecules of Formu1α I or prodrugs, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carriers and optionally included excipients.
The examples mentioned below demonstrate the general synthetic procedures, as well as the specific preparation of paticu1αr compounds. The examples are provided to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.
Experimental details
Various solvents, such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexanes, and dichloromethane, were dried using various drying reagents according to the procedure described in the literature. IR spectra were recorded as nujol mulls or a thin neat film on a Perkin Elmer Paragon instrument, Nuclear Magnetic Resonance (NMR) were recorded on a Varian XL-300 MHz instrument using tetramethylsi1αne as an internal standard.
Example 1: Preparation of (2R. 2S) (1α. 5α. 6α)-N- (3-Benzyl-3-azabicyclo [3.1.0] hex-6-yl-methvl)-2-hydroxy-2-cyclohexyl-2- (4-methoxyphenyl) acetamide (Compound No. 7)
Step a: Preparation of (3-benzyl-3-azabicyclo [3.1.0] hex-6-yl)-methy1αmine
This compound was prepared following the procedure described in EP 0413455.
Step b: Preparation of (2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclohexyl-2-(4-methoxyphenyl) acetamide

A solution of cyclohexyl-hydroxy-phenyl acetic acid (prepared following the procedure described in J. Amer. Chem. Soc., 1953; 75: 2654 and J. Org. Chem., 2000, 65:6283) (1.13 mmole) and (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-methy1αmine (1.25 mmole) in dimethylformamide cooled in an ice bath and 1-hydroxybenzotriazole (1.25 mmole), and N-methylmorpholine (2.26 mmole) were added. The reaction mixture was stirred for 1 hour in ice bath and then l-(3-dimethy1αminopropyl)-3-ethylcarbodiimide hydrochloride (1.189 mmole) was added. The reaction mixture was stirred in ice bath for about 2 hours and then at room temperature overnight. The reaction mixture was poured into saturated bicarbonate solution and extracted with ethyl acetate. The organic 1αyer was washed with water, dried and concentrated under reduced pressure. The residue was purified by column chromatography, eluting the compound with 40% ethyl acetate-hexane.
m. pt: 140-144° (white solid), IR (DCM): 3395.2, 2931.9, 1644.9 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.50 (7H, d, 9Hz), 7.26 (3H, bs), 6.87 (2H, d, 9Hz), 6.62 (1H, bs), 3.78 (3H, s), 3.57 (2H, s), 3.10-2.91 (5H, m), 2.33 (3H, bs), 1.68-0.91 (14H, m), Mass: m/z 449.5 (M+l, 100%)
Simi1αrly, the following compounds were prepared analogously, following the procedure described above with the appropriate substitutions of the reagents:
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-methyl-2-phenyl acetamide (Compound No. 45)
IR (DCM): 1653.6 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.53-7.56 (2H, m), 7.23-7.37 (8H, m), 6.50 (1H, brs), 3.56 (2H, s), 3.03-3.09 (2H, m), 2.90-2.93 (2H, m), 2.30-2.33 (2H, m), 1.80 (3H, s), 1.35-1.39 (m, 1H), 1.23-1.28 (m, 2H), Mass: m/z 351 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-bydroxy-2-(4-methylphenyl)-2-pheny1αcetamide (Compound No. 25)
H1-NMR (CDC13, 300MHz) δ-values: 7.45-7.23 (14H, m), 6.34 (1H, brs), 3.58-3.56 (2H, m), 3.18-3.13 (2H, m), 2.95-2.92 (2H, m), 2.34-2.22 (5H, m), 1.48-1.46 (3H, m)
Mass: m/z427.41 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-fluorophenyI)-2-pheny1αcetamide (Compound No. 27)
H1-NMR (CDC13, 300MHz) δ-values: 7.44-7.12 (14H, m), 6.43 (1H, brs), 3.59 (1H, brs), 3.18-3.14 (2H, m), 2.97-2.94 (4H, m), 2.37-2.35 (2H, m), 1.47-1.30 (3H, m) Mass: m/z 431.49 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-methylphenyl)-2-pheny1αcetamide (Compound No. 30)
H1-NMR (CDC13, 300MHz) δ-values: 7.44-7.11 (14H, m), 6.38 (1H, brs), 3.61 (1H, m), 3.18-1.14 (2H, m), 2.99-2.96 (4H, m), 2.39-2.31 (5H, m), 1.31-1.28 (3H, m)
Mass: 427.46 (M+l)
(2R) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopent-l-enyl-2-pheny1αcetamide (Compound No. 2)
IR (DCM): 1659.8 cm'1, 1H-NMR (CDC13) δ-values: 7.48-7.51 (m, 2H), 7.27-7.37 (m, 8H), 6.23 (brs, 1H), 5.67 (s, 1H), 3.63 (s, 2H), 2.97-3.18 (m, 6H), 2.37-2.42 (m, 2H), 1.88-2.08 (m, 4H), 1.23-1.31 (m, 3H)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-pentyl)-2-pheny1αcetamide (Compound No. 6)
m.p: 100-104°C, IR (KBr): 1659.3 cm'1, 1H-NMR (CDC13) δ-values: 7.61-7.63 (m, 2H), 7.22-7.35 (m, 8H), 6.66 (brs, 1H), 3.56 (s, 2H), 2.88-3.07 (m, 4H), 2.81 (s, 1H), 2.29-2.33 (m, 3H), 1.20-1.41 (m, 7H), 0.99-1.04 (t, 3H, J=9Hz), 0.77-0.82 (t, 3H, J=9Hz), Mass: 407 (M-t-1)
(1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2,2-di(4-fluorophenyl) acetamide (Compound No. 38)
IR (DCM): 3408.9, 1665 cm'1, 1H-NMR (CDC13, 300MHz) δ-values: 7.41-6.78 (13H, m), 6.44 (1H, bs), 4.00 (1H, bs), 3.57 (2H, s), 3.15 (2H, m), 2.93 (2H, m), 2.33 (2H, m), 1.47-1.25 (3H, m), Mass: m/z 449.2 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(4-methylphenyl) acetamide (Compound No. 42)
1H-NMR (CDCl3) δ-values: 7.48-7.45 (2H, m), 7.29-7.12 (7H, m), 6.46 (1H, brs), 3.56 (2H, s), 3.17(1 H, s), 3.04-2.97 (5H, m), 2.92-2.89 (5H, m), 1.36-1.28 (11H, m) Mass: 419.48 (M+l)
(1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2,2-di(3-methylphenyl) acetamide (Compound No. 48)
IR: 3403.1, 1658.8 cm"', 1H-NMR (CDC13, 300MHz) δ-values: 7.32-7.11 (13H, m), 6.32 (1H, bs, NH), 4.0 (1H, bs), 3.57 (2H, s), 3.16 (2H, t, 6Hz), 2.93 (2H, m), 2.32 (8H, s), 1.27 (3H, m), Mass: m/z 441.35 [100%] (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclohex-2-enyl-2-phenyIacetamide (Compound No. 15)
IR: 3407, 1652.3 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.61 (2H, d, 7.5Hz), 7.37-7.22 (8H, m), 6.54 (1H, bs, NH), 5.67 (2H, m), 3.55 (2H, s), 3.15-2.98 (2H, m), 2.90 (2H, m), 2.7 (1H, bs), 2.30 (2H, m), 2.16-2.04 (3H, m), 1.70 (2H, bs), 1.48-1.34 (2H, m), 1.24 (2H, m), Mass: 417.6 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetamide (Compound No. 35)
Example 2: Preparation of (1α, 5α. 6α)-N-(3-Benzyl-3-azabicyclor3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-(N-ethyl)-2-pheny1acetamide (Compound No. 8)
Step a: Preparation of (3-benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-ethy1αmine
To a solution of mesy1αte in ethanol, ethy1αmine solution was added in a steel bomb which was tightened and p1αced in an oil bath at about 80 °C for overnight. It was cooled down to -78 °C and was opened up. The content was evaporated. It was diluted with hydrochloride
and ethyl acetate. Organic 1αyer was separated. Aqueous 1αyer was basified with 10% aqueous sodium hydroxide solution and extracted with dichloromethane. The dichloromethane 1αyer was dried and evaporated to get the required product.
Step b: Preparation of (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-(N-ethyl)-2-pheny1αcetamide
To a cold solution of benzillic acid (2.2 mmole, commercially avai1αble) and (3-benzyl-3-azabicyclo [3.1.0] hex-6-ylmethyl)-ethy1αmine (2.2 mmole) in dimethylformamide, N-methylmorpholine (4.4 mmole) and 1-hydroxybenzotriazole (2.2 mmole) were added at 0°C and the mixture was stirred at 0°C for about 1 hour. After 1 hour, l-(3-dimethy1αminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 mmole) was added to it. The reaction mixture was then stirred at same temperature for about 20 mins and then at room temperature overnight. Reaction mixture was quenched by addition of water and the organic 1αyer extracted with ethyl acetate. The organic 1αyer was washed with water, brine, dried over anhydrous sodium sulphate and then concentrated to get crude compound. Purification was done by column chromatography using 20% ethyl acetate-hexane as eluent.
IR: 3315.9, 1628 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.40-7.15 (15H, bm), 6.25 (1H, bs), 3.61 (2H, s), 3.43-3.36 (2H, m), 3.14 (1H, bd, 6Hz), 2.99 (1H, d, 6Hz), 2.86 (1H, bs), 2.63 (1H, bs), 2.37 (1H, bs), 2.71 (1H, bs), 1.47 (1H, bs), 1.25 (3H, bs), 0.77 (1H, bs), Mass: m/z 441.8 (M+l) Simi1αrly, the following compounds were prepared analogously, following the above procedure
with appropriate substitutions of reagents:
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yI-methyl)-2-hydroxy-2-cyclopentyl-(N-ethyl)-2-pheny1αcetamide (Compound No. 9)
IR: 3408.1, 1619.8 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.42-7.2 (10H, m), 5.55 (1H, bs, OH), 3.5-3.51 (3H, bs), 3.21 (2H, m), 2.89 (4H, bs), 2.28 (2H, bs), 1.84 (2H, m), 1.73-1.45 (5H, m), 1.30 (3H, bs), 1.08 (3H, t, 6Hz), 0.88 (2H, m), Mass: m/z 433.4 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclohexyl-(N-ethyl)-2-pheny1αcetamide (Compound No. 10)
tn.pt: 101.4-1.5°C, IR: 3299, 1613.2 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.41-7.17 (10H, m), 5.38 (1H, bs), 3.53 (2H, bs), 3.29 (4H, m), 2.84 (4H, m), 1.51-1.20 (12H, m), 1.08 (3H, t, 6Hz), 0.88 (2H, m), Mass: m/z 447.4
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yI-methyl)-2-hydroxy-2-(4-methylphenyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 26)
IR: 1630.6 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.40-7.14 (14H, m), 3.59-3.32 (4H, m), 3.12-2.34 (11H, m), 1.33-1.30 (3H, m), Mass: 441.43 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-fluorophenyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 29)
H1-NMR (CDC13, 300MHz) δ-values: 7.35-7.02 (14H, m), 3.60-2.35 (11H, m), 1.32-1.30 (3H, m), Mass: 445.40 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-methylphenyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 31)
H1-NMR (CDC13, 300MHz) δ-values: 7.38-7.11 (14H, m), 3.44-2.00 (14H, m), 1.31-1.28 (3H, m), Mass: 441.56 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyI)- 2-hydroxy-2-(3-pentyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 11)
IR (DCM): 1621.4 cm'1, 1H-NMR (CDC13) δ-values: 7.21-7.40 (m, 10H), 3.35-3.53 (m, 3H), 2.75-2.81 (m, 5H), 2.26 (m, 2H), 1.33-1.66 (m, 6H), 0.88-1.02 (m, 9H), Mass: 421 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(sec-butyI)-(N-methyl)-2-pheny1αcetamide (Compound No. 12)
IR(DCM): 1621.7 cm'1, 1H-NMR (CDC13) δ-values: 7.23-7.43 (m, 10H), 5.05 (brs, 1H), 3.53 (s, 2H), 2.52-2.83 (m, 5H), 2.25-2.28 (m, 2H), 1.58-1.70 (m, 3H), 0.83-1.00 (m, 11H), Mass: 407 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-isopropyl-(N-methyl)-2-pheny1αcetamide (Compound No. 13)
IR (DCM): 1622.5 cm'1, 1H-NMR (CDC13) δ-values: 7.22-7.44 (m, 10H), 5.21 (brs, 1H), 3.34-3.53 (m, 3H), 2.78-2.99 (m, 5H), 2.25 (m, 2H), 1.57 (m, 2H), 0.71-1.06 (m, 9H), Mass: 393
(M+l)
(2R) (1α, 5α, 6α)-N-(3-benzyI-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-(N-methyl)-2-pheny1αcetamide (Compound No. 41)
IR (DCM): 1623.9 cm'1, 1H-NMR (CDC13, 300MHz) δ-values: 7.39-7.42 (2H, m), 7.23-7.33 (8H, m), 3.54 (2H, s), 2.76-2.96 (7H, m), 2.28 (2H, brs), 1.30-1.85 (9H, m), 0.88 (3H, brs), Mass: m/z 419 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-methyl-(N-methyl)-2-pheny1αcetamide (Compound No. 50)
IR(DCM): 1723.9cm'1, 1H-NMR (CDC13) δ-values: 7.14-7.58 (m, 1 OH), 3.72 (m, 2H), 3.17-3.24 (m, 2H), 2.96 (s, 3H), 2.88 (s, 3H), 2.49-2.63 (m, 2H), 1.77-1.95 (m, 2H), 1.46 (m, 1H), 0.88-0.98 (m, 2H), Mass : 365 (M+l)
Example 3: Preparation of (2R. 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-vl-methyl)-2-hydroxY-2-cyclobutyl-2-phenyl acetic acid ester (Compound No. 39)
Method for the preparation of 3-benzyl-6-bromomethyl-3-azabicyclo [3.1.0] hexane
To a solution of 3-benzyl-3-azabicyclo[3.1.0]hex-6-yl methanol (Synlett, 1996, 1097-99) (0.203gm, 1 mmol) in carbon tetrachloride, phosphorous bromide (0.04ml, 0.05mmol) was added dropwise at room temperature. Reaction mixture was refluxed for about 5 hours (during refluxing a white precipitate appeared which turned to sticky yellow) then stirred at room temperature for overnight. Reaction mixture was quenched with water. Organic 1αyer was separated. The sticky material was stirred in excess of chloroform. The combind organic 1αyer
was washed with 10% aquoues solution of sodium hydroxide, water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
To a solution of 2-cyclobutyl-2-hydroxy-2-phenyl acetic acid (prepared following the procedure described in J. Amer. Chem. Soc., 75: 2654 (1953) and J. Org. Chem., 65:6283 (2000); 0.932 mmole) and 3-benzyl-6-bromomethyl-3-azabicyclo [3.1.0] hexane (as prepared above, 0.932 mmole) in benzene, 1,8-diazabicyclo [5.4.0] undecane-7-ene (1.11 mmole) was added and the mixture was refluxed for about 4 hours and then cooled to room temperature and stirred for overnight. The reaction mixture was quenched by addition of water, extracted with ethyl acetate. The organic 1αyer was washed with water, then brine and dried over anhydrous sodium sulphate. The organic 1αyer was evaporated to obtain the crude product, which was purified by column chromatography.
1H-NMR (CDC13, 300MHz) δ-values: 7.57 (2H, d, 7Hz), 7.32-7.21 (8H, m), 4.05-3.92 (2H, m), 3.79 (1H, s), 3.57 (2H, s), 3.31 (1H, m), 2.91 (2H, m), 2.32 (1H, 9Hz), 2.09-2.0 (2H, m), 1.86-1.77(4H, m), 1.61-7.56 (2H,m), 1.29(2H,m)
Simi1αrly, the following compounds were prepared analogously, following the above procedure with appropriate substitutions of reagents:
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-fluorophenyl)-2-phenvl acetic acid ester (Compound No. 28)
IR (DCM): 1726.2 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.45-6.96 (14H, m), 4.25 (1H, s), 4.12-4.09 (2H, m), 3.58-3.56 (2H, m), 2.93-2.90 (2H, m), 2.32-2.30 (2H, m), 1.31-1.25 (3H, m), Mass: 432.41 (M+l)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-methylphenyl)-2-phenyl acetic acid ester (Compound No. 32)
H1-NMR (CDC13, 300MHz) δ-values: 7.46-7.09 (14H, m), 4.23-4.21 (1H, m), 4.11-4.08 (2H, m), 3.56-3.47 (2H, m), 2.92-2.89 (2H, m), 2.32-2.30 (5H, m), 1.30-1.28 (3H, m), Mass: 428.39
(M+l)
(1α, 5α, 6α)-(3-benzyI-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2,2-di(4-fluorophenyl) acetic acid ester (Compound No. 37)
1H-NMR (CDC13, 300 MHz) δ-values: 7.42-7.26 (9H, m), 6.99 (4H, m), 4.27 (1H, s), 4.11 (2H, d, 9Hz), 3.57 (2H, s), 3.92 (2H, d, 9Hz), 2.32 (2H, d, 9Hz), 1.64-1.24 (3H, m)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-2-(4-methylphenyl) acetic acid ester (Compound No. 43)
1H-NMR (CDC13) δ-values: 7.46-7.43 (2H, m), 7.33-7.28 (10H, m), 7.12-7.10 (2H, m), 4.20
(1H, s), 4.11-4.08 (2H, m), 3.57 (2H, s), 2.92-2.89 (2H, m), 2.33-2.29 (5H, m), 1.31-1.28 (3H,
m)
Mass: 428.40 (M+l)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-methyl-2-phenyl acetic acid ester (Compound No. 44)
IR (DCM): 1726.3 cm'1, 1H-NMR (CDC13) δ-values: 7.55-7.57 (m, 2H), 7.23-7.35 (m, 8H), 4.00 (d, J=9Hz, 2H), 3.56 (s, 2H), 2.88-2.93 (m, 2H), 2.28-2.33 (m, 2H), 1.78 (s, 3H), 1.58-1.60 (m,
3H), Mass: 352 (M+l)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-isopropyl-2-phenyl acetic acid ester (Compound No. 46)
IR(DCM): 1721.4 cm'1, 1H-NMR (CDC13) δ-values: 7.64-7.67 (m, 2H), 7.23-7.34 (m, 8H), 3.94-4.07 (m, 2H), 3.57 (s, 8H), 2.89-2.93 (m, 2H), 2.63 (m, 1H), 2.29-2.33 (m, 2H), 1.57-1.63 (m, 3H), 0.99 (d, J=6Hz, 2H), 0.70 (d, J=6Hz, 2H), Mass: 380 (M+l)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-pentyl)-2-phenyl acetic acid ester (Compound No. 49)
IR (DCM): 1718.6 cm'1, 1H-NMR (CDC13) δ-values: 7.65-7.68 (m, 2H), 7.23-7.34 (m, 8H), 3.94-4.05 (m, 2H), 3.70 (s, 1H), 3.58 (s, 2H), 2.90-2.94 (m, 2H), 2.31-2.33 (m, 2H), 2.25 (m, 1H), 1.62-1.64 (m, 3H), 1.19-1.32 (m, 4H), 0.98 (t, J=6Hz, 3H), 0.72 (t, J=6Hz, 3H), Mass: 408 (M+l)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetic acid ester (Compound No. 33)
Example 4: Preparation of (2R. 2S) (1α. 5α. 6α1-N-[3-(4-tert-buty-benzyl)-3-
azabicyclo[3.1.0]hex-6-yl-methyl]-2-hvdroxy-2-cyclopentyl-2-pheny1acetamide (Compound No.
14}
Step a: Preparation of (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide
This compound was prepared following the procedure described in Example 1.
Step b: Preparation of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-pheny1αcetamide
A solution of (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide in methanol, containing ammonium formate (4.06 mmole), pal1αdium on carbon (10% w/w) was heated at 80 °C for about 2 hours. The reaction mixture was filtered through celite bed and washed with methanol. The filterate was evaporated under reduced pressure to get the desired compound.
Step c: Preparation of (2R, 2S) (1α, 5α, 6α)-N-[3-(4-tert-butyl-benzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide
A solution of N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-pheny1αcetamide (1.59 mmole), l-tert-butyl-4-chloromethyl-benzene (1.908 mmole) in dimethylformamide containing potassium carbonate (3.18 mmole) and potassium iodide (3.18 mmole) were stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic 1αyer was dried and concentrated under reduced pressure. The residue was purified by column chromatography eluting the compound with 25% ethyl acetate-hexane.
m. pt : 140-143°C, H1-NMR (CDC13, 300MHz) δ-values: 7.60 (2H, d, 6Hz), 7.35-7.15 (7H, m), 6.41 (1H, bs, NH), 3.52 (2H, s), 3.19 (1H, bs), 3.03 (3H, m), 2.90 (2H, d, 9Hz), 2.30 (2H, d, 9Hz), 1.71-1.55 (9H, m), 1.25 (9H, s), 1.21 (2H, m), Mass: 461.7 (M+l)
Simi1αrly, the following compound was prepared analogously, following the above procedure with appropriate substitution of reagents:
(2R, 2S) (1α, 5α, 6α)-N-[3-(3-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 24)
m. pt: 101.0-102.4°C, H1-NMR (CDC13, 300MHz) δ-values: 7.61-7.09 (9H, m) & 6.46 (1H, brs), 3.60-3.57 (2H, m), 3.16-2.98 (6H, m), 2.40-2.34 (4H, m), 1.65-1.41 (11H, m), Mass: 419.42 (M+l)
Example 5: Preparation of (1α. 5α. 6α)-N- [3-(4-methylbenzyl)-3-azabicyclo [3.1.0] hex-6-yl-methyl]-2-hydroxy-2, 2-dipheny1acetamide (Compound No. 16)
Step a: Preparation of (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide
This compound was prepared following the procedure described in Example 1. Step b: Preparation of (3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-diphenyl acetamide
A solution of (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide in methanol, containing ammonium formate (4.06 mmole), pal1αdium on carbon (10% w/w) was heated at 80 °C for about 2 hours. The reaction mixture was filtered through celite bed and washed with methanol. The filterate was evaporated under reduced pressure to get the desired compound.
Step c: Preparation of (1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide
To a stirred solution of (3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-diphenyl acetamide (0.62 mmole) in acetonitrile were added p-methyl benzyl bromide (0.68 mmole) followed by potassium carbonate (1.6) and potassium iodide (0.62 mmole) and reaction mixture was refluxed for about 4 '/2 hours and then at room temperature overnight. The reaction mixture was quenched by addition of water and organic 1αyer extracted with ethyl acetate. The organic 1αyer was washed • with water, brine, dried over anhydrous sodium sulphate and then concentrated to get crude compound. Purification was done by column chromatography using dichloromethane, which was gradually changed to 2% methanol in dichloromethane.
IR: 3405, 1657.4 cm'1, H1-NMR (CDCI3, 300MHz) δ-values: 7.44-7.25 (10H, m), 7.12 (4H, m), 6.33 (1H, bs), 3.54 (2H, s), 3.15 (2H, t, 7.2Hz), 2.94 (2H, d, 9Hz), 2.33 (5H, s), 1.43 (2H, m), 0.88 (1H, m), Mass: 427.25 (M+l)
Simi1αrly, the following compounds were prepared analogously, following the above procedures with appropriate substitution of reagents:
(2R, 2S) (1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 17)
m. pt: 142.1-146.2°C, H1-NMR (CDC13, 300MHz) δ-values: 7.60 (2H, d, 6Hz), 7.36-7.23 (3H, m), 7.16-7.09 (4H, m), 6.43 (1H, bs), 3.49 (2H, s), 3.19 (1H, bs), 3.04 (3H, m), 2.91 (2H, m), 2.33 (5H, s), 1.55-1.33 (11H, m), 0.88 (1H, m), Mass: 419.34 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-cyclohexylmethyl-3-azabicyclo [3.1.0] hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 40)
'1H-NMR (CDC13) δ-values: 7.61-7.33 (5H, m), 6.41 (1H, brs), 3.20 (1H, s), 3.05-2.90 (5H, m), 2.21-2.15 (4H, m), 1.68-1.32 (22H, m), Mass: 411.33 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-{3-[4-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-butyl]-3-azabicyclo[3.1.0]hex-6-yl-methyl}-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 1)
m.p: 113-114°C, 1R (DCM): 1711.4, 1663.8 cm'1, 1H-NMR (CDC13) δ-values: 7.83-7.85 (m, 2H), 7.72-7.73 (m, 2H), 7.59-7.62 (m, 2H), 7.32-7.36 (m, 3H), 6.41 (brs, 1H), 3.65-3.70 (m, 2H), 3.24 (s, 1H), 2.95-3.06 (m, 5H), 2.39-2.41 (m, 2H), 2.23-2.25 (m, 2H), 1.42-1.67 (m, 4H), 1.23-1.37 (m, 10H), 0.88 (m, 1H), Mass: 516 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-Isopropyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 3)
IR (DCM): 1666.8 cm'1, 1H-NMR (CDCI3) δ-values: 7.60-7.63 (m, 2H), 7.32-7.37 (m, 3H), 6.99 (brs, 1H), 3.69 (m, 1H), 3.36-3.41 (m, 2H), 2.85 (m, 3H), 2.23-2.41 (m, 2H), 1.46-1.66 (m, 14H), 1.26 (s, 2H), 0.88 (m, 1H), Mass: 357 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-Diphenylmethyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 4)
m.p: 161-163°C, IR (KBr): 1658.6 cm'1, 1H-NMR (CDC13) δ-values: 7.89-7.91 (m, 4H), 7.56-7.80 (m, 5H), 7.16-7.43 (m, 6H), 6.88 (brs, 1H), 4.79-4.82 (m, 1H), 3.57-3.61 (m, 2H), 3.03-3.16(m,4H), 2.58 (brs, 1H), 1.11-1.62 (m, 11H), Mass: 481 (M+l)
(2R, 2S) (1α, 5α, 6α)-N-(3-sec-butyl-3-azabicyclo[3.1.0]hex-6-yl-methyI)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 5)
m.p: 109-110°C, IR (DCM): 1653.3 cm'1, 1H-NMR (CDC13) δ-values: 7.59-7.62 (m, 2H), 7.24-7.37 (m, 3H), 6.39 (brs, 1H), 3.22 (s, 1H), 3.01-3.05 (m, 3H), 2.88-2.93 (m, 2H), 2.10-2.37 (m, 3H), 1.47-1.69 (m, 5H), 1.21-1.29 (m, 8H), 0.93-0.95 (m, 3H), 0.79-0.84 (m, 3H), Mass: 372 (M+2)
(1α, 5α, 6α)-N-(3-methyl-3-azabicycIo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-(N-methyl)-2-pheny1αcetamide (Compound No. 47)
m. pt: 119.3-123.4°C, IR: 3061.2, 1637.2 cm'1, 1H-NMR (CDC13, 300MHz) δ-values: 7.33 (10H, bs), 6.06 (1H, bs), 3.42 (2H, bs), 2.98 (2H, m), 2.52 (3H, bs), 2.30 (6H, bs), 1.47-0.88 (3H, m)
(1α, 5α, 6α)-N-[3-(3-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide (Compound No. 19)
m. pt: 111.2-112.6°C, H1-NMR (CDC13, 300MHz) δ-vaIues: 7.44-7.26 (11H, m), 7.07 (3H, m), 6.5 (1H, bs), 3.59 (2H, bs), 3.17 (2H, t, 6Hz), 2.98 (2H, bs), 2.34 (5H, s), 1.49 (2H, bs), 0.88 (1H, m), Mass: 427.90 (M+l)
(lα, 5α, 6α)-N-[3-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide (Compound No. 20)
m. pt: 107.8-108.4°C, H1-NMR (CDC13, 300MHz) δ-values: 7.44-7.2 (11H, m), 7.02-6.89 (3H, m), 6.36 (1H, bs), 3.56 (2H, s), 3.17 (3H, t, 6Hz), 2.94 (2H, d, 9Hz), 2.33 (2H, d, 9Hz), 1.27 (2H, m), 0.88 (1H, m), Mass: 431.6 (M+l)
(2R, 2S) (lα, 5α, 6α)-N-[3-(3-nuorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyI]-2-hydroxy-2-cyclohexyl-2-pheny1αcetamide (Compound No. 21)
m. pt: 99.5-101.8°C, H'-NMR (CDC13, 300MHz) 8-values: 7.60 (2H, d, 7.8Hz), 7.36-7.19 (4H, m), 7.01-6.88 (3H, m), 6.64 (1H, bs), 3.54 (2H, s), 3.10-2.86 (5H, m), 2.40-2.28 (3H, m), 1.36-1.12 (12H, m), 0.88 (2H, m), Mass: 437.4 (M+l)
(2R, 2S) (lα, 5α, 6α)-N-[3-(2,4-difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cycIohexyl-2-pheny1αcetamide (Compound No. 22)
m. pt: 98.2-100.4°C, H1-NMR (CDC13, 300MHz) δ-values: 7.61-7.31 (6H, m), 6.84-6.73 (2H, m), 6.64 (1H, brs), 3.58 (2H, s), 3.08-2.84 (6H, m), 1.69-1.21 (14H, m), Mass: 455.80 (M+l)
(lα, 5α, 6α)-N-[3-(2,4-difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide (Compound No. 23)
m. pt: 116.3-116.9°C, IR (DCM): 1655.0 cm'1, H1-NMR (CDC13, 300MHz) δ-values: 7.44-7.32 (11H, m), 6.82-6.79 (2H, m), 6.35 (1H, brs), 3.60 (1H, brs), 3.18-3.14 (2H, m), 3.01-2.98 (2H, m), 2.93-2.90 (2H, m), 2.38-2.35 (2H, m), 1.39-1.36 (3H, m) Mass: 449.200 (M+l)
Example 6: Preparation of (2R. 2S) (lα, 5α. 6α)-N-[3-(4-methylbenzyl)-3-
azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclohexyl-2-pheny1αcetamide (Compound No.
18}
Step a: Preparation of (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hy droxy-2-cyc lohexy l-2-pheny 1αcetam ide
This compound was prepared following the procedure described in Example 1.
Step b: Preparation of (3-azabicyclo[3.1.0]hex-6-ylmethyI)-2-cyclohexyl-2-hydroxy-2-phenyl acetamide
A solution of (1α, 5α, 6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclohexyl-2-pheny1αcetamide in methanol, containing ammonium formate (4.06 mmole), pal1αdium on carbon (10% w/w) was heated at 80 °C for about 2 hours. The reaction mixture was filtered through celite bed and washed with methanol. The filterate was evaporated under reduced pressure to get the desired compound.
Step c: Preparation of (2R, 2S) (1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyciohexyl-2-pheny1αcetamide
To a solution of (3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclohexyl-2-hydroxy-2-phenyl acetamide (1 mmole) in tetrahydrofuran p-methylbenzaldehyde (2.9 mmole) was added followed
by hydride [NaB(OAC)3H] reagent. The white suspension was stirred at room temperature overnight, then quenched by addition of aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to give crude mixture. This was purified by column chromatography using silica gel with dichloromethane and 2% methanol in dichloromethane.
H1-NMR (CDC13, 300MHz) δ-values: 7.60 (2H, d, 7.5Hz), 7.36-7.26 (3H, m), 7.11 (4H, bs), 6.61 (1H, bs), 3.52 (2H, s), 3.06-2.83 (4H, m), 2.39-2.28 (5H, m), 1.41-0.88 (14H, m), Mass: 433.8 (M+l)
Example 7: Preparation of (2R. 2S) 1α. 5α. 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cvclopentyl-2-(3-methylphenyl) acetic acid ester tartarate salt (Compound No. 34)
L-(+)-Tartaric acid (0.322 mmole) was added to the solution of (la, 5α, 6α)-(3-benzyl-
3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetate
(prepared following the procedure described in example 1) in ethanol (0.322 mmole) and heated at 60°C for about half an hour. The reaction mixture was concentrated under reduced pressure. Ether was added to the reaction mixture. The ethereal layer was decanted off and residue dried.
H1-NMR (CDC13, 300MHz) δ-values: 7.38-7.33 (7H, m), 7.12 (1H, m), 6.98 (1H, m), 4.39 (2H, s), 4.07-3.98 (3H, m), 3.26-3.10 (5H, m), 1.59-1.41 (9H, m), 1.26 (3H, m)
Example 8: Preparation of (2R, 2S) (la. 5α. 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetamide tartarate salt (Compound No. 36}
L-(+)-Tartarate salt was prepared following the procedure described in Example 7 using (la, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetamide (prepared following the procedure described in Example 1).
H1-NMR (CDC13, 300MHz) δ-values: 7.42-7.34 (7H, m), 7.21 (1H, m), 6.99 (1H, m), 4.41 (2H, s), 4.19 (2H, s), 3.03 (3H, bs), 2.26 (3H, s), 1.59-1.27 (10H, m), 1.17 (2H, m)
Biological Activity Radioligand Binding Assays:
The affinity of test compounds for M2 and M3 muscarinic receptor subtypes was determined by [3H]-N-methylscopolamine binding studies using rat heart and submandibular gland respectively as described by Moriya et al., (Life Sci, 1999,64(25): 2351-2358) with minor modifications.
Membrane preparation: Submandibular glands and heart were isolated and placed in ice-cold homogenising buffer (HEPES 20mM, l0mM EDTA, pH 7.4) immediately after sacrifice. The tissues were homogenised in 10 volumes of homogenising buffer and the homogenate was

filtered through two layers of wet gauze and filtrate was centrifuged at 500g for l0min. The supernatant was subsequently centrifuged at 40,000g for 20 min. The pellet thus obtained was resuspended in same volume of assay buffer (HEPES 20 mM, EDTA 5mM, pH 7.4) and were stored at -70°C until the time of assay.
Ligand binding assay: The compounds were dissolved and diluted in DMSO. The membrane homogenates (150-250 µg protein) were incubated in 250 µl of assay buffer (HEPES 20 mM, pH 7.4) at 24-25°C for 3h. Non-specific binding was determined in the presence of 1 µM atropine. The incubation was terminated by vacuum filtration over GF/B fiber filters (Wallac). The filters were then washed with ice cold 50mM Tris HCI buffer (pH 7.4). The filter mats were dried and bound radioactivity retained on filters was counted. The IC50 & Kd were estimated by
using the non-linear curve-fitting program using G Pad Prism software. The value of inhibition constant Ki was calculated from competitive binding studies by using Cheng & Prusoff equation (Biochem Pharmacol, 1973,22: 3099-3108), Ki = IC$Q /(1+L/K.d), where L is the concentration
of [3H] NMS used in the particular experiment.
The Ki results of the compounds observed were in the range of 2 nM to 1122 nM for M2
receptor and 0.1 nM to >1000 for Ma receptor.
Functional Experiments using isolated rat bladder:
Methodology:
Animals are euthanized by overdose of urethane and whole bladder is isolated and removed rapidly and placed in ice cold Tyrode buffer with the following composition (mMol/L) NaCl 137; KC1 2.7; CaCl2 1.8; MgCl2 0.1; NaHCO3 11.9; NaH2PO4 0.4; Glucose 5.55 and continuously gassed with 95% O2 and 5 % CO2.
The bladder is cut into longitudinal strips (3mm wide and 5-6 mm long) and mounted in 10 ml organ baths at 30° C, with one end connected to the base of the tissue holder and the other end connected to a polygraph through a force displacement transducer. Each tissue is maintained at a constant basal tension of 2 g and allowed to equilibrate for 1 hour during which the Physiological Salt Solution (PSS) is changed every 15 min. At the end of equilibration period the stabilization of the tissue contractile response is assessed with lµmol/L of Carbachol consecutively for 2-3 times. Subsequently a cumulative concentration response curve to carbachol (10~9 moI/L to 3 X 10-5 mol/L) is obtained. After several washes, once the baseline is achieved, cumulative concentration response curve is obtained in presence of New Chemical Entity (NCE) [NCE added 20 min. prior to the second Cumulative Response Curve (CRC)].
The contractile results are expressed as % of control E max. ED50 values are calculated by fitting a non-linear regression curve (Graph Pad Prism). pKB values are calculated by the

formula pKB = - log [ (molar concentration of antagonist/ (dose ratio-1))]
where,
dose ratio = ED50 in the presence of antagonist/ED50 in the absence of antagonist.
In vivo experiments using anaesthetized rabbit Methodology
Male rabbits are anaesthetized with urethane 1.5g/kg intravenously. Trachea is cannulated to maintain the patency of airway. Femoral vein and femoral arteries of both sides are cannulated for the administration of vehicle or drug substances for the measurement of BP and administration of carbachol intra-arterially respectively.
Polyethylene tubing is introduced into the bladder through the urethra and tied at the neck of the bladder. The other end of the catheter is connected to the Grass polygraph through a
Statham pressure transducer. The bladder is filled with warm (37°C) saline. Both the ureters are ligated and cut proximally to drain the urine coming from kidneys. A stabilization period of 30-60 is allowed for stabilization of parameters from surgical procedures.
Salivary response is assessed by measuring the weight of a preweighted cotton gauze kept for 2 minutes in the buccal cavity immediately after the carbachol challenge.
At the end of stabilization period 2 control responses to carbachol (1.5µg/kg intra-arterial) on bladder pressure and salivation are obtained and this response is considered as 100%. Subsequently, the effect of increasing dose of NCE (ranging from 3 µg/kg to Img/kg) or vehicle (i.v., 15 min before carbachol challenge) is examined.
The change in bladder pressure and salivation are expressed as % change from pretreatment control averages. The ID50 values for salivation and bladder pressure inhibition are calculated using Graph Pad Prism software, by fitting the values at dose into non-linear regression curve. Oxybutynin and Tolterodine are used as standards for comparison.
The bladder selectivity to salivation is calculated by using following formula and expressed as fold of selectivity of oxybutinin in the same model.
ID50 Salivary response ID50 Bladder pressure
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

WE C1AIM:
1. A compound having the structure of Formu1α
(Formula Removed)
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters,
enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein
RI and R2 are independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl
or optionally substituted phenyl wherein optional substituent(s) is/are selected from C1-C3
alkyl, C1-C3 alkoxy or halogen;
R3 represents C1-C6 alkyl wherein 1-3 hydrogen atom(s) may be rep1αced by C5-C7
cycloalkyl, 1,3-dioxo-l, 3-dihydro-isoindolyl or optionally substituted phenyl wherein the
optional substituent is/are selected from C1-C4 alkyl or halogen;
Z represents oxygen or NR4 wherein R4 represents hydrogen or C1-C3 alkyl.
2. A compound selected from:
(2R, 2S) (1α, 5α, 6α)-N- {3-[4-(l,3-dioxo-l, 3-dihydro-isoindol-2-yl)-butyl]-3-azabicyclo [3.1.0] hex-6-yl-methyl}-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 1)
(2R) (1α, 5 a, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopent-l-enyl-2-pheny1αcetamide (Compound No. 2)
(2R, 2S) (1α, 5α, 6α)-N-(3-Isopropyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 3)
(2R, 2S) (1α, 5 a, 6α)-N-(3-Diphenylmethyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 4)
(2R, 2S) (1α, 5α, 6α)-N-(3-sec-butyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 5)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-pentyl)-2-pheny1αcetamide (Compound No. 6)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclohexyl-2-(4-methoxyphenyl) acetamide (Compound No. 7)
(1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-(N-ethyl)-2-pheny1αcetamide (Compound No. 8)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-(N-ethyl)-2-pheny1αcetamide (Compound No. 9)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclohexyl-(N-ethyl)-2-pheny1αcetamide (Compound No. 10)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)- 2-hydroxy-2-(3-pentyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 11)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(sec-butyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 12)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-isopropyl-(N-methyl)-2-pheny1αcetamide (Compound No. 13)
(2R, 2S) (1α, 5α, 6α)-N-[3-(4-tert-butyl-benzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 14)
(2R, 2S) (1α, 5α, 6α)-N-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclohex-2-enyl-2-pheny1αcetamide (Compound No. 15)
(1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide (Compound No. 16)
(2R, 2S) (1α, 5α, 6α)-N-[3-(4-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 17)
(2R, 2S) (1α, 5α, 6α)-N-[3-(4-methylbenzy!)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclohexyl-2-pheny1αcetamide (Compound No. 18)
(1α, 5α, 6α)-N-[3-(3-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide (Compound No. 19)
(1α, 5α, 6α)-N-[3-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide (Compound No. 20)
(2R, 2S) (1α, 5α, 6α)-N-[3-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclohexyl-2-pheny1αcetamide (Compound No. 21)
(2R, 2S) (1α, 5α, 6α)-N-[3-(2,4-difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyc!ohexyl-2-pheny1αcetamide (Compound No. 22)
(1α, 5α, 6α)-N-[3-(2,4-difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2,2-dipheny1αcetamide (Compound No. 23)
(2R, 2S) (1α, 5α, 6α)-N-[3-(3-methylbenzyl)-3-azabicyclo[3.1.0]hex-6-yl-methyl]-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 24)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-methylphenyl)-2-pheny1αcetamide (Compound No. 25)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-methylphenyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 26)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-fluorophenyl)-2-pheny1αcetamide (Compound No. 27)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyc!o[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-fluorophenyl)-2-phenyl acetic acid ester (Compound No. 28)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(4-fluorophenyl)-(N-methyl)-2-pheny1αcetamide (Compound No. 29)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-methylphenyl)-2-pheny1αcetamide (Compound No. 30)
(2R, 2S) (lα, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-methylphenyl)-(N-methyl)-2-phenyIacetamide (Compound No. 31)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-methylphenyl)-2-phenyl acetic acid ester (Compound No. 32)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetic acid ester (Compound No. 33)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetic acid ester tartarate salt (Compound No. 34)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetamide (Compound No. 35)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(3-methylphenyl) acetamide tartarate salt (Compound No. 36)
(1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2,2-di(4-
fluorophenyl)acetic acid ester (Compound No. 37)
(1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2,2-di(4-fluorophenyl)-acetamide (Compound No. 38)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclobutyl-2-phenyl acetic acid ester (Compound No. 39)
(2R, 2S) (1α, 5α, 6α)-N-(3-cyclohexylmethyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-pheny1αcetamide (Compound No. 40)
(2R) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-(N-methyl)-2-pheny1αcetamide (Compound No. 41)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-cyclopentyl-2-(4-methylphenyl) acetamide (Compound No. 42)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-2-(4-methylphenyl) acetic acid ester (Compound No. 43)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-methyl-2-phenyl acetic acid ester (Compound No. 44)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxyv2-methyl-2-phenyl acetamide (Compound No. 45)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-isopropyl-2-phenyl acetic acid ester (Compound No. 46)
(1α, 5α, 6α)-N-(3-methyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-phenyl-(N-methyl)-2-pheny1αcetamide (Compound No. 47)
(1α, 5α, 6α)-N- (3-benzyI-3-azabicyclo [3.1.0] hex-6-yl-methyl)-2-hydroxy-2, 2-di (3-methylphenyl) acetamide (Compound No. 48)
(2R, 2S) (1α, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-(3-pentyl)-2-phenyl acetic acid ester (Compound No. 49)
(2R, 2S) (1α, 5α, 6α)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-methyl)-2-hydroxy-2-methyl-(N-methyl)-2-pheny1αcetamide (Compound No. 50)
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound
as defined in claim 1 or 2 together with pharmaceutically acceptable carriers, excipients or
diluents.
4. Use of a compound having the structure of Formula I,
(Formula Removed)or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein R], R2, R3 and Z are the same as defined in claim 1, in the manufacture of medicament for treatment or prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory, urinary and gastrointestinal systems, wherein the disease or disorder is mediated through muscarinic receptors.
5. Use of the pharmaceutical composition according to claim 3 for treatment or prophylaxis of
an animal or a human suffering from a disease or disorder of the respiratory, urinary and
gastroinstestinal systems, wherein the disease or disorder is mediated through muscarinic
receptors.
6. The use according to claim 4 or 5 wherein the disease or disorder is urinary incontinence,
lower urinary tract symptoms (LUTS), bronchial asthma, chronic obstructive pulmonary
disorders (COPD), pulmonary fibrosis, irritable bowel syndrome, obesity, diabetes or
gastrointestinal hyperkinesis.
7. A process of preparing a compound of Formula VI,
(Formula Removed)and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein R1 , R2
and R3 are the same as defined in claim 1 and R4 represents hydrogen or C1-C3 alkyl,
comprising:
(a) condensing a compound of Formula II with a compound of Formula III
(Formula Removed)to give a protected compound of Formula IV (P is any protecting group for an amino group and is selected from benzyl and t-butyloxy carbonyl groups),
(Formula Removed) (b) deprotecting the compound of Formula IV in the presence of a deprotecting agent
to give an unprotected intermediate of Formula V,(Formula Removed)(c) the intermediate of Formula V is N-alkylated or benzylated with an alkylating or
benzylating agent, L-R3 (L is any leaving group selected from halogen, O-mestyl and O-tosyl groups and R3 is the same as defined earlier), to give a compound of Formula VI.
8. The process according to claim 7 wherein:
(i) the reaction of a compound of Formula II is carried out in the presence of N-methylmorpholine and 1-hydroxybenzotriazole and a condensing agent selected from 1-(3-dimethyl amino propyl)-3-ethyl carbodiimide hydrochloride (EDC), 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) or 1,3-dicyclohexylcarbodiimide (DCC) in a solvent selected from dimethylformamide, dimethyl sulfoxide, toluene, xylene or chloroform at a temperature ranging from 0°C to 140°C.
(ii) the deprotection of a compound of Formula IV is carried out with a deprotecting agent selected from palladium on carbon and hydrogen, ammonium formate and palladium on carbon, trifluoroacetic acid (TFA) and hydrochloric acid in an organic solvent selected from methanol, ethanol, tetrahydrofuran and acetonitrile.
(iii) the N-alkylation or benzylation of a compound of Formula V is carried out with an alkylating or benzylating agent, L-R3 in the optional presence of potassium carbonate and potassium iodide in an organic solvent selected from dimethylformamide, dimethylsulfoxide, tetrahydrofuran and acetonitrile.
9. A process of preparing a compound of Formula X,
(Formula Removed)and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters,
enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein R1 , R2
and R3 are the same as defined in claim 1, comprising:
(a) condensing a compound of Formula II with a compound of Formula VII (R' is any
protecting group for a hydroxy group selected from p-toluene sulfonyl or methane sulfonyl
groups),
(Formula Removed)to give a protected compound of Formula VIII (P is any protecting group for an amino group selected from benzyl and t-butyloxy carbonyl groups),
(Formula Removed) (b) deprotecting the compound of Formula VIII in the presence of a deprotecting agent to give an unprotected intermediate of Formula IX,
(Formula Removed)
(c) the intermediate of Formula IX is N-alkylated or benzylated with an alkylating or benzylating agent, L-R3 to give a compound of Formula X.
10. The process according to claim 9 wherein:
(i) the reaction of a compound of Formula II is carried out in the presence of a condensing agent selected from l,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) and l,4-diazabicyclo[2.2.2]octane (DABCO) in a solvent selected from benzene, toluene or xylene at a temperature ranging from 0 °C to 140°C.
(ii) the deprotection of a compound of Formula VIII is carried out with a deprotecting agent selected from palladium on carbon and hydrogen gas and ammonium formate and palladium on carbon in an organic solvent selected from methanol and ethanol.
(iii) the N-alkylation or benzylation of a compound of Formula IX is carried out with a suitable alkylating or benzylating agent, L-R3 in an organic solvent selected from dimethylformamide, dimethylsulfoxide, tetrahydrofuran and acetonitrile.