ZA200500952B - 3,6 Disubstituted azabicyclo (3.1.0) hexane derivatives useful as muscarinic receptor antagonists. - Google Patents

Description

3,6-DISUBSTITUTED AZABICYCLO [3.1.0]JHEXANE DERIVATIVES USEFUL

AS MUSCARINIC RECEPTOR ANTAGONISTS

FIELD OF THE INVENTION

S

This invention generally relates to the derivatives of novel 3,6-disubstituted azabicyclo[3.1.0] hexanes.

The compounds of this invention are muscarinic receptor antagonists which are useful, inter-alia, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors.

The invention also relates 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) "20 are composed of a family of 5 receptor sub-types (M;, My, Ms, My 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 M; subtype is located primarily in neuronal tissues such as cereberal cortex and autonomic ganglia, the M, subtype is present mainly in the heart where it mediates cholinergically induced bradycardia, and the Mj subtype is located predominantly on smooth muscle and salivary glands (Nature, 1986; 323: 411; Science, 1987; 237: 527).

A review in Current opinions in Chemical Biology, 1999; 3: 426, as well as in

Trends in Pharmacological Sciences, 2001; 22: 409 by Eglen et. al, describe the biological potentials of modulating muscarinic receptor subtypes by ligands in different disease conditions like Alzheimer’s disease, pain, urinary disease condition, chronic obstructive pulmonary disease etc. 1

CONFIRMATION COPY

A review in J. Med. Chem., 2000; 43: 4333 by Christian C. Felder et. al. describes therapeutic opportunities for muscarinic receptors in the central nervous system and elaborates on muscarinic receptor structure and function, pharmacology and their therapeutic uses.

The pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists are presented in a review in Molecules, 2001, 6: 142.

N.J.M. Birdsall et. al. in Trends in Pharmacological Sciences, 2001; 22: 215 have also summarized the recent developments on the role of different muscarinic receptor subtypes using different muscaranic 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 classical muscarinic antagonists such as atropine are potent bronchodilators, 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 them are not ideal anti-cholinergic bronchodilators due to lack of selectivity for muscarinic receptor sub-types. The existing compounds offer limited therapeutic benefit due to their lack of selectivity resulting in dose limiting side- effects such as thirst, nausea, mydriasis and those associated with the heart such as tachycardia mediated by the M; receptor.

Annual review of Pharmacological Toxicol, 2001; 41: 691, 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 bladder 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. (W.D.Steers et. al. in Curr. Opin. Invest. Drugs, 2: 268, C.R. Chapple et. al. in Urology, 55: 33), Steers WD, Barrot DM, Wein AJ, 1996, Voiding dysfunction: diagnosis oo cl WO 2004/004629 PCT/1B2002/002663 & classification and management. In Adult and Pediatric Urology, ed. JY Gillenwatter, JT

Grayhack, SS Howards, JW Duckett, pp 1220-1325, St. Louis, MO; Mosby. 3 edition.)

Despite these advances, 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 Laid, 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. U.S.

Patent Nos. 6,174,900, 6,130,232 and 5,948,792; WO 97/45414 are related to 1,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated, 1,4-disubstitued piperidine derivatives; WO 93/16018 and W(096/33973 are other close art references.

A report in J. Med. Chem., 2002; 44:984, describes cyclohexylmethyl piperidinyl triphenylpropioamide derivatives as selective M; antagonist discriminating against the other receptor subtypes.

SUMMARY OF THE INVENTION

The present invention provides novel 3,6-disubstituted azabicyclo[3.1.0Jhexanes as muscarinic receptor antagonists which are useful as safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems, and process for the synthesis of the novel compounds.

The invention also provides pharmaceutical compositions containing the novel compounds together with acceptable carriers, excipients or diluents which are useful for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems.

The present invention also includes within its scope prodrugs of the novel compounds. In general, such prodrugs will be functionalized derivatives of these compounds which readily get converted in vivo into the defined compounds.

e @ o WO 2004/004629 PCT/IB2002/002663

Conventional procedures for the selection and preparation of suitable prodrugs are known to the artisan skilled in the art.

The invention also includes 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.

The invention further includes pharmaceutical compositions comprising the compounds of the present invention, 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 advantages of the invention 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 objects and the advantages of the invention may be realized and obtained by means of the mechanisms and combinations pointed out in the appended claims.

In accordance with one aspect of the present invention, there is provided a compound having the structure of Formula I:

H Ry

R, : w—|-u—g—x—v—z—a N—Ry

Ra 0 H

H Rs

Formula I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein

Ar represents an aryl or a heteroaryl ring having 1-2 hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen atoms, the aryl or heteroaryl rings may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (Ci-Ca), lower perhalo alkyl (C,-Cs), cyano, hydroxy, nitro, lower alkoxy (C;-

é

Sf WO 2004/004629 PCT/IB2002/002663

Ca), lower perhalo alkoxy (C;-Cs), unsubstituted amino, N-lower alkyl (C;-C,) amino or

N-lower alkyl (C,-C,) amino carbonyl;

R; represents a hydrogen, hydroxy, hydroxy methyl, amino, alkoxy, carbamoyl or halogen (e.g. fluorine, chlorine, bromine and iodine);

R; represents alkyl, C;-C; cycloalkyl ring, a C3-C; cyclo alkenyl ring, an aryl or a heteroaryl ring having 1 to 2 hetero atoms selected from a group consisting of oxygen, sulphur and nitrogen atoms; the aryl or a heteroaryl ring may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C;-Ca), lower perhalo alkyl (C,-C4), cyano, hydroxy, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C;-Cs), lower perhalo alkoxy (C,-C), unsubstituted amino, N-lower alkylamino (C1-C4), N-lower alkylamino carbonyl (C;-Cy);

Ww represents (CHz),, where p represents 0 to 1;

X represents an oxygen, sulphur, nitrogen or no atom;

Y represents CHRsCO wherein Rs represents hydrogen or methyl or (CH;)q wherein q represents 0 to 4; :

Z represents oxygen, sulphur, NRj,, wherein R represents hydrogen, C,.¢ alkyl; ’

Q represents (CHa), wherein n represents O to 4, or CHRg wherein Rg represents H, . OH, Ci, alkyl, alkenyl alkoxy or CH,CHRg wherein Ry represents H, OH , lower alkyl (C,-Cy) or lower alkoxy (C-Cy);

Rs and Ry are independently selected from COOH, H, CHs, CONH;, NH,, CH;NH;

Ry represents C;-Cys saturated or unsaturated aliphatic hydrocarbon groups in which any 1 to 6 hydrogen atoms may be substituted with the group independently selected from halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulphur atoms with option that any 1 to 3 hydrogen atoms on the ring in said arylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted with lower alkyl (C;-Cs), lower perhalo alkyl (C;-

C4), cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C;-C,), lower perhaloalkoxy (C,-Cs4), unsubstituted amino, N-lower alkylamino (C;-Cs), N-lower alkylamino carbonyl (C,-Cy).

S

%

In accordance with a second aspect of the present invention, there is provided a compound having the structure of Formula II (Formula I, when Rg and R7 = H) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein Ar,

RL,Ry,W, XY, Z, Q, and R, are as defined for Formula I. d

R¢ H

R, lo} By

H

Formula II

In accordance with a third aspect of the present invention, there is provided a compound having the structure of Formula III (Formula I wherein W is (CH,)p where p = 0, X is no atom and Y is (CH;)q where q = 0, Rg = H, R; = H) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereorners,

N-oxides, polymorphs, prodrugs, metabolites, wherein Ar, Ry, Ra, Z, Q and Ry are as defined for Formula I.

H

Ry : w—t—g—z—an N—R,

R, O 1

H .

Formula IIT

In accordance with a fourth aspect of the present invention, there is provided a compound having the structure of Formula IV (Formula I wherein W is (CH;)p where p = 0, X is no atom and Y is (CH;)q whete q= 0, Rg=H,R; =H, R2 = —4, ) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein Ar,

Ry, Z, Q and Ry are as defined for Formula and ris 1 to 4.

u %!

Ho gmzar NTR 0 Ela

Ir H

Formula IV

In accordance with a fifth aspect of the present invention, there is provided a compound having the structure of Formula V (Formula I wherein W is (CHz)p where p = 0, X is no atom and Y is (CHz)q where q=0, Rs = H, R= H, R; 20 , Ry is hydroxy,

Ar is phenyl), and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein Ry, Z and Q are the same as defined for Formula I, s represents 1 to 2.

H read 0 :

Is H

Formula V

In accordance with a sixth aspect of the present invention, there is provided a method 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.

In accordance with a seventh aspect of the present invention, there is provided a method for treatment or prophylaxis 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 an eighth aspect of the present invention, there is provided a method for treatment or prophylaxis of an animal or a human suffering from a disease

. < i. WO 2004/004629 PCT/IB2002/002663 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 ninth aspect of the present invention, there are provided processes for preparing the compounds as described above.

The compounds of the present invention are novel and exhibit significant potency in terms of their activity, which was determined by ir vitro receptor binding and functional assays and in vivo experiments using anaesthetized rabbit. The compounds that were found active in in vitro assay were tested in vivo. Some of the compounds of the present invention were found to be potent muscarinic receptor antagonists with high affinity towards Ms receptors. Therefore, the present invention provides the pharmaceutical compositions for the possible treatment for the disease or disorders associated with muscarinic receptors. In addition, the compounds of the present invention can be administered oraily or parenterally.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following novel and inventive reaction sequences: :

&

Scheme X .

H Ry

Ry 1 w—|w—g—on + H—X—Y—Z— N—P ! ] Ry o :

H Re

Formula-Vll Condensing agent Formula VI : Ry

Ry s i w—tw—g—x—v—z—a N—P

R, o :

H Rg

Formula - VII! | Deprotection

H Ry rR, : wr—fw—g—x—v—z—a N—H

R, 0 H

A Rs

Formula - IX LRy | N-Alkylation/Benzyl ation , 4 25 . H

Ry :

Ar} w—g—x—r—z—a N—R,

Ry o :

H Re

Formula

SO WO 2004/004629 PCT/IB2002/002663

The compounds of Formula I of the present invention may be prepared by the reaction sequence as shown in Scheme I The preparation comprises condensing a compound of Formula VII with the compound of Formula VI wherein Ar represents an aryl or a heteroaryl ring having 1-2 hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen atoms, the aryl or heteroaryl rings may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C1-Ca), lower perhalo alkyl (C;-Cs), cyano, hydroxy, nitro, lower alkoxy (C,-Cs), lower perhalo alkoxy (C;-Cy), unsubstituted amino, N-lower alkyl (C;-C4) amino or N-lower alkyl (Cy-

C4) amino carbonyl;

R) represents a hydrogen, hydroxy, hydroxy methyl, amino, alkoxy, carbamoyl or halogen (e.g. fluorine, chlorine, bromine and iodine);

R; represents alkyl, C;-C; cycloalkyl ring, a C3-C; cyclo alkenyl ring, an aryl or a heteroaryl ring having 1 to 2 hetero atoms selected from a group consisting of oxygen, sulphur and nitrogen atoms; the aryl or a heteroaryl ring may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C1-Ca), lower perhalo alkyl (C,-Cs), cyano, hydroxy, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C1-Cys), lower perhalo alkoxy (C,-Cs), unsubstituted amino, N-lower alkylamino (C;-Cy4), N-lower alkylamino carbonyl (C1-Ca);

Ww represents (CHy),, where p represents 0 to 1;

X represents an oxygen, sulphur, nitrogen or no atom,

Y represents CHRsCO wherein Rs represents hydrogen or methyl or (CH,)q wherein q represents 0 to 4;

V4 represents oxygen, sulphur, NR;o, wherein Ro represents hydrogen, Cy alkyl;

Q represents (CH), wherein n represents 0 to 4, or CHRg wherein Rg represents H,

Ol], Cys, alkyl, alkenyl alkoxy or CH,CHRg wherein Ry represents H, OH , lower alkyl (C,-Cy) or lower alkoxy (C;-Cq);

R¢ and R; are independently selected from COOH, H, CHs, CONH,, NH,, CH,NH;

P is any protecting group for an amino group, in the presence of a condensing agent to give a protected compound of Formula VIII which on deprotection in the presence of a deprotecting agent in an organic solvent gives an unprotected intermediate of Formula IX

J WO 2004/004629 PCT/IB2002/002663 which is finally N-alkylated or benzylated with a suitable alkylating or benzylating agent

L-R4 to give a compound of Formula I wherein L is any leaving group and Ry is as defined above.

P is any protecting group for an amino group for a compound of Formula VI and is selected from benzyl and t-butyloxy carbonyl groups.

The reaction of the compound of Formula VII with a compound of Formula VI to give a compound of Formula VIII is carried out in the presence of a condensing agent which is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU).

The reaction of the compound of Formula VII with a compound of Formula VI to give a compound of Formula VIII is carried out in a suitable solvent selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, toluene, and xylene at a temperature ranging from about 0-140°C.

The deprotection of the compound of Formula VIII to give a compound of

Formula IX is carried out with a deprotecting agent which is selected from the group consisting of palladium on carbon, trifluoroacetic acid (TFA) and hydrochloric acid.

The deprotection of the compound of Formula VIII to give a compound of

Formula IX is carried out in a suitable organic solvent selected from the group consisting of methanol, ethanol, tetrahydrofuran and acetonitrile at temperatures ranging from about 10-50°C.

The N-alkylation or benzylation of the compound of Formula IX to give a compound of Formula I is carried out with a suitable alkylating or benzylating agent, L-

R4 wherein L is any leaving group, known in the art, preferably selected from halogen, O- mestyl and O-tosyl group.

o WO 2004/004629 PCT/IB2002/002663

The N-alkylation or benzylation of the compound of Formula IX to give a compound of Formula I is carried out in a suitable organic solvent such as N,N- dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and acetonitrile, at temperatures ranging from about 25-100°C. 5 .

In the above scheme, where specific bases, condensing agents, protecting groups, deprotecting agents, N-alkylating/benzylating agents, solvents, catalysts etc. are mentioned, it is to be understood that other bases, condensing agents, protecting groups, deprotecting agents, N-alkylating/benzylating agents, solvents, catalysts etc. known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs.

Alternatively, the compounds of the invention may be prepared by condensing compounds of formula VI with an aryl alpha keto ester (Ar{CO)COOR’ wherin R’ denotes a lower alkyl group) and the compounds thus formed may be subsequently reacted with the condensate R”M , wherein R” groups include groups such as phenyl, C4- 6 alkyl etc. and M may be alkali metal or MgX, wherein x is a halogen atom. Alpha keto esters may in turn be prepared by following J.O.C., 46,213(1981), or synthetic communication, 11, 943(1981).

The compounds of the invention may also be prepared by reacting R”M (wherein

M and R” have the same as described above) with the aryl alpha keto ester (Ar(CO)COOR’ wherin R’ denotes a lower alkyl group) to form an alpha hydroxy ester.

This product is further reacted with compound of formula VI and then the protecting group is removed to give compounds of formula VIII.

Suitable salts of the compounds represented by the Formula I 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, \artarate, citrate, fumarate, maleate, tolounesulphonate and methanesulphonate).

When carboxyl group is included in the Formula I as a substituent , it may be an alkali metal salt(e.g. sodium, potassium, calcium, magnesium, and the like). These salts may be a WO 2004/004629 PCT/IB2002/002663 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

Scheme I as shown in Table-I include:

Compound Chemical Name

No. 1. (la,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2,2-diphenyl acetamide 2. (la,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0}hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2-cyclohexyl-2-phenyl acetamide 3. (lo,50,60)-N-[3-benzyl-3-azabicyclo[ 3.1.0]hexyl-6-(aminomethyl)-yl}-2-hydroxy- 2-cyclopentyl-2-phenyl acetamide 4. (lo,50,60)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2,2- diphenyl acetate 5. (lao,5a,60)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl] -2-hydroxy-2- cyclohexyl-2-phenyl acetate 6. (la,5a,60)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl])-2-hydroxy-2- cyclopentyl-2-phenyl acetafe 7. (lo,5a,60)-[3-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-3-azabicyclo[ 3.1.0] hexyl-6- (methyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetate 8. (la,50.,60)-[3-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (methy!)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetate 9. (lo,5a,60)-N-[3-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0Thexyl- 6-(aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide 10. (la,50,60)-N-[3-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0}hexyl- 6-(aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide 11. (la,5a,60)-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (methyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetate 12. (la,50,60)-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (methyl)-yl1]-2-hydroxy-2-cyclohexyl-2-phenyl acetate 13. (lo,50,60.)-N-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide 14. (la,50,60)-N-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0Jhexyl-6- (aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide 15. (la,50,60)-N-[3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)- yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide

LS —pe ne 16. (la,5a,6a)-N-[3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)- yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide 17. (la,50,6a)-[3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetate 18. (la,50,60)-[3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetate 19. (la,5a,6a)-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetate 20. (la,50,6a)-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy- 2-cyclohexyl-2-phenyl acetate 21. (lo,5a,6a)-N-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hex yl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetamide 22. (la,50,6a)-N-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide 23. (lo,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]Thexyl-6-(1-aminoethyl)-yl]-2-hydroxy- 2,2-diphenyl acetamide 24. (1a,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(1-aminoethyl)-yl]-2-hydroxy- 2-cyclohexyl-2-phenyl acetamide 25. (1o,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(1-aminoethyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetamide 26. (la,5a,60)-[3-(3-methyl-2-butenyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetate 27. (la,5a,60)-[3-(3-methyl-2-butenyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetate : 25 28. (2R)-(+)- (1a,5a,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetamide 29. (2R)-(+)- (1a,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide 30. (2R) (+)-(1o,50,6a)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy- 2-cyclohexyl-2-phenyl acetate 31. (2R) (+)- (1a,50,601)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetate 32. (2S)-(-)- (1a,50a,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide 33. (25)-(-)- (1a,50,60)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetate 34. (la,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]Thexyl-6-(aminomethyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetamide L-(+)-tartrate salt 35. (25)-(-)- (1a,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- 40 hydroxy-2-cyclopentyl-2-phenyl acetamide. L-( + )-tartrate salt 14

AMENDED SHEET

-)

S WO 2004/004629 : PCT/1B2002/002663 36. (2R)~(+)- (lo,5a,601)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide. L-( + )-tartrate salt 37. (la,5a,60.)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl}-2-hydroxy- 2-cyclobutyl-2-phenyl acetamide 38. (la,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2-cyclopropyl-2-phenyl acetamide 39. (la,5a,60)-N-[ 3-(3-methyl-2-butenyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)- yl]-2-hydroxy-2-hexyl-2-phenyl acetamide : 40. (lo,5 0, 600-[ 3-(3,4- methylenedioxyphenyl)methyl-3-azabicyclo[3.1.0]jhexyl-6- (methyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetate 41. (la,50,60)-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (methyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetate. L-( + )-tartrate salt 42. (1o,50,60)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yi]-2-hydroxy-2,2 diphenyl acetate L(+)-tartrate salt 43. (lo,50,60)- [3-benzyl-3-azabicyclo3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclohexyl-2-phenyl acetate L(+)-tartrate salt 44. (la,50,60)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclopentyl-2-phenyl acetate L(+)-tartrate salt. 45. (lo,5o,60)-N-[3 -(3-pyridylmethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl}- 2-hydroxy-2-cyclohexyl-2-phenyl acetamide 46. (lo,50,60)-N-[3~(4-pyridylmethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]- 2-hydroxy-2-cyclohexyl-2-phenyl acetatamide 47. (lo,50.,60)-N-[3-(2-pyridylmethyl)-3-azabicyclo[3.1.0Jhexyl-6-(aminomethyl)-yl]- 2-hydroxy-2-cyclohexyl-2-phenyl acetamide 48. (lo,50,60)-N-{3-(4-pyridylmethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-y1]- 2-hydroxy-2-cyclopentyl-2-phenyl acetamide 49. (la,50,60)-N-[3-(3-pyridylmethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]- 2-hydroxy-2,2-diphenyl acetamide 50. (lo,5o,60)-N-[3-(4-pyridylmethyl)-3-azabicyclo[3.1.0Jhexyl-6-(aminomethyl)-yl]- 2-hydroxy-2,2-dipheny] acetamide 51. (lo,50,60)-N-[3-(2~-pyridylmethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl1]- 2-hydroxy-2,2-diphenyl acetamide 52. (lo,50.,600)-N-[3-(2-pyridylmethyl)-3-azabicyclo[3.1.0Jhexyl-6-(aminomethyl)-yl]- 2-hydroxy-2-cyclopentyl-2-phenyl acetamide 53. (la,50,60)-N-[3-(3-pyridylmethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]- 2-hydroxy-2-cyclopentyl-2-phenyl acetamide 54. (la,So,60)-N-[3-(3-methyl-2-butenyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)- yl)-2-hydroxy-2-cyclopentyl-2-phenyl acetamide 55. (1a,5 o,601)-N-[3-(3,4-methylenedioxyphenyl)methyl-3-azabicyclo[3 .1.0]hexyl-6- 40 (aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide

Claims (17)

WE CLAIM:

1. A compound having the structure of Formula I: H Ry w—f-w—g—x—v—z—a N—R4 RO : H Rg FORMULA -1 and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites,wherein Ar represents an aryl or a heteroaryl ring having 1-2 hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen atoms, the aryl or heteroaryl rings may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C;-C,), lower perhalo alkyl (C;-C,), cyano, hydroxy, nitro, lower alkoxy (C;-Cy), lower perhalo alkoxy (C;-C,), unsubstituted amino, N-lower alkyl (C1-C4) amino or N-lower alkyl(C;-C4) amino carbonyl; R, represents a hydrogen, hydroxy, hydroxy methyl, amino, alkoxy , carbamoyl or halogen (e.g. fluorine, chlorine, bromine and iodine); Rj represents alkyl, Cs-C; cycloalkyl ring, a C3-C; cyclo alkenyl ring, an aryl or a heteroaryl ring having 1 to 2 hetero atoms selected from a group consisting of oxygen, sulphur and nitrogen atoms; the aryl or a heteroaryl ring may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C;- Cs), lower perhalo alkyl (C;-Cs), cyano, hydroxy, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C;-Cs), lower perhalo alkoxy (Ci-Cs), unsubstituted amino, N-lower alkylamino (C;-C,), N-lower alkylamino carbonyl (C;-Ca); W represents (CH,),, where p represents 0 to 1; X represents an oxygen, sulphur, nitrogen or no atom;

Y represents CHRsCO wherein Rs represents hydrogen or methyl or (CH,)q wherein q represents 0 to 4; Z represents oxygen, sulphur, NR;,, wherein R;q represents hydrogen, C,.¢ alkyl, Q represents (CH,), wherein n represents 0 to 4, or CHRg wherein Rg represents H, OH, Ci, alkyl, alkenyl alkoxy or CH,CHRy wherein Ry represents H, OH , lower alkyl (C,-C,) or lower alkoxy (C;-Cy); Rg and R; are independently selected from COOH, H, CHj, CONH,, NH,, CH,NH,, Ra represents C;-Cis saturated or unsaturated aliphatic hydrocarbon groups in which any 1 to 6 hydrogen atoms may be substituted with the group independently selected from halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulphur atoms with option that any 1 to 3 hydrogen atoms on the ring in said arylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted with lower alkyl(C;-Ca), lower perhalo alkyl (C;-C,), cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (Ci-Cj), lower perhaloalkoxy (C;-Cs), unsubstituted amino, N-lower alkyl(C,-C4) amino, N-lower alkyl (C,-C4)amino carbonyl.

2. The compound according to claim 1 having the structurc of Formula II (Formula I when Rg and R; = H) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein Ar, Ry, Ry, W, X,Y, Z, Q and R; are as defined for Formula lL H Ry : Es R, : H FORMULA - II

3. The compound according to claim 1 having the structure of Formula III (Formula I wherein W is (CHz)p where p = 0, X is no atom and Y is (CH3)q where q=0, Rs =H, R; = H) and R; its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein Ar, Ry, R,, Z, Q and R, are as defined for Formula I. H Rr, : Trend Ry O : H FORMULA — III

4. The compound according to claim 1 having the structure of Formula IV [Formula I wherein W is (CH,)p where p = 0, X is no atom and Y is (CH;)q where q=0, Rs =H, R;=Hand R, -—4], ] and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein Ar, Ry, Z, Q and Ry are as defined for Formula I, and r is 1 to 4. H Ry p Ar le Juan Ir H Formula IV

5. The compound according to claim 1 having the structure of Formula V (Formula-I wherein W is (CHy)p where p = 0, X is no atom and Y is (CH;)q where ¢=0, Rs =H, R;=H, R, “1 ,» Ry 1s hydroxy, Ar is phenyl), and its pharmaceutically acceptable salts, esters, enantiomers, N-oxides, prodrugs or metabolites; wherein Ry, Z and Q are the same as defined for Formula I, and s represents 1to 2. OH : O Ld S : A Is Formula V

6. A compound selected form the group consisting of: (1a,50,600)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2,2-diphenyl acetamide.(Compound No. 1) (1a,50,601)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-

cyclohexyl-2-phenyl acetamide.(Compound No. 2)

(1a,50,601)-N-[3-benzyl-3-azabicyclo[3.1.0}hexyl-6-(aminomethyl)-yl]-2-hydroxy-2- cyclopentyl-2-phenyl acetamide.(Compound No. 3) (la,50,600)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2,2- diphenyl acetate.(Compound No. 4)

(1a,50,600)-[3-benzyl-3-azabicyclo[ 3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclohexyl-2-phenyl acetate.(Compound No. 5)

(1a,50,60)-[3-benzyl-3-azabicyclo[ 3.1.0} hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclopentyl-2-phenyl acetate.(Compound No. 6) (1a,50,6)-[3-(2-(2,3~-dihydrobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexyl-6-

i5 (methyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetate.(Compound No. 7)

: (1a,50,60)-[3-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (methyl)-y1]-2-hydroxy-2-cyclopentyl-2-phenyl acetate.(Compound No. 8) (1a,50,600)-N-[3-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide.(Compound No. 9)

(1o,50,60)-N-[3-(2-(2,3-dihydrobenzofuran-5-yi)ethyl)-3-azabicyclo[3.1.0}hexyl-6- (aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide.(Compound No. 10) (1a,50,600)-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (methyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetate.(Compound No. 11) (1a,5a,60)-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6-

(methyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetate.(Compound No. 12) (1a,50,6)-N-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide.(Compound No. 13) (1a,50.,60)-N-{3-(2-(3,4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0]hexyl-6- (aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide.(Compound No. 14)

(1ot,50.,60)-N-[3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)- yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide.(Compound No. 15) (1a,50,60)-N-[3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hex yl-6-(aminomethyl)- yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide.(Compound No. 16) (1a,50,60)-[3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-

hydroxy-2-cyclohexyl-2-phenyl acetate.(Compound No. 17)

(1a, 50,60)-[ 3-(4-methyl-3-pentenyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetate.(Compound No. 18) (1o,50,60)-[3-(1-phenylethyl)-3-azabicyclo[3.1.0Jhexyl-6-(methyl)-y1]-2-hydroxy-2- cyclopentyl-2-phenyl acetate. (Compound No. 19)

(1a,50,60)-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclohexyl-2-phenyl acetate.(Compound No. 20) (lo,50,60)-N-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetamide.(Compound No. 21)

(1a,50,60t)-N-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide.(Compound No. 22) (Ta,5a,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hex yl-6-(1-aminoethyl)-yl]-2-hydroxy- 2,2-diphenyl acetamide.(Compound No. 23) (1a,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(1-aminoethyl)-yl]-2-hydroxy-2-

cyclohexyl-2-phenyl acetamide.(Compound No. 24) (1a,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(1-aminoethyl)-yl]-2-hydroxy-2- cyclopentyl-2-phenyl acetamide.(Compound No. 25) (1a,5a,6a)-[3-(3-methyl-2-butenyl)-3-azabicyclo[ 3. 1.0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetate.(Compound No. 26)

(1a,50,6a)-[3-(3-methyl-2-butenyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetate.(Compound No. 27)

(2R)-(+)- (1a,50,601)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetamide.(Compound No. 28) (2R)-(+)- (1a,5a,6a)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-

hydroxy-2-cyclopentyl-2-phenyl acetamide.(Compound No. 29)

(ZR) (H)-(1a,5a,60at)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclohexyl-2-phenyl acetate.(Compound No. 30) (2R) (H)-(1a,5a,60)-[3-benzyl-3-azabicyclo[ 3. 1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclopentyl-2-phenyl acetate.(Compound No. 31)

(2S)-(-)- (1a,50,6a)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl}-2- hydroxy-2-cyclopentyl-2-phenyl acetamide.(Compound No. 32) (29)-(-)-(1a,5a,60)-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclopentyl-2-phenyl acetate.(Compound No. 33) (1a,50,6a)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2-

cyclopentyl-2-phenyl acetamide L-(+)-tartrate salt.(Compound No. 34)

(2S)-(-)- (1a,5a,6a)-N-[3-benzyl-3-azabicyclo[ 3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetamide.

L-( + )-tartrate salt.(Compound No. 35)

(2R)-(1)- (1a,5a,6)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide.

L-( + )-tartrate salt.(Compound No. 36)

3s (1a,50,60.)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-hydroxy-2- cyclobutyl-2-phenyl acetamide.(Compound No. 37) (1o,50,60)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl}-2-hydroxy-2- cyclopropyl-2-phenyl acetamide.(Compound No. 38)

(1a,5a,60)-N-[ 3-(3-methyl-2-butenyl)-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-

40 yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide.(Compound No. 39)

61 AMENDED SHEET

(Lo,5a,600)-[ 3-(3,4- methylenedioxyphenyl)methyl-3-azabicyclo[3.1 .Olhexyl-6- (methyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetate.(Compound No. 40) (lo,5a,600)-[3-(2-(3,4-methylenedioxyphenyl)ethyl)-3 -azabicyclo[3.1.0]hexyl-6- (methyl)-yl)-2-hydroxy-2-cyclopentyl-2-phenyl acetate.

L-(+)-tartrate salt.(Compound No. 41) (1a,5a,600)-[3-benzyl-3-azabicyclo[3.1 .0]hexyl-6-(methyl)-yl]-2-hydroxy-2,2 diphenyl acetate L(+)-tartrate salt .(Compound No. 42) (lot,5a,6a1)- [3-benzyl-3-azabicyclo[3.1 .OJhexyl-6-(methyl)-yl]-2-hydroxy-2- cyclohexyl-2-phenyl acetate L(+)-tartrate salt.(Compound No. 43)

(lat,50,600)-[3-benzyl-3-azabicyclo[3.1.0] hexyl-6-(methyl)-yl}-2-hydroxy-2- cyclopentyl-2-phenyl acetate L(+)-tartrate salt. (Compound No. 44)

(lot, 501,600)-N-[3-(3-pyridylmethyl)-3-azabicyclo[3.1 .0]hexyl-6-(aminomethyl)-y1}-2- hydroxy-2-cyclohexyl-2-phenyl acetamide (Compound No. 45) (1os”a,600)-N-[3-(4-pyridylmethyl)-3-azabicyclo[3.1 .O]Jhexyl-6-(aminomethyl)-yl]-2- i5 hydroxy-2-cyclohexyl-2-phenyl acetamide (Compound No.46) (Lot, 501,601)-N-[3-(2-pyridylmethyl)-3-azabicyclo[3.1 .O]hexyl-6-(aminomethyl)-y1]}-2- hydroxy-2-cyclohexyl-2-phenyl acetamide (Compound No.47) (1o,501,60)-N-[3-(4-pyridylmethyl)-3-azabicyclo[3.1 .0Jhexyl-6-(aminomethyl)-y1]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No.48)

(1ot,50,600)-N-[3-(3-pyridylmethyl)-3-azabicyclo[3.1 .O]hexyl-6-(aminomethyl)-yl]-2- hydroxy-2,2-dipheny! acetamide (Compound No.49) (1a,50,60)-N-[3-(4-pyridylmethyl)-3-azabicyclo[3.1 .O]Jhexyl-6-(aminomethyl)-yl]-2- hydroxy-2,2-diphenyl acetamide (Compound No.50)

(lo, 50,60)-N-[3-(2-pyridylmethyl)-3 -azabicyclo[3.1.0Jhexyl-6-(aminomethyl)-yi]-2-

hydroxy-2,2-diphenyl acetamide (Compound 51)

(la,5 a,6a)-N-[3-(2-pyridylmethyl)-3-azabicyclo[3.1 .OJhexyl-6-(aminomethyl)-yl]-2- hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No.52) (lat, 5a,601)-N-[3-(3-pyridylmethyl)-3-azabicyclo[3.1 .0]hexyl-6-(aminomethyl)-ylj-2- hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No.53)

(la, 50,601)-N-[3-(3-methyl-2-butenyl)-3-azabicyclo[3.1 .0]hexyl-6-(aminomethyl)- yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No.54) (1o,50,60)-N-[3 -(3,4-methylenedioxyphenyl)methyl-3-azabicyclo[3.1 .0lhexyl-6- (aminomethyl)-yl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No.55) (1o,50,600)-N-[3-(3 ,4-methylenedioxyphenyl)methyl-3-azabicyclo[3.1.0Jhexyl-6-

(aminomethyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetamide (Compound 56)

(lo, 50,600)-[3 -(4-methyl-3-pentenyl)-3-azabicyclo[3.1 .0]hexyl-6-(methyl)-yl]-2- hydroxy-2-cyclohexyl-2-phenyl acetate (+) tartrate salt(Compound 57) (lo, 5a,6a)-[3-(2-(3 ;4-methylenedioxyphenyl)ethyl)-3-azabicyclo[3.1.0Thexyl-6- (methyl)-yl]-2-hydroxy-2-cyclohexyl-2-phenyl acetate.

L(+) tartrate salt(Compound 40 58)

(lo, 5a,60)-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexyl-6-(methyl)-yl]-2-hydroxy-2- cyclopentyl-2-phenyl acetate. L(+) tartrate salt(Compound 59) (Ia,5a,601)-N-[3-benzyl-3-azabicyclo [3.1.0]-hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetamide .hydrochloride salt (Compound No. 60) (Ta, 5a,60)-N-[3-benzyl-3-azabicyclo [3.1.0]-hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetamide . L(-) malic acid salt (Compound No. 61) (Ia,5a,601)-N-[3-benzyl-3-azabicyclo [3.1.0]-hexyl-6-(aminomethyl)-yl]-2-hydroxy- 2-cyclopentyl-2-phenyl acetamide. maleate salt (Compound No. 62)

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1, 2, 3, 4, 5 or 6 together with pharmaceutically acceptable carriers, excipients or diluents.

8. A process of preparing a compound of Formula I, z R R, pi grea RO : H Re Formula I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein Ar represents an aryl or a heteroaryl ring having 1-2 hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen atoms, the aryl or heteroaryl rings may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C,-Cs), lower perhalo alkyl (C;-Cs), cyano, hydroxy, nitro, lower alkoxy (C;-Ca), lower perhalo alkoxy (C;-C4), unsubstituted amino, N-lower alkyl (C,-C4) amino or N-lower alkyl(C,-C4) amino carbonyl; R, represents a hydrogen, hydroxy, hydroxy methyl, amino, alkoxy , carbamoyl or halogen (e.g. fluorine, chlorine, bromine and iodine); 63 AMENDED SHEET

R; represents alkyl, C;-C; cycloalkyl ring, a C;-C; cyclo alkenyl ring, an aryl or a heteroaryl ring having 1 to 2 hetero atoms selected from a group consisting of oxygen, sulphur and nitrogen atoms; the aryl or a heteroaryl ring may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (Ci- C4), lower perhalo alkyl (C;-Cs), cyano, hydroxy, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C;-C4), lower perhalo alkoxy (C;-Cs), unsubstituted amino, N-lower alkyl(C;-C4)amino, N-lower alkyl(C,-Cs)amino carbonyl; W represents (CH,),, where p represents 0 to 1; X represents an oxygen, sulphur, nitrogen or no atom; Y represents CHRsCO wherein Rs represents hydrogen or methyl or (CH;)q wherein q represents 0 to 4; Z represents oxygen, sulphur, NR,o, wherein R represents hydrogen, Cc alkyl.

Q represents (CH;), wherein n represents 0 to 4, or CHRg wherein Rg represents H, OH, C\., alkyl, alkenyl alkoxy or CH,CHRy wherein Ry represents H, OH , lower alkyl (C,-Cy) or lower alkoxy (C;-Cy); Re and R; are independently selected from COOH, H, CH;, CONH,, NH,, CH,NH,, Ry represents C,-C;s saturated or unsaturated aliphatic hydrocarbon groups in which any 1 to 6 hydrogen atoms may be substituted with the group independently selected from halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulphur atoms with option that any 1 to 3 hydrogen atoms on the ring in said arylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted with lower alkyl(C-C,), lower perhalo alkyl (C,-Cs), cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C,-Cs), lower perhaloalkoxy (C,-C,), unsubstituted amino, N-lower alkyl(C,-C4) amino, N-lower alkyl (C,-C4)amino carbonyl, comprising (a) condensing a compound of Formula-VII with a compound of Formula VI 64 AMENDED SHEET

H Ry R ; pr—f—w—c—on H—X—Y—2Z—Q N—FP R, lo} : H Rs Formula VII Formula VI wherein Ar, Rj, Ry, W, X,Y, Z, Q, Rg, and R; have the same meanings as defined earlier for Formula I, to give a protected compound of Formula VIII wherein Ar, Ry, Ra, W, X,Y, Z, Q, are the same as defined earlier and P is a protecting group for an amino group H Ry R : w—fw—c—x—v—z—a N—FP R, 0 : H Rs Formula VIII (b) deprotecting the compound of Formula VIII in the presence of a deprotecting agent to give an unprotected intermediate of Formula IX wherein Ar, R;, R;, W, X, Y, Z, and Q are the same as defined earlier, d Ry Ry ; w—f-w-g—x—v—z—a N—H R, 0} : H Re Formula IX (c) the intermediate of Formula IX is N-alkylated or benzylated with a suitable alkylating or benzylating agent to give a compound of Formula I wherein Ar, R), R,, WwW, X,Y, Z, Q, Rs and R; are the same as defined earlier.

9. The process according to claim 8 wherein P is any protecting group for an amino group and is selected from the group consisting of benzyl and t-butyloxy carbonyl groups. 65 AMENDED SHEET

10. The process according to claim 8 wherein the reaction of a compound of Formula VI with a compound of Formula VII to give a compound of Formula VIII is carried out in the presence of a condensing agent which is selected from the group consisting of 1-(3-dimethyl amino propyl)-3-ethyl carbodiimide hydrochloride (EDC) and 1,8- diazabicyclo [5.4.0]undec-7-ene (DBU).

11. The process according to claim 8 wherein the reaction of a compound of Formula VI with a compound of Formula VII to give a compound of Formula VIII is carried out in a suitable polar aprotic solvent selected from the group consisting of N,N- dimethylformamide, dimethyl sulfoxide, toluene, and xylene.

12. The process according to claim 8 wherein the reaction of compound of Formula VI with a compound of Formula VII is carried out at 0-140°C.

13. The process according to claim 8 wherein the deprotection of a compound of Formula VIII to give a compound of Formula IX is carried out with a deprotecting agent which is selected from the group consisting of palladium on carbon, trifluoroacetic acid (TFA) and hydrochloric acid

14. The process according to claim 8 wherein the deprotection of a compound of Formula VIII to give a compound of Formula IX is carried out in a suitable organic solvent selected from the group consisting of methanol, ethanol, tetrahydrofuran and acetonitrile.

15. The process according to claim 8 wherein the N-alkylation or benzylation of a compound of Formula IX to give a compound of Formula I is carried out with a suitable alkylating or benzylating agent, L-R4 wherein L is any leaving group and R, is the same as defined earlier.

16. The process according to claim 14 wherein the leaving group is selected from the group consisting of halogen, O-mestyl and O-tosyl groups. 66 AMENDED SHEET

17. The process according to claim 14 wherein the N-alkylation or benzylation of a compound of Formula IX to give a compound of Formula I is carried out in a suitable organic solvent selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and acetonitrile. 67 AMENDED SHEET

26:8. A process of preparing a compound of Formula I, : Rr R : aE RO : H Re Formula I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein

Ar represents an aryl or a heteroaryl ring having 1-2 hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen atoms, the aryl or heteroaryl rings may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C;-C,), lower perhalo alkyl (C,-C,), cyano, hydroxy, nitro, lower alkoxy (C,-C,), lower perhalo alkoxy (C,-C,), unsubstituted amino, N-lower alkyl (C,-C4) amino or N-lower alkyl(C,-C,4) amino carbonyl;

R| represents a hydrogen, hydroxy, hydroxy methyl, amino, alkoxy , carbamoyl or halogen (e.g. fluorine, chlorine, bromine and iodine);

R, represents alkyl, C3-C5 cycloalkyl ring, a C3-C; cyclo alkenyl ring, an aryl or a heteroaryl ring having 1 to 2 hetero atoms selected from a group consisting of oxygen, sulphur and nitrogen atoms; the aryl or a heteroaryl ring may be unsubstituted or substituted by one to three substituents independently selected from lower alkyl (C,- Cs), lower perhalo alkyl (C,-Cs), cyano, hydroxy, nitro, lower alkoxycarbonyl,

halogen, lower alkoxy (C,-C4), lower perhalo alkoxy (C;-C4), unsubstituted amino, N-lower alkyl(C,-C4)amino, N-lower alkyl(C;-C4)amino carbonyl;

W represents (CH,),, where p represents 0 to 1; X represents an oxygen, sulphur, nitrogen or no atom; Y represents CHRsCO wherein Rs represents hydrogen or methyl or (CH,)q wherein q represents 0 to 4; Z represents oxygen, sulphur, NR;o, wherein Ro represents hydrogen, C, alkyl. 68 AMENDED SHEET

Q represents (CH), wherein n represents 0 to 4, or CHRg wherein Rg represents H, OH, C,., alkyl, alkenyl alkoxy or CH,CHRy wherein Rg represents H, OH , lower alkyl (C,-C,) or lower alkoxy (C;-Cy); Rg and R; are independently selected from COOH, H, CH3;, CONH,, NH,, CH,;NH;, Ry represents C,-C;s saturated or unsaturated aliphatic hydrocarbon groups in which any 1 to 6 hydrogen atoms may be substituted with the group independently selected from halogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulphur atoms with option that any 1 to 3 hydrogen atoms on the ring in said arylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted with lower alkyl(C-Cy), lower perhalo alkyl (C;-C,), cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C;-C4), lower perhaloalkoxy (C;-C,), unsubstituted amino, N-lower alkyl(C,-C,) amino, N-lower alkyl (C,-C,)amino carbonyl, comprising (a) condensing a compound of Formula-VII with a compound of Formula VI

. H R; R : t Ar W—G—oH H—X—Y—Z—Q N—FP Ry lo] BR H Rs Formula VII Formula VI wherein Ar, Ry, Ry, W, X,Y, Z, Q, Re, and R; have the same meanings as defined earlier for Formula I, to give a protected compound of Formula VIII wherein Ar, Ry, Ry, W, X,Y, Z, Q, are the same as defined earlier and P is a protecting group for an amino group H Rr R, : w—w—g—x—v—z—a N—P R, (0) H H Rs Formula VIII