FIELD OF THE INVENTION
This present invention generally relates 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 relates to the process for the prepration of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and the methods for treating 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 (M1, M2, M3, M4 and M5) 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 M1 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 M3 subtype is located predominantly on smooth muscle and salivary glands {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 modulating 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 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, 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 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 these are not ideal anti-cholinergic bronchodilators, due to lack 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 M2 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 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. (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. Gillenwatteret al., 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 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. Also, U.S. Patent Nos. 6,174,900, 6,130,232 and 5,948,792; WO 93/16018 and W096/33973 are other references of interest; WO 97/45414 are related to 1,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated, 1,4-disubstitued piperidine derivatives; US Patent No. 5,397,800 discloses l-azabicyclo[2.2.l]heptanes. US Patent
No.5, 001,160 describes 1-aryl-l-hydroxy-l-substituted-3-(4-substituted-l-piperazinyl)-2-propanones. WO 99/43657 describes 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives as muscarinic receptors antagonists. WO 01/090082 describes substituted 1-amino-alkyl lactams and their use as muscarinic receptor antagonists. WO 01/47893 describes azabicycloctane derivatives useful in the treatment of cardiac arrhythmias. WO 01/42213 describes 2-biphenyl-4-piperidinyl ureas. WO 01/42212 describes carbamate derivatives. WO 01/90081 describes amino alkyl lactam. WO 02/53564 describes novel quinuclidine derivatives. WO 02/00652 describes carbamates derived from arylalkyl amines. WO 02/06241 describes l,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives. U.S. application No. 20030105071 describes thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonic receptors and transporters, and method of use thereof WO 03/033495 describes quinuclidine derivatives and their use as M2 and/or M3 muscarinic receptor antagonists. US2003/0171362 describes amino-tetralin derivatives as muscarinic receptor antagonists. US2003/0162780 describes 4-piperidinyl alkyl amine derivatives as muscarinic receptor antagonists. US 5,179,108 disclose derivatives of 4-(aminomethyl) piperidine and their therapeutic applications. WO 03/048125 discloses aminotetralin derivatives as muscarinic receptor antagonists. WO 03/048124 discloses 4-piperidinyl alkylamine derivatives as muscarinic receptor antagonists. WO 2004/052857 and WO 04/004629 disclose 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists. WO 04/005252 discloses azabicyclo derivatives as musacrinic receptor antagonists, discloses WO 04/014853, WO 04/067510 and WO 04/014363 disclose derivatives of 3,6-disubstituted azabicyclohexane useful as muscarinic receptor antagonists. WO 2004/056810 discloses xanthine derivatives as muscarinic receptor antagonists. WO 2004/056811 discloses flaxavate derivatives as muscarinic receptor antagonists. WO 2004/056767 discloses l-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonists. WO 2004/018422 disclose fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo[3.1.0] hexane derivatives as muscarinic receptor antagonists.
J.Med.Chem., 44, p. 984 (2002), describes cyclohexylmethylpiperidinyl-triphenylpropioamide derivatives as selective M3 antagonist discriminating against the other receptor subtypes.
J.Med.Chem., 36, p. 610 (1993), describes the synthesis and antimuscarinic activity of some 1-cycloalkyl-l-hydroxy-l-phenyl-3-(4-substituted piperazinyl)-2-propanones and related compounds.
J.Med.Chem., 34, p.3065 (1991), describes analogues of oxybutynin, synthesis and antimuscarinic activity of some substituted 7-amino-l-hydroxy-5-heptyn-2-ones and related compounds.
SUMMARY OF THE INVENTION
In one aspect, there are provided muscarinic receptor antagonists, which can be useful as safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems. Also provided are processes for synthesizing 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 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 the compounds, their 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.
In accordance with one aspect, there are provided compounds having the structure of Formula I (as shown in the accompanied drawings) and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, metabolites, wherein
Ri is
• hydrogen
• lower (C1-C6) alky 1
• lower (C2-C7) alkenyl
• lower (C2-C7) alkynyl
• cycloalkyl
• amino
• substituted amino
• -ORz wherein Rz is selected from the group consisting of

> hydrogen
> -Si(CH3)3
> lower (C1-C6) alkyl
> lower (C2-C6) alkenyl
> lower (C2-C6) alkynyl
> cycloalkyl
> aryl
> -C(=0)NHRr wherein Rr is selected from the group consisting of
0 hydrogen
0 lower(C1-C6) alkyl
0 lower (C2-C6) alkenyl
0 lower (C2-C6) alkynyl
0 aryl
0 cycloalkyl;
R2is
• carboxy
• -SO2R6 wherein R6 is selected from the group consisting of

> alkyl
> alkenyl
> alkynyl
> cycloalkyl
> -NRpRq wherein Rp and Rq are selected from the group consisting of
o hydrogen
0 alkyl
0 alkenyl
0 alkynyl
0 cycloalkyl

0 aryl
o aralkyl
o heterocyclyl
o heteroaryl
o heterocyclylalkyl
0 heteroarylalkyi
> aryl
> aralkyl
> heteroaryl
> heterocyclyl
> heterocyclylalkyl
> heteroarylalkyi;
Rp and Rq may also together join to form a heterocyclyl ring.
• -C(=0)0R7 wherein Ry is selected from the group consisting of
> alkyl
> alkenyl
> alkynyl
> cycloalkyl
> aryl
> aralkyl
• -C(=0)NRxRy wherein Rx and Ry are each independently selected from the group consisting of
o hydrogen
0 hydroxy (as restricted by the definition that both Rx and Ry cannot be
hydroxy at the same time) 0 alkyl 0 alkenyl 0 alkynyl 0 aryl o aralkyl
0 S(0)2R6 wherein R6 is the same as defined above 0 heteroaryl o heterocyclyl

0 heteroarylalkyl
o heterocyclylalkyl; Rx and Ry may also together join to form a heterocyclyl ring, acyl
halogen (F, C1, Br, I) cyano
-NRxRy (wherein Rx and Ry are the same as defined above) -C(=0)CH20Rx (wherein Rx is the same as defined above);
R 3 is
• alkyl
• alkenyl
• alkynyl
• cycloalkyl
• aryl
• aralkyl
• heterocyclyl
• heteroaryl
• heterocyclylalkyl
• heteroarylalkyl;
R4 and R5 are independently selected from the group consisting of
• hydrogen
• lower (C1-C6) alkyl
• lower (C2-C7) alkenyl
• lower (C2-C7) alkynyl;
Xis
• oxygen
• -NR7 wherein R7 is selected from the group consisting of

□ hydrogen
□ lower (C1-C6) alkyl
□ lower (C2-C7) alkenyl
□ lower (C2-C7) alkynyl
□ aralkyl
□ aryl;
Ar is
• aryl
• heteroaryl
• heterocyclyl;
In accordance with a second aspect, 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. The method includes administration of at least one compound having the structure of Formula 1.
In accordance with a third aspect, 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 of a muscarinic receptor antagonist compound as described above.
In accordance with a fourth aspect, there is provided a method for treatment or prophylaxis 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, and the like; 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, there are provided processes for preparing the compounds as described above.
The compounds described herein exhibit significant potency in terms of their activity, as determined by in vitro receptor binding and functional assays and in vivo experiments using anaesthetized rabbits. The compounds that were found active in vitro were tested in vivo. Some of
the compounds are potent muscarinic receptor antagonists with high affinity towards M3 receptors. Therefore, pharmaceutical compositions for the possible treatment for the disease or disorders associated with muscarinic receptors are provided. In addition, the compounds can be administered orally or parenterally.
The following definitions apply to terms as used herein
The term "alkyl" unless and otherwise specified refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
It may further be substituted with one or more substituents selected form the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, 0x0, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, aminosulfonyl, -COOR7 (wherein R7 is same as defined earlier), -NHC(=0)Rx, -NRxRy, -C(=0)NRxRy, -NHC(=0)NR,Ry, -C(=0) heteroaryl, C(=0)heterocyclyl, -0-C(=0)NRxRy (wherein Rx and R.are the same as defined earlier), nitro, -S(0)mR6 (wherein m is an integer from 0-2 and R6 is the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRxRy, -C(=0)NRxRy, -OC(=0)NRxRy, -NHC(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(0)mR6 (where R6 and m are the same as defined earlier). Alkyl group as defined above may also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa- [where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, acyl, aralkyl,-C(=0)0R7 (wherein R7 is the same as defined earlier)], S(0)2R6 (where Re is as defined earlier), -C(=0)NRxRy (wherein Rx and Ry are as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRxRy, -C(=0)NRxRy, -0-C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(0)mR6 (where m and R6 are the same as defined earlier).
The term "alkenyl" unless and otherwise specified refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or
trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, -NHC(=0)Rx, -NRxRy, -C(=0)NRxRy, -NHC(=0)NRxRy, -0-C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR7 (wherein R7 is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, alkoxyamino, nitro, S(0)m R6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF3, cyano, -NRxRy, -C(=0)NRxRy, -0-C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier) and -S(0)m R6 (where R6 and m are the same as defined earlier).
The term "alkynyl" unless and otherwise specified refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms. In the event that alkynyl is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom.
It may further be substituted with one or more substituents selected from the group
consisting of alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, 0x0, thiocarbonyl, carboxy, -COOR7 (wherein R7 is the same
as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, -NHC(=0)Rx NRxRy, NHC(=0)NRxRy, -C(=0)NRxRy, -0C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), -S(0)mR6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR7 (wherein R7 is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=0)NRxRy, -NHC(=0)NRxRy, -C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), cyano and -S(0)mR6 (where R6 and m are the same as defined earlier).
The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic
bonds, unless or otherwise constrained by the definition. Such cycloalkyl groups may optionally be benzofused and include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR7 (wherein R7 is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, -NRxRy, -NHC(=0)NRxRy, -NHC(=0)Rx -C(=0)NR,Ry, -0-C(=0)NR,Ry (wherein Rx and Ry are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, S(0)m R6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR7 (wherein R7 is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=0)NRxRy, -NHC(=0)NRxRy , -0-C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), cyano, and -S(0)mR6 (where R6 and m are the same as defined earlier).
The term "aralkyl" refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6 and aryl is as defined below. The examples of aralkyl groups are benzyl and the like.
The term "aryl" herein refers to a carbocyclic aromatic group, for example phenyl, biphenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from the group consisting of halogen (F, C1, Br, I), hydroxy, alkyl, alkenyl, carboxy, -COOR7 (wherein R7 is the same as defined earlier), alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, cyano, nitro, -NHC(=0)Rx, -NRxRy, -C(=0)NRxRy, -NHC(=0)NRxRy, -0C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), -S(0)m R6 (wherein R6 and m are the same as defined earlier), heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl. The said aryl group may optionally be fused with cycloalkyl group, wherein the said cycloalkyl group may optionally contain heteroatoms selected from the group consisting of O, N, S.
The term "carboxy" as defined herein refers to -C(=0)OH.
The term "heteroaryl" unless and otherwise specified refers to an aromatic ring structure containing 5 or 6 carbon atoms, or a bicyclic aromatic group having 8 to 10 carbon atoms, with one or more heteroatom(s) independently selected from the group consisting of N, O and S optionally substituted with 1 to 3 substituent(s) selected from the group consisting of halogen (F, C1, Br, 1), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, -COOR7 (wherein R7 is the same as defined earlier), aryl, alkoxy, aralkyl, cyano, nitro, -NRxRy, -C(=0)NRxRy and -NHC(=0)NRxRy, -S(0)mR6 (wherein m and R6 are the same as defined earlier), -0-C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier). Unless or otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom.
Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
The term 'heterocyclyl" unless and otherwise specified refers to a non aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms in which 1 to 3 carbon atoms in a ring are replaced by heteroatoms selected from the group comprising of O, S or N, and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from the group consisting of halogen (F, C1, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, 0x0, carboxy, -COOR7 (wherein R7 is the same as defined earlier), -C(=0)NRxRy, -S(0)mR6 (wherein m and R6 are the same as defined earlier), -OC(=0)NRxRy, -NHC(=0)NRxRy, -NRxRy (wherein Rx and Ry are the same as defined earlier). Unless or otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom. Also unless or otherwise constrained by the definition the said heterocyclyl ring may optionally contain one or more olefinic bond(s). Examples of heterocyclyl groups are tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl or piperazinyl.
"Heteroarylalkyl" refers to heteroaryl group (wherein heteroaryl group is the same as defined above) linked through alkyl portion (wherein alkyl is the same as defined earlier).
"HeterocyclylalkyI" refers to heterocyclyl group (wherein heterocyclyl group is the same as defined above) linked through alkyl portion (wherein alkyl is the same as defined earlier).
"acyl" refers to -C(=0)R" wherein R" is selected from the group alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
"Substituted amino" unless and otherwise specified refers to a group -N(Rk)2 wherein each Rk is independently selected from the group hydrogen provided that both Rk groups are not hydrogen (defined as "amino"), alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, S(0)m R6 (wherein m and R6 is the same as defined above), -C(=Rv)NRxRy (wherein Ry is O or S & Rx and Ry are the same as defined earlier) or NHC(=Rv)NRyRx (wherein Rv, Ry and Rx are the same as defined earlier).
Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, -COOR7 (wherein R7 is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, -C(=Rv)NRxRy (wherein Rv is the same as defined earlier), -0(C=0)NRxRy, -OC(=Rv)NRxRy (wherein Rx, Ry and Rv are the same as defined earlier), -S(0)mR6 (where R6 and m is the same as defined above).
The term "leaving group" generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, of being easily separated from synthetic products under defined conditions. Examples of such leaving groups includes but not limited to halogen (F, C1, Br, I), trifiates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
The term "Protecting groups" is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T.W. Greene and P.G.M. Wuts,
"Protective groups in organic synthesis", 2nd ED, John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting group employed is not so critical so long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without distrupting the remainder of the molecule.
The compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomieric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixture(s) thereof are envisioned as part of the invention. Although amino acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural forms are envisioned as part of the invention.
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 the reaction schemes I, II and III of the accompanied drawings.
Scheme
The compounds of Formulae VI and VII may be prepared according to scheme I (as shown in the accompanied drawings). The preparation comprises condensing a compound of Formula II (wherein Ar, R1 and R3 are the same as defined earlier) with a compound of Formula III (wherein X, R4 and R5 are the same as defined earlier and P is a protecting group for example, aralkyl or acyl) to give a compound of Formula IV which is deprotected to give a compound of Formula V, Path a: the compound of Formula V is reacted with a compound of Formula L-Y-Ro (wherein L is a leaving group for example halogen (F, C1, Br, I), Y is -C(=0), SO2 and R6 is the same as defined earlier) to give a compound of Formula VI.
Path b: the compound of Formula V is reacted with a compound of Formula
hal-C(=0)0R7 (wherein R7 is the same as defined earlier and hal is halogen (Br, C1, I)) to give a compound of Formula VII.
The condensation of a compound of Formula II with a compound of Formula III is carried out in the presence of a condensing agent (for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride or dicyclohexylcarbodiimide in an organic base (for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, triethylamine, diisopropylethylamine or pyridine) in an organic solvent (for example, N,N-dimethylformamide, chloroform, tetrahydrofuran, dioxane, diethylether, benzene or toluene) to give a compound of Formula IV which on deprotection (for example, hydrogenatically utilizing palladium on carbon under catalytic hydrogenation transfer conditions of ammonium formate and palladium on carbon) in an organic solvent (for example, methanol, ethanol, tetrahydrofuran and acetonitrile) gives a compound of Formula V which on reaction with a compound of Formula L-Y-Re {Path a) in the presence of a base (for example, triethylamine, diisopropylethylamine or pyridine) in an organic solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride) gives a compound of Formula VI. The reaction of a compound of Formula V {Path b) with a compound of Formula hal-C(=0)0R7 is carried out in the presence of a base (for example, triethylamine, diisopropylethylamine or pyridine) in an organic solvent (for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride) gives a compound of Formula VII.
Compounds prepared following Scheme I are listed below (also shown in Table I and II):
N-{[(lα, 5a, 6a)-3-(4-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 4),
N-{[(lα,5a,6a)-3-Benzenesulfonyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 5),
N-{[(lα,5a,6a)-3-(3,5-Dinitrobenzoyl)-3-azabicyclo[3.I.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 6),
N-{[(lα,5a,6a)-3-(2-Benzyloxyacetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 7),
N-{[(lα,5a,6a)-3-Benzoyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 8),
N-{[(lα,5a,6a)-3-(3-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 9),
N-{[(lα,5a,6a)-3-(2-Benzo[l,3]dioxol-5-yl-acetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 10),
N-{[(lα,5a,6a)-3-(4-Trifluoromethylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 11),
N-{[(la,5a,6a)-3-[2-(3,5-Difluoro-phenyl)-acetyl]-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 13),
N-{[(lα,5a,6a)-3-(4-Tert-butylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 14),
N-{[(la, 5a, 6a)-3-(2-Fluorobenzoyl)-3-azabicyclo [3.1.0]hex-6-ylmethyl}]-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 15),
N-{[(la, 5a, 6a)-3-(3,4,5-Trimethoxybenzoyl)-3-azabicyclo [3.1.0]hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 16),
N-{[(lα, 5a, 6a)-3-Phenylacetyl-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 18),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid-4-nitro-benzyl ester (Compound No. 19),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid isobutyl ester (Compound No. 20),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid 4-nitro-phenyl ester (Compound No. 21),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (Compound No. 22),
N-{[(lα, 5a, 6a)-3-(4-Fluorobenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl}]-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 23)
N-{[(lα, 5a, 6a)-3-(2,4,6-Trisopropylbenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 24)
N-{[(la, 5a, 6a)-3-(3,5-Dimethylbenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.27)
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound No.35)
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid butyl ester (Compound No.36)
N-{[(la, 5a, 6a)-3-(Methanesulphonyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 37)
N-{[(la, 5a, 6a)-3-(4-Methoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 39)
N-{[(la, 5a, 6a)-3-(3-Benzo[l,3]-dioxol-5-yl-propionyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.40)
N-{[(la, 5a, 6a)-3-(Dimethylsulfamoyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cycIopentyl-2-hydroxy-2-phenyl acetamide (Compound No.41)
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymorphs.
Scheme 11
The compounds of Formulae IX and XI may be prepared according to scheme II (as shown in the
accompanied drawings), thus
Path a: the compound of Formula VIII (wherein X, R1, R3, R4 and R5 are the same as defined
earlier) undergoes N-derivatization to give a compound of Formula IX [wherein P1 is halogen (F,
C1, Br or I), cyano or -C(=0)0R7 (R7 is the same as defined earlier)].
Path b: the compound of Formula Vlll is reacted with a compound of Formula X (wherein Rx is the
same as defined earlier) to give a compound of Formula XI.
The N-derivatization of a compound of Formula VIII (Path a) (when P1 is halogen) is carried out with halogenating agent (for example, sodium hypochlorite, sodium hypobromite or sodium hypoiodite) in an organic solvent (for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride) to give a compound of Formula IX. The N-derivatization of a compound of Formula VIII (when P1 is cyano) is carried out with a nitrilating agent (for example, cyanogen bromide) in the presence of an organic base (for example, triethylamine, diisopropylethylamine or pyridine) in an organic solvent (for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride) to give a compound of Formula IX. The N-derivatization of a compound of Formula Vlll (when P1 is -C(=0)0R7) is carried out with anhydrides (for example, ditert-butoxycarbonyl anhydride, dipropoxycarbonyl anhydride, dimethoxycarbonyl anhydride or diethoxycarbonyl anhydride) in the presence of an organic base (for example, triethylamine, diisopropylethylamine or pyridine) in an organic solvent (for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride) to give a compound of Formula IX. The compound of Formula Vlll (Path b) is reacted with an isocyanate of Formula X in an organic solvent (for example, dichloroethane, dichloromethane, chloroform or carbon tetrachloride) to give a substituted urea of Formula XI.
Alternatively, the compound of Formula XI can also be prepared by reacting a compound of Formula VIII with an appropriate amine in the presence of carbonyldiimidazole (CDI) or with carbamates such as phenyl carbamate or p-nitrophenyl carbamate.
Compounds prepared following Scheme II are listed below (also listed in Table I):
N-{[(1 α,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Compound No. I)
N-{[(]a,5α,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzylamide (Compound No.3)
N-{[(lα,5α,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (4-trifluoromethyl-phenyl)-amide (Compound No. 12)
N-{[(Iα,5α,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (4-fluorophenyl)-amide (Compound No. 17)
N-{[(1α,5a,6a)-6-{[(2-CycIopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid allylamide (Compound No.25)
N-{[(lα,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (2,4-dimethoxy-phenyl)-amide (Compound No.26)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (4-benzyloxy-phenyl)-amide (Compound No.28)
N-{[(la,5a,6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 29)
N-{[(lα,5α,6α)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid amide (Compound No.30)
N-{[(la, 5a, 6a)-3-Cyano-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 31)
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide hydrochloride salts (Compound No. 32)
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclohexyl-2-hydroxy-2-phenyl acetamide (Compound No. 33)
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-hydroxy-2-diphenyl acetamide (Compound No. 34)
N-{[(lα,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (2,4-difluoro-phenyl)-amide (Compound No.38)
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymorphs.
Scheme 111
The compound of Formula XIV may be prepared by following Scheme III (as shown in the accompanied drawings). The preparation comprises reacting a compound of Formula XII (where in X, R2, R3, R4 and R5 are the same as defined earlier) with trimethyl silyl chloride to give a compound of Formula XIII, which undergoes 0-alkylation to give a compound of Formula XIV (wherein Rt is alkyl).
The reaction of a compound of Formula XII with trimethyl silyl chloride is carried out in an organic base (for example, imidazole, triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine) in an organic solvent (for example, dimethylformamide, tetrahydrofuran, dioxane or diethylether) to give a compound of Formula XIII which undergoes 0-alkylation in the presence an organic base (for example, sodium hydride or sodium cyanoboro hydride) in an organic solvent (for
example, tetrahydrofuran, dimethylformamide, diethylether or dioxane) to give a compound of Formula XIV.
Compound prepared following Scheme III is listed below (also listed in Table I):
N-{[(la, 5a, 6a)-3-Terbutyl-carboxy-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-methoxy-2-phenyl acetamide (Compound No. 2).
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymorphs.
Also, in all the above representative examples wherever amines are specified, one skilled in an art would optionally convert them to their respective salts, for example amines can be converted to corresponding hydrochloride salts with ethanolic hydrochloric acid solution in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
In the above schemes, where specific bases, solvents, condensing agents, etc. are mentioned, it is to be understood that other acids, bases, solvents, condensing agents, hydrolyzing agents, etc, known to those skilled in an art may also be used. Similarly the reaction temperature and duration of the reactions may be adjusted according to desired needs.
Table I
(where Ar is phenyl, R4=R5=H, X is -NH and R1 is -ORz)

(Table Removed)
Table II
(Table Removed)
Because of their valuable pharmacological properties, the compounds described herein may be administered to an animal for treatment orally, or by a parenteral route.
The pharmaceutical compositions described herein can be 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 relatively free of toxicity. The compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
The compounds described herein can be produced and formulated as their enantiomers, diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as metabolites having the same type of activity. Pharmaceutical compositions comprising the molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carrier and optionally included excipient can also be produced.
EXAMPLES
Various solvents, such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexanes, and dichloromethane, were dried using various drylng reagents according to procedures described in 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 Varian XL-300 MHz instument using tetramethylsilane as an internal standard.
Synthesis of (la, 5a, 6a)-6-aminomethvl-3-benzvl-3-azabicvclo[3.1.0]hexane
This compound was synthesised following the procedure described in EP 0413455 A2.
Synthesis of 2-hvdroxv-2-cvclopentvl-phenvl acetic acid
The compound was synthesised following the procedure described in soul. B. Kadin and Joseph G.
cannon. J. Org. Chem. 1962, 27, 240-245.
Svnthesis ofN-(lα, 5a, 6a)-(3-benzvl-3-azabicvclo[3.1.0]hex-6-vlmethvl)-2-cvclopentvl-2-
hvdroxv-2-phenvl-acetamide.
Step a: Synthesis of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid
This was prepared following the procedure described in J.Amer. Chem. Soc. 75, 265(1953).
Step b: Synthesis of (la, 5a, 6a)-6-aninomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane.
The compound was prepared following the procedure described in EP 0 413 455 A2.
Step c: Synthesis of (la, 5a, 6a)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl acetamide.
To a solution of a compound obtained from step b above (29.9 mmole, 6.05 g) in dimethylformamide (100 ml) was added 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid (commercially available) (27.2 mmole, 6.0 g) followed by the addition of l-(3-dimethylaminopropyl)-3-ethyl carbodiimide and cooled at 0°C. The reaction mixture was treated with hydroxy benzotriazole (29.9 mmole, 4.04 gm) followed by addition of N-methyl morpholine (54.4 mmole, 5.2 g) and was stirred at 0°C for 1 hour and at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic compound was extracted with ethyl acetate. The organic layers were washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yleld the title compound with 95% yleld.
The analogs of (I a, 5a, 6a)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl-acetamide described below, can be prepared by replacing appropriate acid in place of 2-hydroxy 2-cyclopentyl phenyl acetic acid.
N-(lα, 5α, 6a)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclobutyl-2-hydroxy-2-phenyl acetamide
N-(lα, 5α, 6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclohexyl-2-hydroxy-2-phenyl acetamide
N-(lα, 5α, 6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-phenyl acetamide
Synthesis of N-(lα, 5a, 6a)-(3-azabicyclo[3.1.01hex-6-vlmethyl)-2-cvclopentyl-2-hydroxy-2-phenyl acetamide.
To a solution of N-(lα, 5α, 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (1.0 g, 2.48 mmole) in dry methanol (25.0 ml), was added palladium on carbon (5%, 0.2 g) under N2 atmosphere followed by the addition of ammonium formate (0.8 g, 12.38 mmole) under constant stirring. The reaction mixture was refluxed for half an hour under N2 atmosphere. The reaction mixture was cooled to room temperature and the reaction mixture was filtered through hyflo bed. The hyflo bed was washed with methanol (75.0 ml), ethyl acetate (25.0 ml) and water (25.0 ml). The filtrate was concentrated under vacuum. The residue thus obtained was diluted with water and pH of the resulting solution was adjusted to pH~14 with sodium hydroxide. The compound was extracted with ethyl acetate (2x50 ml) and the ethyl acetate layer was washed with water and brine solution. The layer was dried over anhydrous sodium sulphate and concentrated to give the title compound with 96.2% yleld.
The analogs of N-(lα, 5α, 6α)-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl acetamide described below, can be prepared by deprotection of appropriate amine, as applicable in each case.
N-(lα, 5α, 6α)-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclobutyl-2-hydroxy-2-phenyl acetamide
N-(1α, 5α, 6α)-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclohexyl-2-hydroxy-2-phenyl acetamide
N-(lα, 5α, 6α)- (3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-diphenyl acetamide
SCHEME I, PATH A PROCEDURE
Example 1: Synthesis of N-{[(la, 5a, 6a)-3-(4-nitrobenzenesulphonvl)-3-azabicvclo[3.1.0]hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenvl acetamide (Compound No. 4) To a solution of N-(la, 5a, 6a)-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (0.796 mmole) and triethyl amine (1.592 mmol) in dichloromethane (10.0 ml) at 0°C was added p-nitro phenyl sulphonyl chloride (0.955 mmole). The reaction mixture was stirred for 1 hour at 0°C and then at room temperature for overnight. The solid thus separated was filtered, washed thoroughly with dichloromethane and dried to get the title compound with 60% yleld.
M.P: 225.3-227. 10C
1R(KBr): 1642.5 cm"'
'H NMR (DMSO-d6):5 8.39-8.42 (m, 2H), 7.91-7.99 (m, 2H), 7.54-7.56 (m, 2H), 7.22-7.32 (m,
3H), 5.47 (s, 1H), 3.06-3.09 (m, 3H), 2.90-2.92 (m, 2H), 2.76-2.79 (m, 2H), 1.42-1.47 (m, 9H),
1.25-1.28 (m,2H), 0.61 (brs, 1H).
Mass (m/z): 500 (M1), 482 (M+-OH).
Analogs of N-{[(la, 5a, 6a)-3-(4-nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 4) described below, can be prepared by replacing appropriate sulfonyl group in place of n-nitro phenyl sulfonyl chloride, as applicable in each case.
N-{[( 1 a, 5a, 6a)-3-Benzenesulfonyl-3-azabicyclo[3.1.0]hex-6-ylmethyl] }-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 5)
N-{ [(1 a,5a,6a)-3-(3-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl] }-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 9)
N-{[(lα,5α,6α)-3-(4-Trifluoromethylbenzenesulfonyl)-3-azabicyclo[3.1.0]-hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 11)
N-{[(lα,5α,6α)-3-(4-Tert-butylbenzenesulfonyl)-3-azabicyclo[3.1.0]-hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 14)
N-{[(]a, 5a, 6a)-3-(4-Fluorobenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}{-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 23)
N-{[(lα, 5a, 6a)-3-(2,4,6-Trisopropylbenzenesulfonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 24)
N-{[(]a, 5a, 6a)-3-(Methanesulfonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 37)
N-{[(la, 5a, 6a)-3-(Dimethylsulfamoyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No.41)
Example 2: Synthesis of N-{[(la,5a.6a)-3-[2-(3,5-difluorophenvl)-acetvl]-3-azabicvclo (3.1.0)-
hex-6-ylmethvl}-2-cyclopentvl-2-hydroxv-2-phenyl acetamide (Compound No. 13)
The compound was prepared following the procedure as described for the synthesis of Compound
No. 4, Example-1 by using 2,4-difluoro phenyl acetyl chloride in place of p-nitro phenyl sulphonyl
chloride with 54% yleld.
IR(KBr): 1640.9 cm-'
'H NMR (CDC13): 6 7.59-7.61 (m, 2H), 7.19-7.37 (m, 4H), 6.76-6.86 (m, 2H), 6.65 (brs, 1H), 3.73-
3.77 (m, 1H), 3.40-3.51 (m, 4H, including-OH), 3.22-3.23 (m, 7H).
Analogs of N-{[(la,5a,6a)-3-[2-(3,5-difluorophenyl)-acetyl]-3-azabicyclo-(3.1.0)-hex-6-
ylmethyl}-2-hydroxy-2-phenyl acetamide (Compound No. 13) described below, can be prepared by replacing appropriate acyl halide group in place of 2,4-difluoro phenyl acetyl chloride, as applicable in each case.
N-{[(lα,5α,6α)-3-(3,5-Dinitrobenzoyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 6),
N-{[{la,5a,6a)-3-(2-Benzyloxyacetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 7),
N-{[(la,5a,6a)-3-Benzoyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 8),
N-{[(la,5a,6a)-3-(2-Benzo[l,3]dioxol-5-yl-acetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 10),
N-{[(la, 5a, 6a)-3-(2-Fluorobenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 15),
N-{[(la, 5a, 6a)-3-(3,4,5-Trimethoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 16),
N-{[(lα, 5α, 6α)-3-Phenylacetyl-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 18),
N-{[(la, 5a, 6a)-3-(3,5-Dimethylbenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.27).
Example 3:Svnthesis of N-|[(la, 5a. 6a)-3-(4-methoxy-benzoyl)-3-azabicvclo [3.1.0] hex-6-yl methyl]}-2-cvclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 39) The compound was synthesised following the procedure as described for the synthesis of compound No. 4, Example-1 by using 4-methoxy benzoyl chloride in place of p-nitro benzene sulfonyl chloride with 90% yleld.
M.P: 58.3-59.6°C
IR(KBr): 1656.3, 1610.3 cm"'
'H NMR (CDC13): 5 7.57-7.60 (m, 2H), 7.21-7.41 (m, 5H), 6.87-6.90 (m, 2H), 3.83 (s, 3H), 3.40-3.59 (m, 3H), 3.03-3.10 (m, 4H), 1.42-1.65 (m, 9H), 1.26-1.40 (m, 2H), 0.72-0.74 (m, 1H). Mass (m/z): 449 (M1), 431 (M+-OH)
Analogs of N-{[(la, 5a, 6a)-3-(4-methoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 39) described below, can be prepared by replacing appropriate acyl halide group in place of 4-methoxy benzoyl chloride as applicable in each case.
N-{[(la, 5a, 6a)-3-(3-Benzo[l,3]-dioxol-5-yl-propionyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.40),
SCHEME I, PATH B PROCEDURE
Example 4: Synthesis N-|[(la, 5a, 6a)-6-[(2-cyc!opentyl-2-hydroxy-2-phenyl-acetylamino)-methvl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 4-nitro-benzyl ester (Compound No. 19) The title compound was prepared following the procedure described for the synthesis of Compound No. 4, Example-1 by using 4-nitrobenzyl chloroformate in place of 4-methoxy benzoyl chloride with 46% yleld.
M.P:73.1-74.3°C
1R(KBr): 1635.0 cm"'
1H NMR (CDCl3):5 7.59-7.62 (m, 2H), 7.29-7.37 (m, 4H), 6.63-6.74 (m, 2H), 6.59 (brs, 1H), 5.91
(s, 2H), 3.72-3.76 (m, 1H), 3.02-3.37 (m, 6H, including -OH), 2.85 (t, 2H, J=6Hz), 2.42 (t, 2H,
J=6Hz), 1.26-1.66 (m, I1H), 0.75(m, 1H).
Mass (m/z): 491 (M^l), 473 (M+-OH).
Analogs of N-{[(la, 5a, 6a)-6-[(2-cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 4-nitro-benzyl ester (Compound no. 19) described below, can be prepared by replacing appropriate chloroformate in place of 4-nitro benzyl chloroformate, as applicable in each case.
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid isobutyl ester (Compound No. 20),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid 4-nitro-phenyl ester (Compound No. 21),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (Compound No. 22),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound No.35),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-
bicyclo[3.1.0]hexane-3-carboxylic acid butyl ester (Compound No.36),
SCHEME II, PATH A PROCEDURE
Example 5: Synthesis of N-|[(la. 5a, 6a)-3-chloro-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cvclopentvl-2-hvdroxv-2-phenvl acetamide (Compound No. 29)
To a solution of N-(la, 5a, 6a)-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl acetamide in dichloromethane (10.0 ml), was added sodium hypochlorite (4.0 ml) at room temperature and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform and water followed by stirring it for five minutes. The organic layer was separated, washed thoroughly with water, dried and concentrated to get the title organic compound with 90% yleld.
M.P: 130.7-131.9°C
IR(KBr): 1656.8 cm"'
'H NMR (CDCl3):6 7.59-7.61 (m, 2H), 7.30-7.38 (m, 3H), 3.61-3.68 (m, 2H), 3.03-3.17 (m, 4H),
1.49-1.69 (m,9H), 1.11-1.26 (m, 2H), 0.83 (s, 1H).
Mass (m/z): 349 (M=1), 331 (M+-OH).
Analogs of N-{[(lα, 5a, 6a)-3-chloro-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 29) described below, can be prepared by replacing appropriate amine in place of (la, 5a, 6a)-N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl-acetamide, as applicable in each case.
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclohexyl-2-hydroxy-2-phenyl acetamide (Compound No. 33),
N-{[(lα, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-hydroxy-2-diphenyl acetamide (Compound No. 34).
Example 6: Synthesis of hvdrochloride salt of N-|[(lα, 5a, 6a)-3-chloro-3-azabicvclo [3.1.0] hex-6-vlmethvl1l-2-cvclopentyl-2-hvdroxy-2-phenyl acetamide hydrochloride salt (Compound No. 32) To a solution of the compound No. 29 (0.15 g) in dichloromethane (5.0 ml), was added ethanolic hydrochloric acid solution (3N, 0.5 ml) and stirred the reaction mixture for 10 minutes. The solvent was evaporated off under reduced pressure and the residue thus obtained was triturated with diethylether to get the solid. The solid was dried under vacuum to furnish the title compound with 90% yleld.
1H NMR (DMSO-de): 8.02 (t, 1H, J=6Hz), 7.56-7.59 (m, 2H), 7.19-7.32 (m, 3H), 5.55 (s, 1H), 2.98-3.16 (m, 4H, including -OH), 2.85-2.94 (m, 3H), 1.24-1.53 (m, 11H), 1.07 (t, 1H, J=3Hz).
Example 7: Synthesis ofN-|[(la. 5a, 6a)-3-cyano-3-azabicvclo [3.1.0] hex-6-vlmethyl]}-2-cyclopentyl-2-hydroxy-2-phenvl acetamide (Compound No. 31)
To a solution of N-(la, 5a, 6a)-(3-azabicyclo[3.1.0]hex-l-ylmethyl)-2-cyclopentyl-2-hydorxy-2-phenyl acetamide (0.25 g) and triethylamine (0.22 ml) in dichloromethane (5.0 ml) at room temperature, was added cyanogen bromide (0.25 g) and the reaction mixture was stirred at the same temperature for half on hour. The reaction mixture was cooled to 0°C followed by the addition of sodium hydroxide (0.5 N) and stirred for 10 minutes. Organic layer was separated, washed with brine solution, dried and concentrated under reduced pressure. The residue was purified by column chromatography using ethylacetate in hexane solvent mixture as an eluent to furnish the title organic compound with 74% yleld.
M.P: 122.6-123.8°C.
IR(KBr): 2213.5, 1648.4 cm"'.
1H NMR (CDCl3):§ 7.59-7.61 (m, 2H), 7.30-7.38 (m, 3H), 6.65 (brs,lH), 3.32-3.47 (m, 4H,
including-OH), 3.09-3.22 (m,3H), 1.19-1.57 (m, I1H), 0.91 (brs, 1H).
Mass (m/z): 340 (M^+OH), 322 (M^-OH).
Example 8: Synthesis of N-([(la,5a,6a)-6-|[(2-cyclopentvl-2-hvdroxy-2-phenvl-acetylamino)-methvl]|-3-aza-bicyclo[3.l.01hexane-3-carboxvlic acid tert-butvl ester (Compound No. 1) To a cold solution of N-(la, 5a, 6a)-(3-azabicyclo[3.1.0]hex-l-ylmethyl)-2-cyclopentyl-2-hydroxy acetamide (5.1 mmole) in dichloromethane, was added triethylamine (10.1 mmole) followed by the addition of di-tertbutoxy carbonyl anhydride (6.1 mmole). The reaction mixture was stirred at same temperature for 30 minutes and then at room temperature for 31/2 hour. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated. The crude organic compound was purified by column chromatography using ethyl acetate in hexane solvent mixture as eluent to furnish the title compound with 75% yleld.
'H NMR (CDC13): 5 7.61-7.59 (2H, m), 7.37-7.28 (3H, m), 6.55 (1H, brs), 3.48-3.45 (2H, m), 3.29-3.26 (2H, m), 3.08-3.03 (3H, m), 1.69-1.55 (8H, m), 1.42-1.36 (9H, m), 1.23-1.18 (2H, m), 0.74-0.72 (lH,m). Mass (m/z): 414 (M1).
SCHEME II, PATH B PROCEDURE
Example 9: Synthesis of N-U(lα,5a.6a)-6-l[(2-cyclopentyl-2-hvdroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.l.01hexane-3-carboxvlic acid benzylamide (Compound No.3) To a solution of N-(la, 5a, 6a)-(3-azabicyclo[3.I.0]hex-l-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (0.8 mmole) in dichloroethane (100 ml), was added benzyl isocyanate (0.955 mmole) at room temperature and stirred for 1 hour at the same temperature. The reaction mixture was directly absorbed onto the silica gel and purified by column chromatography using methanol in chloroform as an eluent with 85% yleld.
m.p: 76-78°C
IR(KBr): 1636.4, 1527.7 cm"'
'H NMR (CDCl3):5 7.58-7.61 (m, 2H), 7.23-7.36 (m, 8H), 6.62 (brs, 1H), 4.39 (s, 2H), 3.33-3.47
(m, 4H), 3.06-3.16 (m, 4H), 1.45-1.70 (m, 9H), 1.25 (brs, 2H), 0.79 (t, 1H, J=6Hz).
Mass (m/z): 448 (M++l), 430 (M+-OH).
The analogs of N-{[(la,5a,6a)-6-{[(2-cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzylamide (Compound No.3) described below, can be prepared by replacing appropriate isocyanate in place of benzyl isocyanate, as applicable in each case.
N-{[(lα,5α,6α)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid-(4-trifluoromethyl-phenyl)-amide (Compound No. 12)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid-(4-fluoro-phenyl)-amide (Compound No. 17)
N-{[(]a,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid allylamide (Compound No.25)
N-{[(lα,5α,6α)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid-(2,4-dimethoxy-phenyl)-amide (Compound No.26)
N-{[(lα,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid-(4-benzyloxy-phenyl)-amide (Compound No.28)
N-{[(lα,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.].0] hexane-3-carboxylic acid amide (Compound No.30)
N-{[(lα,5α,6α)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid-(2,4-ditluoro-phenyl)-amide (Compound No.38)
SCHEME III PROCEDURE
Example 10: Synthesis of N-{[(la, 5a. 6a)-3-terbutvl-carboxv-3-azabicvclo [3.1.0] hex-6-vl methvn}-2-cvclopentyl-2-methoxv-2-phenyl acetamide (Compound No. 2) Step a: Synthesis of 4-[(2-cyclopentyl-2-hydroxy-2-phenyl acetainide)-methyl]-3-inethyl piperidine-1-carboxylic acid tert-butyl ester
To a solution of (la, 5a, 6a)-N-(3-azabicyclo[3.1.0]hex-l-ylmethyl)-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (0.3 g, 1 mmole) in dichloromethane was added trimethyl amine at 0°C followed by the addition of ditert-butoxy carboxyl anhydride (0.261 g, 1.2 mmole) in dichloromethane. Reaction mixture was stirred at 0°C for 30 minutes then at room temperature for 3/4 hours. The reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous was purified by column chromatography to give the title compound.
Step b: Synthesis of 4-[(2-cyclopentyl-2-phenyl-2-trimethylaryloxy-acetyIamino)-methyl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester
To a solution of a compound obtained form step a above (0.414 g, 1 mmole) in dimethylformamide, was added imidazole (0.251 g, 3.7 mmole) followed by the addition of trimethyl silyl chloride (0.293 g, 2.7 mmole) at room temperature and stirred at same temperature for 2 hours. Reaction mixture was poured into water and extracted with diethylether. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure crude organic compound was purified by column chromatography.
Step c: Synthesis of N-{[(la, 5a, 6a)-3-terbutyl-carboxy-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-methoxy-2-phenyl acetamide (Compound No. 2)
To a solution of a compound obtained from step b above (0.486 g, 1 mmole) in dry tetrahydrofuran at 0°C, was added sodium hydride (0.080 g, 2 mmole, 60% suspension in mineral oil) followed by the addition of tetra n-butyl ammonium iodide (0.025 g, 0.07 mmole). The reaction mixture was stirred at same temperature for 30 minutes and then at room temperature for 1 hour followed by cooling the reaction mixture at 0°C.
To the reaction mixture iodomethane (1.28 g, 9 mmole) was added. The reaction mixture was allowed to warm at room temperature and then stirred overnight. The reaction mixture was quenched with ammonium chloride solution and the organic compound was extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude organic compound was purified by column chromatography to furnish the title compound with 34% yleld.
IR(KBr): 1657.8 cm-1'
'H NMR (CDC13): 5 7.26-7.46 (m, 5Ar-H), 6.99 (s, 1H), 3.17-3.25 (m, 2H), 3.15 (s, 3H), 2.87-3.00
(m, 6H), 1.67-1.85 (m, 8H), 0.86-0.88 (m, 2H).
Mass (m/z): 428 (M1).
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. In competition binding studies, specific binding of [3H] NMS was also determined using membranes from Chinese hamster ovary (CHO) cells expressing cloned human M1, M2, M3, M4 and M5 receptors. Selectivities were calculated from the Ki values obtained on these human cloned membranes.
Membrane preparation.- Submandibular glands and heart were isolated and placed in ice cold homogenising buffer (HEPES 20mM, lOmM 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 lOmin. The supernatant was subsequently centrifuged at 40,000g for 20 min. The pellet thus obtained was resuspended in
assay buffer (HEPES 20 mM, EDTA 5mM, pH 7.4) and were stored at -70OC 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 volume (HEPES 20 mM, pH
7.4) at 24-250C 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 HCl 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 = IC50 /(1+L/Kd), where L is the concentration of [3H]NMS
used in the particular experiment, pki is -log [Ki].
Functional Experiments using isolated rat bladder:
Methodology:
Animals were euthanized by overdose of thiopentone and whole bladder was isolated and removed rapidly and placed in ice cold Tyrode buffer with the following composition (mMol/L) NaCl 137; KCl 2.7; CaCb 1.8; MgCb 0.1; NaHCOj 11.9; NaH2P04 0.4; Glucose 5.55 and continuously gassed with 95% O2 and 5 % CO2.
The bladder was 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 through a force displacement transducer. Each tissue was maintained at a constant basal tension of 1 g and allowed to equilibrate for 1 "^ hour during which the Tyrode buffer was changed every 15-20 min. At the end of equilibration period the stabilization of the tissue contractile response was assessed with l|imol/L of Carbachol till a reproducible response is obtained. Subsequently a cumulative concentration response curve to carbachol (10" mol/L to 3 X 10" mol/L) was obtained. After several washes, once the baseline was achieved, cumulative concentration response curve was obtained in presence of NCE (NCE added 20 min. prior to the second cumulative response curve.
The contractile results were expressed as % of control E max. ED50 values were calculated by fitting a non-linear regression curve (Graph Pad Prism). pKb values were 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. The results of in-vitro tests are found to be < 10.
While the present invention has been described in terms of its specific embodiments, certain modification 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 CLAIM:
1. Compounds having the structure of Formula I (as shown in the accompanied drawings) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymoRphs, wherein R, is
hydrogen
lower (C1-C6) alkyl
lower (C2-C7) alkenyl
lower (C2-C7) alkynyl
cycloalkyl
amino
substituted amino
-ORz wherein Rz is selected from the group consisting of
> hydrogen
> -Si(CH3)3
> lower (Ci-Co) alkyl
> lower (C2-C6) alkenyl
> lower (C2-C6) alkynyl
> cycloalkyl
> aryl
> -C(=0)NHRr wherein Rr is selected from the group consisting of
0 hydrogen
0 lower (C1-C6) alkyl
0 lower (C2-C6) alkenyl
o lower (C2-C6) alkynyl
0 aryl
0 cycloalkyl;
R2 is
• carboxy
• -SO2R6 wherein R6 is selected from the group consisting of

> alkyl
> alkenyl
> alkynyl
> cycloalkyl
> -NRpRq wherein Rp and Rq are selected from the group consisting of
o hydrogen
0 alkyl
o alkenyl
0 alkynyl
o cycloalkyl
o aryl
0 aralkyl
o heterocyclyl
0 heteroaryl
o heterocyclylalkyl
0 heteroarylalkyl;
> aryl
> aralkyl
> heteroaryl
> heterocyclyl
> heterocyclylalkyl
> heteroarylalkyl
Rp and Rq may also together join to form a heterocyclyl ring.
• -C(=0)0R7 wherein Ry is selected from the group consisting of
> alkyl
> alkenyl
> alkynyl
> cycloalkyl
> aryl
> aralkyl
• -C(=0)NRxRy wherein Rx and Ry are each independently selected from the group consisting of
o hydrogen
0 hydroxy (as restricted by the definition that both Rx and Ry cannot be hydroxy at the same time)
(Table Removed)
R4 and R5 are independently selected from the group consisting of
• hydrogen
• lower (C1-C6) alkyl
• lower (C2-C7) alkenyl
• lower (C2-C7) alkynyl;
Xis
• oxygen
• -NR7 wherein R7 is selected from the group consisting of

□ hydrogen
□ lower (C1-C6) alkyl
□ lower (C2-C7) alkenyl
a lower (C2-C7) alkynyl
□ aralkyl
□ aryl;
Ar is
• aryl
• heteroaryl
• heterocyclyl;
s -ORz and Rz is hydrogen.
s-ORz and Rz is alkyl.
s -ORz and Rz is alkyl for example, methyl.
s -COOR7, -C(-0)NRxRy, SO2R6, -
2. A compound according to claim 1, wherein Ar is aryl, heteroaryl or heterocyclyl.
3. A compound according to claim 1, wherein Ar is aryl.
4. A compound according to claim 1, wherein Ar is phenyl
5. A compound according to claim 1, wherein R1 is -ORz.
6. A compound according to claim 1, wherein R1 is -ORz and Rz is hydrogen, alkyl, alkenyl or alkynyl.

7. A compound according to claim 1, wherein R1
8. A compound according to claim 1, wherein R1
9. A compound according to claim 1, wherein R1
10. A compound according to claim 1, wherein R2 C(=0)CH20Rx, acyl, halogen or cyano.
11. A compound according to claim 1, wherein R2 is -COOR7.
12. A compound according to claim 1, wherein R2 is -COOR7 wherein R7 is optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl.

13. A compound according to claim 1, wherein R2 is -COOR7 wherein R? is optionally substituted alkyl wherein optionally substituted alkyl is tert-butyl, isobutyl, fluorinemethyl, isopropyl or butyl.
14. A compound according to claim I, wherein R2 is -COOR7 wherein R? is optionally substituted aryl or aralkyl wherein optionally substituted aryl or aralkyl are nitrophenylmethyl, nitrophenyl or benzyl
15. A compound according to claim I, wherein R2 is -C(=0)NRxRy.
16. A compound according to claim 1, wherein R2 is-C(=0)NRxRy wherein Rx is hydrogen and Ry is hydrogen, alkenyl, optionally substituted aralkyl, optionally substituted aryl.
17. A compound according to claim 1, wherein R2 is-C(=0)NRxRy wherein Ry is hydrogen.
18. A compound according to claim 1, wherein R2 is-C(=0)NRxRy wherein Ry is alkenyl for example, propenyl.
19. A compound according to claim 1, wherein R2 is-C(=0)NRxRy wherein Ry is optionally substituted aralkyl for example, benzyl.
20. A compound according to claim 1, wherein R2 is-C(=0)NRxRy wherein Ry is optionally substituted aryl for example, fluorophenyl, trifluoromethylphenyl, difluorophenyl, dimethoxyphenyl or benzyloxyphenyl.
21. A compound according to claim 1, wherein R2 is SO2R6.
22. A compound according to claim 1, wherein R2 is SO2R6 wherein R6 is optionally substituted aryl, alkyl orNRpRq.
23. A compound according to claim 1, wherein R2 is SO2R6 wherein R6 is optionally substituted aryl and optionally substituted aryl is phenyl, nitrophenyl, trifluoromethylphenyl, tert-butylphenyl, fluorophenyl, phenyl or tri-isopropyl.
24. A compound according to claim I, wherein R2 is SO2R6 wherein R6 is alkyl for example, methyl.
25. A compound according to claim I, wherein R2 is SO2R6 wherein R6 is -NRpRq.
26. A compound according to claim I, wherein R2 is SO2R6 wherein R6 is-NRpRq. wherein Rp and Rqare alkyl.
27. A compound according to claim I, wherein R2 is SO2R6 wherein R6 is-NRpRq. wherein Rp and Rq are alkyl for example methyl.
28. A compound according to claim I, wherein R2 is -C(=0)CH20Rx.
29. A compound according to claim 1, wherein R2 is -C(=0)CH20Rx wherein Rx is aralkyl.
30. A compound according to claim 1, wherein R2 is -C(=0)CH20Rx wherein Rx is aralkyl for example, benzyl.
31. .A compound according to claim 1, wherein R2 is cyano.
32. A compound according to claim 1, wherein R2 is halogen.
33. A compound according to claim 1, wherein R2 is halogen for example, chlorine.
34. A compound according to claim 1, wherein R2 is acyl.
35. A compound according to claim 1, wherein R2 is acyl for example, benzylcarbonyl, trimethoxymethylbenzoyi, difluorobenzylcarbonyl, benzodioxolmethylcarbonyl, fluorobenzoyl, benzoyl or dinitrobenzoyl.
36. A compound according to claim 1, wherein R3 is cycloalkyl or aryl.
37. A compound according to claim 1, wherein R3 is cycloalkyl.
38. A compound according to claim 1, wherein R3 is cycloalkyl for example, cyclopentyl.
39. A compound according to claim 1, wherein R3 is aryl.
40. A compound according to claim 1, wherein R3 is aryl for example phenyl.
41. A compound according to claim 1, wherein R4 is hydrogen, alkyl, alkenyl or alkynyl.
42. A compound according to claim 1, wherein R4 is hydrogen.
43. A compound according to claim 1, wherein R5 is hydrogen, alkyl, alkenyl or alkynyl.
44. A compound according to claim 1, wherein R5 is hydrogen.
45. A compound according to claim 1, wherein X is oxygen or -NR.
46. A compound according to claim 1, wherein X is oxygen.
47. A compound selected from
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Compound No. 1),
N-{[(la, 5a, 6a)-3-Terbutyl-carboxy-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-methoxy-2-phenyl acetamide (Compound No. 2),
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyI]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzylamide (Compound No.3),
N-{[(la, 5a, 6a)-3-(4-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 4),
N-{[(la, 5a, 6a)-3-Benzenesulfonyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 5),
N-{[(la,5a,6a)-3-(3,5-Dinitrobenzoyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 6),
N-{[(la,5a,6a)-3-(2-Benzyloxyacetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 7),
N-{[(la,5a,6a)-3-Benzoyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 8),
N-{[(la,5a,6a)-3-(3-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 9),
N-{[(la,5a,6a)-3-(2-Benzo[],3]dioxol-5-yl-acetyl)-3-azabicyclo[3.1.0]hex-6-yimethyl]}-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 10),
N-{[(la,5a,6a)-3-(4-Trifluoromethylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 11),
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (4-trifluoromethyl-phenyl)-amide (Compound No.12),
N-{ [(1 a,5a,6a)-3-[2-(3,5-Difluoro-phenyl)-acetyl]-3-azabicyclo[3.1.0]hex-6-ylmethyl] }-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 13),
N-{[(la,5a,6a)-3-(4-Tert-butylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 14),
N-{[(la, 5a, 6a)-3-(2-Fluorobenzoyl)-3-azabicyclo [3.1.0]hex-6-ylmethyl}]-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 15),
N-{[(la, 5a, 6a)-3-(3,4,5-Trimethoxybenzoyl)-3-azabicyclo [3.1.0]hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 16),
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (4-fluorophenyl)-amide (Compound No. 17),
N-{[(la, 5a, 6a)-3-Phenylacetyl-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyI-2-hydroxy-2-phenyl acetamide (Compound No. 18),
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid-4-nitro-benzyl ester (Compound No. 19),
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid isobutyl ester (Compound No. 20),
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 4-nitro-phenyl ester (Compound No. 21),
N-{[(la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (Compound No. 22),
N-{[(la, 5a, 6a)-3-(4-Fluorobenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl}]-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 23),
N-{[(lα, 5a, 6a)-3-(2,4,6-Trisopropylbenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 24),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid allylamide (Compound No.25),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (2,4-dimethoxy-phenyi)-amide (Compound No.26),
N-{[(lα, 5a, 6a)-3-(3,5-Dimethylbenzoyl)-3-azabicyclo [3.1.0] hex-6-y!methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.27),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (4-benzyloxy-phenyl)-amide (Compound No.28),
N-{[(la, 5a, 6a)-3-Chioro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 29),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid amide (Compound No.30),
N-{[(la, 5a, 6a)-3-Cyano-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 31),
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide hydrochloride salts (Compound No. 32),
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclohexyl-2-hydroxy-2-phenyl acetamide (Compound No. 33),
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-hydroxy-2-diphenyl acetamide (Compound No. 34),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound No.35),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid butyl ester (Compound No.36),
N-{[(la, 5a, 6a)-3-(Methanesulphonyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 37),
N-{[(lα, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-aza-bicyclo[3.1.0] hexane-3-carboxylic acid (2,4-difluoro-phenyl)-amide (Compound No.38),
N-{[(lα, 5a, 6a)-3-(4-Methoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 39),
N-{[(lα, 5a, 6a)-3-(3-Benzo[l,3]-dioxol-5-yl-propionyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.40),
N-{[(la, 5a, 6a)-3-(Dimethylsulfamoyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.41).
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymoRphs.
A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1-47 together with pharmaceutically acceptable carriers, excipients or diluents.
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, comprising administering to said animal or human, a therapeutically effective amount of a compound having the structure of Formula 1
The method according to claim 49, 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.
The 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, comprising administering to said animal or human, a therapeutically effective amount of the pharmaceutical composition according to claim 48.
A process of preparing a compound of Formulae VI and VII (as shown in Scheme I of the accompanied drawings) and its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, stereoisomers or polymoRphs, which comprises condensing a compound
of Formula II (wherein Ar, R1 and R3 are the same as defined earlier) with a compound of
Formula III (wherein X, R4 and R5 are the same as defined earlier and P is a protecting group
for example, aralkyl or acyl) to give a compound of Formula IV which is deprotected to give
a compound of Formula V,
Path a: the compound of Formula V is reacted with a compound of Formula L-Y-R6
(wherein Lisa leaving group for example halogen (F, C1, Br, I), Y is -C(=0), SO2 and R6 is
the same as defined earlier) to give a compound of Formula VI.
Path b: the compound of Formula V is reacted with a compound of Formula
hal-C(=0)0R7 (wherein R7 is the same as defined earlier and hal is halogen (Br, C1, I)) to
give a compound of Formula VII.
A process according to claim 52, wherein the condensation of a compound of Formula II
with a compound of Formula III to give a compound of Formula IV is carried out in the
presence of a condensing agent selected from the group consisting of l-(3-
dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and dicyclohexylcarbodiimide in
an organic base selected from the group consisting of l,8-diazabicyclo[5.4.0]undec-7-ene,
N-methylmoRpholine, triethylamine, diisopropylethylamine and pyridine.
A process according to claim 52, wherein the condensation of a compound of Formula II
with a compound of Formula III to give a compound of Formula IV is carried in an organic
solvent selected from the group consisting of N,N-dimethylformamide, chloroform,
tetrahydrofuran, dioxane, diethylether, benzene and toluene.
A process according to claim 52, wherein the compound of Formula IV undergoes
deprotection to give a compound of Formula V by hydrogenatically utilizing palladium on
carbon under catalytic hydrogenation transfer conditions of ammonium formate and
palladium on carbon.
A process according to claim 52, wherein the compound of Formula IV undergoes
deprotection to give a compound of Formula V in an organic solvent selected from the group
consisting of methanol, ethanol, tetrahydrofuran and acetonitrile.
A process according to claim 52, wherein the compound of Formula V is reacted with a
compound of Formula L-Y-R6 {Path a) to give a compound of Formula VI
in the presence of a base selected from the group consisting of triethylamine,
diisopropylethylamine and pyridine.
A process according to claim 52, wherein the compound of Formula V is reacted with a compound of Formula L-Y-R6 {Path a) to give a compound of Formula VI in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
A process according to claim 52, wherein the compound of Formula V {Path b) is reacted with a compound of Formula hal-C(=0)0R7 to give a compound of Formula VII in the presence of a base selected from the group consisting of triethylamine, diisopropylethylamine and pyridine.
A process according to claim 52, wherein the reaction of a compound of Formula V {Path b) with a compound of Formula hal-C(=0)0R7 gives a compound of Formula VII in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
A process of preparing a compound of Formulae IX and XI (as shown in Scheme II of the accompanied drawings) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymoRphs, in which
Path a: the compound of Formula VIII (wherein X, Rj, R3, R4 and R5 are the same as defined earlier) undergoes N-protection to give a compound of Formula IX [wherein Pi is halogen (F, C1, Br or I), cyano or -C(=0)0R7 (R? is the same as defined earlier)]. Path b: the compound of Formula VIII is reacted with a compound of Formula X (wherein Rx is the same as defined earlier) to give a compound of Formula XI. A process according to claim 61, wherein the N-derivatization of a compound of Formula Vlll (Path a) (when P1 is halogen) to give a compound of Formula IX is carried out with halogenating agent selected form the group consisting of sodium hypochlorite, sodium hypobromite and sodium hypoiodite.
A process according to claim 61, wherein the N-derivatization of a compound of Formula VIII (Path a) (when P1 is halogen) to give a compound of Formula IX is carried out in an organic solvent selected form the group consisting of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
A process according to claim 61, wherein the N-derivatization of a compound of Formula Vlll (when P| is cyano) to give a compound of Formula IX is carried out with a nitrilating agent selected as cyanogen bromide.
A process according to claim 61, wherein the N-derivatization of a compound of Formula Vlll (when P1 is cyano) to give a compound of Formula IX is carried out in the presence of
an organic base selected form the group consisting of triethylamine, diisopropylethylamine
and pyridine.
A process according to claim 61, wherein the N-derivatization of a compound of Formula
VIII (when P1 is cyano) to give a compound of Formula IX is carried out in an organic
solvent selected form the group consisting of dichloromethane, dichloroethane, chloroform
and carbon tetrachloride.
A process according to claim 61, wherein the N-derivatization of a compound of Formula
VIII (when P1 is -C(=0)0R7) to give a compound of Formula IX is carried out with
anhydrides selected form the group consisting of ditert-butoxycarbonyl anhydride,
dipropoxycarbonyl anhydride, dimethoxycarbonyl anhydride and diethoxycarbonyl
anhydride.
A process according to claim 61, wherein the N-derivatization of a compound of Formula
VIII (when P1 is -C(=0)0R7) to give a compound of Formula IX is carried out in the
presence of an organic base selected form the group consisting of triethylamine,
diisopropylethylamine and pyridine.
A process according to claim 61, wherein the N-derivatization of a compound of Formula
Vlll (when P1 is -C(=0)0R7) to give a compound of Formula IX is carried out in an organic
solvent selected form the group consisting of dichloromethane, dichloroethane, chloroform
and carbon tetrachloride).
A process according to claim 61, wherein the compound of Formula VIII (Path b) is reacted with an isocyanate of Formula X to give a substituted urea of Formula XI in an organic solvent selected form the group consisting of dichloroethane, dichloromethane, chloroform and carbon tetrachloride).
A process of preparing a compound of Formula XIV (as shown in Scheme III of the accompanied drawings) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymoRphs, which comprises reacting a compound of Formula XII (where in X, R2, R3, R4 and R5 are the same as defined earlier) with trimethyl silyl chloride to give a compound of Formula XIII, which undergoes 0-alkylation to give a compound of Formula XIV (wherein Rt is alkyl).
72. A process according to claim 71, wherein reaction of a compound of Formula XII with trimethyl silyl chloride to give a compound of Formula XIII is carried out in an organic base selected from the group consisting of imidazole, triethylamine, N-methylmoRpholine, diisopropylethylamine and pyridine.
73. A process according to claim 71, wherein reaction of a compound of Formula XII with trimethyl silyl chloride to give a compound of Formula XIII is carried out in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, dioxane and diethylether.

1. A process according to claim 71, wherein a compound of Formula XIII undergoes 0-alkylation to give a compound of Formula XIV in the presence of an organic base selected from the group consisting of sodium hydride and sodium cyanoborohydride.
2. A process according to claim 71, wherein a compound of Formula XIII undergoes 0-alkylation to give a compound of Formula XIV in an organic solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, diethylether and dioxane.
3. The process for the preparation of compounds of Formulae VI, VII, IX, XI and XIV substantially as herein described and illustrated by example herein.