PYRROLIDINE DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
This invention relates to pyrrolidine derivatives, which are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds and the methods for treating the diseases mediated through muscarinic receptors are also provided
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 distnbution 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 chohnergically 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 hgands 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 muscannic receptor subtypes using different muscannic receptor of knock out mice
Muscannic agonists such as muscanne 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 muscannic 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 quaternary denvatives of atropine such as ipratropium bromide are better tolerated than parenterally administered options, but most of these are not ideal anti-chohnergic bronchodilators, due to lack of selectivity for muscannic receptor sub-types, resulting in dose-limiting side-effects such as thirst, nausea, mydnasis 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 unnary tract infections Although anti-muscannic agents such as oxybutynin and tolterodine that act non-selectively on muscannic 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 muscannic antagonists, which can interact with distinct subtypes, thus avoiding the occurrence of adverse effects
Compounds having antagonistic activity against muscannic receptors have been descnbed 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, US PatentNo 5,281,601 Also, U S PatentNos 6,174,900, 6,130,232 and 5,948,792, WO 97/45414 are related to 1,4-disubstituted pipendine denvatives, WO 98/05641 descnbes fluonnated, 1,4-disubstitued pipendine denvatives, WO
93/16018 and W096/33973 are other references of interest 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-piperazmyl)-2-propanones WO 01/42213 describes 2-biphenyl-4-pipendinyl ureas WO 01/42212 describes carbamate derivatives WO 01/90081 describes amino alkyl lactam WO 02/53564 describes novel quinuchdine derivatives WO 02/00652 describes carbamates derived from arylalkyl amines WO 02/06241 describes 1,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives
A report in J Med Chem , 44, p 984 (2002), describes cyclohexylmethyl pipendinyl tnphenylpropioamide derivatives as selective M3 antagonist discriminating against the other receptor subtypes
PCT applications WO 98/00109, 98/00132, 98/00133 and 98/00016 disclose isomers of glycopyrolate
Pharmazie, 57(2), 138 (2002) discloses glycopyrolate analogues
U S Patent No 6,307,060 discloses enantiomencally pure basic N-heterocychcaryl cycloalkyl hydroxy carboxyhc esters and their use in medicaments
U S Patent No 6,204,285 discloses methods and compositions for treating urinary incontinence using enantiomencally enriched (R, R)-glycopyrrolate
WO 03/087094 discloses new pyrrolidmium derivatives
SUMMARY OF THE INVENTION
In one aspect, pyrrolidine derivatives are provided as muscarinic receptor antagonists which can be useful as safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the respiratory, unnary and gastrointestinal systems Also provided are processes for synthesizing such compounds
In another aspect, pharmaceutical compositions containing such compounds are provided together with acceptable earners, excipients or diluents which can be useful for the treatment of vanous diseases of the respiratory, unnary and gastrointestinal systems
The stereoisomers, 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 compnsing the compounds, their metabolites, stereoisomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable earner 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, stereoisomers, N-oxides, polymorphs, prodrugs or metabolites, wherein R1 and R2 can be independently selected from
o alkyl
o haloalkyl
o cycloalkyl
o aryl
o heteroaryl R3 can represent
o hydrogen
o lower alkyl
o hydroxy
o amino
o alkoxy X can represent
o oxygen
o sulphur
o NR8 wherein R8 can represent hydrogen, lower alkyl or aralkyl n can represent an integer ranging from 0 to 3
R4, R5 and R6 can be independently selected from hydrogen or alkyl
R7 can represent
o hydrogen
o alkyl
o CHR9R10 wherein R9 and R10 can be independently selected from
• hydrogen
• alkyl
• aryl
o (CH2)m-R11 wherein R11 is aryl or heteroaryl and m can be an integer from 1 to 3
with the provisto that R1, R2 and R3 can not be phenyl, cycloalkyl and hydroxy, respectively, when R9 and R10 are hydrogen and phenyl, and with the further provisw that when R7 is (CH2)m-R11, R3 is hydrogen
In accordance with a second aspect, there is provided a method for treatment or prophylaxis of an animal or 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 I
In accordance with a third aspect, there is provided a method for treatment or prophylaxis of an animal or 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, there is provided a method for treatment or prophylaxis of an animal or 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 muscannic 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, which was determined by in vitro receptor binding assays Compounds were tested in vitro Some compounds were found to function as potent muscarinic receptor antagonists with high affinity towards M3 receptors Therefore, pharmaceutical compositions for the possible treatment for the disease or disorders associated with muscannic receptors are provided In addition, the compounds can be administered orally or parenterally
As used herein the term "alkyl" 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
As used herein the term "cycloalkyl" refers to (un)saturated cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, cyclopropylene, cyclobutylene and the like, or multiple ring structures such as adamantanyl, and bicyclo [2 2 l]heptane
As used herein the term "alkoxy" refers to the group O-alkyl wherein alkyl is the same as defined above
As used herein the term "haloalkyl" refers to alkyl substituted with halogen
As used herein the term "halogen" refers to fluoro, bromo, chloro or lodo As used herein the term "aryl" refers to phenyl or naphthyl ring and the like
optionally substituted with 1 to 3 substituents selected from the group consisting of halogen
(F, CI, Br, I), hydroxy, alkyl, cyano, nitro and carboxy
As used herein the term "carboxy" refers to -C(=O)O-R12 wherein R12 is selected
from the group consisting of hydrogen, alkyl and cycloalkyl
As used herein the term "heteroaryl" refers to an aromatic ring structure containing 5 or 6 carbon atoms, or a bicychc 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, CI, Br, I), hydroxy alkoxy, cyano, nitro, optionally substituted amino Examples of heteroaryl groups are pyndinyl, pyrazinyl, pyndazinyl, pynmidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, tnazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, benzo[l,3]dioxol-5-yl-ethyl, and the like
The term "pharmaceutically acceptable solvates" refers to solvates with waters (1 e hydrates) or pharmaceutically acceptable organic solvents Such solvates are also encompassed within the scope of this invention
The phrase "pharmaceutically acceptable salts" of the compounds of Formula I include acid addition salts such as hydrochloride, hydrobromide, hydrofluoric, sulphate, bisulfate, phosphate, hydrogen phosphate, acetate, brosylate, citrate, fumarate, glyconate, lactate, maleate, mesylate, succinate, and tartarate Quaternary ammonium salts such as alkyl salts, aralkyl salts, and the like, of the organic bases may be readily formed by treatment of the organic bases with the appropnate quaternary salts forming substances, which include, for
example methyl chloride, methyl bromide, methyl iodide, methyl sulphate, methyl benzene sulphonate, methyl p-toluene sulphonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-propyl iodide, isopropyl bromide, n-butyl chloride, n-butyl bromide, isobutyl bromide, sec-butylbromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, benzyl bromide, and ethyl sulphate
The present invention also includes within its scope prodrugs of these agents In general, such "prodrugs" will be functional denvatives of these compounds, which are readily convertible in vivo into the required compound Conventional procedure for the selection and preparation of suitable prodrug denvatives are descnbed, for example, in "design of prodrugs", ed H Bundgaard and, Elsevier, 1985
The present invention also includes metabolites, which become active upon introduction into the biological system
The crystalline or amorphous forms of compounds disclosed herein may exist as polymorphs and as such are intended to be included in the present invention
The compounds of present invention include stereoisomers The term "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space These include , diastereomers, geometncal isomers, atropisomer and comformational isomers Geometnc isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural ngidity An enantiomer is a stereoisomer of a reference molecule that is the nonsupenmposable mirror image of the reference molecule A diastereomer is a stereoisomer of a reference molecule that has a shape that is not the mirror image of the reference molecule An atropisomer is a conformational of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about a bonds, and are often rapidly interconverting at room temperature Racemic mixtures are also encompassed within the scope of this invention
DETAILED DESCRIPTION OF THE INVENTION
The compounds disclosed herein 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 reaction sequences as depicted in Schemes I, II and III of the accompanied drawings
Scheme I
The compounds of Formula IV can be prepared by the reaction sequence, as shown in scheme I of the accompanied drawings The preparation comprises coupling a compound of Formula II with a compound of Formula III to give a compound of Formula IV (wherein Rj, R2 and R3 are the same as defined earlier)
The reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be earned out in the presence hydroxy benztnazole and N-methylmorphohne and a coupling agent, for example, l-(3-dimethylaminopropyl)-3-ethyl carbodnmide hydrochloride (EDC HCL) or 1,3-dicyclohexylcarbodnmide (DCC)
The reaction of a compound of Formula II with a compound of Formula III can be carried out in a solvent, for example, dimethylformamide, chloroform or dimethylsulphoxide
Scheme II
The compounds of Formula VIII can be prepared by the reaction sequence, as shown in scheme II of the accompanied drawings The preparation comprises reactmg 1-benzyl-pyrrohdin-3-ol of Formula V with a compound of Formula VI to give a compound of Formula VII (wherein R1, R2 and R3 are the same as defined earlier), which on debenzylation gives a compound of Formula VIII
The reaction of l-benzyl-pyrrohdin-3-ol of Formula V with a compound of Formula VI to give a compound of Formula VII can be earned out in a solvent, for example, heptane, hexane, toluene or xylene
The reaction of l-benzyl-pyrrohdin-3-ol of Formula V with a compound of Formula VI can be earned out in the presence of a base, for example, sodium, sodium methoxide or sodium hydnde
The debenzylation of a compound of Formula VII to give a compound of Formula VIII can be earned out in the presence of a debenzylating agent, for example, palladium on carbon and hydrogen or ammonium formate and palladium on carbon
The debenzylation of a compound of Formula VII to give a compound of Formula VIII can be earned out in a solvent, for example, methanol, ethanol or losproanol, at temperatures ranging from about 50 to about 110 °C
Scheme III
The compounds of Formula XII and XIII can be prepared by the reaction sequence, as shown in scheme III of the accompanied drawings The preparation compnses reacting 1-benzyl-3-[(methylsulfonyloxy)methyl]-pyrrohdine of Formula IX with a compound of Formula III to give a compound of Formula X (wherein R1, R2 and R3 are the same as defined earlier), which on debenzylation gives a compound of Formula XI, which on reaction with
(a) formaldehyde gives a compound of Formula XII,
(b) a compound of Formula R7-L (wherein L is any leaving group known in the art, for example, halogen, O-mesyl or O-tosyl group) gives a compound of Formula XIII (wherein R7 is -(CH2)m-R11 wherein R11 and m are the same as defined earlier)
The condensation of a compound of Formula IX with a compound of Formula III to give a compound of Formula X can be earned out in a solvent, for example, benzene, toluene or xylene
The condensation of a compound of Formula IX with a compound of Formula III can be carried out in the presence of a condensing agent, for example, 1,8-diazabicyclo[5 4 0]undecan-7-ene (DBU) or l,4-diazabicyclo[2 2 2]octane (DABCO)
The debenzylation of a compound of Formula X to give a compound of Formula XI can be earned out in a solvent such as methanol or ethanol
The debenzylation of a compound of Formula X to give a compound of Formula XI can be earned out in the presence of a catalyst such as palladium on carbon and hydrogen gas or ammonium formate and palladium on carbon
The reaction of a compound of Formula XI with formaldehyde is earned out in the presence of a reducing agent, for example, sodium cyanoborohydnde or sodiumtnacetoxyborohydnde in a solvent, for example, acetomtnle
The reaction of a compound of Formula XI with a compound of Formula R7-L to give a compound of Formula XII can be earned out in a solvent, for example, dimethylsulfoxide, acetomtnle or dimethylformamide
In the above scheme, where specific bases, coupling agents, reducing agents, protecting groups, deprotecting agents, N-alkylating/benzylating agents, solvents, catalysts etc are mentioned, it is to be understood that other bases, coupling agents, reducing agents, deprotecting agents, N-alkylating/benzylating agents, solvents etc known to those skilled in art may be used Similarly, the reaction temperature and duration may be adjusted according to the desired needs
Particular compounds are shown here (also shown in Table I)
(2R, 2S)-[(3'R, 3'S)- l'-((R)-α-methyl-benzyl)-pyrrohdm-3'-ylmethyl]-2-hydroxy-2-cycopentyl-2-phenylacetic acid ester (Compound No 1)
[(3'R, 3'S)- l'-((R)-α-methyl-benzyl)-pyrrohdin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No 2)
(2R, 2S)-[(3'R, 3'S)- l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclohexyl-2-phenylacetic acid ester (Compound No 3)
(2R, 2S)-N-[(3'R, 3'S)- l'-((R)-α-methyl-benzyl)-pyrrohdin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No 4)
(2R, 2S)-N-[(3'R, 3'S)-1 '-((R)-α-methyl-benzyl)-pyrrohdin-3'-ylmethyl]-2-hydroxy-2-cyclohexyl-2-phenylacetamide (Compound No 5)
N-[(3'R, 3'S)- 1 '-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetamide (Compound No 6)
(2R,2S)-[(3'R)-l'-((R)-α-methyl-benzyl)-pyrrohdin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 7)
2R-[(3'R)-l'-((R)-α-methyl-benzyl)-pyrrohdin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 8)
2S-[(3'R)-l'-((R)-α-methyl-benzyl)-pyrrohdin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 9)
[(3'R)-1 '-((R)-α-methyl-benzyl)-pyrrohdin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No 10)
2R-[(3'R)-pyrrohdin-3'-yl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 11)
(2R, 2S)-[((3'R, 3'S)-1 '-benzyl-pyrrohdin-3'-ylmethyl)-2-hydroxy-2-(tnfluoromethyl)-2-phenyl acetic acid ester (Compound No 12)
(2R, 2S)-[((3'R, 3'S)-pyrrohdin-3'-yl methyl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 13)
[((3'R, 3'S)-r-benzyl-pyrrolidin-3'-yl-methyl)-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No 14)
(2R, 2S)-[((3'R, 3'S)-l'-methyl-pyrrohdin-3'-yl methyl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 15)
(2R, 2S)-[((3'R, 3'S)-pyrrohdin-3'-yl methyl)-2-hydroxy-2-cyclohexyl-2-phenyl acetic acid ester (Compound No 16)
(2R, 2S)-[((3'R, 3'S)-l'-methyl-pyrrohdin-3'-yl methyl)-2-hydroxy-2-cyclohexyl-2-phenyl acetic acid ester (Compound No 17)
[((3'R, 3'S)-pyrrohdin-3'-yl methyl)-2-hydroxy-2,2-diphenyl acetic acid ester (Compound
No 18)
[((3'R, 3'S)-l'-methyl-pyrrolidin-3'-yl methyl)-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No 19)
[((3'R, 3'S)-r-benzyl-pyrrohdin-3-yl methyl)-2,2-diphenyl acetic acid ester (Compound No 20)
[((3'R, 3'S)-pyrrohdin-3'-yl methyl)-2,2-diphenyl acetic acid ester (Compound No 21)
[((3'R, 3'S)-l'-(benzo[l,3]dioxol-5-yl-ethyl)-pyrrohdin-3'-yl methyl)-2,2-diphenyl acetic acid ester (Compound No 22),
and their pharmaceutical^ acceptable salts, pharmaceutical^ acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites
(Formula Removed)

Table I [wherein *R3=OH, R4=R5=R6=H, **n=l]

(Table Removed)

* R3=H for compound No 20, 21 and 22
** n=0 for compound No 11
Because of their valuable pharmacological properties, the compounds descnbed herein may be administered to an animal for treatment orally, or by a parenteral route The pharmaceutical compositions descnbed herein can be produced and administered in dosage units, each unit containing a certain amount of at least one compound descnbed herein and/or at least one physiologically acceptable addition salt thereof The dosage may be vaned 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 descnbed herein can be produced and formulated as their stereoisomers, 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, stereoisomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable earner and optionally included excipient can also be produced
The examples mentioned below demonstrate general synthetic procedures, as well as specific preparations of particular compounds The examples are provided to illustrate the details of the invention and should not be constrained to limit the scope of the present invention
Examples
Various solvents, such as acetone, methanol, pyndine, ether, tetrahydrofuran, hexane
and dichloromethane were dned using vanous drying reagents according to the procedures
well known in the literature IR spectra were recorded as nujol mulls or a thin neat film on a
Perkin Elmer Paragon instrument, Nuclear Magnetic Resonance (NMR) were recorded on a
Vanan XL-300 MHz instrument using tetramethylsilane as an internal standard
Example 1 Preparation of (2R. 2S)-[(3'R. 3'S)-1-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyll-2-hydroxy-2-cycopentyl-2-phenylacetic acid ester (Compound No 1)
To a solution of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid (prepared following the procedure descnbed in J Amer Chem Soc 75, 2654(1953), J Org Chem 2000,65, 6283-6287) (0 59 g, 2 7 mm) and l'-((R)-α-methyl benzyl)-3'-pyrrohdin methanol (0 5 g, 2 4
mm) (prepared according to the method described in J Med Chem , 1987, 30, 1711) in dimethylformamide (10 0 ml) at about 0-5 °C, hydroxy benzotnazole (0 36 g, 2 7 mm) and N-methylmorpholine (0 54 ml, 4 9 mm) were added and stirred at the same temperature for about 1 hour l-(3-dimethylaminopropyl)-3-ethyl carbodnmide hydrochlonde (0 48 g, 2 4 mm) was added and stirring was continued for about 1 hour at about 0-5 °C The reaction mixture was stirred at about 25 to 30 °C for about 15 hours The reaction mixture was poured onto water, extracted with ethyl acetate and ethyl acetate layer was washed with water and brine solution, dried over anhydrous sodium sulphate and concentrated The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane to get the title product in 17% (0 17 g) yield IR(DCM) 1722 9 cm"1
1H NMR (CDCl3) δ 7 59-7 61 (m, 2H), 7 29-7 39 (m, 8H), 4 06-4 07 (m, 2H), 3 68-3 78 (m, 1H), 3 50 (m, 1H), 3 14-3 16 (m, 1H), 2 84 (m, 1H), 2 36-2 56 (m, 4H), 2 10 (s, 1H), 1 70-1 80 (m, 1H), 1 50-1 69 (m, 8H), 1 34-1 47 (m, 3H) Mass 408 (M+l)
Similarly the following compounds were prepared following the procedure described above
[(3'R. 3'S)-1-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2.2-diphenvl acetic
acid ester (Compound No 2)
IR(DCM) 1731 8 cm"1
1H NMR (CDCI3) δ 7 00-7 45 (m, 15H), 4 16-4 24 (m, 2H), 3 08-3 10 (m, 1H), 2 31-2 50
(m, 4H), 2 02-2 07 (m, 2H), 1 82-1 84 (m, 2H), 1 30-1 33 (m, 3H)
Mass 416 (M+l)
(2R. 2S)-[(3'R. 3'S)-1-((R)-α-methyl-benzyl)-pyrrolidin-3,-ylmethyl1-2-hydroxy-2-
cyclohexyl-2-phenylacetic acid ester (Compound No 3)
IR(DCM) 1724 0 cm-1
1H NMR (CDCI3) δ 7 58-7 60 (m, 2H), 7 30-7 41 (m, 8H), 4 04-4 09 (m, 2H), 3 70 (m, 1H),
3 52 (m, 1H), 3 15-3 50 (m, 2H), 2 37-2 62 (m, 4H), 2 10-2 17 (m, 2H), 1 64-1 83 (m, 3H),
108-1 40 (m, 11H)
Mass 423 (M+l)
(2R,2S)-N-[(3'R. S'S)-1-((R)-α-methyl-benzyn-pyrrohdin-3'-ylmethyl]-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide (Compound No 4)
IR(DCM) 1652 5 cm-1
1H NMR (CDCl3) δ 7 56-7 77 (m, 2H), 7 00-7 32 (m, 8H), 3 04-3 21 (m, 4H), 2 56 (m, IH),
2 22-2 42 (m, 4H), 1 87 (m, IH), 1 56-1 60 (m, 6H), 1 15-1 30 (m, 8H)
Mass 408 (M+l)
(2R, 2S)-N-[(3'R. 3,S)-l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl1-2-hydroxy-2-
cyclohexyl-2-phenvlacetamide (Compound No 5)
IR(DCM) 1654 2 cm-1
Mass 422 (M+l)
N-[(3'R. 3'S)-1,-((R)-α-methyl-benzyn-pyrrolidin-3'-ylmethyll-2-hydroxy-2.2-diphenyl
acetamide (Compound No 6)
IR(DCM) 1658 5 cm-1
Mass 415 (M+l)
(2R.2S)-[(3'R)-l'-((R)-α-methyl-benzyl)-pvrrolidin-3'-ylmethyl1-2-hydroxy-2-cyclopentvl-2-
phenyl acetic acid ester (Compound No 7)
IR(DCM) 1723 5 cm-1
1H NMR (CDCI3) δ 7 59-7 63 (m, 2H), 7 12-7 42 (m, 8H), 4 03-4 08 (m, 2H) 3 68 (m, IH),
3 49 (s, 3H), 3 16-3 18 (m, IH), 2 10-2 53 (m, 6H), 1 30-1 73 (m, 9H)
Mass 407 (M+l)
2R-[(3'R)-1-((R)-α-methyl-benzyl)-pvrrolidin-3'-ylmethyll-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 8)
IR(DCM) 1726 2 cm-1 Mass 408 (M+l)
2S-[(3 'R)-1 '-((R)-α-rnethyl-benzyl)-pyrrolidin-3 '-ylmethyl"l-2-hydroxy-2-evclopentvl-2-phenyl acetic acid ester (Compound No 9) IR(DCM) 1725 1cm-1 Mass 408 (M+l)
[(3'R)-1-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl1-2-hydroxy-2.2-diphenyl acetic acid ester (Compound No 10)
IR(DCM) 1729 1cm-1
1H NMR (CDCI3) δ 7 23-7 41 (m, 15H), 4 12-4 20 (m, 2H), 3 06-3 10 (m, IH), 2 58 (m, IH), 2 40-2 42 (m, 2H), 2 25-2 27 (m, IH), 2 04-2 08 (m, IH), 1 85 (m, IH), 1 50 (m, 4H) Mass 416 (M+l)

Example 2 Preparation of 2R-[(3,R)-pyrrolidm-3-yl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No 11)
Step a. Preparation of (3'R)-l-benzyl-pvrrolidin-3'-ol
The compound (3'R)-pyrrohdin-3'-ol hydrochloride (2 2 g, 17 8 mM) was dissolved in dichloromethane (25 0 ml) and tnethylamine (5 0 ml, 35 6 mM) was added at room temperature with constant stirring for about 5 minutes Benzyl bromide (2 5 ml, 21 4 nM) was added to it in one lot at the same temperature followed by refluxing for about 15 hours The reaction mixture was diluted with chloroform and IN sodium hydroxide (15 0 ml) was added with constant stirring for about 10 minutes The organic layer was separated and washed with aqueous sodium bicarbonate and brine solution It was further dned over anhydrous sodium sulphate and concentrated to get the title compound
Step b Preparation of 2R-[((3'R)-1-benzyl-pyrrolidin-3'-yl)l-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester
A mixture of methyl (2R)-2-cyclopentyl-2-hydroxy-2-phenyl acetic acid ester (4 5 g, 19 2 mm) and (3'R)-l'-benzyl-pyrrohdin-3-ol (3 5 g, 19 8 mm) in heptane (600 0 ml) was refluxed under a Dean and Stark apparatus with the addition of piece of sodium (20 mg cover) at 0°C After about 5 hours refluxing, methanol (3 0 ml) was added at room temperature followed by water (50 0 ml) The organic layer was separated and aqueous layer was extracted with n-heptane The combined organic layer was washed with water and brine solution Dned, evaporated and the residue was punfied by silica gel column chromatography using ethyl acetate in hexane to afford the product in 62% (4 5 g) yield IR(DCM) 1703 8 cm-1
1H NMR (CDCl3) δ 7 64-7 66 (m, 2H), 7 28-7 35 (m, 8H), 5 21-5 23 (m, 1H), 3 49-3 75 (m, 3H), 2 70-2 91 (m, 3H), 2 46-2 52 (m, 2H), 2 24-2 29 (m, 1H), 1 90 (m, 1H), 1 31-1 66 (m, 8H) Mass 380 (M+l)
Step c Preparation of 2R-[((3'R)-1-pyrrohdin-3'-yl)l-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester
To a solution of 2R-[((3'R)-l'-benzyl-pyrrolidin-3'-yl)]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (1 3g, 30 5mmole) in dry methanol (25 0 mL), 5% palladium on carbon (0 2 g), (50% wet) was added under nitrogen Then anhydrous ammonium formate (0 8 g, 12 38 mmole) was added under stirring and the reaction mixture was refluxed for half an hour under nitrogen atmosphere Cooled to room temperature and the reaction mixture was filtered through a bed of hyflo The hyflo bed was washed with methanol (75 0 mL), ethyl acetate (25 0 mL) and water (25 0 mL) The filterate was concentrated under vaccum The residue was diluted with water and pH of the resulting solution was adjusted to (pH~14) with IN sodium hydroxide Extracted with ethyl acetate (2x50 mL) and the ethyl acetate layer was washed with water and brine solution Dried over anhydrous sodium sulphate and concentrated to give the title compound IR(DCM) 1727 1cm-1
1H NMR (CDCl3) δ 7 62-7 64 (m, 2H), 7 24-7 36 (m, 3H), 5 32 (m, 1H), 2 89-3 17 (m, 6H), 2 09 (m, 1H), 1 90 (m, 1H), 1 29-1 65 (m, 9H) Mass 290 (M+l)
Example 4 Preparation of (2R. 2S)-[(3'R. 3'S)-l'-benzyl-pvrrolidin-3'-ylmethylV2-hydroxy-2-(tnfluoromethyl)-2-phenyl acetic acid ester (Compound No 12)
To a solution of 2-tnfluoromethyl-2-hydroxy-2-phenylacetic acid (prepared following the procedure described in J Amer Chem Soc 75, 2654 (1953), J Org Chem 2000,65, 6283-6287) (1 9 g, 8 33 mmol) and (3'R, 3'S)-l-benzyl-3-[(methylsulfonyloxy)methyl]-pyrrohdine (prepared following the procedure described in J Med Chem , 1987, 30, 1711) (2 4 g, 8 5 mmol) in toluene (20 ml), l,8-diazabicyclo[5 4 0]undecan-7-ene (DBU) (1 6 g, 8 33 mmol) was added and the mixture was refluxed for overnight It was quenched by addition of aqueous sodium bicarbonate solution The organic layer was separated and washed with water, brine and dried over anhydrous sodium sulphate The organic layer was filtered and evaporated to give crude product The crude product was purified by silica gel column chromatography IR(DCM) 1747 2 cm-1
1H NMR (CDCI3) δ 7 74-7 76 (m, 2H0, 7 31-7 39 (m, 8H), 4 23-4 35 (m, 2H), 3 54-3 67 (m, 2H), 2 41-2 67 (m, 5H), 1 98-2 04 (m, 1H), 1 53-1 56 (m, 1H), 1 28 (m, 1H) Mass 394 (M+l)
Similarly, the following compounds were prepared following the procedure descnbed above
K(3'R. 3'S)-1-benzyl-pvrrolidin-3'-yl-methyl)-2-hydroxy-2.2-diphenyl acetic acid ester
(Compound No 14)
IR(DCM) 1731 1cm-1
1H NMR (CDCl3) δ 7 26-7 41 (m, 15H), 4 14-4 20 (m, 2H0, 3 51 (s, 2H), 2 37-2 53 (m, 5H),
2 09-2 13 (m, 1H), 1 83-1 89 (m, 2H)
Mass 402 (M+l)
[((3'R, 3S)-1-benzyl-pyrrohdin-3-yl methyl)-2,2-diphenyl acetic acid ester (Compound No
20)
IR(DCM) 1735 2 cm-1
1H NMR (CDCI3) δ 7 24-7 33 (m, 15H), 5 00 (s, 1H), 4 03-4 13 (m, 2H), 3 54 (s, 2H), 2 44-
2 64 (m, 4H), 2 10-2 19 (m, 2H), 1 42-1 44 (m, 1H)
Mass 386 (M+l)
Example 5 Preparation of (2R. 2S)-[(C3'R. 3,S)-Pvrrohdin-3'-yl methyl)-2-hydroxy-2-
cyclopentyl-2-phenyl acetic acid ester (Compound No 13)
To a solution of ((3'R)-l'-benzyl-pyrrohdin-3'-yl methyl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (prepared as in example 2) (1 3g, 30 5mmole) in dry methanol (25 0 mL), 5% palladium on carbon (0 2 g), (50% wet) was added under nitrogen Then anhydrous ammonium formate (0 8 g, 12 38 mmole) was added under stirring and the reaction mixture was refluxed for half an hour under nitrogen atmosphere Cooled to room temperature and the reaction mixture was filtered through a bed of hyflo. The hyflo bed was washed with methanol (75 0 mL), ethyl acetate (25 0 mL) and water (25 0 mL) The filterate was concentrated under vaccum The residue was diluted with water and pH of the resulting solution was adjusted to (pH~14) with IN sodium hydroxide Extracted with ethyl acetate (2x50 mL) and the ethyl acetate layer was washed with water and brine solution Dried over anhydrous sodium sulphate and concentrated to give the title compound IR(DCM) 1726 6 cm-1 Mass 304 (M+l)
Similarly, the following compounds were prepared following the procedure descnbed above (2R. 2S)-[((3'R. 3'S)-pyrrolidin-3'-vl methylV2-hydroxy-2-cyclohexyl-2-phenvl acetic acid ester (Compound No 16) IR(DCM) 1727 2 cm-1
1H NMR (CDCI3) δ 7 61-7 64 (m, 2H), 7 24-7 36 (m, 3H), 4 07-4 15 (m, 2H), 2 91-3 01 (m,
3H), 2 57-2 62 (m, 5H), 2 44 (m, 1H), 1 83 (m, 2H), 1 65-1 66 (m, 2H), 1 13-1 45 (m, 7H)
Mass 318 (M+l), 300 (M-OH)
[((3'R, 3'S)-pyrrolidin-3'-yl methyl)-2-hydroxy-2,2-diphenyl acetic acid ester (Compound
No 18)
IR(DCM) 1734 0 cm-1
1H NMR (CDCI3) δ 7 25-7 40 (m, 10H), 4 16-4 22 (m, 2H), 2 81-2 91 (m, 2H), 2 53-2 59
(m, 1H), 2 40-2 42 (m, 1H), 1 81-1 83 (m, 1H), 1 28-1 37 (m, 3H)
Mass 312 (M+l)
[(((3'R. 3'S)-pyrrolidin-3'-yl methyl)-2,2-diphenvl acetic acid ester (Compound No 21)
IR(DCM) 1737 8 cm1
Mass 296 (M+l)
Example 6 Preparation of (2R. 2S)-f((3'R. 3'S)-l'-methyl-pvrrohdin-3'-vl methyl)-2-
hydroxy-2-cyclopentvl-2-phenyl acetic acid ester (Compound No 15)
To a solution of (2R, 2S)-[((3'R, 3'S)-(l-pyrrohdm-3'-ylmethyl)]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (prepared in example-5) (0 3 g, 0 99 mm) in acetomtnle (18 0 ml), formaldehyde (37 1ml, 2.5 mm) and sodium cycnoborohydnde (0 23 g) were added at room temperature and stirred for about 1 hour Acetic acid (0 5 ml) was added to the reaction mixture and stirring continued for 2 more hours at room temperature Acetomtnle was evaporated and the residue was diluted with water (50 0 ml) and basified with aqueous sodium hydroxide Extracted with ethyl acetate (6x500 ml) and the ethyl acetate layer was washed with water and bnne solution dned, evaporated and the residue was punfied by silica gel column chromatography using 10% methanol in dichloromethane to get product in 60% yield IR(DCM) 1729 6 cm-1
1H NMR (CDCI3) δ 7 62-7 65 (m, 2H), 7 28-7 36 (m, 3H), 4 07-4 1H (m, 2H), 2 91-2 94 (m, 1H), 2 51-2 62 (m, 4H), 2 35 (s, 3H), 2 26 (m, 11H), 1 90-2 00 (m, 1H), 1 28-1 62 (m, 10H) Mass 318 (M+l)
Similarly, the following compounds were prepared following the procedure descnbed above (2R. 2S)-[((3'R. 3'S)-r-methyl-pvrrolidin-3'-vl methyl)-2-hydroxy-2-cyclohexyl-2-phenvl acetic acid ester (Compound No 17)
IR(DCM) 1728 5 cm-1
1H NMR (CDCI3) δ 7 61-7 63 (m, 2H), 7 23-7 35 (m, 3H), 4 06-4 14 (m, 2H), 2 52-2 59 (m,
4H), 2 33-2 34 (d, J=3Hz, 3H), 2 22-2 25 (m, 2H), 2 01 (m, 1H), 1 80 (m, 1H), 1 63-1 65 (m,
2H), 1 11-1 46 (m, 9H)
Mass 332 (M+l)
[((3'R, 3'S)-1-methyl-pvrrohdrn-3'-vl methyl)-2-hydroxy-2.2-diphenvl acetic acid ester
(Compound No 19)
IR(DCM) 1737 4 cm-1
1H NMR (CDCI3) δ 7 35-7 41 (m, 10H), 4 29-4 31 (m, 2H), 4 09 (m, 1H), 2 60-2 80 (m, 2H),
2 51-2 53 (m, 3H), 2 45-2 46 (m, 1H), 2 00-2 01 (m, 1H), 1 61 (m, 2H)
Mass 326 (M+l)
Example 7 Preparation of [((3'R. 3'S)-l'-(benzori.31dioxol-5-vl-ethyl)-pvrrohdin-3'-vl
methyl)-2.2-diphenyl acetic acid ester (Compound No 22)
The compound [((3'R, 3'S)-(r-pyrrohdin-3'-yl methyl)-2,2-diphenyl acetic acid ester was dissolved in acetonitnle and 5-(2-bromoethyl-l,3-benzodioxole was added To the reaction mixture, potassium carbonate and potassium iodide were added The reaction mixture was heated under refluxed for about 9 hours The reaction mixture was cooled to room temperature and acetonitnle was evaporated under vaccum The residue was partitioned between ethyl acetate and water The organic layer was washed with water and bnne solution followed by drying over anhydrous sodium sulphate and then concentrated The residue was punfied by silica gel column chloromatography using 20% methanol in chloroform to get the title compound IR(DCM) 1734 7 cm-1
1H NMR (CDCI3) δ 7 27-7 30 (m, 3H), 6 96 (s, 1H), 6 58-6 85 (m, 6H), 5 92-5 95 (m, 4H), 5 57 (d, J=18Hz, 1H), 5 12 (d, J=12Hz, 1H), 3 27-3 32 (m, 2H), 3 06-3 11 (m, 2H), 2 80-2 82 (m, 1H), 1 55 (s, 3H), 1 28-1 42 (m, 5H)
Biological Activity
Radioligand Binding Assays
The affinity of test compounds for M2 and M3 muscannic receptor subtypes was determined by [3H]-N-methyl scopolamine binding studies using rat heart and submandibular
gland, respectively as described by Monya et al, (Life Sci, 1999,64(25) 2351-2358) with minor modifications
Membrane preparation Submandibular glands and heart were isolated and placed in ice cold homogenizing buffer (HEPES 20 mM, 10 mM EDTA, pH 7 4) immediately after sacrifice The tissues were homogenized in 10 volumes of homogenizing buffer and the homogenate was filtered through two layers of wet gauze and filtrate was centnfuged at 500g for 10mm The supernatant was subsequently centnfuged at 40,000g for 20 mm The pellet thus obtained was resuspended in same volume of assay buffer (HEPES 20 mM, EDTA 5 mM, pH 7 4) and were stored at -70°C until the time of assay
Ligand binding assay The compounds were dissolved and diluted in DMSO The membrane homogenates (150-250 ug protein) were incubated in 250 u.1 of assay buffer (HEPES 20 mM, pH 7 4) at 24-25°C for 3 hours Non-specific binding was determined in the presence of 1 uM atropine The incubation was terminated by vacuum filtration over GF/B fiber filters (Wallac) The filters were then washed with ice-cold 50 mM Tns HCI buffer (pH 7 4) The filter mats were dried and bound radioactivity retained on filters was counted The IC50 & Kd were estimated by using the non-linear curve-fitting program using G Pad Pnsm 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 expenment
The Ki results of the compounds observed were in the range of 0 5 nM to >1000 nM for M2 receptor and 0 1 nM to >1000 nM for M3 receptor
Functional Expenments using isolated rat bladder
Methodology
Animal are euthanized by overdose of urethane and whole bladder is isolated and removed rapidly and placed in ice cold Tyrode buffer with the following composition (mMol/L) sodium chlonde 137, KC1 2 7, CaCl2 1 8, MgCl2 0 1, NaHC03 11 9, NaH2P04 0 4, Glucose 5 55 and continuously gassed with 95% 02 and 5% C02
The bladder is cut into longitudinal strips (3 mm wide and 5-6 mm long) and mounted in 10 ml organ baths at 30°C, with one end connected to the base of the tissue holder and the other end connected to a polygraph through a force displacement transducer Each tissue is maintained at a constant basal tension of 2 g and allowed to equilibrate for 1 hour during which the PSS is changed every 15 mm At the end of equilibration period, the stabilization of the tissue contractile response is assessed with 1 µ mol/L of carbachol consecutively for 2-3 times Subsequently, a cumulative concentration response curve to carbachol (10-9 mol/L to 3 x 10-5 mol/L) is obtained After several washes, once the baseline is achieved, cumulative concentration response curve is obtained in the presence of NCE (NCE added 20 mm pnor to the second CRC)
The contractile results are expressed as % of control E max ED50 values are calculated by fitting a non-linear regression curve (Graph Pad Prism) pKB values are calculated by the formula pKB = -log [(molar concentration of antagomst/(dose ratio-1))]
where,
dose ratio =ED50 in the presence of antagonist/ED50 in the absence of antagonist
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

WE CLAIMS:-
1. A compound having the structure of Formula I, as shown in the accompanied
drawings, and their pharmaceutically acceptable salts, pharmaceutically acceptable
solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites,
wherein
R1 and R2 are independently selected from
o alkyl
o haloalkyl
o cycloalkyl
o aryl
o heteroaryl R3 represents
o hydrogen
o lower alkyl
o hydroxy
o amino
o alkoxy X represents
o oxygen
o sulphur
o NR8 wherein R8 represents hydrogen, lower alkyl or aralkyl n represents an integer ranging from 0 to 3 R4, R5 and R6 are independently selected from hydrogen or alkyl R7 represents
o hydrogen
o alkyl
o CHR9R10 wherein R9 and R10 are independently selected from
• hydrogen
• alkyl
• aryl
o (CH2)m-R11 wherein Rn is aryl or heteroaryl and m is an integer from 1 to 3
with theprovisio that R1, R2 and R3 can not be phenyl, cycloalkyl and hydroxy, respectively, when R9 and R10 are hydrogen and phenyl, and with the further provisio that when Ry is (CH2)m-R11, R3 is hydrogen.
2. A compound according to claim 1 wherein R1 is aryl.
3. A compound according to claim 1 wherein R1 is phenyl.
4. A compound according to claim 1 wherein R2 is aryl.
5. A compound according to claim 1 wherein R2 is phenyl.
6. A compound according to claim 1 wherein R2 is cycloalkyl.
7. A compound according to claim 1 wherein R2 is cyclopentyl.
8. A compound according to claim 1 wherein R2 is cyclohexyl.
9. A compound according to claim 1 wherein R2 is haloalkyl.
10. A compound according to claim 1 wherein R2 is trifluoromethyl.
11. A compound according to claim 1 wherein R3 is hydrogen.
12. A compound according to claim 1 wherein R3 is hydroxy.
13. A compound according to claim 1 wherein X is oxygen.
14. A compound according to claim 1 wherein X is NH.
15. A compound according to claim 1 wherein n=0.
16. A compound according to claim 1 wherein n is 1.
17. A compound according to claim 1 wherein R4, R5 and R6 are hydrogen.
18. A compound according to claim 1 wherein R7 is hydrogen.
19. A compound according to claim 1 wherein R7 is alkyl.
20. A compound according to claim 1 wherein R7 is methyl.
21. A compound according to claim 1 wherein R7 is CHR9R10 wherein R9 is hydrogen and R10 is aryl.
22. A compound according to claim 1 wherein R7 is CHR9R10 wherein R9 is hydrogen and R10 is phenyl.
23. A compound according to claim 1 wherein R7 is CHR9R10 wherein R9 is methyl and R10 is aryl.
24. A compound according to claim 1 wherein R7 is CHR9R10 wherein R9 is methyl and R10 is phenyl.
25. A compound according to claim 1 wherein R7 is (CH2)m-R11 wherein R11 is heteroaryl and m is 2.
A compound according to claim 1 wherein R7 is (CH2)m-R11 wherein R11 is
benzo[l,3]dioxol-5-yl-ethyl and m is 2.
A compound which is:
(2R, 2S)-[(3'R, 3'S)- l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cycopentyl-2-phenylacetic acid ester (Compound No. 1)
[(3'R, 3'S)- 1 '-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No. 2)
(2R, 2S)-[(3'R, 3'S)- l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclohexyl-2-phenylacetic acid ester (Compound No. 3)
(2R, 2S)-N-[(3'R, 3'S)- l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 4)
(2R,2S)-N-[(3'R,3'S)-l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclohexyl-2-phenylacetamide (Compound No. 5)
N-[(3'R, 3'S)-l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetamide (Compound No. 6)
(2R,2S)-[(3'R)-l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No. 7)
2R-[(3'R)-l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No. 8)
2S-[(3'R)-r-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No. 9)
[(3'R)-l'-((R)-α-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No. 10)
2R-[(3'R)-pyrrolidin-3'-yl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No. 11)
(2R, 2S)-[((3'R, 3'S)-1'-benzyl-pyrrolidin-3'-ylmethyl)-2-hydroxy-2-(trifluoromethyl)-2-phenyl acetic acid ester (Compound No. 12)
(2R, 2S)-[((3'R, 3'S)-pyrrolidin-3'-yl methyl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No. 13)
[((3'R, 3'S)-l'-benzyl-pyrrolidin-3'-yl-methyl)-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No. 14)
(2R, 2S)-[((3'R, 3'S)-l'-methyl-pyrrolidin-3'-yl methyl)-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No. 15)
(2R, 2S)-[((3'R, 3'S)-pyrrolidin-3'-yl methyl)-2-hydroxy-2-cyclohexyl-2-phenyl acetic acid ester (Compound No. 16)
(2R, 2S)-[((3'R, 3'S)-l'-methyl-pyrrolidin-3'-yl methyl)-2-hydroxy-2-cyclohexyl-2-phenyl acetic acid ester (Compound No. 17)
[((3'R, 3'S)-pyrrolidin-3'-yl methyl)-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No. 18)
[((3'R, 3'S)-r-methyl-pyrrolidin-3'-yl methyl)-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No. 19)
[((3'R, 3'S)-l'-benzyl-pyrrolidin-3-yl methyl)-2,2-diphenyl acetic acid ester (Compound No. 20)
[((3'R, 3'S)-pyrrolidin-3'-yl methyl)-2,2-diphenyl acetic acid ester (Compound No. 21)
[((3'R, 3'S)-l'-(benzo[l,3]dioxol-5-yl-ethyl)-pyrrolidin-3'-ylmethyl)-2,2-diphenyl acetic acid ester (Compound No. 22),
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites.
28. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 optionally together with pharmaceutically acceptable carriers, excipients or diluents.
29. 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 according to claim 1.
30. The method according to claim 29 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.
31. 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, where 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 the claim 28.
32. The method according to claim 31 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 and gastrointestinal hyperkinesis.
33. A process of preparing a compound of Formula IV, as shown in Scheme I of the accompanied drawings, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites, wherein
R1 and R.2 are independently selected from
o alkyl
o haloalkyl
o cycloalkyl
o aryl
o heteroaryl R.3 represents
o hydrogen
o lower alkyl
o hydroxy
o amino
o alkoxy
X represents oxygen or NH, which method comprises coupling a compound of Formula II with a compound of Formula III, to give a compound of Formula IV (wherein R1, R2, R3 and X are the same as defined earlier), as shown in Scheme I of the accompanied drawings.
34. The process according to claim 33 wherein the coupling 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 hydroxy benztriazole and N-methylmorpholine and a coupling agent selected from l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC. HCL) and 1,3-dicyclohexylcarbodiimide (DCC).
35. The process according to claim 33 wherein the coupling of a compound of Formula II with a compound of Formula III is carried out in a solvent selected from dimethylformamide, chloroform and dimethylsulphoxide.
36. A process of preparing a compound of Formula VIII, as shown in Scheme II of the accompanied drawings, and its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or
metabolites, wherein
R1 and R2 are independently selected from
o alkyl
o haloalkyl
o cycloalkyl
o aryl
o heteroaryl
R3 represents
o hydrogen
o lower alkyl
o hydroxy
o amino
o alkoxy,
which method comprises reacting l-benzyl-pyrrolidin-3-ol of Formula V with a compound of Formula VI, to give a compound of Formula VII (wherein R1, R2 and R3 are the same as defined earlier), which on debenzylation gives a compound of Formula VIII, as shown in Scheme II of the accompanied drawings.
37. The process according to claim 36 wherein the reaction of l-benzyl-pyrrolidin-3-ol of Formula V with a compound of Formula VI to give a compound of Formula VII is carried out in a solvent selected from heptane, hexane, toluene and xylene.
38. The process according to claim 36 wherein the reaction of l-benzyl-pyrrolidin-3-ol of Formula V with a compound of Formula VI is carried out in the presence of a base a selected from sodium, sodium methoxide and sodium hydride.
39. The process according to claim 36 wherein the debenzylation of a compound of Formula VII to give a compound of Formula VIII is carried out in the presence of a debenzylating agent selected from palladium on carbon and hydrogen and ammonium formate and palladium on carbon.
40. The process according to claim 36 wherein the debenzylation of a compound of Formula VII to give a compound of Formula VIII is carried out in a solvent selected from methanol, ethanol and isopropanol.
41. A process of preparing a compound of Formula XII, as shown in Scheme III of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or
metabolites, wherein
R1 and R2 are independently selected from
o alkyl
o haloalkyl
o cycloalkyl
o aryl
o heteroaryl
R3 represents
o hydrogen
o lower alkyl
o hydroxy
o amino
o alkoxy,
which method comprises reacting l-benzyl-3-[(methylsulfonyloxy)methyl]-
pyrrolidine of Formula IX with a compound of Formula III, to give a compound of
Formula X (wherein R1, R2 and R3 are the same as defined earlier), which on
debenzylation gives a compound of Formula XI, which on reaction with
formaldehyde gives a compound of Formula XII, as shown in Scheme III of the
accompanied drawings.
42. The process according to claim 41 wherein the condensation of l-benzyl-3-[(methylsulfonyloxy)methyl]-pyrrolidine of Formula IX with a compound of Formula III to give a compound of Formula X is carried out in a solvent selected from benzene, toluene and xylene.
43. The process according to claim 41 wherein the condensation of l-benzyl-3-[(methylsulfonyloxy)methyl]-pyrrolidine of Formula IX with a compound of Formula III is carried out in the presence of a condensing agent selected from 1,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) and l,4-diazabicyclo[2.2.2]octane (DABCO).
44. The process according to claim 41 wherein the debenzylation of a compound of Formula X to give a compound of Formula XI is carried out in a solvent selected from methanol and ethanol.
45. The process according to claim 41 wherein the debenzylation of a compound of
Formula X to give a compound of Formula XI is carried out in the presence of a
catalyst selected from palladium on carbon and hydrogen gas and ammonium formate and palladium on carbon.
46. The process according to claim 41 wherein the reaction of a compound of Formula XI with formaldehyde to give a compound of Formula XII is carried out in a solvent selected from acetonitrile.
47. The process according to claim 41 wherein the reaction of a compound of Formula XI with formaldehyde is carried out in the presence of a reducing agent selected from sodium cyanoborohydride or sodiumtriacetoxyborohydride.
48. A process of preparing a compound of Formula XIII, as shown in Scheme III of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites, wherein
R1 and R.2 are independently selected from
o alkyl
o haloalkyl
o cycloalkyl
o aryl
o heteroaryl
R3 represents
o hydrogen
o lower alkyl
o hydroxy
o amino
o alkoxy
R7 represents
-(CH2)m-R11 wherein R11 is aryl or heteroaryl and m is an integer from 1 to 3,
which method comprises reacting a compound of Formula XI, with a compound of
Formula R7-L (wherein L is any leaving group known in the art, for example,
halogen, O-mesyl or O-tosyl group) to give a compound of Formula XIII, as shown in
Scheme III of the accompanied drawings.
49. The process according to claim 48 wherein the reaction is carried out in a solvent
selected as dimethylsulfoxide, acetonitrile and dimethylformamide.
50. The processes for the preparation of compounds of Formulae IV, VIII, XII and XIII,
substantially as herein described and illustrated by the examples herein.