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 described compounds,
pharmaceutical compositions containing the described 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, Ma, M4 and MS) and are activated by the
neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and
tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission.
The regional distribution of these receptor sub-types in the brain and other organs has been
documented. For example, the MI subtype is located primarily in neuronal tissues such as
cereberal cortex and autonomic ganglia, the M2 subtype is present mainly in the heart where it
mediates cholinergically induced bradycardia, and the MS 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 quaternary derivatives of atropine such as ipratropium bromide are better
tolerated than parenterally administered options, but most of these are not ideal anti-cholinergic
nchodilators, due to lack of selectivity for muscarinic receptor sub-types, resulting in doselimiting
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 97/45414 are related to 1,4-disubstituted piperidine derivatives; WO 98/05641
describes fluorinated, 1,4-disubstitued piperidine derivatives; WO 93/16018 and WO96/33973 are
other references of interest. US Patent No. 5,397,800 describes l-azabicyclo[2.2.1]heptanes. US
Patent No.5, 001,160 describes l-aryl-l-hydroxy-l-substituted-3-(4-substituted-l-piperazinyl)-2-
propanones. WO 01/42213 describes 2-biphenyl-4-piperidinyl ureas. WO 01/42212 describes
carbamate derivatives. WO 01/90081 describes amino alkyl lactam. WO 02/53564 describes
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.
WO 2004/005252 describes azabicyclo derivatives described as musacrinic receptor
antagonists. WO 2004/004629, WO 2004/052857, WO 2004/067510, WO 2004/014853, WO
2004/014363 describes 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives described as useful
muscarinic receptor antagonists. WO2004/056811 describes flavoxate derivatives as muscarinic
receptor antagonists. WO2004/056810 describes xanthene derivatives as muscarinic receptor
antagonists. WO2004/056767 describes l-substituted-3-pyrrolidine derivatives as muscarinic
receptor antagonists. WO2004/089363, WO2004/089898, WO04069835, WO2004/089900 and
WO2004089364 describes substituted azabicyclohexane derivatives as muscarinic receptor
antagonists. WO 98/00109, 98/00132, 98/00133 and 98/00016 describe isomers of glycopyrolate.
U. S. Patent No. 6,307,060 describes enantiomerically pure basic N-heterocyclicaryl cycloalkyl
hydroxy carboxylic esters and their use in medicaments.
U. S. Patent No. 6,204,285 describes methods and compositions for treating urinary
incontinence using enantiomerically enriched (R, R)-glycopyrrolate. WO 03/087094 describes
new pyrrolidinium derivatives. A report in J. Med. Chem., 44, p. 984 (2002), describes
cyclohexylmethyl piperidinyl triphenylpropioamide derivatives as selective MS antagonist
discriminating against the other receptor subtypes. Bio-Organic Medicinal Chemistry Letters, 15,
p.2093 (2005) describes synthesis and activity of analogues of Oxybutynin and Tolterodine.
Pharmazie, 57(2), 138 (2002) describes glycopyrolate analogues.
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, 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 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 comprising the
compounds, their metabolites, stereoisomers, 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, and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
esters, stereoisomers, N-oxides, polymorphs, prodrugs or metabolites,
FORMULA I R?
wherein
RI and R2 can be independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl
orheteroaryl.
RS can represent hydrogen, lower alkyl, hydroxy, amino or alkoxy.
X can represent oxygen, sulphur or NRs (wherein Rg can represent hydrogen, lower alkyl or
aralkyl).
n can represent an integer ranging from 0 to 3.
R4, RS and R& can be independently selected from hydrogen or alkyl.
RI can represent hydrogen, alkyl, -CHRgRio (wherein RQ and RIO can be independently selected
from hydrogen, alkyl or aryl), -(CH2)m-Rn (wherein RH is aryl or heteroaryl and m can be an
integer from 1 to 3) or -CORn (wherein Ri2 represent alkyl, cycloalkyl, aryl, aralkyl
heteroaryl).
with the proviso that R/, R2 and Rj cannot be phenyl, cycloalkyl and hydroxy, respectively, when
Rg and RIO are hydrogen and phenyl, and with the further proviso that when R? is (Cfyjm-Rn, RS
is hydrogen.
In accordance with a second aspect, there are provided methods for the 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 methods include administration of at least one compound having the structure of
Formula I.
In accordance with a third aspect, there are provided methods for the 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 aspect, there are provided methods for the 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 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,
which was determined by in vitro receptor binding assays. Some compounds were found to
function as potent muscarinic receptor antagonists with high affinity towards MS 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 term "alkyl," unless otherwise specified, refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be
exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tbutyl,
n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may
be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy,
cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen,
hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol,
alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)Rt-, -NRfRq, -
C(=O)NR,Rq, -NHC(=O)NRfRq>, -C(=O)heteroaryl, C(=O)heterocyclyl, -OC(=
O)NRfRq {wherein Rf and Rqare independently selected from alkyl, alkenyl, cycloalkyl,
cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -
SO2R6 (wherein R6 is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl,
heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl
substituents may be further substituted by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -
C(=O)NRtRq, -OC(=O) NRfRq, -NHC(=O)NRfRq (wherein Rf and Rq are the same as defined
earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R6, (wjjerein R6 are the same as defined
earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected
from oxygen, sulfur or -NRa- {wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORf (wherein Rf is the same as defined earlier),
SO2R6 (where R6 is as defined earlier), or -C(=O)NRfRq (wherein Rf and Rq are as defined
earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted
further by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C (=O)NRfRq, -O-C(=O)NRfRq
(wherein Rf and Rq are the same as defined earlier) hydroxy, alkoxy, halogen, CF3, cyano, and -
SO2R6 (where Re is same as defined earlier); or an alkyl group as defined above that has both
substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term "cycloalkyl," unless otherwise specified, 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 otherwise constrained by the definition. Such
cycloalkyl groups can include, for example, single ring structures, including cyclopropyl,
cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including
adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group,
for example, indane, and the like. Spiro and fused ring structures can also be included.
Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl,
arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRfRq, -
NHC (=O) NRfRq, -NHC (=O) Rf, -C (=O) NRfRq, -O-C (=O)NRfRq (wherein Rf and Rq are
the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or
SO2-R6 (wherein Re is same as defined earlier). Unless otherwise constrained by the definition,
cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from
alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq, -
OC(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano or -SC^Re (where R6 is
same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl
portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
As used herein the term "alkoxy" refers to the group 0-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 iodo.
The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for
example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1 to 3
substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl,
alkoxy, acyl, aryloxy, CFs, cyano, nitro, COORe (wherein Reis hydrogen, alkyl, alkenyl,
cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -
NHC(=O)NRfRq, -O-C(=O)NRtRq (wherein Rf and Rq are the same as defined earlier), -SO2R6
(wherein R6 is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl,
heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a
cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from
O,NorS.
The term "aralkyl," unless otherwise specified, refers to alkyl-aryl linked through an alkyl
portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and
aryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl and the like.
As used herein the term "carboxy" refers to -C(=O)O-Ri2 wherein Ri2 is selected from the
group consisting of hydrogen, alkyl and cycloalkyl.
The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure
containing 5 or 6 ring atoms, or a bicyclic aromatic group having from 8 to 10 ring atoms, with
one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to
4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl,
cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRfRq,
CH=NOH, -(CH2)wC(=O)Rg {wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy,
OR,, NRtRq, -NHORZ or -NHOH}, -C(=O)NRfRq and -NHC(=O)NRfRq, -SO2R6, -OC(=
O)NRfRq> -O-C(=O)Rf, -O-C(=O)ORf (wherein R6, Rf and Rq are as defined earlier,
and Rz is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl).
Unless otherwise constrained by the definition, the substituents are attached to a ring atom, carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl,
pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl,
benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like.
The term "pharmaceutically acceptable solvates" refers to solvates with waters (i.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 appropriate 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, npropyl
iodide, isopropyl bromide, n-butyl chloride, n-butyl bromide, isobutyl bromide, secbutylbromide,
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 derivatives of these compounds, which are readily convertible
in vivo into the required compound. Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, 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 described 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, geometrical
isomers, atropisomer and comformational isomers. Geometric isomers may occur when a
compound contains a double bond or some other feature that gives the molecule a certain amount
of structural rigidity. An enantiomer is a stereoisomer of a reference molecule that is the
nonsuperimposable 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 described 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 accompanying drawings.
-10-
SCHEME I (when X is O or NH)
FORMULA IV
The compounds of Formula IV can be prepared, for example, by the reaction sequence as
shown in Scheme I. The preparation comprises coupling a compound of Formula II with a
compound of Formula III to give a compound of Formula IV (wherein X, R), R2 and RS 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 carried out in the presence hydroxybenzotriazole and Nmethylmorpholine
and a coupling agent, for example, l-(3-dimethylaminopropyl)-3-ethyl
carbodiimide hydrochloride (EDC. HC1) or 1,3-dicyclohexylcarbodiimide (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.
The compounds of Formula VIII can be prepared, for example, by the reaction sequence
as shown in Scheme II. The preparation comprises reacting l-benzyl-pyrrolidin-3-ol of Formula
V with a compound of Formula VI to give a compound of Formula VII (wherein R\, R2 and R3
are the same as defined earlier), which on debenzylation gives a compound of Formula VIII.
The reaction of l-benzyl-pyrrolidin-3-ol of Formula V with a compound of Formula VI to
give a compound of Formula VII can be carried out in a solvent, for example, heptane, hexane,
toluene or xylene. The reaction of l-benzyl-pyrrolidin-3-ol of Formula V with a compound of
Formula VI can be carried out in the presence of a base, for example, sodium, sodium methoxide
or sodium hydride.
The debenzylation of a compound of Formula VII to give a compound of Formula VIII
can be carried 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 carried out in a solvent, for example,
methanol, ethanol or iosproanol, at temperatures ranging from about 50 to about 110
The compounds of Formula XII and XIII can be prepared by the reaction sequence, as
shown in scheme III. The preparation 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 RI, R2 and R3 are the same as defined earlier), which on
debenzylation gives a compound of Formula XI, which on reaction with
Path a: formaldehyde gives a compound of Formula XII, or
Path 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-Ri i wherein RI i 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 carried 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, l,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
carried 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 carried 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 (path a) to give a
compound of Formula XII is carried out in the presence of a reducing agent, for example, sodium
cyanoborohydride or sodiumtriacetoxyborohydride in a solvent, for example, acetonitrile.
The reaction of a compound of Formula XI with a compound of Formula Ry-L (path b) to
give a compound of Formula XIII can be carried out in a solvent, for example,
dimethylsulphoxide, acetonitrile 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)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cycopentyl-
2-phenylacetic acid ester (Compound No. 1),
[(3'R, 3'S)- l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetic acid
ester (Compound No. 2),
(2R, 2S)-[(3'R, 3'S)- l'-((R)-a-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)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide (Compound No. 4),
(2R, 2S)-N-[(3'R, 3'S)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-
cyclohexyl-2-phenylacetamide (Compound No. 5),
N-[(3'R, 3'S)- 1 '-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl
acetamide (Compound No. 6),
(2R,2S)-[(3'R)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-
phenyl acetic acid ester (Compound No. 7),
2R-[(3'R)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl
acetic acid ester (Compound No. 8),
2S-[(3'R)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl
acetic acid ester (Compound No. 9),
[(3'R)-1 '-((R)-a-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)-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-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)-l'-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'-yl methyl)-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.
The compounds of Formula XV, XVI, XVIII and XIX can be prepared by following the
procedure described in Scheme IV. Thus the preparation comprises condensing a compound of
Formula XIV (wherein X is the same as defined earlier) with a compound of Formula III (wherein
RI, R2 and R3 are the same as defined earlier) to give a compound of Formula XV, which
undergoes deprotection to give a compound of Formula XVI,
Path a: which is reacted with a compound of Formula XVII (wherein hal is Cl, Br or I and R\2 is
the same as defined earlier) to give a compound of Formula XVIII, or
Path b: which undergoes reductive amination with a compound of Formula RgCHO (wherein Rg is
the same as defined earlier) to give a compound of Formula XIX.
The condensation of a compound of Formula XIV with a compound of Formula III to give
a compound of Formula XV can be carried out in an organic solvent (for example,
dimethylformamide, tetrahydrofuran, diethyl ether, chloroform or dioxane) in the presence of a
base (for example, N-methylmorpholine, triethylamine, diisopropylethylamine or pyridine) with a
condensing agent (for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC.HC1) or dicyclohexylcarbodiimide).
The deprotection of a compound of Formula XV to give a compound of Formula XVI can
be carried out in an organic solvent (for example, methanol, ethanol, propanol or
isopropylalcohol) in the presence of a deprotecting agent (for example, palladium on carbon in
presence of hydrogen gas or palladium on carbon with a source of hydrogen gas (for example,
ammonium formate solution, cyclohexene or formic acid)).
The reaction of a compound of Formula XVI with a compound of Formula XVII (Path a)
to give a compound of Formula XVIII can be carried out in an organic solvent (for example,
dichloromethane, dichloroethane, carbon tetrachloride or chloroform) in the presence of a base
-15-
(for example, triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine) and catalyst
(for example, dimethylaminopyridine, 4-(pyrrolidino)pyridine.
The reductive amination of a compound of Formula XVI with a compound of Formula
R9CHO to give a compound of Formula XIX (Path b) can be carried out in an organic solvent (for
example, selected from, dichloromethane, dichloroethane, chloroform or carbon tetrachloride)
with reducing agent (for example, sodium triacetoxyborohydride or sodium cyanoborohydride).
Some illustrative compounds prepared following Scheme IV are:
Hydroxy-diphenyl-acetic acid l-(2-benzyloxy-acetyl)-pyrrolidin-3-ylmethyl ester (CompNo. 23),
2-Hydroxy-2-phenyl-pent-4-ynoic acid l-benzyl-pyrrolidin-3-ylmethyl ester (Compound No. 24),
N-(l-Benzyl-pyrrolidin-3-ylmethyl)-2-cyclopentyl-2-hydroxy-N-methyl-2-phenyl-acetamide
(Compound No. 25),
2-Cyclopentyl-2-hydroxy-N-methyl-2-phenyl-N-pyrrolidin-3-ylmethyl-acetamide (Compound
No. 26),
2-Cyclopentyl-2-hydroxy-N-methyl-N-(l-methyl-pyrrolidin-3-ylmethyl)-2-phenyl-acetamide
(Compound No. 27),
N-(l-Benzyl-pyrrolidin-3-ylmethyl)-2-cyclohexyl-2-hydroxy-N-methyl-2-phenyl-acetamide
(Compound No. 28),
N-(l-Benzyl-pyrrolidin-3-ylmethyl)-2-hydroxy-N-methyl-2,2-diphenyl-acetamide (Com No. 29),
2-Cyclohexyl-2-hydroxy-N-methyl-2-phenyl-N-pyrrolidin-3-ylmethyl-acetamide (Com No. 30),
N-[l-(2-Benzyloxy-acetyl)-pyrrolidin-3-ylmethyl]-2-cyclopentyl-2-hydroxy-N-methyl-2-phenylacetamide
(Compound No. 31),
and its pharmaceutically accepted salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides.
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 may be formulated into ordinary dosage forms such as, for example,
tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by
conventional methods with conventional pharmaceutical excipients.
The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral
(including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms
may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and
lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms
may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or
intravenous administration, dry powders to be reconstituted with sterile water for parenteral
administration, and the like.
The compounds described 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 carrier 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, pyridine, ether, tetrahydrofuran, hexane and
dichloromethane were dried using various 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 Varian XL-
300 MHz instrument using tetramethylsilane as an internal standard.
Example A: Synthesis of (l-benzyl-pyrrolidin-3-ylmethyl)-methyl-amine
Step a: Synthesis of l-(benzyl-pyrrolidin-3-yl)-methanoI
A solution of the compound l-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl
(1.0 eq.) (commercially available) in toluene was cooled to 0°C under inert atmosphere. To the
mixture was added solution of borane (3.75 eq.) in dimethyl sulphide and refluxed the mixture for
16 hours at 100°-110°C. The resulting reaction mixture was cooled to room temperature and
subsequently to -5° to -10°C followed by the addition of sodium bicarbonate solution dropwise.
The mixture was slowly brought to room temperature and subsequently refluxed the reaction
mixture for 2 hours. The mixture was cooled and organic layer was separated. Aqueous layer was
extracted with toluene. The combined toluene layers were washed with water and brine solution.
The organic solvent was evaporated under reduced pressure to furnish the title compound. Yield:
99.14%.
-17-
Step b: Synthesis of l-benzyl-3-methanesulphonyl-pyrrolidine
To a solution of the compound obtained from step a above (1.0 eq.) in dichloromethane
(10ml) was added triethylamine (2 eq.) and dimethylaminopyridine (catalytic amount). The
mixture was cooled to 0°C followed by the addition of methane sulphonyl chloride (1.5 eq.)
dropwise and stirred the mixture for 14 hours at room temperature. The mixture was diluted with
dichloromethane, washed with saturated sodium bicarbonate solution, water and brine, dried over
anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue thus
obtained was purified by column chromatography to furnish the title compound. Yield: 90.53%
Step c: Synthesis of l-benzyl-pyrrolidin-3-ylmethyl)-methyl-amme
To a solution of the compound obtained from step b above (4.0 g) in methanol (40 ml) was
added aqueous methylamine (40%, 40 ml) and heated the mixture for 16 hours at 85-90°C in
autoclave. The solvent was evaporated under reduced pressure and the residue thus obtained was
diluted with water and acidified with hydrochloric acid (1:1) and washed with dichloromethane.
The aqueous layer was basified with sodium hydroxide solution (20%). The mixture was
extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate
and concentrated under reduced pressure to furnish the title compound. Yield: 84.72%.
Example 1: Preparation of (2R. 2S)-[(3'R. 3'SV l'-((R)-a-methvl-benzvl)-pvrrolidin-3'-vlmethvl1-
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 described in J. Amer. Chem. Soc. 75, 2654 (1953); J. Org. Chem. 2000, 65, 6283-6287)
(0.59 g, 2.7 mm) and l-((R)-a-methyl benzyl)-3-pyrrolidin 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 benzotriazole (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 carbodiimide hydrochloride (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): 1722.9cm'1
'H NMR (CDC13): 8 7.59-7.61 (m, 2H), 7.29-7.39 (m, 8H), 4.06-4.07 (m, 2H), 3.68-3.78 (m, IH),
3.50 (m, IH), 3.14-3.16 (m, IH), 2.84 (m, IH), 2.36-2.56 (m, 4H), 2.10 (s, IH), 1.70-1.80 (m,
IH), 1.50-1.69 (m, 8H), 1.34-1.47 (m, 3H)
Mass: 408 (M+l)
Similarly the following illustrative compounds were prepared following the procedure described
above.
[(3'R, 3'S)- l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetic acid
ester (Compound No. 2)
IR(DCM): 1731.8cm"1
'H NMR (CDC13): 8 7.00-7.45 (m, 15H), 4.16-4.24 (m, 2H), 3.08-3.10 (m, IH), 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)- l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclohexyl-
2-phenylacetic acid ester (Compound No. 3)
IR(DCM): 1724.0cm-'
'H NMR (CDC13): 8 7.58-7.60 (m, 2H), 7.30-7.41 (m, 8H), 4.04-4.09 (m, 2H), 3.70 (m, IH), 3.52
(m, IH), 3.15-3.50 (m, 2H), 2.37-2.62 (m, 4H), 2.10-2.17 (m, 2H), 1.64-1.83 (m, 3H), 1.08-1.40
(m, 11H)
Mass: 423 (M+l)
(2R,2S)-N-[(3'R, 3'S)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3"-ylmethyl]-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide (Compound No. 4)
IR(DCM): 1652.5cm'1
'H NMR (CDC13): 8 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)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-
cyclohexyl-2-phenylacetamide (Compound No. 5)
IR(DCM): 1654.2 cm'1
Mass: 422 (M+l).
N-[(3'R, 3'S)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-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)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-
phenyl acetic acid ester (Compound No. 7)
IR(DCM): 1723.5cm'1
'H NMR (CDC13): 5 7.59-7.63 (m, 2H), 7.12-7.42 (m, 8H), 4.03-4.08 (m, 2H) 3.68 (m, 1H), 3.49
(s, 3H), 3.16-3.18 (m, 1H), 2.10-2.53 (m, 6H), 1.30-1.73 (m, 9H)
Mass: 407 (M+l)
2R-[(3'R)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl
acetic acid ester (Compound No. 8)
IR(DCM): 1726.2cm'1
Mass: 408 (M+l)
2S-[(3'R')-r-((RVa-methvl-benzvlN)-pvrrolidin-3'-vlmethvl1-2-hvdroxv-2-cvclopentvl-2-phenvl
acetic acid ester (Compound No. 9)
IR(DCM): 1725.1 cm'1
Mass: 408 (M+l)
[(3'R)-1 '-((R)-a-methyl-benzyl)-pyrrolidin-3'-vlmethvl]-2-hvdroxv-2,2-diphenyl acetic acid ester
(Compound No. 10)
IR(DCM): 1729.1cm'1
'H NMR (CDC13): 8 7.23-7.41 (m, 15H), 4.12-4.20 (m, 2H), 3.06-3.10 (m, 1H), 2.58 (m, 1H),
2.40-2.42 (m, 2H), 2.25-2.27 (m, 1H), 2.04-2.08 (m, 1H), 1.85 (m, 1H), 1.50 (m, 4H)
Mass: 416 (M+l).
Example 2: Preparation of 2R-[(3'R)-pvrrolidin-3'-vl)-2-hydroxv-2-cyclopentyl-2-phenyl acetic
acid ester (Compound No. 11)
Step a: Preparation of (3R)-l-benzyl-pyrrolidin-3-ol
The compound (3R)-pyrrolidin-3-ol hydrochloride (2.2 g, 17.8 mM) was dissolved in
dichloromethane (25.0 ml) and triethylamine (5.0 ml, 35.6 mM) was added at room temperature
with constant stirring for about 5 minutes. Benzyl chloride (2.5 ml, 21.4 mM) 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 dried over anhydrous sodium sulphate and
concentrated to get the title compound.
Step b: Preparation of 2R-[((3'R)-l'-benzyl-pyrrolidin-3'-yl)]-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 (3R)-l-benzyl-pyrrolidin-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. Dried, evaporated and the
residue was purified by silica gel column chromatography using ethyl acetate in hexane to afford
the product in 62% (4.5 g) yield.
IR(DCM): 1703.8cm"1
'H NMR (CDC13): 8 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)-l'-pyrrolidin-3'-yl)]-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 fllterate was concentrated under vacuum. 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
'H NMR (CDC13): 8 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)
ample 4: Preparation of (2R. 2SVF(f3'R. 3'S)-l'-benzvl-pvrrolidin-3'-vlmethvl)-2-hvdroxv-2-
(trifluoromethvl)-2-phenvl acetic acid ester (Compound No. 12)
To a solution of 2-trifluoromethyl-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 (3R, 3S)-l-benzyl-3-[(methylsulfonyloxy)methyl]-pyrrolidine (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): 1747.2cm'1
'H NMR (CDC13):S 7.74-7.76 (m, 2H), 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).
Similarly, the following illustrative compounds were prepared following the procedure
described above
[((3'R, 3'S)-l'-benzyl-pyrrolidin-3'-yl-methyl)-2-hydroxy-2,2-diphenyl acetic acid ester
(Compound No. 14)
IR(DCM): 1731.1cm-'
'H NMR (CDC13): 5 7.26-7.41 (m, 15H), 4.14-4.20 (m, 2HO, 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, 3'S)-l'-benzyl-pyrrolidin-3-yl methyl)-2,2-diphenyl acetic acid ester (Compound No. 20)
IR(DCM): 1735.2cm'1
'H NMR (CDC13):8 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)-[((3'R. 3'SVpvrrolidin-3'-vl methvl)-2-hvdroxv-2-
cvclopentyl-2-phenyl acetic acid ester (Compound No. 13)
To a solution of ((3'R)-l'-benzyl-pyrrolidin-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.
Similarly, the following illustrative compounds were prepared following the procedure described
above
(2R. 2S)-IY(3'R. 3'S)-pvrrolidin-3'-vl methvl)-2-hvdroxv-2-cvclohexvl-2-phenvl acetic acid ester
(Compound No. 16)
IR(DCM): 1727.2cm'1
'H NMR (CDC13):5 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)-pvrrolidin-3'-vl methvl)-2-hvdroxv-2.2-diphenyl acetic acid ester (Comp No. 18)
IR(DCM): 1734.0cm'1
'HNMR (CDC13): S 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): 1737.8cm'1
Example 6: Preparation of (2R. 2S)-RY3'R, 3'SM'-methvl-pvrrolidin-3'-vl methvl)-2-hvdroxv-2-
cyclopentyl-2-phenvl acetic acid ester (Compound No. 15)
To a solution of (2R, 2S)-[((3'R, 3'S)-(l-pyrrolidin-3'-ylmethyl)]-2-hydroxy-2-
cyclopentyl-2-phenyl acetic acid ester (prepared in example-5) (0.3 g, 0.99 mm) in acetonitrile
(18.0 ml), formaldehyde (37.1ml, 2.5 mm) and sodium cyanoborohydride (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. Acetonitrile 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
brine solution dried, evaporated and the residue was purified by silica gel column chromatography
using 10% methanol in dichloromethane to get product in 60% yield.
IR(DCM): 1729.6cm-'
'H NMR (CDC13): 5 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 illustrative compounds were prepared following the procedure described
above
(2R. 2S)-IY(3'R. 3'S)-r-methyl-pvrrolidin-3'-vl methvl)-2-hvdroxv-2-cvclohexvl-2-phenvl acetic
acid ester (Compound No. 17)
IR(DCM): 1728.5cm-'
'H NMR (CDC13): 5 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)-r-methvl-pyrrolidin-3'-vl methvl)-2-hvdroxy-2,2-diphenyl acetic acid ester
(Compound No. 19)
IR(DCM): 1737.4cm-'
'H NMR (CDC13): 8 7.35-7.41 (m, 1 OH), 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).
Example 7: Preparation of [((3'R. 3'S)-l'-(benzoH J1dioxol-5-vl-ethvl)-pvrrolidin-3'-vl methvl)-
2.2-diphenvl acetic acid ester (Compound No. 22)
The compound [((3'R, 3'S)-(l'-pyrrolidin-3'-yl methyl)-2,2-diphenyl acetic acid ester was
dissolved in acetonitrile 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
acetonitrile was evaporated under vacuum. The residue was partitioned between ethyl acetate and
water. The organic layer was washed with water and brine solution followed by drying over
anhydrous sodium sulphate and then concentrated. The residue was purified by silica gel column
chromatography using 20% methanol in chloroform to get the title compound.
IR(DCM): 1734.7cm'1
'H NMR (CDC13): 5 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)
Example 8: Synthesis of N-(l-benzvl-pvrrolidin-3-ylmethvl)-2-cyclopentyl-2-hydroxy-N-methyl-
2-phenvl-acetamide (Compound No. 25)
To a solution of the compound 2-cyclopentyl-2-hydroxy-2-phenyl acetic acid (leq.) in
dimethylformamide was added hydroxybenzotriazole (1.5eq.), l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (leq.) and dimethylaminopyridine (catalytic amount). The reaction
mixture was stirred at 15-20°C for 2 hours followed by the addition of N-methylmorpholine (2 eq.) and a
solution of the compound (l-benzyl-pyrrolidin-3-ylmethyl)-methyl-amine (1 eq.) in dimethylformamide
(10 ml). The resulting reaction mixture was stirred at 15-20°C for 1 hour and subsequently at room
temperature for 14 hours. To the mixture was added water and stirred for 15 minutes. The aqueous layer
was extracted with ethylacetate. The organic layer was washed with sodium bicarbonate solution, water
and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue
thus obtained was purified by column chromatography to furnish the title compound.
IR: 1623.8 cm'1, 2951.2 cm'1, 3357.5 cm'1.
'HNMR: 1.256-1.663 (m, 10H), 2.014-2.559 (m, 6H), 2.713-2.951 (m, 4H), 3.399-3.461 (m, 2H),
3.801 (s, 2H), 7.105-7.334 (m, 10H).
The following illustrative compounds were prepared similarily by coupling an appropriate
acid with an appropriate amine or alcohol,
-25-
2-Hvdroxv-2-phenvl-pent-4-ynoic acid l-benzyl-pyrrolidin-3-vlmethyl ester (Comp No. 24)
Mass(m/z): 364.0 (M++l)
IR: 1745.2 cm", 2923.7 cm", 3412.7 cm'
'HNMR: 1.86-1.96 (m, 4H), 2.03-2.59 (m, 6H), 2.79-2.91 (m, 3H), 4.04-4.09 (m, 2H), 7.31-7.74
(m, 10H).
N-(l -Benzyl -pvrrolidin-3-vlmethvl)-2-cvclohexvl-2-hydroxv-N-methyl-2-phenvl- acetamide
(Compound No. 28)
Mass(m/z): 421.0(M++1)
IR: 1623.0 cm'1, 2925.3 cm"1, 3383.8 cm'1
'H NMR (CDC13): 1.17-1.37 (m, 6H), 1.41-1.48 (m, 2H), 1.72-2.61 (m, 12H), 2.75-3.62 (m, 6H),
7.20-7.39 (m, 10H).
N-(l-Benzyl-pyrrolidin-3-vlmethyl)-2-hydroxy-N-methyl-2,2-diphenyl-acetamide (Compound
IR: 1747.5 cm'1, 2925.1 cm'1, 3421.4 cm'1
'H NMR (CDC13): 1.20-2.01 (m, 3H), 2.12-2.43 (m, 4H), 2.87-2.91 (m, 2H), 2.95-3.27 (m, 4H),
3.77 (s, 2H), 7.01-7.32 (m, 15H).
Example 9: Synthesis of 2-cvclopentyl-2-hydroxv-N-methvl-2-phenvl-N-pvrrolidin-3-vlmethylacetamide
(Compound No. 26)
To a solution of the Compound No. 25 (1 eq.) in methanol (20 times) was added palladium
on carbon (10% dry) and ammonium formate. The mixture was refluxed for 25 minutes. The
mixture was cooled and filtered through celite bed. The bed was washed with dichloromethane
and basified the aqueous layer with sodium hydroxide (2N) to a pH 14. The mixture was extracted
with ethylacetate. The organic layer was washed with water and brine, dried over anhydrous
sodium sulphate, filtered and concentrated under reduced pressure to furnish the title compound.
Yield: 96.36%
Mass(m/z): 317.
IR: 1625.7 cm'1, 2958.0 cm'1, 3375.7 cm'1
'H NMR: 1.25-1.32 (m, 2H), 1.60-1.72 (m, 6H), 1.95-2.05 (m, 5H), 2.77-3.04 (m, 8H), 3.17-3.48
(m, 2H), 7.28-7.42 (m, 5H).
-26-
The following illustrative compounds were prepared similarity.
2-Cyclohexyl-2-hydroxv-N-methyl-2-phenyl-N-pvrrolidin-3-ylmethyl-acetamide (Comp No. 30)
Mass(m/z): 331.0 (M++l)
IR: 1620.0 cm'1, 2926.7 cm'1, 3385.4%
'H NMR (CDC13): 1. 10-1. 32 (m, 10H), 1.66-1.70 (m, 4H), 1.98-2.04 (m, 4H), 2.40-2.87 (m, 5H),
3.35 (s, 2H).
Example 10: Synthesis of 2-cvclopentvl-2-hydroxv-N-methvl-N-(l-methyl-pyrrolidin-3-
vlmethyl)-2-phenyl-acetamide (Compound No. 27)
To a solution of the Compound No. 4 (0.2 g) in acetonitrile (10-15 ml) was added 37%
aqueous formaldehyde (1.7 ml) and sodium triacetoxyborohydride (0.16 g) and stirred at room
temperature for one hour. Added acetic acid till the pH of reaction mixture is neutral. The
reaction mixture was stirred for 2 hours at room temperature. Evaporated acetonitrile completely
and added water. Basified to pH 14 with aqueous sodium hydroxide solution (10%). Extracted
with ethyl acetate. The organic layer was separated, washed with water and brine, dried over
anhydrous sodium sulphate, filtered and concentrated under reduced pressure to furnish the title
compound. Yield: 52.67%.
Mass(m/z):
IR: 1623.6 cm'1, 2925.6 cm'1, 3383.7 cm"1
'H NMR: 1.256-1.334 (m, 4H), 1.450-1.513 (m, 7H), 1.587-1.764 (m, 8H), 2.449-2.754 (m, 2H),
2.970-3.409 (m, 4H), 7.30-7.415 (m, 5H).
Example 11: Synthesis of N-[l-(2-benzyloxv-acetvl)-pyrrolidin-3-ylmethyl]-2-cvclopentyl-2-
hydroxy-N-methyl-2-phenyl-acetamide (Compound No. 31)
To a solution of the Compound No. 26 (leq.) in dichloromethane (10 ml) was added
triethylamine (2 eq.) and dimethylaminopyridine (catalytic amount). The mixture was cooled to 0-
5°C and added benzyloxy acetyl chloride (1.5 eq.). The reaction mixture was stirred at 0-5°C for
30 minutes followed by stirring at room temperature for 16 hours. The mixture was quenched
with saturated sodium bicarbonate solution. The organic layer was separated and aqueous layer
was extracted with dichloromethane. The combined organic layers were washed with water and
brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The
residue thus obtained was purified by column chromatography to furnish the title compound.
Yield: 88.53%
Mass (m/z): 465 (M++l), 487 (M++Na).
IR: 1630 cm'1, 2927.1 cm", 3391.9 cm-.
'HNMR: 1.12-1.26 (m, 4H), 1.61-1.75 (m, 6H), 2.32-2.37 (m, 6H), 2.88-3.38 (m, 4H), 4.13-4.63
(m,6H), 7.23-7.41 (m, 10H).
The following illustrative compound was prepared similarily.
Hvdroxv-diphenvl-acetic acid l-(2-benzvloxv-acetvl)-pvrrolidin-3-vlmethvl ester (Compound No.
Mass(m/z): 460.0 (M++l).
IR: 1707.9 cm'1, 2926.8 cm'1, 3031.6 cm'1
'HNMR: 1.255 (s, 2H), 3.30-3.88 (m, 2H), 3.966-4.250 (m, 4H), 4.485-4.87 (m, 5H),
5.285 (m, 1H), 7.225-7.406 (m, 15H).
Biological Activity
Radioligand Binding Assays:
The affinity of test compounds for Ma and MT, muscarinic receptor subtypes were determined by
[3H]-N-Methylscopolamine (NMS) 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. Specific binding of [3H]-NMS was also determined using membranes from
Chinese hamster ovary (CHO) cells expressing cloned human muscarinic receptor subtypes.
Membrane preparation:
(a) Rat tissues
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 ten 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
homogenising buffer (HEPES 20 mM, EDTA lOmM, pH 7.4) and were stored at -70°C until the
time of assay.
(b) CHO cells expressing human recombinant receptors
The cell pellets were homogenised for 30sec at 12,000 to 14,000 rpm, with intermittent gaps of
10-15 sec in ice-cold homogenising buffer (20mM HEPES, lOmM EDTA, pH 7.4).
homogenate was then centrifuged at 40,000g for 20 min at 4°C. The pellet thus obtained was
resuspended in homogenising buffer containing 10% sucrose and was stored at -70°C until the
time of assay.
Ligand binding assay:
The compounds were dissolved and diluted in dimethyl sulphoxide. The membrane homogenates
(5-10 ng protein) were incubated in 250 uL of assay buffer (20mM HEPES, pH 7.4) at 24-25 °C
for 3hrs. Non-specific binding was determined in the presence of 1 \iM Atropine. The incubation
was terminated by vacuum filtration over GF/B fiber filter mats (Wallac) using Skatron cell
harvester. The filters were then washed with ice-cold 50mM Tris HC1 buffer (pH 7.4). The filter
mats were dried and transferred to 24 well plates (PET A No Cross Talk) followed by addition of
500 ul of scintillation cocktail. Radioactivity retained on filters was counted in Microbeta
scintillation counter. The ICso & Kd were estimated by using the non-linear curve-fitting program
using GraphPad Prism software. The value of inhibition constant, Ki was calculated from
competitive binding studies by using Cheng & Prusoff s equation (Biochem Pharmacol, 1973,22:
3099-3108), Ki = IC50 / (l+[L]/Kd), where [L] is the concentration of ligand [3H]-N-methyl
scopolamine used in the particular experiment and Kd is the estimate of affinity of receptors to the
ligand. The final result is expressed as the pKi value - the negative logarithm of Ki.
Compound Nos. 1-31 exhibited Kj in the range of about 1000 nM to about 0.4 nM at rat
MI muscarinic receptors, for example, from about 40 nM to about 0.4 nM, or from about 6 nM to
about 0.4 nM. Compound Nos. 1-31 exhibited Kj in the range of about 1000 nM to about 0.1 nM
at rat M3 muscarinic receptors, for example from about 65 nM to about 0.1 nM, or from about 10
nM to about 0.1 nM.
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 CLAIM:
1. A compound having the structure of Formula I,
IFORMULA
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters,
stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites, wherein
Ri and RZ can be independently selected from alkyl, alkenyl, alkynyl, haloalkyl,
cycloalkyl, aryl or heteroaryl.
R3 can represent hydrogen, lower alkyl, hydroxy, amino or alkoxy.
X can represent oxygen, sulphur or NR8 (wherein R8 can represent hydrogen, lower alkyl
or aralkyl).
n can represent an integer ranging from 0 to 3.
R4, R5 and Re can be independently selected from hydrogen or alkyl.
R7 can represent hydrogen, alkyl, -COR12 (wherein Ri2 represent alkyl, cycloalkyl, aryl, aralkyl or heteroaryl), -CHR9R10 (wherein R9 and R10 can be independently selected from hydrogen, alkyl or aryl) or -(CH2)m-R11 (wherein R11 is aryl or heteroaryl and m can be an integer from 1 to 3).
with the proviso that R1, R2 and RS cannot be phenyl, cycloalkyl and hydroxy, respectively, when Rg and RIO are hydrogen and phenyl, and with the further proviso that when R? is (CH2)m- is hydrogen.
2. A compound which is:
R, 2S)-[(3'R, 3'S)- l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cycopentyl-2-phenylacetic acid ester (Compound No. 1),
[(3'R, 3'S)- 1 '-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetic acid ester (Compound No. 2),
(2R, 2S)-[(3'R, 3'S)- l'-((R)-a-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)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide (Compound No. 4),
(2R, 2S)-N-[(3'R, 3'S)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-
cyclohexyl-2-phenylacetamide (Compound No. 5),
N-[(3'R, 3'S)- l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2,2-diphenyl acetamide (Compound No. 6),
(2R,2S)-[(3'R)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-phenyl acetic acid ester (Compound No. 7), 2R-[(3'R)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-
phenyl acetic acid ester (Compound No. 8), 2S-[(3'R)-l'-((R)-a-methyl-benzyl)-pyrrolidin-3'-ylmethyl]-2-hydroxy-2-cyclopentyl-2-
phenyl acetic acid ester (Compound No. 9), [(3'R)-l'-((R)-a-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)-r-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)-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-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)-l'-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'-yl methyl)-2,2-diphenyl acetic
acid ester (Compound No. 22),
Hydroxy-diphenyl-acetic acid l-(2-benzyloxy-acetyl)-pyrrolidin-3-ylmethyl ester
(Compound No. 23),
2-Hydroxy-2-phenyl-pent-4-ynoic acid l-benzyl-pyrrolidin-3-ylmethyl ester (Compound
No. 24),
N-(l-Benzyl-pyrrolidin-3-ylmethyl)-2-cyclopentyl-2-hydroxy-N-methyl-2-phenyl-acetamide (Compound No. 25),
2-Cyclopentyl-2-hydroxy-N-methyl-2-phenyl-N-pyrrolidin-3-ylmethyl-acetamide (Compound No. 26),
2-Cyclopentyl-2-hydroxy-N-methyl-N-(l-methyl-pyrrolidin-3-ylmethyl)-2-phenyl-acetamide (Compound No. 27),
N-(l-Benzyl-pyrrolidin-3-ylmethyl)-2-cyclohexyl-2-hydroxy-N-methyl-2-phenyl-acetamide (Compound No. 28),
N-(l-Benzyl-pyrrolidin-3-ylmethyl)-2-hydroxy-N-methyl-2,2-diphenyl-acetamide (Compound No. 29),
2-Cyclohexyl-2-hydroxy-N-methyl-2-phenyl-N-pyrrolidin-3-ylmethyl-acetamide (Compound No. 30),
N-[l-(2-Benzyloxy-acetyl)-pyrrolidin-3-ylmethyl]-2-cyclopentyl-2-hydroxy-N-methyl-2-phenyl-acetamide (Compound No. 31),
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites.
3. A pharmaceutical composition comprising a therapeutically effective amount of a
compound as defined in claim lor 2 optionally together with pharmaceutically acceptable
carriers, excipients or diluents.
4. 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
or 2.
5. The method according to claim 4 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
6. 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 3.
7. The method according to claim 6 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.
8. A process of preparing a compound of Formula IVand its pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, esters, stereoisomers, N-oxides, polymorphs,
prodrugs or metabolites, wherein the reaction comprises of following steps:
and X are the same as defined in claim 1.
9. A process of preparing a compound of Formula VIII, and its pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, esters, stereoisomers, N-oxides, polymorphs, prodrugs or metabolites, wherein the reaction comprises of following steps:



RI, RI, RB and X are the same as defined in claim 1.
10. A process of preparing a compound of Formulae XII and XIII and its pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, esters, stereoisomers, N-oxides,
polymorphs, prodrugs, or metabolites, wherein the reaction comprises of the following

RI, R2, RS and X are the same as defined in claim 1.
L is any leaving group selected from halogen, O-mesyl or O-tosyl group.
11. A process of preparing a compound of Formula XV, XVI, XVIII and XIX and its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters,
stereoisomers, N-oxides, polymorphs, prodrugs, or metabolites wherein the reaction
comprises of following steps: