FIELD OF THE INVENTION
This present invention generally relates to muscarinic receptor antagonists, which are useful,
among other uses, for the treatment of various diseases of the respiratory, urinary and
gastrointestinal systems mediated through muscarinic receptors. The invention also relates to the
process for the preparation of disclosed compounds, pharmaceutical compositions containing the
disclosed compounds, and the methods for treating diseases mediated through muscarinic
receptors.
BACKGROUND OF THE INVENTION
Physiological effects elicited by the neurotransmitter acetylcholine are mediated through its
interaction with two major classes of acetylcholine receptors - the nicotinic and muscarinic
acetylcholine receptors. Muscarinic receptors belong to the superfamily of G-protein coupled
receptors and five molecularly distinct subtypes are known to exist (M1, M2, M3, M4 and M5).
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 Ma subtype is present mainly in the heart and bladder smooth muscle, 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 Curr. Opin. Chem. Biol., 3, p. 426 (1999), as well as in Trends in Pharmacol. Sci.,
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.
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 Pharmacol. Sci., 22, p. 215 (2001) has also summarized the recent
developments on the role of different muscarinic receptor subtypes using different muscarinic
receptor of knock out mice.
Almost all the smooth muscles express a mixed population of M2 and M3 receptors. Although the
Ma receptors are the predominant cholinoreceptors, the smaller population of M3- receptors
appears to be the most functionally important as they mediate the direct contraction of these
Page 2 of 2
smooth muscles. Muscarinic receptor antagonists are known to be useful for treating various
medical conditions associated with improper smooth muscle function, such as overactive bladder
syndrome, irritable bowel syndrome and chronic obstructive pulmonary disease. However the
therapeutic utility of antimuscarinics has been limited by poor tolerability as a result of treatment
related, frequent systemic adverse events such as dry mouth, constipation, blurred vision,
headache, somnolence and tachycardia. Thus, there exists a need for novel muscarinic receptor
antagonists that demonstrate target organ selectivity.
WO 04/005252 discloses azabicyclo derivatives described as musacrinic receptor
antagonists. WO 04/004629, WO 04/052857, WO 04/067510, WO 04/014853, WO
discloses 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives described as useful muscarinic
receptor antagonists. WO 2004/056811 discloses flaxavate derivatives as muscarinic receptor
antagonists. WO 2004/056810 discloses xanthene derivatives as muscarinic receptor antagonists.
WO 2004/056767 discloses l-substituted-3-pyrrolidine derivatives as muscarinic receptor
antagonists. WO 9914200, WO 031027060, US 6,200, 991, WO 00/56718 disclose heterocycle
derivatives as muscarinic receptor antagonists. WO2004/089363, WO2004/089898,
WO04069835, WO2004/089900 and WO2004089364 disclose substituted azabicyclohexane
derivatives as muscarinic receptor antagonists. WO2006/018708 disclose pyrrolidine derivatives
as muscarinic receptor antagonists. WO2006/35303 discloses azabicyclo derivatives as
muscarinic receptor antagonists.
J. Med. Cham., 44, p. 984 (2002), describes cyclohexylmethylpiperidinyl-triphenylpropioamide
derivatives as selective M3 antagonist discriminating against the other receptor subtypes. J. Med.
Chem., 36, p. 610 (1993), describes the synthesis and antimuscarinic activity of some 1-
cycloalkyl-l-hydroxy-l-phenyl-3-(4-substituted piperazinyl)-2-propanones and related
compounds. J. Med. Chem., 34, p.3065 (1991), describes analogues of oxybutynin, synthesis and
antimuscarinic activity of some substituted 7-amino-l-hydroxy-5-heptyn-2-ones and related
compounds. Bio-Organic Medicinal Chemistry Letters, 15, p.2093 (2005) describes synthesis and
activity of analogues of Oxybutynin and Tolterodine. Chem. Pharm. Bull. 53(4), 437, 2005
discloses thiazole carboxamide derivatives.
The present invention fills the need of muscarinic receptor antagonists useful in the
treatment of disease states associated with improper smooth muscle function and respiratory
disorders
SUMMARY OF THE INVENTION
In one aspect, there are provided muscarinic receptor antagonists, which can be useful as
safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the
respiratory, urinary and gastrointestinal systems. Also provided are processes for synthesizing
such compounds.
In another aspect, pharmaceutical compositions containing such compounds are provided
together with acceptable carriers, excipients or diluents which can be useful for the treatment of
various diseases of the respiratory, urinary and gastrointestinal systems.
The enantiomers, diastereomers. N-oxides, polymorphs, pharmaceutically acceptable salts
and pharmaceutically acceptable solvates of these compounds as well as metabolites having the
same type of activity are also provided, as well as pharmaceutical compositions comprising the
compounds, their metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or
pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable
carrier and optionally included excipients.
Other aspects will be set forth in the description which follows, and in part will be
apparent from the description or may be learnt by the practice of the invention
In accordance with one aspect, there are provided compounds having the structure of
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides wherein
represents a single bond when G is -OH and double bond when G is -O;
R1 and R2are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl,
aryl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl;
R3 is selected from the group selected from hydrogen, hydroxy, alkoxy, alkenyloxy or
alkynyloxy;
X is selected from oxygen, -NH, -NR (wherein R is alkyl, alkenyl, alkenyl, alkynyl or sulphur or no atom;
Het is heterocyclyl or heteroaryl;
n is an integer from 1 to 6;
With the proviso that when RI and RI are phenyl, R3 is hydroxy and X is no atom then Het cannot
be a saturated heterocyclyl group.
The following definitions apply to terms as used herein:
The term ''alkyl" unless and otherwise specified refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. Groups such as
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the
like exemplify this term. Alkyl may further be substituted with one or more substituents selected
from the group consisting of alkenyl, alkynyl, hydroxy, alkoxy, aryloxy, cycloalkyl, acyl,
acylamino, acyloxy, -NRXC(=O)OR2 (wherein Rx is the same as defined below), azido, cyano,
halogen, thiocarbonyl, substituted thiocarbonyl, carboxy, -COOR2 (wherein R2 is same as defined
above), thiol, alkoxyamino, -NRxRy (wherein Rx and Ry are independently selected from
hydrogen, alkyl, cycloalkyl, aryl, halogen, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl; Rx and Ry may also together join to form a heterocyclyl ring), -C(=O)NRxRy, -
OC(=O)NRxRy, -NRxC(=O)NRxRy, (wherein Rx and Ry are the same as defined earlier), nitro, -
S(O)nRp (wherein Rp is alkyl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, heteroarylalkyl,
heterocyclylalkyl or NRxRy (wherein Rx and Ry are defined earlier) and n is 0, 1 or 2). otherwise constrained by the definition, all substituents may be further substituted by 1-3
substituents chosen from alkyl, carboxy, -COOR2 (wherein R2 is the same as defined earlier), -
NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy, -NRxC(=O)NRxRy, -NRXC(=O)OR2, (wherein Rx and Ry
are the same as defined earlier), hydroxy, alkoxy, halogen, -CFa, cyano and -S(O)nRp (where n
and RP are the same as defined earlier).
Alkyl group as defined above may also be interrupted by 1-5 atoms of groups independently
chosen from oxygen, sulfur and -NRS (where Rs is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heteroaryl or heterocyclyl).
The term "alkenyl" unless and otherwise specified refers to a monoradical of a branched
or unbranched unsaturated hydrocarbon group preferably having 2 to 20 carbon atoms with cis or
trans geometry. Preferred alkenyl groups include ethenyl or vinyl, 1-propylene or allyl, isopropylene,
bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to the
heteroatom, the double bond cannot be alpha to the heteroatom.
Page 5 of 5
It may further be substituted with one or more substituents selected from the group consisting of
alkyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -CF3, -NRxRy, -C(=O)NRxRy, -OC(=0)NRxRy, -
NRxC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), -NRXC(=O)OR2, azido,
cyano, halogen, hydroxy, thiocarbonyl, substituted thiocarbonyl, carboxy, -COOR2 (wherein R2 is
the same as defined earlier), thiol, aryl, aralkyl, aryloxy, cycloalkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, heteroarylalkyl, alkoxyamino, nitro, S(O)nRp (wherein n and Rpare the same as
defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be
further substituted by 1-3 substituents chosen from alkyl, carboxy, -COORa (wherein R2 is the
same as defined earlier), hydroxy, alkoxy, halogen, -CFs, cyano, -NRxRy, -C(=O)NRxRy, -
OC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier) and -S(O),,Rp (where Rp and n
are the same as defined earlier).
The term "alkynyl" unless and otherwise specified refers to a monoradical of an
unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms. Preferred alkynyl groups
include ethynyl, propargyl or propynyl, and the like. In the event that alkynyl is attached to the
heteroatom, the triple bond cannot be alpha to the heteroatom. It may further be substituted with
one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, cycloalkyl,
acyl, acylamino, alkoxyamino, acyloxy, -NRXC(=O)OR2, azido, cyano, halogen, hydroxy,
thiocarbonyl, substituted thiocarbonyl, -CFj, carboxy, -COOR2 (wherein R2 is the same as defined
earlier), thiol, aryl, aralkyl, aryloxy, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl,
heteroarylalkyl, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy, -NRxC(=O)NRxRy (wherein Rx and Ry
are the same as defined earlier), -S(O),,Rp (wherein n and Rp are the same as defined earlier).
Unless otherwise constrained by the definition, all substituents may optionally be further
substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR2 (wherein R2 is the same as
defined earlier), hydroxy, alkoxy, halogen, -CF3, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy
(wherein Rx and Ry are the same as defined earlier), cyano and -S(O)nRp (wherein Rp and n are the
same as defined earlier).
The term "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above.
The term "aryl" herein refers to a carbocyclic aromatic group, for example, phenyl,
biphenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from
the group consisting of halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, aryl, aralkyl,
cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl, alkoxy, aryloxy, -CFa,
nitro, -NRxRy, acyl, cyano, acylamino, thiocarbonyl, substituted thiocarbonyl, -C(=O)NRxRy, -
C(=NOH)NH2, -NRxC(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are the same as defined
Page 6 of 6
earlier), carboxy, -S(O)nRP (where RP and n are the same as defined earlier), -COOR2 (wherein R2
is the same as defined earlier), -NRXC(=O)OR2. The aryl group may also be fused with a
heterocyclic ring, heteroaryl or cycloalkyl ring.
The term "aralkyl" refers to aryl linked through alkyl (wherein alkyl is the same as defined
above) portion and the said alkyl portion contains carbon atoms from 1 -6 and aryl is as defined
above.
The term "cycloalkyl" refers to cyclic alkyl groups containing 3 to 20 carbon atoms
having a single cyclic ring or multiple condensed rings, which may optionally contain one or
more olefinic bonds, unless or otherwise constrained by the definition. Such cycloalkyl groups
include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures such
as adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused with an aryl
group, for example indane or tetrahydro-naphthalene and the like.
It may further be substituted with one or more substituents selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, aryl aralkyl, -
NRXC(=O)OR2, azido, cyano, halogen, hydroxy, thiocarbonyl, substituted thiocarbonyl, carboxy, -
COOR2 (wherein R2 is the same as defined earlier), thiol, aryl, aralkyl, aryloxy, -NRXRY, -
NRxC(=O)NRxRy, -C(=O)NRxRy, -OC(=O)NRXRV (wherein Rx and Ry are the same as defined
earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -CFs, -S(O),,RP
(wherein RP and n are the same as defined earlier). Unless otherwise constrained by the definition,
all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl,
carboxy, hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=O)NRxRy, -NRxC(=O)NRxRy, -
OC(=O)NRxRy (wherein Rx and R> are the same as defined earlier), cyano and -S(O),,RP (where RP
and n are the same as defined earlier).
The term "carboxy" as defined herein refers to -C(=O)OH.
The term "aryloxy" denotes the group O-aryl, wherein aryl is as defined above.
The term "heteroaryl" unless and otherwise specified refers to monocyclic aromatic ring
structure containing 5 or 6 carbon atoms, a bicyclic or a tricyclic aromatic group having 8 to 10
carbon atoms, wherein any one or more carbon atoms of the ring are replaced with one or more
heteroatom(s) independently selected from the group consisting of N, O and S. The said
heteroaryl ring may optionally substituted with 1 to 3 substituent(s) selected from the group
Page 7 of 7
consisting of halogen (F, Cl, Br, I), hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, acyl, acylamino,
thiocarbonyl, substituted thiocarbonyl, alkoxyamino, -NRXC(=O)OR2, carboxy, -S(O)nRP (where
RI> and n are the same as defined earlier), -Cp3, -COOR2 (wherein R2 is the same as defined
earlier), cyano, nitro, -NRxRy, -C(=O)NRxRy, -NRxC(=0)NRxRy and -OC(=O)NRxRy (wherein Rx
and Ry are the same as defined earlier). Examples of heteroaryl groups are pyridinyl, pyridazinyl,
pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, pyrazolyl,
imidazolyl, benzimidazolone, pyrazolone, benzofuranyl, indolyl, benzothiazolyl, xanthene,
benzoxazolyl, and the like.
The term "heterocyclyl" unless and otherwise specified refers to a non aromatic
monocyclic, bicyclic (fused, bridged, or spiro) or tricyclic cycloalkyl group having 5 to 10 atoms
in which 1 to 3 carbon atoms in a ring are replaced by heteroatoms selected from the group
comprising of O, S and N, and are optionally benzofused or fused heteroaryl of 5-6 ring members
and the said heterocyclyl group is optionally substituted wherein the substituents are selected from
the group consisting of halogen (F, Cl, Br, I), hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl, acyl, acylamino,
thiocarbonyl, substituted thiocarbonyl, cyano, alkoxyamino, -NRXC(=O)OR2, nitro, -CFs,
carboxy, -S(O)nRp (where R= and n are the same as defined earlier), -COOR2 (wherein R2 is the
same as defined earlier), -NRxC(=O)NRxRy -C(=O)NRXRV, -OC(=O)NRxRy (wherein Rx and Ry
are the same as defined earlier). Examples of heterocyclyl groups are tetrahydrofuranyl,
dihydrofuranyl, dihydropyridinyl, isoxazolinyl, piperidinyl, morpholine, piperazinyl,
dihydrobenzofuryl, azabicyclohexyl, azabicyclooctyl, dihydroindolyl, imidazoline, and the like.
"Heteroarylalkyl" refers to heteroaryl (wherein heteroaryl is same as defined earlier)
linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl
portion contains carbon atoms from 1-6.
"Heterocyclylalkyl" refers to heterocyclyl (wherein heterocyclyl is same as defined
earlier) linked through alkyl (wherein alkyl is the same as defined above) portion and the said
alkyl portion contains carbon atoms from 1-6.
"Acyl" refers to -C(=O)R" wherein R" is selected from the group hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl.
Page 8 of 8
"Thiocarbonyl" refers to -C(=S)H.
"Substituted thiocarbonyl" refers to -C(=S)R" wherein R" is selected is the same as
defined earlier.
The term "leaving group" generally refers to groups that exhibit the desirable properties of
being labile under the defined synthetic conditions and also, of being easily separated from
synthetic products under defined conditions. Examples of such leaving groups includes but not
limited to halogen (F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals
and the like.
The term "Protecting Groups" is used herein to refer to known moieties, which have thedesirable property of preventing specific chemical reaction at a site on the molecule undergoing
chemical modification intended to be left unaffected by the particular chemical modification. Also
the term protecting group, unless or other specified may be used with groups such as hydroxy,
amino, carboxy and example of such groups are found in T.W. Greene and P.G.M. Wuts,
"Protective Groups in Organic Synthesis", 2nd Edn. John Wiley and Sons, New York, N.Y., which
is incorporated herein by reference. The species of the carboxylic protecting groups, amino
protecting groups or hydroxy protecting group employed is not so critical so long as the
derivatised moiety/moieties is/are stable to conditions of subsequent reactions and can be
removed at the appropriate point without disrupting the remainder of the molecule.
The term "pharmaceutically acceptable salts" refers to derivatives of compounds that can
be modified by forming their corresponding acid or base salts. Pharmaceutically acceptable salts
may also be formed by complete derivatization of the amine moiety e,g. quaternary ammonium
salts.
In accordance with a second aspect, there is provided a method for treatment or
prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory,
urinary and gastrointestinal systems, wherein the disease or disorder is mediated through
muscarinic receptors. The method includes administration of at least one compound having the
structure of Formula I.
In accordance with a third aspect, there is provided a method for treatment or prophylaxis
of an animal or a human suffering from a disease or disorder associated with muscarinic
receptors, comprising administering to a patient in need thereof, an effective amount of a
muscarinic receptor antagonist compound as described above.
Page 9 of 9
In accordance with a fourth aspect, there is provided a method for treatment or prophylaxis
of an animal or a human suffering from a disease or disorder of the respiratory system such asbronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, and the
like; urinary system which induce such urinary disorders as urinary incontinence, lower urinary
tract symptoms (LUTS), etc.; and gastrointestinal system such as irritable bowel syndrome,
obesity, diabetes and gastrointestinal hyperkinesis with compounds as described above, wherein
the disease or disorder is associated with muscarinic receptors.
In accordance with a fifth aspect, there are provided processes for preparing the
compounds as described above.
The compounds described herein exhibit significant potency in terms of their activity, as
determined by in vitro receptor binding and functional assays and in vivo experiments using
anaesthetized rabbits. The compounds that were found active in vitro were tested in vivo. Some
of the compounds are potent muscarinic receptor antagonists with high affinity towards MI and
Mi receptors than M2 and/or 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.
Detailed Description of the Invention
The compounds disclosed herein may be prepared by methods represented by the reaction
sequences, for example, as generally shown in Scheme I:
The compounds of Formula IV can be prepared by following the procedure as depicted in Scheme
I wherein the reaction comprises reacting a compound of Formula II (wherein RI, Ra and Ra are
the same as defined earlier) with a compound of Formula III [wherein n is an integer from 1-6 and
Page 10 of 10
Y is -OH, -Omesyl, -Otosyl, -Otriflyl or -NH2. HC1 or -NHR. HC1 wherein R is the
defined earlier and RI' is selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl and is always a substitutent on the
carbon atoms of imidazolyl ring) to give a compound of Formula IV (wherein X is the same as
defined earlier). The Compound of Formula IV can be further quaternized with a compound of
Formula Q-Z (wherein Q can be selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl, heteroaryl, aralkyl, heteroarylalkyl or heterocyclylalkyl and Z is an anion disclosed in
International Journal of pharmaceutics, 33 (1986), page 202, for example, but not limited to,
acetate, tartarate, chloride, bromide, iodide, sulphate, phosphate, nitrate, carbonate, fumarate,
glutamate, citrate, methanesulphonate, toulenesulphonate, benzenesulphonate, maleate or
succinate) to give a compound of Formula IVa.
The coupling of a compound of Formula II with a compound of Formula III (when Y NH. HC1 or -NHR. HC1) can be carried out in an organic solvent (for example,
dimethylformamide, chloroform, tetrahydrofuran, diethyl ether 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 (DCC)).
The coupling of a compound of Formula II with a compound of Formula III (when Y is -
OH or -SH) can be carried out in an organic solvent, for example, tetrahydrofuran,
dimethylformamide, diethyl ether or dioxane in the presence of a coupling agent, for example,
carbonyldiimidazole l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1)
or dicyclohexylcarbodiimide (DCC).
Alternatively, coupling of a compound of Formula II with a compound of Formula III (when Y is
-OH or -SH) can be carried out in an organic solvent (for example, toluene, heptane or xylene) in
the presence of a base (for example, sodium hydride or sodium methoxide) to give a compound of
Formula IV.
The coupling of a compound of Formula II with a compound of Formula III (when Y is -
Omesyl, -Otosyl or -Otriflyl) can be carried out in an organic solvent (for example, toluene,
heptane or xylene) in the presence of a base (for example, l,8-diazabicyclo[5.4.0]undecen-7-ene
(DBU) or l,4-diazabicyclo[2.2.2]octane) to give a compound of Formula IV.
The quaternization of a compound of Formula IV to give a compound of Formula IVa carried out by reacting the compound of Formula IV with a compound of Formula
Q-Z in an optional organic solvent selected from acetonitrile, dichloromethane, dichloroethane,
carbon tetrachloride, chloroform, toluene, benzene, DMF, DMSO.
Following compounds are prepared by scheme I:
3-(4-Bromobenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 1)
!-[2-({(2R)-2-[(lR)-3, 3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2,3-
dimethyl-lH-imidazol-3-ium iodide (Compound No. 2)
l-(2-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}ethyl)-2-methyl-3-(4-methylbenzyl)-lH-imidazol-
3-ium bromide (Compound No. 3)
!-[2-({(2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)emyl]-2-methyl-3-
(4-methylbenzyl)-lH-imidazol-3-ium bromide (Compound No. 4)
!-[3-({(2R)-2-[(lR)-3, 3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]- dimethyl-lH-imidazol-3-ium iodide (Compound No. 5)
1 l-(3-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2,3-dimethyl-lH-imidazol-3-ium iodide
(Compound No. 6)
l-(3-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2-methyl-3-(4-methylbenzyl)-lHimidazol-
3-ium bromide (Compound No. 7)
3-(4-Bromobenzyl)-l-(3-([cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 8)
3-(4-Bromobenzyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 9)
!-[2-({(2R)-2-[(lR)-3, 3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
(4-methylbenzyl)-lH-imidazol-3-ium bromide (Compound No. 10)
!-[2-({(2R)-2-[(lR)-3, 3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-(4-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium bromide (Compound No. 11)
3-[2-(l, 3-Benzodioxol-5-yl) ethyl]-!-(3-[cycloheptyl(hydroxy)phenylacetyl]oxyjpropyl)-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 12)
!-[3-({(2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-(4-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium (Compound No. 13)
l-(3-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-3-(4-fluorobenzyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 14)
3-(4-Bromobenzyl)-l-[2-({(2R)-2-[(lS)-3, 3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl} oxy)
ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 15)
Page 12 of 12
3-(4-Fluorobenzyl)-l-[2-({(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)ethylJ-2-methyl-lH-imidazol-3-ium bromide (Compound No. 16)
3-Benzyl-l-[2-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl} oxy) ethyl]-
2-methyl-lH-imidazol-3-ium chloride (Compound No. 17)
3-Benzyl-l-[2-({(2R)-2-[(lS)-3, 3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl} oxy)ethyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 18)
!-[2-({(2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2,3-
dimethyl-lH-imidazol-3-iurn bromide (Compound No. 19)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-3-
isopropyl-2-methyl-lH-imidazol-3-ium bromide (Compound No. 20)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium iodide (Compound No. 21)
3-(Cyclopropylmethyl)-l-[3-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}
oxy) propyl]-2-methyl-l H-imidazol-3-ium bromide (Compound No. 22)
3-(Cyclohexylmethyl)-l-[3-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}
oxy) propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 23)
!-[3-({(2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl} oxy) propylJ-2-methyl-
3-[4-(trifluoromethyl) benzyl]-lH-imidazol-3-ium chloride (Compound No. 24)
3-(4-Chlorobenzyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium chloride (Compound No. 25)
3-(3-Bromobenzyl)-l-[3-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}
oxy) propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 26)
!-[3-({(2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl} oxy) propyl]-3-(4-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium chloride (Compound No. 27)
3-Benzyl-l-[3-({(2/?)-2-[( l/?)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl} oxy) propyl]-
2-methyl-lH-imidazol-3-ium chloride (Compound No. 28)
!-[3-({(2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl} oxy) propyl]-2-methyl-
3-(2-phenylethyl)-l H-imidazol-3-ium bromide (Compound No. 29)
!-[3-({(2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetylj oxy) propyl]-2,3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 30)
!-[3-({(2R)-2-[(lR)-3, 3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl} oxy) propyl]-3-(4-
fluorobenzyl)-2-methyl-l H-imidazol-3-ium bromide (Compound No. 31)
3-benzyl-l-{3-[2-Cycloheptyl (hydroxy)phenylacetoxy]propyl}-2-methyl-lH-imidazol-3-ium
chloride (Compound No. 32)
1 -(3- {[2-Cycloheptyl(hydroxy)phenylacetyl]oxy }propyl)-2,3-dimethyl-1 H-imidazol-3-ium
bromide (Compound No. 33)
Page 13 of 13
-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl} oxy) butyl]-2,3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 34)
3-Benzyl-l-[4-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)butyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 35)
3-Benzyl-l-[2-({(2R)-2-[(lR)-3, 3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl} oxy) ethyl]-2-
methyl-lH-imidazol-3-iumn bromide (Compound No. 36)
3-Benzyl-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium chloride (Compound No. 37)
!-[4-({(2R)-2-[(lR)-3, 3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetylj oxy) butyl]-2,3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 38)
3-Benzyl-l-[4-({(2R)-2-[(tR)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl) oxy) butyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 39)
3-(4-tert-Butylbenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}
oxy) ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 40)
3-(Biphenyl-4-ylmethyl)-l-[2-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetylj oxy) ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 41)
3-(2, 5-Difluorobenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 42)
3-(2, 4-Difluorobenzyl)-l-[2-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}
oxy) ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 43)
3-(3, 5-Difluorobenzyl)-l-[2-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}
oxy) ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 44)
3-(3, 4-Difluorobenzyl)-!-[2-({(2R)-2-[(lR)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}
oxy) ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 45)
l-{3-[2-Cyclopentyl (hydroxy)phenylacetoxy]propyl}-2-methyl-3-(pyridin-4-ylmethyl)-lHimidazol-
3-ium bromide (Compound No. 46)
l-[3-(((2R)-2-[(lR)-3, 3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl) oxy) propyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 47)
3-(l, 3-Benzodioxol-5-ylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl} oxy) propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 48)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-
3-propyl-lH-imidazol-3-ium bromide (Compound No. 49)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-3-isobutyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 50)
Page 14 of 14
3-Butyl-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 51)
l-(2-[2-Hydroxy(phenyl)2-thienylacetoxy]ethyl}-2-methyl-3-(2-phenylethyl)-lH-imidazol-3-ium
bromide (Compound No. 52)
3-(Cyclopropylmethyl)-l-{2-[2-hydroxy(phenyl)-2-thienylacetoxy]ethyl}-2-methyl-lH-imidazol-
3-ium bromide (Compound No. 53)
3-Benzyl-l-{2-[2-hydroxy(phenyl)2-thienylacetoxy]ethyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 54)
l-{2-[2-Hydroxy(phenyl)2-thienylacetoxy]ethyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 55)
3-(Cyclopropylmethyl)-l-(2-{2-hydroxy[bis(3-methylphenyl)]acetoxy}ethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 56)
l-(2-{2-Hydroxy[bis(3-methylphenyl)]acetoxy}ethyl)-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 57)
3-Benzyl-l-(2-{2-hydroxy[bis(3-methylphenyl)]acetoxy}ethyl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 58)
l-{2-[2, 2-Bis(4-fluorophenyl)(hydroxy)acetoxy]ethyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 59)
3-Benzyl-l-{2-[2, 2-bis(4-fluorophenyl)(hydroxy)acetoxy]ethyl}-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 60)
l-{2-[2, 2-Bis(4-fluorophenyl)(hydroxy)acetoxy]ethyl}-3-(cyclopropylmethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 61)
3-Benzyl-l-{3-[2, 2-bis(4-fluorophenyl)(hydroxy)acetoxy]propyl}-2-methyl-lH-imidazol-3-ium
bromide (Compound No.62)
l-{3-[2, 2-/)/.s'(4-Fluorophenyl)(hydroxy)acetoxy]propyl}-3-(cyclopropylmethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 63)
l-(3-[2,2-6/.v(4-Fluorophenyl)(hydroxy)acetoxy]propyl}-3-ethyl-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 64)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-
3-(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 65)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 66)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 67)
l-[3-(}(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isopropyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 68)
Page 15 of 15
3-(Cyclopropylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 69)
3-(Cyclohexylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 70)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
(2-phenylethyl)-lH-imidazol-3-ium bromide (Compound No. 71)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2,3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 72)
l-{3-[2,2-6M'(4-Fluorophenyl)(hydroxy)acetoxy]propyl}-2,3-dimethyl-lH-imidazol-3-ium
bromide (Compound No. 73)
3-(4-Bromobenzyl)-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 74)
3-Benzyl-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 75)
3-(Cyclopropylmethyl)-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxyjpropyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 76)
3-Ethyl-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 77)
l-(3-{2-Hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 78)
3-(4-Bromobenzyl)-l-{3-[2-hydroxy(phenyl)2-thienylacetoxy]propyl}-2-methyl-lH-imidazol-3-
ium bromide (Compound No. 79)
3-Benzyl-l-{3-[2-hydroxy(phenyl)2-thienylacetoxy]propyl}-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 80)
3-(Cyclopropylmethyl)-1 - {3-[2-hydroxy(phenyl)2-thienylacetoxy]propyl} -2-methyl-1Himidazol-
3-ium bromide (Compound No. 81)
3-Ethyl-l-{3-[2-hydroxy(phenyl)2-thienylacetoxy]propyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 82)
l-(3-[2-Hydroxy(phenyl)2-thienylacetoxy]propyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 83)
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 84)
3-(Cyclopropylmethyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 85)
Page 16 of 16
3-Butyl-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 86)
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 87)
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)ethyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 88)
3-Benzyl-l-{2-[2-hydroxy(di-2-thienyl)acetoxy]ethyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 89)
3-(Cyclopropylmethyl)-l-{2-[2-hydroxy(di-2-thienyl)acetoxy]ethyl}-2-methyl-lH-imidazol-3-
ium bromide (Compound No. 90)
3-Ethyl-l-{2-[2-hydroxy(di-2-thienyl)acetoxy]ethyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 91)
l-!2-[2-Hydroxy(di-2-thienyl)acetoxy]ethyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No .92)
l-{3-[2-Hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-3-(2-phenylethyl)-lH-imidazol-3-ium
bromide (Compound No. 93)
l-{3-[2-Hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-3-(3-phenoxypropyl)-lH-imidazol-3-
ium bromide (Compound No. 94)
3-Butyl-l-{3-[2-hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 95)
3-Ethyl-l-{3-[2-hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 96)
l-(3-[2-Hydroxy(di-2-thienyl)acetoxy]propyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 97)
1 -(3- {[(2R)-2-Hydroxy-2-phenyl-2- {(1 S)-3-
[(phenylsulfonyl)amino]cyclopentyl}acetyl]oxy}propyl)-2,3-dimethyl-lH-imidazol-3-ium
bromide (Compound No. 98)
3-Benzyl-l-(3-{[(2R)-2-hydroxy-2-phenyl-2-{(lS)-3-
[(phenylsulfonyl)amino]cyclopentyl}acetyl]oxy}propyl)-2-methyl-lH-imidazol-3-ium bromide
(Compound No.99)
3-(4-Bromobenzyl)-l-(3-{[(2R)-2-hydroxy-2-phenyl-2-{(lS)-3-
[(phenylsulfonyl)amino]cyclopentyl}acetyl]oxy}propyl)-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 100)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-ethyl-2-
methyl-lH-imidazol-3-iuin bromide (Compound No. 101)
Page 17 of 17
!-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 102)
3-Butyl-l-[3-({(2R)-2-[(lS)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 103)
l-[3-(((2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 104)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 105)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 106)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 107)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isopropyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 108)
l-[3-(((2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 109)
!-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isobutyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 110)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 111)
l-[3-(((2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-3-
isopropyl-2-methyl-l H-imidazol-3-ium bromide (Compound No. 112)
3-Butyl-l-[3-({(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-1 H-imidazol-3-ium bromide (Compound No. 113)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 114)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
pentyl-1 H-imidazol-3-ium bromide (Compound No. 115)
3-Butyl-l-[2-({(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-1 H-imidazol-3-ium bromide (Compound No. 116)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
propyl-1 H-imidazol-3-ium bromide (Compound No. 117)
!-[2-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-ethyl-2-
methyl-1 H-imidazol-3-ium bromide (Compound No. 118)
Page 18 of 18
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2,3-dimethyllH-
imidazol-3-ium bromide (Compound No. 119)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 120)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-isopropyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 121)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 122)
3-Butyl-l-[2-({(2R)-2-[(lS)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 123)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 124)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 125)
2-(2-Methyl-lH-imidazol-l-yl)ethyl (2R)-[(lR)-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 126)
3-(2-methyl-l//-imidazol-l-yl)propyl (2^)-[(l^)-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 127)
3-(2-Methyl-lH-imidazol-l-yl)propyl cycloheptyl(hydroxy)phenylacetate (Compound No. 128)
2-(2-methyl-l//-imidazol-l-yl)ethyl (2/?)-[(LS>33-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 129)
4-(2-Methyl-lH-imidazol-l-yl)butyl (2R)-[(lR)-3,3-difluorocyclopentyl](hydroxy)phenylacetate
(Compound No. 130)
4-(2-Methyl-lH-imidazol-l-yl)butyl (2R)-[(lR)-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 131)
2-(2-Methyl-1 //-imidazol-1 -yl)ethyl hydroxy(phenyl)-2-thienylacetate
(Compound No. 132)
2-(2-Methyl-1 //-imidazol-1 -yl)ethyl hydroxy[bis(3-methylphenyl)]acetate
(Compound No. 133)
2-(2-Methyl-lH-imidazol-l-yl)ethyl bis(4-fluorophenyl)(hydroxy)acetate (Compound No. 134)
3-(2-Methyl-lH-imidazol-l-yl)propyl bis(4-fluorophenyl)(hydroxy)acetate (Compound No. 135)
3-(2-Methyl-lH-imidazol-l-yl)propyl hydroxy[bis(3-methylphenyl)]acetate (Compound No. 136)
3-(2-Methyl-l//-imidazol-l-yl)propyl hydroxy(phenyl)2-thienylacetate (Compound No. 137)
2-(2-Methyl-l//-imidazol-l-yl)ethyl hydroxy(di-2-thienyl)acetate (Compound No. 138)
3-(2-Methyl-l//-imidazol-l-yl)propyl hydroxy(di-2-thienyl)acetate (Compound No. 139)
-(2-Methyl-lH-imidazol-l-yl)propyl-(2R)-hydroxy(phenyl){(lS)-3-
[(phenylsultbnyl)amino]cyclopentyl}acetate (Compound No. 140)
3-(2-Methyl-1 H-imidazol-1 -yl)propyl-(2R)-[( 1 S)-3,3-
difluorocyclohexyl](hydroxy)phenylacetate (Compound No. 141)
In the above schemes, where specific bases, condensing agents, protecting groups,
deprotecting agents, solvents, catalysts, temperatures, etc. are mentioned, it is to be understood
that other bases, condensing agents, protecting groups, deprotecting agents, solvents, catalysts,
temperatures, etc. known to those skilled in the art may be used. Similarly, the reaction
temperature and duration may be adjusted according to the desired needs.
Suitable salts of the compounds represented by the Formula I were prepared so as to
solubilize the compound in aqueous medium for biological evaluations, as well as to be
compatible with various dosage formulations and also to aid in the bioavailability of the
compounds. Examples of such salts include pharmacologically acceptable salts such as inorganic
acid salts (for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate), organic
acid salts (for example, acetate, tartarate, citrate, fumarate, maleate, tolounesulphonate and
methanesulphonate). When carboxyl groups are included in the Formula 1 as substituents, they
may be present in the form of an alkaline or alkali metal salt (for example, sodium, potassium,
calcium, magnesium, and the like). These salts may be prepared by various techniques, such as
treating the compound with an equivalent amount of inorganic or organic, acid or base in a
suitable solvent.
The compounds described herein can be produced and formulated as their enantiomers,
diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as
metabolites having the same type of activity. Pharmaceutical compositions comprising the
molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs,
solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically
acceptable carrier and optionally included excipient can also be produced.
Where desired, the compounds of Formula I and/ or their pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs,
metabolites, polymorphs or N-oxides may be advantageously used in combination with one or
more other therapeutic agents. Examples of other therapeutic agents, which may be used in
combination with compounds of Formula I of this invention and/ or their pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates,
prodrugs, metabolites, polymorphs or N-oxides include but are not limited to, corticosteroids, beta
agonists, leukotriene antagonists, 5-lipoxygenase inhibitors, anti-histamines, antitussives,
Page 20 of 20
dopamine receptor antagonists, chemokine inhibitors, p38 MAP Kinase inhibitors, and PDE-IV
inhibitors.
The compositions can be administered by inhalation.
Compositions for inhalation or insufflation include solutions and suspensions in
pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The
liquid or solid compositions may contain suitable pharmaceutically acceptable excipients. The
compositions can be administered by the nasal respiratory route for local or systemic effect.
Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed
directly from the nebulizing device or the nebulizing device can be attached to a face masks tent,
or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions
can be administered nasally from devices, which deliver the formulation in an appropriate
manner.
Alternatively, compositions can be administered orally, rectally, parenterally
(intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally,
intraperitoneally or topically.
Solid dosage forms for oral administration may be presented in discrete units, for example,
capsules, cachets, lozenges, tablets, pills, powders, dragees or granules, each containing a
predetermined amount of the active compound. In such solid dosage forms, the active compound
is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or
dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose,
mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin,
polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d)
disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example
paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g)
wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for
example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the
case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight
polyethylene glycols. and the like.
Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and
others well known in this art. They may contain opacifying agents, and can also be of such
composition that they release the active compound or compounds in a certain part of the intestinal
Page 21 of 21
tract in a delayed manner. Examples of embedding compositions which can be used are polymeric
substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or
more of the above mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the
liquid dosage forms may contain inert diluents commonly used in the art, such as water or other
solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, for example,
wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents,
colorants or dyes.
Suspensions, in addition to the active compounds, may contain suspending agents, as for
example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or
mixtures of these substances, and the like.
Dosage forms for topical administration of a compound of this invention include powder,
spray, inhalant, ointment, creams, salve, jelly, lotion, paste, gel, aerosol, or oil. The active
component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any
needed preservatives, buffers or propellants as may be required. Opthalmic formulations, eye
ointments, powders and solutions are also contemplated as being within the scope of this
invention.
Compositions suitable for parenteral injection may comprise pharmaceutically acceptable
sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or dispersions. These preparations may
contain anti-oxidants, buffers, bacteriostats and solutes, which render the compositions isotonic
with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions may
include suspending agents and thickening agents. The compositions may be presented in unit-dose
or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freezedried
or lyophilized condition requiring only the addition of the sterile liquid carrier, for example,
saline or water-tor-injection immediately prior to use. Examples of suitable aqueous and
nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene
glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such
Page 22 of 22
as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of a coating such as lecithin, by the maintenance of the required particle
size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying,
and dispensing agents. Prevention of the action of microorganisms can be ensured by various
antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and
the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride
and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by
the use of agents delaying absorption, for example, aluminum monosterate and gelatin.
Suppositories for rectal administration of the compound of Formula I can be prepared by
mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene
glycols or a suppository wax, which are solid at ordinary temperatures but liquid at body
temperature and which therefore melt in the rectum or vaginal cavity and release the drug.
If desired, and for more effective distribution, the compounds can be incorporated into
slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in
sterile water, or some other sterile injectable medium immediately before use.
Actual dosage levels of active ingredient in the compositions of the invention and spacing
of individual dosages may be varied so as to obtain an amount of active ingredient that is effective
to obtain a desired therapeutic response for a particular composition and method of
administration. It will be understood, however, that the specific dose level for any particular
patient will depend upon a variety of factors including the compound chosen, the body weight,
general health, sex, diet, route of administration, the desired duration of treatment, rates of
absorption and excretion, combination with other drugs and the severity of the particular disease
being treated and is ultimately at the discretion of the physician.
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 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, hexanes, and
dichloromethane, were dried using various drying reagents according to procedures described in
the literature. IR spectra were recorded as nujol mulls or a thin neat film on a Perkin Elmer
Paragon instrument, Nuclear Magnetic Resonance (NMR) were recorded on a Varian XL-300
MHz or Bruker 400 MHz instrument using tetramethylsilane as an internal standard.
Synthesis of methanesulphonic acid 2-(2-methvl-imidazol-l-yl)-ethyl ester
Step a: Synthesis of (2-bromo-ethoxy)-tert-butyl-dimethyl-silane
To a solution of the 2-bromoethanol (5 g, 40 mmol) in dimethylformamide (25 ml) was added
tert-butydimethylsilyl chloride (7.29 g, 48 mmol) and imidazole (6.86 g, 100 mmol). The reaction
mixture was stirred overnight followed by quenching with water and extraction with ethyl acetate.
The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced
pressure to furnish the title compound. Yield: 8 g.
Step b: Synthesis of l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-lH-imidazoIe
Sodium hydride (8.4 g, 210 mmol) was added slowly to dry dimethylformamide (40 ml)
precooled at -10 °C under nitrogen atmosphere. To the resulting suspension was added 2-methyl
imidazole (20.67 g, 252 mmol) at -10 °C and the reaction mixture was allowed to warm to room
temperature. The reaction mixture was stirred for 1 hour at room temperature followed by
cooling to 0 °C. To the mixture was added solution of the compound obtained from step a above
(20 g, 84 mmol) in dimethylformamide (10 ml) and stirred at room temperature for overnight.
The mixture was quenched with aqueous ammonium chloride solution and extracted with
dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulphate and
concentrated under reduced pressure to furnish the title compound. Yield: 12.5 g.
Step c: Synthesis of hydrochloride salt 2-(2-methyl-imidazol-l-yl)-ethanol
To a compound obtained from step b above (12.5 g, 55.6 mmol) was added a solution of ethanolic
hydrochloric acid solution (2 %, 90 ml) at room temperature and stirred the mixture overnight.
The reaction mixture was concentrated under reduced pressure. The residue thus obtained washed
with diethyl ether to furnish the title compound. Yield: 3.9 g.
Following compounds were prepared similarly,
Hydrochloride salt of 2-(2-methyl-imidazol-l-yl)-propanol
Page 24 of 24
Hydrochloride salt of 2-(2-methyl-imidazol-l-yl)-butanol
Step d: Synthesis of methanesulphonic acid 2-(2-methyl-imidazol-l-yl)-ethyl ester
To a solution of the compound obtained from step c above (4 g, 24.6 mmol) in dichloromethane
(60 ml) was added triethylamine (10.27 ml, 73.8 mmol) and dimethylaminopyridine (150 mg) at 0
°C. The reaction mixture was stirred until the compound obtained from step c above becomes
completely soluble. The mixture was cooled down to -5 °C followed by the addition methane
sulphonyl chloride (2.86 ml, 36.9mmol) dropwise with stirring. The mixture was stirred for 3
hours at -5 °C and then at room temperature for overnight. The mixture was diluted with sodium
bicarbonate solution and extracted with dichloromethane. The dichloromethane layer was dried
over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title
compound. Yield: 3.8 g.
'HNMR ( CDC13) - 6.94 (d, 1H), 6.89-6.90 (d, 1H), 4.38-4.41 (t, 2H), 4.19-4.22 (t, 2H), 2.85 (s,
3H),2.42(s, 3H).
Synthesis of methanesulphonic acid 2-(2-methyl-imidazol-l-yl)-propyl ester
To a solution of hydrochloride salt of 2-(2-methyl-imidazol-l-yl)-propanol (1.5 g, 0.0078 mol) and
4-dimethylaminopyridine (catalytic amount) in dry dichloromethane cooled to -30 °C was added
triethylamine (5.5.ml, 0.0393 mol) drop wise and allowed to warm to 20 °C. The reaction mixture
was again cooled to -50 °C and methanesulphonyl chloride (0.9 ml, 0.0117 mol) was added drop
wise. The reaction mixture was allowed to warm to 20 °C and stirred at same temperature for 1
hour. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with
dichloromethane. The combined organic layer was washed with water and brine, dried over
anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was
purified by column chromatography using methanol: trithylamine: dichloromethane (1:2:7) as
eluent to furnish the desired compound. Yield: 1.3 g.
1HNMR (CDC13):8 6.87-6.88 (d, 1H), 7.04 (d, 1H), 3.9 (m, 2H), 4.1(m, 2H), 3.0 (s, 3H), 2-2.05
(m, 2H).
Following compound was prepared similarly,
Methanesulphonic acid 2-(2-methyl-imidazol-l-yl)-butvl ester
Synthesis of (5S)-2-/er/-butvl-5-[(lR)-3-oxocvclohexvl1-5-phenvl-1.3-dioxolan-4-one and (5R)-2-
Step a: Synthesis of (5R)-2-/er/-butyl-5-phenyl-l, 3-dioxolan-4-one
Page 2 5 of 2 5
(R)-Mandelic acid (36.8 g, 0.2419 mol), pivaldehyde (86.13 g, 0.2903 mol) and trifluoromethane
sulphonic acid (0.9 ml, 0.0096 mol) were taken in n-pentane (350 ml). The reaction mixture was
refluxed for 5-6 hours and water was azetotropically removed with Dean stark apparatus. The
reaction mixture was concentrated under reduced pressure. The residue thus obtained was taken in
ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was
separated, washed with water and brine, dried over anhydrous sodium sulphate and concentrated
under reduced pressure to furnish the title compound. Yield: 50.0 g.
Step b: (5R)-2-ter/-butyl-5-[(lR)-3-oxocyclohexyl]-5-phenyl-l, 3-dioxolan-4-one te [(lS)-3-oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one
To a solution of compound obtained from step a (15 gm, 0.0681 mol) in dry tetrahydrofuran (700
ml) was added hexamethylphosphoric acid (54 ml) and cooled to -78 °C and then added lithium
diisopropylamine (38 ml, 0.0749 mol, 2 Molar solution in tetrahydrofuran). The reaction mixture
was stirred at same temperature for 30 minutes, then added cyclohexenone (9.9 ml, 0.1022 mol).
The reaction mixture was again stirred at -78 °C for 2 hours. The reaction mixture was quenched
with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined
organic layer was washed with water and brine, dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The residue was purified over silica gel using ethyl acetate
(2:8) to furnish the desired diastereomers.
Yield of (5R)-2-/cjrr-butyl-5-[(lS)-3-oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one: 4.5
Yield of (5R)-2-/er/'-butyl-5-[(lR)-3-oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one: 1.4
'HNMR (CDC13) of (5R)-2-^rr-butyl-5-[(lR)-3-oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one: 8
7.63-7.65 (m, 2H), 7.31-7.52 (m, 3H), 5.38 (s, 1H), 1.04-2.48 (m, 9H), 0.89 (s, 9H).
'HNMR (CDC13) of (5R)-2-^rt-butyl-5-[(lS)-3-oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one: 8
7.64-7.65 (m, 2H), 7.31-7.52 (m, 3H), 5.38 (s, 1H), 1.25-2.48 (m, 9H), 0.89 (s,9H)
Synthesis of (5R)-2-/'g^-butyl-5-[(17?)-3,3-difluorocvclohexyl]-5-phenvl-l,3-dioxolan-4-one
To a solution of (5R)-2-/err-butyl-5-[(lR)-3-oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one (1.4 g,
0.0044 mol) in chloroform (15 ml) cooled to 0 °C was added diethylaminosulfur trifluoride
(DAST) (1.8 ml, 0.0146 mol) under nitrogen atmosphere. After addition at 0°C, the reaction
mixture was allowed to stir at room temperature for two days. The reaction mixture was cooled on
an ice bath and slowly quenched with aqueous ammonium chloride solution. The organic layer
was separated and aqueous layer was extracted twice with dichloromethane. The combined
organic layer was washed with water and brine and dried over anhydrous sodium sulphate and
concentrated to get crude compound. The crude compound was purified over silica using 2-5 %
ethyl acetate in hexane. Yield: 650 mg.
'HNMR (CDC13): 5 7.62-7.64 (m, 2H), 7.30-7.51 (m, 3H), 5.38 (s, 1H), 1.04-2.29 (m,
Following compound was prepared similarly by using (5R)-2-ter/-butyl-5-[(lS)-3-
oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one in place of (5R)-2-/£7t-butyl-5-[(lR)-3-
oxocyclohexyl]-5-phenyl-l,3-dioxolan-4-one,
(5R)-2-/fr<-Butyl-5-[(lS)-3. 3-difluorocvclohexvl]-5-phenyl-l, 3-dioxolan-4-one
Synthesis of (2/0-[(l^-3,3-difluorocyclohexvl1(hvdroxv)phenylacetic acid
To a solution of (5R)-2-^er/-butyl-5-[(l/?)-3,3-difluorocyclohexyl]-5-phenyl-l,3-dioxolan-4-one
(330 mg, 0.0009 mol) in methanol (15 ml) cooled to 0 °C was added dropwise solution of sodium
hydroxide (5 ml, 3 N, 10 eq., 0.009 mol). The reaction mixture was stirred at 0 °C for 30 minutes
and the stirred at room temperature for overnight. The reaction mixture was concentrated under
reduced pressure. The residue was taken in water and washed with dichloromethane. The aqueous
layer was acidified with concentrated HC1 and then extracted with ethyl acetate. The combined
organic layer was washed with water and brine and dried over anhydrous sodium sulphate and
concentrated under reduced pressure to furnish the desired compound. Yield: 240 mg.
'HNMR (CDCl.0 5 = 7.62-7.65 (m, 2H), 7.28-7.40 (m, 3H), 2.59-2.62 (m, 1H), 1.11-2.06 (m,
8H).
Following compound was prepared similarly;
(2/?)-[( 150-3,3-Difluorocyclohexyl](hydroxy)phenylacetic acid
Example 1: Synthesis of 2-(2-methvl-lH-imidazol-l-yl)ethvl (2R)-f(lR)-3.3-
difluorocyclohexyl](hvdroxy)phenylacetate (Compound No. 126)
To a solution of the compound (2R)-[(l/?)-3,3-difluorocyclohexyl](hydroxy)phenylacetic acid
(300 mg, 1.11 mmoles), methanesulphonic acid 2-(2-methyl-imidazol-l-yl)-ethyl ester (226 mg,
1.11 mmoles) and toluene (20 ml) was added l,8-diazabicyclo[5.4.0]undecen-7-ene (338 mg,
2.22 mmoles) and stirred the mixture overnight under reflux for overnight. The organic solvent
was evaporated under reduced pressure and the residue thus obtained was purified by column
chromatography. Yield: 280 mg.
Following compounds were prepared similarly,
Page 27 of 27
3-r2-Methvl-l//-imidazol-l-vl)propyl(2/?)-r(l/gV3.3-difluorocyclohexyl](hydroxv)phenvIacetate
(Compound No. 127)
3-(2-Methyl-l H-imidazol-l-vl)propyl cycloheptyl(hydroxyl)phenylacetate (Compound No. 128)
2-(2-Methvl-1 //-imidazol-1 -vDethyl (2R)-\( 1S)-3,3-
difluorocvclohexyl](hydroxv)phenylacetate (Compound No, 129)
4-(2-Methvl-1 H-imidazol-1 -vDbutvi (2R)-[( 1 RV3.3- difluorocvclopentvl(hydroxvl)phenvlacetate
(Compound No. 130)
4-(2-Methyl-1 H-imidazol-1 -ypbutyl (2R)-[( 1 R)-3,3-difluorocvclohexvl(hydroxyl)phenylacetate
(Compound No. 131)
2-(2-Methyl-1 //-imidazol-1 -vDethyl hvdroxy(phenvl)-2-thienylacetate
(Compound No. 132)
2-(2-Methy 1-1//-imidazol-1-vDethyl hydroxy[bis(3-methylphenyl)]acetate (Compound No. 133)
2-(2-Methyl-lH-imidazol-1-vDethyl bis[4-fluorophenyl)(hydroxyl)acetate (Compound No. 134)
3-(2-Methyl-l H-imidazol-l-vl)propyl bis(4-fluorophenyl)(hydroxy)acetate (Compound No. 135)
3-(2-Methyl-1 H-imidazol-l-vl)propyl hvdroxy[bis(3-methvlphenyl)]acetate (Compound No. 136)
3-(2-Methyl-l//-imidazol-l-vl)propyl h.ydroxy(phenyl)2-thienylacetate (Compound No. 137)
2-(2-Methyl-l H-imidazol-1-vDethyl hydroxyl(di-2-thienyl)acetate (Compound No. 138)
3-(2-Methyl-l H-imidazol-l-yl)propyi hydroxyl (di-2-thienvl)acetate (Compound No. 139)
3-(2-Methvl-lH-imidazol-l-vl)propvl(2R)-hvdroxv(phenvl)j(lS)-3-
[(phenylsulfonyl)amino]cvclopentvl}acetate (Compound No. 140)
3-(2-Methyl-l H-imidazol-lyl)propyl difluorocvclohexyl (hydroxvl)phenylacetate (Compound
No. 141)
Example 6: Synthesis of 3-(4-bromobenzyl)-l-[2-(|(2R)-2-[(lR)-3.3-difluorocvclohexvl]-
hydroxy-2-phenylacetyl}oxy)ethvl]-2-methvl-lH-imidazol-3-iuin bromide (Compound No. 1)
To the solution of the Compound No. 126 (30 mg) in acetonitrile (1.5 ml), 4-bromobenzylbromide
(excess) was added and the reaction mixture was stirred at 55° C overnight and subsequently at
room temperature for further 24 hours. The reaction mixture was then concentrated under reduced
pressure. The residue was washed with diethyl ether several times and dried under vacuum to
furnish the desired compound. Yield: 20 mg.
Mass Spectrum (M/z): 547 (M+)
Following analogues were prepared similarly by using appropriate alkyl halide, varying the
temperature and time and in the presence of optional co-solvent (such as dichloromethane or
chloroform), as applicable in each case.
Page 28 of 28
3-(4-Bromobenzvn-l-[2-(U2RV2-r(lRV3.3-difluorocvclohexvl1-2-hvdroxv-2-
phenvlacetvlloxv)ethvl1-2-methvl-lH-imidazol-3-ium bromide (Compound No. 1)
l-[2-(i(2R)-2-[(lR)-3,3-Difluorocvclohexvl]-2-hvdroxv-2-phenvlacetvl|oxy)ethvl]-2,3-dimethvllH-
imidazol-3-ium iodide (Compound No. 2)
l-(2-(rCvcloheptvl(hvdroxv)phenvlacetvl1oxy}ethvlN)-2-methvl-3-(4-methvlbenzvl)-lH-imidazol-
3-ium bromide (Compound No. 3)
l-[2-({(2R)-2-l(lR)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvlioxv)ethvl1-2-methyl-3-
(4-methylbenzyl)-lH-imidazol-3-ium bromide (Compound No. 4)
l-r3-(!(2R)-2-[(lR)-3.3-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvl}oxy)propvl1-2.3-
dimethyl-lH-imidazol-3-ium iodide (Compound No. 5)
1, l-(3-{[Cvcloheptyl(hvdroxv)phenvlacetvl]oxy}propvl)-2,3-dimethvl-lH-imidazol-3-ium iodide
(Compound No. 6)
l-(3-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2-methyl-3-(4-methylbenzyl)-lHimidazol-
3-ium bromide (Compound No. 7)
3-(4-Bromobenzyn-l-(3-{[cvcloheptyl(hvdroxv)phenylacetyl]oxy}propvl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 8)
3-(4-Bromobenzvl)-l-[3-(l(2R)-2-r(lR)-3.3-difluorocvclohexvl1-2-hvdroxv-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 9)
l-[2-([(2R)-2-|(lR)-3J-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvlioxv)ethvl]-2-methvl-3-
(4-methylbenzyl)-lH-imidazol-3-ium bromide (Compound No. 10)
l-[2-({(2R)-2-[(lR)-3.3-Difluorocyclohexvl1-2-hydroxy-2-phenylacetyUoxv)ethvn-3-(4-
fluorobenzyn-2-methyl-lH-imidazol-3-ium bromide (Compound No. 11)
3-[2-(l,3-Benzodioxol-5-vl)ethyl]-l-(3-[cvcloheptyl(hydroxy)phenvlacetvl]oxy}propvl)-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 12)
l-f3-({(2R)-2-|'(lR)-3.3-Difluorocyclopentvl]-2-hvdroxy-2-phenvlacetvUoxv)propvl]-3-f4-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium bromide (Compound No. 13)
l-(3-{[Cycloheptyl(hvdroxv)phenylacetyl]oxy}propyl)-3-(4-fluorobenzyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 14)
3-(4-Bromobenzvl)-l-[2-(U2R)-2-[(lS)-3,3-difluorocvclohexvl1-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 15)
3-(4-Fluorobenzvl)-l-r2-(l(2R)-2-f(lS)-3.3-difluorocvclohexvl1-2-hvdroxv-2-
phenylacetyl|oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 16)
3-Benzvl-l-[2-(f(2R)-2-r(lR)-3.3-difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvl}oxy)ethvl]-2-
methyl-lH-imidazol-3-ium chloride (Compound No. 17)
3-Benzvl-l-[2-({(2R)-2-r(lS)-3.3-difluorocvclohexyl]-2-hvdroxy-2-phenylacetvl}oxy)ethyl]-2-
rnethyl-lH-imidazol-3-ium bromide (Compound No. 18)
1 -f 2-(! (2R)-2-[( 1 R)-3.3-Difluorocvclopentvl]-2-hydroxv-2-phenvlacetvUoxv)ethvn-2.3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 19)
1 -[3-( {(2R)-2-[( 1 R)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetyl I oxv)propvl1 -3-
isopropyl-2-methvl-lH-imidazol-3-ium bromide (Compound No. 20)
l-[3-({(2R)-2-[(lR)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvl|oxy)propvl1-3-ethvl-2-
methyl-lH-imidazol-3-ium iodide (Compound No. 21)
3-fCyclopropylmethvn-l-[3-(U2R)-2-[(lR)-3,3-difluorocvclopentvl]-2-hvdroxv-2-
phenvlacetvl}oxy)propvl1-2-methyl-lH-imidazol-3-ium bromide (Compound No. 22)
3-(Cvclohexvlmethvl)-l-p-(U2R)-2-[(lR)-3J-difluorocvclopentvl1-2-hvdroxv-2-
phenylacetvUoxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 23)
l-[3-(U2R)-2-[(lR)-3,3-Difluorocyclopentvl1-2-hvdroxv-2-phenvlacetyl}oxv)propyl]-2-methyl-
3-[4-(trifluoromethvl)benzyl1-l H-imidazol-3-ium chloride (Compound No. 24)
3-(4-Chlorobenzvl)-l-r3-(U2R)-2-[(lR)-3.3-difluorocvclopentvl1-2-hvdroxv-2-
phenvlacetyl}oxy)propvn-2-methvl-lH-imidazol-3-ium chloride (Compound No. 25)
3-(3-Bromobenzyl)-l-[3-(U2R)-2-[(lR)-3.3-difluorocyclopentyl1-2-hydroxy-2-
phenylacetvUoxv)propyl]-2-methvl-l H-imidazol-3-ium bromide (Compound No. 26)
l-[3-(f(2R)-2-|(lR)-3,3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvl}oxv)propvn-3-(4-
fluorobenzvD-2-methyl-lH-imidazol-3-ium chloride (Compound No. 27)
3-Benzvl-l-[3-(U2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hvdroxv-2-phenvlacetvl}oxv)propyl]-2-
methyl- lH-imidazol-3-ium chloride (Compound No. 28)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenvlacetyl|oxy)propvl]-2-methyl-
3-(2-phenylethyl)-lH-imidazol-3-ium bromide (Compound No. 29)
l-[3-(U2R)-2-f(lR)-3.3-Difluorocyclopentyl1-2-hydroxy-2-phenvlacetyUoxv)propvn-2.3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 30)
l-[3-(U2R)-2-[(lR)-3.3-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvlioxv)propyl1-3-(4-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium bromide (Compound No. 31)
3 -Benzyl-1 - {3 - [2-cycloheptyl(hydroxy)phenylacetoxy]propy 11 -2-methyl-1 H-imidazol-3-ium
chloride (Compound No. 32)
l-(3-![2-Cvcloheptyl(hydroxy)phenylacetvl1oxv}propvl)-2.3-dimethvl-lH-imidazol-3-ium
bromide (Compound No. 33)
l-[4-({(2R)-2-[(lR)-3.3-Difluorocvclopentvn-2-hydroxy-2-phenvlacetvUoxy)butvn-2.3-
dimethyl-1 H-imidazol-3-ium bromide (Compound No. 34)
3-Benzvl-l-[4-(U2R)-2-r(lRV3.3-difluorocycIopentyl1-2-hvdroxv-2-phenvlacetvlloxy)butyn-2-
methyl-lH-imida2ol-3-ium bromide (Compound No. 35)
3-Benzvl-l-[2-(U2R)-2-[(lRV3,3-difluorocvclohexyl1-2-hvdroxv-2-phenvlacetvUoxv')ethvl1-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 36)
3-Benzvl-1 -[3-( {(2R)-2-[( 1 R)-3 J-difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvUoxv)propyl1-2-
methyl-lH-imidazol-3-ium chloride (Compound No. 37)
l-[4-(i(2R)-2-r(lR)-3.3-Difluorocvclohexvl]-2-hvdroxv-2-phenvlacetvUoxv)butvn-2.3-dimethyllH-
imidazol-3-ium bromide (Compound No. 38)
3-Benzyl-l-[4-fl(2R)-2-r(lR)-3.3-difluorocyclohexvl1-2-hvdroxv-2-phenylacetvUoxv)butvl1-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 39)
3-(4-ferf-Butylbenzyl)-l-[2-(U2RV2-[(lR)-3.3-difluorocvclopentvl1-2-hydroxy-2-
phenvlacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 40)
3-(Biphenvl-4-ylmethvn-l-[2-(((2R)-2-[(lR)-3,3-difluorocvclopentvl1-2-hvdroxv-2-
phenylacetyl}oxy)ethyl]-2-methyi-lH-imidazol-3-ium bromide (Compound No. 41)
3-(2.5-Difluorobenzvl)-l-[2-(U2R)-2-r(lR)-3.3-difluorocvclopentvl1-2-hvdroxv-2-
phenvlacetylioxv)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 42)
3-(2.4-Difluorobenzvl)-l-[2-(l(2R)-2-[nR)-3.3-difluorocvclopentvl1-2-hvdroxv-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 43)
3-(3,5-Difluorobenzyn-l-[2-({(2R)-2-r(lR)-3.3-difluorocvclopentyl1-2-hydroxy-2-
phenylacetvl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 44)
3-(3,4-Difluorobenzyl)-l-[2-(l(2R)-2-r(lR)-3.3-difluorocyclopentvl1-2-hydroxy-2-
phenylacetyl|oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 45)
l-i3-[2-Cyclopentyl(hydroxy)phenylacetoxv]propvl}-2-methvl-3-(pvridin-4-ylmethvl)-lHimidazol-
3-ium bromide (Compound No. 46)
l-[3-(U2R)-2-r(lR)-3,3-Difluorocvclopentvl]-2-hvdroxv-2-phenvlacetvUoxv)propvl1-3-(lethylpropvl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 47)
3-(l,3-Benzodioxol-5-ylmethvl)-l-r3-(l(2R)-2-rflR)-3.3-difluorocyclopentvn-2-hvdroxy-2-
phenylacetvUoxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 48)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxv-2-phenylacetyl}oxy)propyl1-2-inethyl-
3-propyl-lH-imidazol-3-ium bromide (Compound No. 49)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl1-3-isobutyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 50)
3-Butvl-l-f3-(U2R)-2-[(lR)-3.3-difluorocyclopentyl]-2-hydroxv-2-phenvlacetvl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 51)
Page 31 of 31
l-|2-[2-Hvdroxv(phenyl)-2-thienvlacetoxv]ethvl}-2-methvl-3-(2-phenylethvl)-lH-imidazol-3-
ium bromide (Compound No. 52)
3-(Cvclopropvlmethvn-l-{2-[2-hvdroxv(phenyl')-2-thienvlacetoxv1ethyl}-2-methvl-lH-imidazol-
3-ium bromide (Compound No. 53)
3-Benzvl-l-{2-[2-hvdroxv(phenvl)-2-thienvlacetoxv]ethvl}-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 54)
l-{2-[2-Hydroxy(phenvl)-2-thienylacetoxy]ethyl}-2.3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 55)
3-(Cvclopropylmethyl)-l-(2-{2-hydroxv[bis(3-methvlphenvl)1acetoxy}ethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 56)
l-(2-{2-Hydroxy[bis(3-methylphenyl)]acetoxy}ethyl)-2.3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 57)
3-Benzyl-l-(2-{2-hvdroxv[bis(3-methylphenvl)]acetoxy}ethvl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 58)
l-{2-[2,2-Bis(4-fluorophenvl)(hydroxy)acetoxy]ethyl}-2,3-dimethvl-lH-imidazol-3-ium bromide
(Compound No. 59)
3-Benzvl-l-{2-[2,2-bis(4-fluorophenyl)(hydroxy)acetoxy]ethvl|-2-methvl-lH-imidazol-3-ium
bromide (Compound No. 60)
l-{2-[2,2-iJ?»'(4-Fluorophenyl)(hydroxy)acetoxy]ethyl|-3-(cyclopropylmethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 61)
3-Benzyl-1 - {3-[2.2-bis(4-fluorophenyl)(hvdroxv)acetoxv]propyl} -2-methy 1-1 H-imidazol-3-ium
bromide (Compound No. 62)
l-{3-[2.2-/)M'(4-Fluorophenyl)(hydroxy)acetoxy]propyl}-3-(cvclopropylmethyl)-2-methvl-lHimidazol-
3-ium bromide (Compound No. 63)
l-{3-[2,2-^;X4-Fluorophenyl)(hydroxy)acetoxy]propyl}-3-ethyl-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 64)
l-[3-(((2R)-2-[(lR)-3,3-Difluorocyclopentyl1-2-hydroxy-2-phenvlacetyl}oxy)propyl1-2-methyl-
3-(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 65)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl1-2-hvdroxy-2-phenvlacetvl}oxy)propyl1-2-methyl-3-
(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 66)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hvdroxy-2-phenylacetyUoxy)propvl]-2-methyl-3-
propyl-1 H-imidazol-3-ium bromide (Compound No. 67)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hvdroxy-2-phenylacetyl}oxy)propvl]-3-isopropyl-
2-methyl-l H-imidazol-3-ium bromide (Compound No. 68)
Page 32 of 32
3-(Cvclopropylmethvl)-l-[3-(l(2R)-2-[(lR)-3.3-difluorocvclohexvn-2-hydroxv-2-
phenylacetyl}oxv)propvl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 69)
3-(Cvclohexvlmethvn-l-f3-(l(2R)-2-[(lR)-3.3-difluorocvclohexvl1-2-hvdroxv-2-
phenvlacetyl}oxy)propvl]-2-methyl-lH-imidazol-3-ium bromide (Compound No.70)
l-[3-(i(2R)-2-[(lR)-3.3-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvUoxv)propvl1-2-methvl-3-
(2-phenvlethyl)-lH-irnidazol-3-ium bromide (Compound No. 71)
l-[3-(i(2R)-2-[(lR)-3.3-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvl|oxv)propvn-2.3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 72)
l-{3-[2,2-6Mf(4-Fluorophenvl)(hydroxy)acetoxv1propyl}-2,3-dimethyl-lH-imidazol-3-ium
bromide (Compound No. 73)
3-(4-Bromobenzyl)-l-(3-{2-hvdroxy[bis(3-methylphenyl)]acetoxy}propyI)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 74)
3-Benzvl-l-(3-{2-hvdroxv[bis(3-methylphenyl)]acetoxv}propyl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 75)
3-(Cyclopropylmethvl)-l-(3-|2-hydroxy[bis(3-methylphenvl)]acetoxv}propyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No,76)
3-Ethvl-l-(3-{2-hydroxv[bis(3-methvlphenyl)]acetoxy}propvl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 77)
l-(3-!2-Hydroxv[bis(3-methvlphenyl)]acetoxy}propvl)-2,3-dimethvl-lH-imidazol-3-ium bromide
(Compound No. 78)
3-(4-Bromobenzvl)-l-|3-[2-hvdroxv(phenyl)-2-thienylacetoxy]propyli-2-methyl-lH-imidazol-3-
ium bromide (Compound No. 79)
3-Benzyl-l-|3-[2-hydroxy(phenyl)-2-thienvlacetoxv]propyl}-2-methvl-lH-imidazol-3-ium
bromide (Compound No. 80)
3-(Cyclopropvlmethvl)-l-{3-[2-hydroxy(phenvl)-2-thienylacetoxy]propvl|-2-methvl-lHimidazol-
3-ium bromide (Compound No. 81)
3-Ethvl-l-|3-[2-hvdroxy(phenvl)-2-thienvlacetoxv1propyl}-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 82)
l-|3-[2-Hydroxv(phenvl)-2-thienylacetoxv1propvl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 83)
l-r2-({(2R)-2-[(lR)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvl}oxy)ethyl1-2-methvl-3-
(3-phenoxypropvl)-lH-imidazol-3-ium bromide (Compound No. 84)
3-(Cvclopropvlmethvl)-l-[2-(((2R)-2-r(lR)-3.3-difluorocvclopentvl1-2-hvdroxv-2-
phenylacetvl}oxv)ethvl1-2-methyl-lH-imidazol-3-ium bromide (Compound No. 85)
3-Butvl-l-[2-({(2R)-2-[(lRV3.3-difluorocvclopentvl]-2-hvdroxv-2-phenvlacetvl|oxv)ethvl1-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 86)
l-[2-(U2RV2-[(lRV3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvUoxv)ethvl1-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 87)
l-[2-({(2R)-2-[(lR)-3J-Difluorocyclopentyl]-2-hvdroxv-2-phenvlacetvUoxy)ethyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 88)
3-BenzyI-l-(2-[2-hydroxy(di-2-thienyl)acetoxy]ethyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 89)
3-(Cvclopropvlmethvl)-l-i2-[2-hvdroxv(di-2-thienvl)acetoxv]ethvU-2-methvl-lH-imidazol-3-
ium bromide (Compound No. 90)
3-Ethvl-l-{2-[2-hvdroxv(di-2-thienyl)acetoxy]ethyl|-2-methvl-lH-imidazol-3-ium bromide
(Compound No. 91)
l-t2-[2-Hydroxy(di-2-thienvl)acetoxy]ethyl|-23-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 92)
l-!3-[2-HvdrQxy(di-2-thienyl)acetoxy]propyl}-2-methyl-3-(2-phenvlethyl)-lH-imidazol-3-ium
bromide (Compound No. 93)
l-{3-[2-Hvdroxy(di-2-thienvl)acetoxy]propvl}-2-methvl-3-(3-phenoxvpropyl)-lH-imidazol-3-
ium bromide (Compound No. 94)
3-Butyl-l-{3-[2-hydroxy(di-2-thienyl)acetoxv]propyU-2-methvl-lH-imidazol-3-ium bromide
(Compound No. 95)
3-Ethyl-l-{3-[2-hydroxy(di-2-thienyl)acetoxv]propyl}-2-methyl-lH-imidazQl-3-ium bromide
(Compound No. 96)
l-{3-[2-Hydroxy(di-2-thienyl)acetoxy]propyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 97)
1 -(3-1 [(2R)-2-Hydroxy-2-phenyl-2- {(1 S)-3-
[(phenylsiilfonvl)amino]cyclopentyl}acetvl]oxy|propyl)-2,3-dimethyl-lH-imidazol-3-ium
bromide (Compound No. 98)
3-Benzvl-l-(3-U(2R)-2-hvdroxy-2-phenvl-2-{(lS)-3-
[(phenvlsulfonyl)amino1cvclopentvUacetyl]oxy|propvl)-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 99)
3-(4-Bromobenzvl)-1 -(3-1 r(2R)-2-hydroxy-2-phenyl-2- {(1 S)-3-
[(phenylsulfonyl)amino1cyclopentyl}acetvnoxy}propyl)-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 100)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyUoxy)propyn-3-ethyl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 101)
[3-({(2R)-2-[(lS)-3.3-Difluorocyclopentyn-2-hvdroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 102)
3-Butvl-l-r3-fU2R)-2-r(lS)-3,3-difluorocvclopentyl]-2-hydroxv-2-phenylacetyUoxv)propyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 103)
l-[3-(l(2R)-2-[(lS)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvUoxv)propvl1-2-methvl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 104)
l-[3-(U2R)-2-[(lS)-3.3-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvUoxv)propvl1-3-ethvl-2-
methyl-lH-imida2ol-3-ium bromide (Compound No. 105)
l-f3-(U2R)-2-[nS)-3.3-Difluorocyclohexvl1-2-hydroxy-2-phenvlacetvUoxy)propvl1-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 106)
l-[3-(!(2R)-2-[(lS)-3.3-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvUoxv)propvl1-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 107)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isopropyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 108)
l-[3-(l(2R)-2-[(lS)-3.3-Difluorocyclohexvi1-2-hvdroxv-2-phenvlacetvlloxv)propvn-2-methyl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 109)
l-[3-(U2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isobutyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 110)
l-r3-(U2R)-2-[(lS)-3.3-Difluorocyclopentyl1-2-hvdroxy-2-phenvlacetvl)oxy)propyl1-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. I l l )
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetvl}oxy)propyl]-
isopropyl-2-methyl-lH-imidazol-3-ium bromide (Compound No. 112)
3-Butvl-l-|3-(l(2R)-2-l(lS)-33-difluorocvclohexvl]-2-hydroxv-2-phenvlacetvUoxv)propvl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 113)
l-[2-({(2R)-2-[(lS)-3.3-Difluorocyclohexyl1-2-hydroxv-2-phenylacetvlloxv)ethvn-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 114)
1 -[2-( I (2R)-2-[( 1 S)-3.3-Difluorocvclohexvl1-2-hvdroxv-2-phenylacetvl} oxy)ethvl1-2-methvl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 115)
3-Butvl-1 - \1-( l(2R)-2-r( 1 S)-3.3-difluorocyclohexvll -2-hvdroxv-2-phenvlacetvl} oxv)ethv!1-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 116)
l-[2-(U2R)-2-[(lS)-3.3-Difluorocyclohexyl1-2-hydroxy-2-phenylacetvUoxv)ethvl1-2-methvl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 117)
l-[2-({(2R)-2-[(lS)-3.3-Difluorocyclohexyl]-2-hvdroxy-2-phenvlacetvlloxv)ethvl1-3-ethvl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 118)
-[2-(!(2R)-2-[(lS)-3,3-Difluorocvclohexvl1-2-hvdroxv-2-phenvlacetvl)
foxv)ethvl1-2,3-dimethvIlH-
imidazol-3-ium bromide (Compound No. 119)
l-[2-(U2R)-2-[(lS)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvl}oxvkthvl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 120)
1 -[2-( {(2R)-2-[( 1 S)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvl I oxv)ethyl]-3-isopropvl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 121)
l-[2-({(2R)-2-r(lS)-33-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvl}oxv)ethvl1-2-methvl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 122)
3-Butvl-l-[2-({(2R)-2-[(lS)-33-difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvlloxv)ethvl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 123)
l-r2-({(2R)-2-[(lS)-3.3-DifluorocvcIopentvl1-2-hvdroxv-2-phenvlacetvlioxv)ethvl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 124)
l-r2-({(2R)-2-r(lS)-3.3-Difluorocvclopentvl1-2-hvdroxv-2-phenvlacetvUoxv)ethvl1-3-ethvl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 125)
Biological Activity
Radioligand Binding Assays:
The affinity of test compounds for MI, Ma and M?, muscarinic receptor subtypes was determined
by [3H]-N-methylscopolamine binding studies using rat heart and submandibular gland
respectively as described by Moriya et al., (Life Sci, 1999,64(25): 2351-2358) with minor
modifications. In competition binding studies, specific binding of [3H] NMS was also determined
using membranes from Chinese hamster ovary (CHO) cells expressing cloned human MI, M2, M3,
M4 and M? receptors. Selectivities were calculated from the Ki values obtained on these human
cloned membranes.
Membrane preparation; Submandibular glands and heart were isolated and placed in ice-cold
homogenizing buffer (HEPES 20mM, lOmM 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 centrifuged at 500g for 10 min. at 4 supernatant was subsequently centrifuged at 40,000g for 20 min. at 4 °C. The pellet thus obtained
was resuspended in assay buffer (HEPES 20 mM, EDTA 5mM, pH 7.4) and were stored at -70°C
until the time of assay.
Ligand binding assay: The compounds were dissolved and diluted in DMSO. The membrane
homogenates (150-250 ng protein) were incubated in 250 (al of assay volume (HEPES 20 mM,
Page 36 of 36
pH 7.4) at 24-25°C for 3h. Non-specific binding was determined in the presence of 1
atropine. The incubation was terminated by vacuum filtration over GF/B fiber filters (Wallac).
The filters were then washed with ice-cold 50mM Tris HCI buffer (pH 7.4). The filter mats were
dried and bound radioactivity retained on filters was counted. The IC5Q & Kd were estimated by
using the non-linear curve fitting program using G Pad Prism software. The value of inhibition
constant Kj was calculated from competitive binding studies by using Cheng & Prusoff equation
(Biochem Pharmacol, 1973,22: 3099-3108), Ki = IC$Q /(1+L/Kd), where L is the concentration
used in the particular experiment. pKi is -log [Ki].
The Ki at m3 receptor is in the range of 0.1 nM to 500 nM.
Functional Experiments using isolated rat bladder:
Methodology:
Animals are euthanized by overdose of thiopentone and whole bladder is isolated and removed
rapidly and placed in ice cold Tyrode buffer with the following composition (mMol/L) NaCl 137;
KC1 2.7; CaCl2 1.8; MgCl2 0.1; NaHCO3 11.9; NaH2P04 0.4; Glucose 5.55 and continuously
gassed with 95% O2 and 5 % CO2.
The bladder is cut into longitudinal strips (3mm wide and 5-6 mm long) and mounted in 10 ml
organ baths at 30 °C, with one end connected to the base of the tissue holder and the other end
connected through a force displacement transducer. Each tissue is maintained at a constant basal
tension of 1 g and allowed to equilibrate for 1l / 2 hour during which the Tyrode buffer is changed
every 15-20 min. At the end of equilibration period the stabilization of the tissue contractile
Subsequently a cumulative concentration response curve to carbachol (10~9 mol/L to 3 X mol/L) is obtained. After several washes, once the baseline is achieved, cumulative concentration
response curve is obtained in presence of NCE (NCE added 20 min. prior to the second
cumulative response curve.
The contractile results are expressed as % of control E max. ED50 values are calculated by fitting
a non-linear regression curve (Graph Pad Prism). pKb values are calculated by the formula pKb =
- log [ (molar concentration of antagonist/ (dose ratio-1))]
where,
dose ratio = ED50 in the presence of antagonist/ED50 in the absence of antagonist.
In-vitro functional assay
The Guinea Pig (400-600gm) was procured and trachea was removed under anesthesia (sodium
pentobarbital, 300 mg/kg i.p) and was immediately kept it in ice-cold Krebs Henseleit buffer.
Indomethacin (lOuM) was present throughout the KH buffer to prevent the formation of
bronchoactive prostanoids.
Trachea experiments:
The tissue of adherent fascia was cleaned and was cut into strips of equal size (with approx. 4-5
tracheal rings in each strip). The epithelium was removed by careful rubbing, minimizing damage
to the smooth muscle. Trachea was opened along the mid-dorsal surface with the smooth muscle
band intact and made a series of transverse cuts from alternate sides so that they do not transect
the preparation completely. Opposite ends of the cut rings were tied with the help of a thread. The
tissue was mounted in isolated tissue baths containing 10ml Krebs Henseleit buffer maintained at
37°C and bubbled with carbogen, at a basal tension of 1 gm. The buffer was changed 4-5 times for
about an hour. The tissue was equilibrated for 1 hr for stabilization. After 1 hr, the tissue was
challenged with luM carbachol. This was repeated after every 2-3 washes till two similar
consecutive responses were obtained. At the end of stabilization, the tissue was washed for 30
minutes followed by incubation with suboptimal dose of MRA/ Vehicle for 20 minutes prior to
contraction of the tissues with luM carbachol. The contractile response of tissues was recorded
either on Powerlab data acquisition system or on Grass polygraph (Model 7). The relaxation was
expressed as percentage of maximum carbachol response. The data was expressed as mean ± s.e.
mean for n observations. The ECso was calculated as the concentration producing 50% of the
maximum relaxation to luM carbachol. The percent relaxation was compared between the treated
and control tissues using non-parametric unpaired t-test. A p value of < 0.05 was considered to be
statistically significant.
The tested compounds exhibited a pKb in the range of 8.5 to 10.
In-vitro functional assay to evaluate efficacy of "MRA" in combination with "PDE- inhibitors"
Animals and anaesthesia:
The Guinea Pig (400-600gm) is procured and the trachea is removed under anesthesia (sodium
pentobarbital, 300 mg/kg i.p.) and is immediately kept in ice-cold Krebs Henseleit buffer.
Indomethacin (lOuM) is present throughout the KH buffer to prevent the formation of
bronchoactive prostanoids.
Page 3 8 of 3 8
Trachea experiments:
The tissue of the adherent fascia is cleaned and is cut into strips of equal size (with approx. 4-5
tracheal rings in each strip). The epithelium is removed by careful rubbing, minimizing damage to
the smooth muscle. The trachea is opened along the mid-dorsal surface with the smooth muscle
band intact and make a series of transverse cuts from alternate sides so that they do not transect
the preparation completely. The opposite ends of the cut rings are tied with the help of a thread.
The tissue is mounted in isolated tissue baths containing 10ml Krebs Henseleit buffer maintained
at 37°C and bubbled with carbogen, at a basal tension of 1 gm. The buffer is changed 4-5 times
for about an hour. The tissue is equilibrated for 1 hr for stabilization. After 1 hr, the tissue is
challenged with luM carbachol. This is repeated after every 2-3 washes till two similar
consecutive responses are obtained. At the end of stabilization, the tissues are washed for minutes followed by incubation with suboptimal dose of MRA/ Vehicle for 20 minutes prior to
contraction of the tissues with luM carbachol and subsequently assess the relaxant activity of the
PDE-IV inhibitor [10 "9 M to 10 "4 M ] on the stabilized developed tension/response. The
contractile response of tissues is recorded either on Powerlab data acquisition system or on Grass
polygraph (Model 7). The relaxation is expressed as percentage of maximum carbachol response.
The data is expressed as mean ± s.e. mean for n observations. The ECso is calculated as the
concentration producing 50% of the maximum relaxation to luM carbachol. The percent
relaxation is compared between the treated and control tissues using non-parametric unpaired ttest.
A p value of < 0.05 is considered to be statistically significant.
In-vivo assay to evaluate efficacy of MRA inhibitors
Male Guinea pigs are anesthetized with urethane (1.5 g/kg, i.p.). Trachea is cannulated along with
jugular vein (for carbachol challenge) and animals are placed in the Plethysmograph-Box (PLY
3114 model; Buxco Electronics, Sharon, USA.). Respiratory parameters are recorded using
Pulmonary Mechanics Analyzer, Biosystems XA software (Buxco Electronics, USA), which
calculated lung resistance (RL) on a breath-by-breath basis. Bronchoconstriction is induced by
injections of Carbachol (10 ng/kg) delivered into the jugular vein. Increase in RL over a period of
5 min post carbachol challenge is recorded in presence or absence of MRA or vehicle at 2 hrs and
12 hrs post treatment and expressed as % increase in RL from basal
In-vivo assay to evaluate efficacy of MRA in combination with PDE-IV inhibitors
Drug treatment:
MRA (lug/kg to Img/kg) and PDE-IV inhibitor (lug/kg to Img/kg) are instilled intratracheally
under anesthesia either alone or in combination.
Page 39 of 39
Method:
Male wistar rats weighing 200±20gm are used in the study. Rats have free access to food and
water. On the day of experiment, animals are exposed to lipopolysaccharide (LPS, lOOug/ml) for
40 min. One group of vehicle treated rats is exposed to phosphate buffered saline (PBS) for 40
min. Two hours after LPS/PBS exposure, animals are placed inside a whole body plethysmograph
(Buxco Electronics, USA) and exposed to PBS or increasing acetylcholine (1, 6, 12, 24, 48 and 96
mg/ml) aerosol until Penh values (index of airway resistance) of rats attained 2 times the value
(PC-100) seen with PBS alone. The respiratory parameters are recorded online using Biosystem
XA software, (Buxco Electronics, USA). Penh, at any chosen dose of acetylcholine is, expressed
as percent of PBS response and the using a nonlinear regression analysis PC 100 (2 folds of PBS
value) values are computed. Percent inhibition is computed using the following formula.
Where,
PC 100LpS = PC 100 in untreated LPS challenged group
PClOOiBsi = PC 100 in group treated with a given dose of test compound
PC 1 OOPBS = PC 100 in group challenged with PBS
Immediately after the airway hyperreactivity response is recorded, animals are sacrificed and
bronchoalveolar lavage (BAL) is performed. Collected lavage fluid is centrifuged at 3000 rpm for
5 min, at 4°C. Pellet is collected and resuspended in 1ml HBSS. Total leukocyte count is
performed in the resuspended sample. A portion of suspension is cytocentrifuged and stained with
Leishmann's stain for differential leukocyte count. Total leukocyte and Neutrophil counts \ps = Percentage of neutrophil in untreated LPS challenged group
NC||.;sr =Percentage of neutrophil in group treated with a given dose of test compound
= Percentage of neutrophil in group not challenged with LPS
Page 40 of 40
The percent inhibition data is used to compute EDso vales using Graph Pad Prism software
(Graphpad Software Inc., USA).
In-vivo assay to evaluate efficacy of MRA in combination with Corticosteroids
Qvalbumin induced airway inflammation:
Guinea pigs are sensitised on days 0, 7 and 14 with 50-|ag ovalbumin and 10 mg aluminium
hydroxide injected intraperitoneally. On days 19 and 20 guinea pigs are exposed to 0.1% w v"1
ovalbumin or PBS for 10 min, and with 1% ovalbumin for 30 min on day 21. Guinea pigs are
treated with test compound (0.1, 0.3 and 1 mg kg"1) or standard 1 mg kg"1 or vehicle once daily
from day 19 and continued for 4 days. Ovalbumin / PBS challenge is performed 2 hours after
different drug treatment.
24 hrs after the final ovalbumin challenge BAL is performed using Hank's balanced salt solution
(HBSS). Collected lavage fluid is centrifuged at 3000 rpm for 5 min, at 4°C. Pellet is collected
and resuspended in 1ml HBSS. Total leukocyte count is performed in the resuspended sample. A
portion of suspension is cytocentrifuged and stained with Leishmann's stain for differential
leukocyte count. Total leukocyte and eosinophil count are expressed as cell count (millions cells
ml"1 of BAL). Eosinophil is also expressed as percent of total leukocyte count. % inhibition is
computed using the following formula.
EOSOVA - EOSTHST
EOSQVA - EOSCON
Where,
EOSOVA - Percentage of eosinophil in untreated ovalbumin challenged group
EOSTEST =Percentage of eosinophil in group treated with a given dose of test compound
= Percentage of eosinophil in group not challenged with ovalbumin.
In-vivo assay to evaluate efficacy of "MRA" in combination with p38 MAP Kinase inhibitors
Lipopolysaccharide (LPS) induced airway hyperreactivity (AHR) and neutrophilia:
Drug treatment:
MRA (lug/kg to Img/kg) and p38 MAP kinase inhibitor (lug/kg to Img/kg) are instilled
intratracheally under anesthesia either alone or in combination.
Method:
Male wistar rats weighing 200±20gm are used in the study. Rats have free access to food and
water. On the day of experiment, animals are exposed to lipopolysaccharide (LPS, lOOug/ml) for
40 min. One group of vehicle treated rats is exposed to phosphate buffered saline (PBS) for 40
Page 41 of 41
min. Two hours after LPS/PBS exposure, animals are placed inside a whole body plethysmograph
(Buxco Electronics, USA) and exposed to PBS or increasing acetylcholine (1, 6, 12, 24, 48 and 96
mg/ml) aerosol until Penh values (index of airway resistance) of rats attained 2 times the value
(PC- 100) seen with PBS alone. The respiratory parameters are recorded online using Biosystem
XA software, (Buxco Electronics, USA). Penh, at any chosen dose of acetylcholine is, expressed
as percent of PBS response and the using a nonlinear regression analysis PC 100 (2 folds of PBS
value) values are computed. Percent inhibition is computed using the following formula.
Where,
PC 1 00|,ps = PC 1 00 in untreated LPS challenged group
PClOOresi = PC 100 in group treated with a given dose of test compound
PC 1 OOpus = PC 1 00 in group challenged with PBS
Immediately after the airway hyperreactivity response is recorded, animals are sacrificed and
bronchoalveolar lavage (BAL) is performed. Collected lavage fluid is centrifuged at 3000 rpm for
5 min, at 4°C. Pellet is collected and resuspended in 1ml HBSS. Total leukocyte count is
performed in the resuspended sample. A portion of suspension is cytocentrifuged and stained with
Leishmann's stain for differential leukocyte count. Total leukocyte and Neutrophil counts areexpressed as cell count (millions cells ml"1 of BAL). Percent inhibition is computed using
Percentage of neutrophil in untreated LPS challenged group
NCrtisi -Percentage of neutrophil in group treated with a given dose of test compound
NCcoN = Percentage of neutrophil in group not challenged with LPS
he percent inhibition data is used to compute ED50 vales using Graph Pad Prism software
(Graphpad Software Inc., USA).
In-vivo assay to evaluate efficacy of "MRA" in combination with B2-agonists
Drug treatment:
Page 42 of 42
MRA (lμg/kg to Img/kg) and long acting p2 agonist are instilled intratracheally under anesthesia
either alone or in combination.
Method
Wistar rats (250-350gm) or balb/C mice (20-30gm) are placed in body box of a whole body
plethysmograph (Buxco Electronics., USA) to induce bronchoconstriction. Animals are allowed
to acclimatise in the body box and are given successive challenges, each of 2 min duration, with
PBS (vehicle for acetylcholine) or acetylcholine (i.e. 24, 48, 96, 144, 384, and 768 mg/ml). The
respiratory parameters are recorded online using Biosystem XA software, (Buxco Electronics,
USA) for 3 min. A gap of 2 min is allowed for the animals to recover and then challenged with
the next higher dose of acetylcholine (ACh). This step is repeated until Penh of rats attained 2
times the value (PC-100) seen with PBS challenge. Following PBS/ACh challenge, Penh values
(index of airway resistance) in each rat/mice is obtained in the presence of PBS and different
doses of ACh. Penh, at any chosen dose of ACh is, expressed as percent of PBS response. The
Penh values thus calculated are fed into Graph Pad Prism software (Graphpad Software Inc.,USA)
and using a nonlinear regression analysis PC 100 (2 folds of PBS value) values are computed. %
inhibition is computed using the following formula.
PC 1 OOcoN = PC 100 in vehicle treated group
PClOO-fFST ~ PC 100 in group treated with a given dose of test compound
768 = is the maximum amount of acetylcholine used.
While the present invention has been described in terms of its specific embodiments, certain
modification and equivalents will be apparent to those skilled in the art and are intended.

WE CLAIM:
I . Compounds having the structure of Formula I:
and its pharmaceutically accepted salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or-oxides wherein
represents a single bond when G is -OH and double bond when G is -O;
RI and Riare independently selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl,
aryl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl;
is selected from the group selected from hydrogen, hydroxy, alkoxy, alkenyloxy or
alkynyloxy;
X is selected from oxygen, -NH, -NR (wherein R is alkyl, alkenyl, alkenyl, alkynyl or sulphur or no atom;
Met is heterocyclyl or heteroaryl;
n is an integer from 1 to 6;
With the proviso that when R\ and Ra are phenyl, R3 is hydroxy and X is no atom then Het cannot
be a saturated heterocyclyl group.
2. A compound selected from the group consisting of
Following compounds are prepared by scheme I:
3-(4-Bromobenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 1)
Page 44 of 44
-2-[( 1 R)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl ] oxy )ethyl]-2,3-dimethyllH-
imidazol-3-ium iodide (Compound No. 2)
l-(2-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}ethyl)-2-methyl-3-(4-methylbenzyl)-lH-imidazol-
3-ium bromide (Compound No. 3)
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
(4-methylbenzyl)-lH-imidazol-3-ium bromide (Compound No. 4)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]- 3-dimethyl-lH-imidazol-3-ium iodide (Compound No. 5)
1. l-(3-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2,3-dimethyl-lH-imidazol-3-ium iodide
(Compound No. 6)
1 -(3- {[Cycloheptyl(hydroxy)phenylacetyl]oxy }propyl)-2-methyl-3-(4-methylbenzyl)-l Himidazol-
3-ium bromide (Compound No. 7)
3-(4-Bromobenzyl)-l-(3-{[cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 8)
3-(4-Bromobenzyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 9)
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyljoxy)ethyl]-2-methyl-3-
(4-methylbenzyl)-lH-imidazol-3-ium bromide (Compound No. 10)
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3
rluorobenzyl)-2-methyl-lH-imidazol-3-ium bromide (Compound No. 11)
3-[2-(1.3-Benzodioxol-5-yl)ethyl]-l-(3-[cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 12)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-(4-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium (Compound No. 13)
l-(3-{[Cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-3-(4-fluorobenzyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 14)
3-(4-Bromobenzyl)-l-[2-({(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 15)
3-(4-Fluorobenzyl)-l-[2-(|(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 16)
3-Benzyl-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-lH-imidazol-3-ium chloride (Compound No. 17)
3-Benzyl-l-[2-({(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 18)
Page 45 of 45
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2,3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 19)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-
isopropyl-2-methyl-lH-imidazol-3-ium bromide (Compound No. 20)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium iodide (Compound No. 21)
3-(Cyclopropylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 22)
3-(Cyclohexylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 23)
l-[3-(((2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-
3-[4-(trifluoromethyl)benzyl]-lH-imidazol-3-ium chloride (Compound No. 24)
3-(4-Chlorobenzyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium chloride (Compound No. 25)
3-(3-Bromobenzyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 26)
!-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-(4-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium chloride (Compound No. 27)
3-Benzyl-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium chloride (Compound No. 28)
!-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-
3-(2-phenylethyl)-lH-imidazol-3-ium bromide (Compound No. 29)
l-[3-(((2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-2,3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 30)
!-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-
fluorobenzyl)-2-methyl-lH-imidazol-3-ium bromide (Compound No. 31)
3-Benzyl-l-{3-[2-cycloheptyl(hydroxy)phenylacetoxy]propyl}-2-methyl-lH-imidazol-3-ium
chloride (Compound No. 32)
l-(3-{[2-Cycloheptyl(hydroxy)phenylacetyl]oxy}propyl)-2,3-dimethyl-lH-imidazol-3-ium
bromide (Compound No. 33)
l-[4-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)butyl]-2,3-
dimethyl-lH-imidazol-3-ium bromide (Compound No. 34)
3-Benzyl-l-[4-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)butyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 35)
3-Benzyl-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-lH-imidazol-3-iumn bromide (Compound No. 36)
Page 46 of 46
3-Benzyl-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium chloride (Compound No. 37)
l-[4-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)butyl]-2,3-dimethyllH-
imidazol-3-ium bromide (Compound No. 38)
3-Benzyl-l-[4-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenyIacetyl}oxy)butyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 39)
3-(4-/c,r/-Butylbenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 40)
3-(Biphenyl-4-ylmethyl)-1 -[2-({(2R)-2-[(l R)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 41)
3-(2,5-Difluorobenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 42)
3-(2,4-Difluorobenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 43)
3-(3,5-Difluorobenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 44)
3-(3,4-Difluorobenzyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 45)
l-{3-[2-Cyclopentyl(hydroxy)phenylacetoxy]propyl}-2-methyl-3-(pyridin-4-ylmethyl)-lHimidazol-
3-ium bromide (Compound No. 46)
1 -[ 3-( {(2R)-2-[( 1 R)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl} oxy)propyl] -3-( 1 -
ethylpropyl)-2-methyl-lH-imidazol-3-ium bromide (Compound No. 47)
3-(l,3-Benzodioxol-5-ylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 48)
l-[3-(}(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-2-methyl-
3-propyl-lH-imidazol-3-ium bromide (Compound No. 49)
!-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isobutyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 50)
3-Butyl-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 51)
l-{2-[2-Hydroxy(phenyl)-2-thienylacetoxy]ethyl}-2-methyl-3-(2-phenylethyl)-lH-imidazol-3-
ium bromide (Compound No. 52)
3-(Cyclopropylmethyl)-l-(2-[2-hydroxy(phenyl)-2-thienylacetoxy]ethylj-2-methyl-lH-imidazol-
3-ium bromide (Compound No. 53)
3-Benzyl-l-{2-[2-hydroxy(phenyl)-2-thienylacetoxy]ethyl}-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 54)
Page 47 of 47
l-{2-[2-Hydroxy(phenyl)-2-thienylacetoxy]ethyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 55)
3-(Cyclopropylmethyl)-l-(2-{2-hydroxy[bis(3-methylphenyl)]acetoxy}ethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 56)
l-(2-{2-Hydroxy[bis(3-methylphenyl)]acetoxy}ethyl)-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 57)
3-Benzyl-l-(2-{2-hydroxy[bis(3-methylphenyl)]acetoxy}ethyl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 58)
l-{2-[2,2-Bis(4-fluorophenyl)(hydroxy)acetoxy]ethyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 59)
3-Benzyl-1 - {2-[2,2-bis(4-fluorophenyl)(hydroxy)acetoxy]ethyl} -2-methyl-1 H-imidazol-3-ium
bromide (Compound No. 60)
l-{2-[2,2-Bis(4-fluorophenyl)(hydroxy)acetoxy]ethyl}-3-(cyclopropylmethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 61)
3-Benzyl- l-{3-[2,2-bis(4-fluorophenyl)(hydroxy)acetoxy]propyl}-2-methyl-l H-imidazol-3-ium
bromide (Compound No. 62)
l-{3-[2,2-/7/X4-Fluorophenyl)(hydroxy)acetoxy]propyl}-3-(cyclopropylmethyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 63)
l-{3-[2,2-/JM'(4-Fluorophenyl)(hydroxy)acetoxy]propyl}-3-ethyl-2-methyl-l H-imidazol-3-ium
bromide (Compound No. 64)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-2-methyl-
3-(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 65)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 66)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-2-methyl-3-
propyl-1 H-imidazol-3-ium bromide (Compound No. 67)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isopropyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 68)
3-(Cyclopropylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexylJ-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 69)
3-(Cyclohexylmethyl)-l-[3-({(2R)-2-[(lR)-3,3-difluorocyclohexyl]-2-hydroxy-2-
phenylacetyl}oxy)propyl]-2-methyl-lH-imidazol-3-ium bromide (Compound No. 70)
l-[3-({(2R)-2-[(lR)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
(2-phenylethyl)-lH-imidazol-3-ium bromide (Compound No. 71)
1 -[3-( {(2R)-2-[( 1 R)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl }oxy)propyl]-2,3-
dimethyl-1 H-imidazol-3-ium bromide (Compound No. 72)
Page 48 of 48
l-{3-[2,2-/)/'.v(4-Fluorophenyl)(hydroxy)acetoxy]propyl}-2,3-dimethyl-lH-imidazol-3-ium
bromide (Compound No. 73)
3-(4-Bromobenzyl)-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 74)
3-Benzyl-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 75)
3-(Cyclopropylmethyl)-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2-methyl-lHimidazol-
3-ium bromide (Compound No. 76)
3-Ethyl-l-(3-{2-hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 77)
l-(3-{2-Hydroxy[bis(3-methylphenyl)]acetoxy}propyl)-2,3-dimethyl-lH-iniidazol-3-ium bromide
(Compound No. 78)
3-(4-Bromobenzyl)-1 - {3-[2-hydroxy(phenyl)-2-thienylacetoxy]propyl}-2-methyl-1 H-imidazol-3-
ium bromide (Compound No. 79)
3-Benzyl-l-{3-[2-hydroxy(phenyl)-2-thienylacetoxy]propyl}-2-methyl-lH-imidazol-3-ium
bromide (Compound No. 80)
3-(Cyclopropylmethyl)-l-{3-[2-hydroxy(phenyl)-2-thienylacetoxy]propylj-2-methyl-1Himidazol-
3-ium bromide (Compound No. 81)
3-Ethy 1-1 - {3-[2-hydroxy(phenyl)-2-thienylacetoxy]propyl} -2-methyl-1 H-imidazol-3-ium
bromide (Compound No. 82)
l-{3-[2-Hydroxy(phenyl)-2-thienylacetoxy]propyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 83)
l-[2-(((2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl)oxy)ethyl]-2-methyl-3-
(3-phenoxypropyl)-lH-imidazol-3-ium bromide (Compound No. 84)
3-(Cyclopropylmethyl)-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-
phenylacetyl}oxy)ethyl]-2-methyl-l H-imidazol-3-ium bromide (Compound No. 85)
3-Butyl-l-[2-({(2R)-2-[(lR)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-1 H-imidazol-3-ium bromide (Compound No. 86)
l-[2-(((2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
propyl-1 H-imidazol-3-ium bromide (Compound No. 87)
l-[2-({(2R)-2-[(lR)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-ethyl-2-
methyl-1 H-imidazol-3-ium bromide (Compound No. 88)
3-Benzyl-l-{2-[2-hydroxy(di-2-thienyl)acetoxy]ethyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 89)
3-(Cyclopropylmethyl)-l-{2-[2-hydroxy(di-2-thienyl)acetoxy]ethyl|-2-methyl-1 H-imidazol-3-
ium bromide (Compound No. 90)
Page 49 of 49
3-Ethyl-l-{2-[2-hydroxy(di-2-thienyl)acetoxy]ethyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 91)
l-{2-[2-Hydroxy(di-2-thienyl)acetoxy]ethyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 92)
l-{3-[2-Hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-3-(2-phenylethyl)-lH-imidazol-3-ium
bromide (Compound No. 93)
l-{3-[2-Hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-3-(3-phenoxypropyl)-lH-imidazol-3-
ium bromide (Compound No. 94)
3-Buty 1-1 -{3-[2-hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-1 H-imidazol-3-ium bromide
(Compound No. 95)
3-Ethyl-l-{3-[2-hydroxy(di-2-thienyl)acetoxy]propyl}-2-methyl-lH-imidazol-3-ium bromide
(Compound No. 96)
l-{3-[2-Hydroxy(di-2-thienyl)acetoxy]propyl}-2,3-dimethyl-lH-imidazol-3-ium bromide
(Compound No. 97)
1 -(3- {[(2R)-2-Hydroxy-2-phenyl-2- {(1 S)-3-
[(phenylsulfonyl)amino]cyclopentyl}acetyl]oxyjpropyl)-2,3-dimethyl-l H-imidazol-3-ium
bromide (Compound No. 98)
3-Benzyl-l-(3-{[(2R)-2-hydroxy-2-phenyl-2-{(lS)-3-
[(phenylsulfonyl)amino]cyclopentyl}acetyl]oxy}propyl)-2-methyl-l H-imidazol-3-ium bromide
(Compound No. 99)
3-(4-Bromobenzyl)-l-(3-{[(2R)-2-hydroxy-2-phenyl-2-{(lS)-3-
[(phenylsulfonyl)amino]cyclopentyl}acetyl]oxy}propyl)-2-methyl-l H-imidazol-3-ium bromide
(Compound No. 100)
!-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-ethyl-2-
methyl-1 H-imidazol-3-ium bromide (Compound No. 101)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
propyl-1 H-imidazol-3-ium bromide (Compound No. 102)
3-Butyl-l-[3-({(2R)-2-[(lS)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methy 1-1 H-imidazol-3-ium bromide (Compound No. 103)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
pentyl-1 H-imidazol-3-ium bromide (Compound No. 104)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-ethyl-2-
methyl-1 H-imidazol-3-ium bromide (Compound No. 105)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
propyl-1 H-imidazol-3-ium bromide (Compound No. 106)
Page 5Oof 50
l-[3-(((2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 107)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-isopropyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 108)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-methyl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 109)
l-[3-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyljoxy)propyl]-3-isobutyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 110)
l-[3-(i(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. I l l )
l-[3-(((2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-3-
isopropyl-2-methyl-lH-imidazol-3-ium bromide (Compound No. 112)
3-Butyl-l-[3-({(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)propyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 113)
l-[2-([(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 114)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 115)
3-Butyl-l-[2-({(2R)-2-[(lS)-3,3-difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 116)
l-[2-(}(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 117)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 118)
l-[2-(((2R)-2-[(lS)-3,3-Difluorocyclohexyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2,3-dimethyllH-
imidazol-3-ium bromide (Compound No. 119)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-(lethylpropyl)-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 120)
!-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-isopropyl-
2-methyl-lH-imidazol-3-ium bromide (Compound No. 121)
l-[2-({(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-methyl-3-
pentyl-lH-imidazol-3-ium bromide (Compound No. 122)
3-Butyl-l-[2-({(2R)-2-[(lS)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 123)
l-[2-(|(2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl)oxy)ethyl]-2-methyl-3-
propyl-lH-imidazol-3-ium bromide (Compound No. 124)
Page 51 of 51
l-[2-(((2R)-2-[(lS)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetyl}oxy)ethyl]-3-ethyl-2-
methyl-lH-imidazol-3-ium bromide (Compound No. 125)
2-(2-Methyl-lH-imidazol-l-yl)ethyl (2R)-[(lR)-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 126)
3-(2-Methyl-1 //-imidazol-1 -yl)propyl (2R)-[( 1 /0-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 127)
3-(2-Methyl-lH-imidazol-l-yl)propyl cycloheptyl(hydroxy)phenylacetate (Compound No. 128)
2-(2-Methyl-lH-imidazol-l-yl)ethyl (2R)-[(lS)-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 129)
4-(2-Methyl-1 H-imidazol-1 -yl)butyl (2R)-[( 1 R)-3,3-difluorocyclopentyl](hydroxy)phenylacetate
(Compound No. 130)
4-(2-Methyl-l H-imidazol-l-yl)butyl (2R)-[(lR)-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 131)
2-(2-Methyl-l//-imidazol-l-yl)ethyl hydroxy(phenyl)-2-thienylacetate (Compound No. 132)
2-(2-Methyl-l//-imidazol-l-yl)ethyl hydroxy[bis(3-methylphenyl)]acetate (Compound No. 133)
2-(2-Methyl-l H-imidazol-l-yl)ethyl bis(4-fluorophenyl)(hydroxy)acetate (Compound No. 134)
3-(2-Methyl-l H-imidazol-l-yl)propyl bis(4-fluorophenyl)(hydroxy)acetate (Compound No. 135)
3-(2-Methyl-l H-imidazol-l-yl)propyl hydroxy[bis(3-methylphenyl)]acetate (Compound No. 136)
3-(2-Methy 1-1 //-imidazol-1 -yl)propyl hydroxy(phenyl)2-thienylacetate
(Compound No. 137)
2-(2-Methyl-l H-imidazol-l-yl)ethyl hydroxy(di-2-thienyl)acetate (Compound No. 138)
3-(2-Methyl-lH-imidazol-l-yl)propyl hydroxy(di-2-thienyl)acetate (Compound No. 139)
3-(2-Methyl-l H-imidazol- l-yl)propyl (2R)-hydroxy(phenyl){(lS)-3-
[(phenylsulfonyl)amino]cyclopentyl}acetate (Compound No. 140)
3-(2-Methyl-lH-imidazol-l-yl)propyl (2R)-[(lS)-3,3-difluorocyclohexyl](hydroxy)phenylacetate
(Compound No. 141)
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound as
defined in claim 1 or 2 together with pharmaceutically acceptable carriers, excipients or diluents.
4. The use of compounds according to claim 1 or 2 for the manufacture of medicament for treating
or preventing disorder of the respiratory, urinary and gastrointestinal systems, wherein the disease
or disorder is mediated through muscarinic receptors, in animal or human.
5. The use of the compounds as described in claim 4 for the manufacture of medicament for
treating or preventing urinary incontinence, lower urinary tract symptoms (LUTS), bronchial
Page 5 2 of 5 2
asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, irritable bowel
syndrome, obesity, diabetes or gastrointestinal hyperkinesis.
6. The use of the compounds as defined in Claim 3 for the manufacture of a medicament for
the treating or preventing disease or disorder of the respiratory, urinary and gastroinstestinal
systems, wherein the disease or disorder is mediated through muscarinic receptors, in
7. The use of the compounds as defined in claim 6 for the manufacture of a medicament
the treating or preventing urinary incontinence, lower urinary tract symptoms (LUTS), bronchial
asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, irritable bowel
syndrome, obesity, diabetes or gastrointestinal hyperkinesis.
8. A pharmaceutical composition comprising one or more compounds of Formula I
and its pharmaceutically accepted salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers, polymorphs or N-oxides wherein
epresents a single bond when G is -OH and double bond when G is -O;
RI and R2are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl,
aryl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl;
RI is selected from the group selected from hydrogen, hydroxy, alkoxy, alkenyloxy or
alkynyloxy;
X is selected from oxygen, -NH, -NR (wherein R is alkyl, alkenyl, alkenyl, alkynyl or sulphur or no atom;
Het is heterocyclyl or heteroaryl;
With the proviso that when RI and Ra are phenyl, RS is hydroxy and X is no atom then Het cannot
be a saturated heterocyclyl group
and atleast one other active ingredients selected from corticosteroids, beta agonists, leukotriene
antagonists, 5-lipoxygenase inhibitors, anti-histamines, antitussives, dopamine receptor
antagonists, chemokine inhibitors, p38 MAP Kinase inhibitors, and PDE-IV inhibitors
9. A method of making compounds of Formula IVa, and its pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides
wherein the method comprises:
a. coupling a compound of Formula II
RI and R2are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl,
aryl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl;
R3 is selected from the group selected from hydrogen, hydroxy, alkoxy, alkenyloxy alkynyloxy;
X is selected from oxygen, -NH, -NR (wherein R is alkyl, alkenyl, alkenyl, alkynyl or aryl),
sulphur or no atom;
n is an integer from 1 to 6;
is selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, heterocyclylalkyl or heteroarylalkyl and RI' is always a substitutent on the carbon
atoms of imidazolyl ring;
is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,
heteroarylalkyl or heterocyclylalkyl;
Z is an anion selected from tartarate, chloride, bromide, iodide, sulphate, phosphate, nitrate,
carbonate, fumarate, glutamate, citrate, methanesulphonate, benzenesulphonate,;