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 andgastrointestinal systems mediated through muscarinic receptors. The invention also relates to theprocess 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
Muscarinic receptors as members of the G Protein Coupled Receptors (GPCRs) are
composed of a family of 5 receptor sub-types (Mi, Ma, Ma, M4 and MS) and are activated by theneurotransmitter acetylcholine. These receptors are widely distributed on multiple organs andtissues and are critical to the maintenance of central and peripheral cholinergic
neurotransmission. The regional distribution of these receptor sub-types in the brain and otherorgans 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 where it mediates cholinergically induced bradycardia, and the MS subtype is located
predominantly on smooth muscle and salivary glands (Nature, 323, p.411 (1986);
A review in Current Opinions in Chemical Biology, 3, p. 426 (1999), as well as in Trends
in Pharmacological Sciences, 22, p. 409 (2001) by Eglen et. al, describes the biological
potentials of modulating muscarinic receptor subtypes by ligands in different disease conditions,such as Alzheimer's Disease, pain, urinary disease condition, chronic obstructive pulmonary
disease, and the like.A review in J. Med. Chem., 43, p. 4333 (2000), by Felder et. al. describes therapeuticopportunities for muscarinic receptors in the central nervous system and elaborates on muscarinic
receptor structure and function, pharmacology and their therapeutic uses.
The pharmacological and medical aspects of the muscarinic class of acetylcholine agonistsand antagonists are presented in a review in Molecules, 6, p. 142 (2001).
Birdsall et. al. in Trends in Pharmacological Sciences, 22, p. 215 (2001) have also
summarized the recent developments on the role of different muscarinic receptor subtypes usingdifferent muscarinic receptor of knock out mice.
Muscarinic agonists such as muscarine and pilocarpine and antagonists such as atropine
have been known for over a century, but little progress has been made in the discovery of receptorsubtype-selective compounds, making it difficult to assign specific functions to the individualreceptors. Although classical muscarinic antagonists such as atropine are potent bronchodilators,
their clinical utility is limited due to high incidence of both peripheral and central adverse effects
such as tachycardia, blurred vision, dryness of mouth, constipation, dementia, etc. Subsequentdevelopment of the quarterly derivatives of atropine such as ipratropium bromide are bettertolerated than parenterally administered options, but most of these are not ideal anti-cholinergic
bronchodilators, due to lack of selectivity for muscarinic receptor sub-types, resulting in doselimitingside-effects such as thirst, nausea, mydriasis and those associated with the heart such astachycardia mediated by the Iv^ receptor.
Annual Review of Pharmacological Toxicol.,41, p. 691 (2001), describes the
pharmacology of the lower urinary tract infections. Although anti-muscarinic agents such asoxybutynin and tolterodine that act non-selectively on muscarinic receptors have been used for
many years to treat bladder hyperactivity, the clinical effectiveness of these agents has beenlimited due to the side effects such as dry mouth, blurred vision and constipation. Tolterodine isconsidered to be generally better tolerated than oxybutynin. (Steers et. al., in Curr. Opin. Invest.
Drugs, 2, 268; Chappie et. al., in Urology, 55, 33; Steers et al., Adult and Pediatric Urology, ed.Gillenwatteret al., pp 1220-1325, St. Louis, MO; Mosby. 3rd edition (1996)).There remains a need for development of new highly selective muscarinic antagonistswhich can interact with distinct subtypes, thus avoiding the occurrence of adverse effects.Compounds having antagonistic activity against muscarinic receptors have been describedin Japanese patent application Laid Open Number 92921/1994 and 135958/1994; WO 93/16048;U.S. Patent No. 3,176,019; GB 940,540; EP 0325 571; WO 98/29402; EP 0801067; EP 0388054;
WO 9109013; U.S. Patent No. 5,281,601. Also, U.S. Patent Nos. 6,174,900, 6,130,232 and5,948,792; WO 93/16018 and WO96/33973 are other references of interest; WO 97/45414 are
related to 1,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated,1,4-disubstitued piperidine derivatives; U. S. Patent No. 5,397,800 discloses 1-azabicyclo[2.2.]heptanes. U.S. Patent No.5, 001,160 describes l-aryl-l-hydroxy-l-substituted-3-
(4-substituted-l-piperazinyl)-2-propanones. WO 99/43657 describes 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives as muscarinic receptors antagonists. WO 01/090082 describes
substituted 1-amino-alkyl lactams and their use as muscarinic receptor antagonists. WO 01/47893describes azabicycloctane derivatives useful in the treatment of cardiac arrhythmias. WO01/42213 describes 2-biphenyl-4-piperidinyl ureas. WO 01/42212 describes carbamatederivatives. WO 01/90081 describes amino alkyl lactam. WO 02/53564 describes novelquinuclidine derivatives. WO 02/00652 describes
02/06241 describes l,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives. U.S. application No.20030105071 describes thiazole and other heterocyclic ligands for mammalian dopamine,
muscarinic and serotonic receptors and transporters, and method of use thereof. WO 03/033495describes quinuclidine derivatives and their use as MI and/or MS muscarinic receptor antagonists.US2003/0171362 describes amino-tetralin derivatives as muscarinic receptor antagonists.
US2003/0162780 describes 4-piperidinyl alkyl amine derivatives as muscarinic receptor
antagonists. U.S. 5,179,108 disclose derivatives of 4-(aminomethyl) piperidine and theirtherapeutic applications. WO 03/048125 discloses aminotetralin derivatives as muscarinic
receptor antagonists. WO 03/048124 discloses 4-piperidinyl alkylamine derivatives as muscarinic
receptor antagonists. WO 2004/052857 and WO 04/004629 disclose 3,6-disubstituted azabicyclo
[3.1.0] hexane derivatives useful as muscarinic receptor antagonists. WO 04/005252 discloses
azabicyclo derivatives as musacrinic receptor antagonists, discloses WO 04/014853, WO
04/067510 and WO 04/014363 disclose derivatives of 3,6-disubstituted azabicyclohexane useful
as muscarinic receptor antagonists. WO 2004/056810 discloses xanthine derivatives as muscarinic
receptor antagonists. WO 2004/056811 discloses flaxavate derivatives as muscarinic receptor
antagonists. WO 2004/056767 discloses l-substituted-3-pyrrolidine derivatives as muscarinic
receptor antagonists. WO 2004/018422 disclose fluoro and sulphonylamino containing 3,6-
disubstituted azabicyclo[3.1.0] hexane derivatives as muscarinic receptor antagonists.
J.Med.Chem., 44, p. 984 (2002), describes cyclohexylmethylpiperidinyltriphenylpropioamide
derivatives as selective MS antagonist discriminating against the other
receptor subtypes. J.Med.Chem., 36, p. 610 (1993), describes the synthesis and antimuscarinic
activity of some l-cycloalkyl-l-hydroxy-l-phenyl-3-(4-substituted piperazinyl)-2-propanones and
related compounds. J.Med.Chem., 34, p.3065 (1991), describes analogues of oxybutynin,
synthesis and antimuscarinic activity of some substituted 7-amino-l-hydroxy-5-heptyn-2-ones
and related compounds.
Summary of the Invention
In one aspect, there are provided muscarinic receptor antagonists, which can be useful as
safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the
respiratory, urinary and gastrointestinal systems. Also provided are processes for synthesizing
such compounds.
In another aspect, pharmaceutical compositions containing such compounds are providedtogether with acceptable carriers, excipients or diluents which can be useful for the treatment of
various diseases of the respiratory, urinary and gastrointestinal systems.
The enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts
and pharmaceutically acceptable solvates of these compounds as well as metabolites having the
same type of activity are also provided, as well as pharmaceutical compositions comprising the
compounds, their metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or
pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable
carrier and optionally included excipients.
Other aspects will be set forth in the description which follows, and in part will be
apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having the structure of
Formula I
Formula I
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters,
enantiomers, diastereomers, N-oxides, polymorphs, metabolites, wherein
can be hydrogen, lower (Ci-Ce) alkyl, lower (Ca-C?) alkenyl, lower (C2-C?) alkynyl,
cycloalkyl, amino, substituted amino, -ORZ {wherein Rz is selected from, for example, hydrogen,
-Si(CH3)3, lower (Ci-Ce) alkyl, lower (Ci-Ce) alkenyl, lower (Cz-Ce) alkynyl, cycloalkyl, aryl, and
-C(=O)NHRr (wherein Rr is selected from, for example, hydrogen, lower (CpCe) alkyl, lower (C2-
C&) alkenyl, lower (C2-C6) alkynyl, aryl, and cycloalkyl)}.
R2 can be carboxy, -SO2R6 {wherein Ra is selected from, for example, alkyl, alkenyl, alkynyl,
cycloalkyl, -NRpRq (wherein Rpand Rq are selected from, for example, hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, and heteroarylalkyl),
aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl, or Rp and Rq may
also together join to form a heterocyclyl ring}, -C(=O)OR7 (wherein R? is selected from, for
example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl), -C(=O)NRxRy {wherein Rx and Ry
are each independently selected from, for example, hydrogen, hydroxy (as restricted by the
definition that both Rx and Ry cannot be hydroxy at the same time), alkyl, alkenyl, alkynyl, aryl,
aralkyl, 8(0)2 R& wherein Rf, is the same as defined above, heteroaryl, heterocyclyl,
heteroarylalkyl, and heterocyclylalkyl, or Rx and Ry may also together join to form a heterocyclyl
ring}, acyl, halogen (F, Cl, Br, I), cyano, -NRxRy, wherein Rx and Ry are the same as defined
above), or -C(=O)CH2ORX (wherein Rx is the same as defined above).
R3 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl.
R4 and R5 can be independently selected from, for example, hydrogen, lower (Ci-C6) alkyl, lower
(C2-C7) alkenyl, and lower (C2-C7) alkynyl.
X can be oxygen, -NR7 (wherein R7 is selected from, for example, hydrogen, lower (Ci-Ce) alkyl,
lower (C2-C7) alkenyl, lower (C2-C7) alkynyl, aralkyl, and aryl.
Ar can be aryl, heteroaryl, and heterocyclyl.
In accordance with a further 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 another 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
muscarinic receptor antagonist compound as described above.
In accordance with yet a further aspect, there is provided a method for treatment or
prophylaxis of an animal or a human suffering from a disease or disorder of the respiratory system
such as bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis,
and the like; urinary system which induce such urinary disorders as urinary incontinence, lower
urinary tract symptoms (LUTS), etc.; and gastrointestinal system such as irritable bowel
syndrome, obesity, diabetes and gastrointestinal hyperkinesis with compounds as described above,
wherein the disease or disorder is associated with muscarinic receptors.
In accordance with yet another aspect, there are provided processes for preparing the
compounds as described above.
The compounds described herein exhibit significant potency in terms of their activity,
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 MS
receptors. Therefore, pharmaceutical compositions for the possible treatment for the disease or
disorders associated with muscarinic receptors are provided. In addition, the compounds can be
administered orally or parenterally.
The following definitions apply to terms as used herein
The term "alkyl," unless otherwise specified, refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be
exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tbutyl,
n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may
be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy,
cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen,
hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol,
alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)Rf, -NRfRq,
C(=O)NRfRq, -NHC(=O)NRfRq>, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NRfRq
{wherein Rf and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl,
aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SC^Re (wherein R&
is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or
heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be
further substituted by 1 -3 substituents selected from alkyl, carboxy, -NRfRq, -C(=O)NRfRq, -
OC(=O) NRfRq -NHC(=O)NRfRq (wherein Rf-and Rq are the same as defined earlier), hydroxy,
alkoxy, halogen, CFs, cyano, and -S02R6, (wherein R6 are the same as defined earlier); or an
alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen,
sulfur or -NRa- {wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, aryl, acyl, aralkyl,-C(=O)ORf (wherein Rf is the same as defined earlier), SOiRe (where
Re is as defined earlier), or -C(=O)NRfRq (wherein Rt- and Rq are as defined earlier)}. Unless
otherwise constrained by the definition, all substituents may be substituted further by
substituents selected from alkyl, carboxy, -NRfRq, -C (=O)NRfRq, -O-C(=O)NRfRq (wherein Rf
and Rq are the same as defined earlier) hydroxy, alkoxy, halogen, CFa, cyano, and -SO2R6 (where
R& is same as defined earlier); or an alkyl group as defined above that has both substituents as
defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term "alkylene," as used herein, refers to a diradical branched or unbranched saturated
hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be
substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such
as methylene, ethylene, propylene isomers (e.g., -CH2CH2CH2 and -CH(CH3)CH2) and the like.
Alkylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl,
alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen,
hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, heteroaryloxy,
aminosulfonyl, -COOR2 (wherein R2 is the same as defined earlier), -NHC(=O)RX, -NRxRy, -
C(=O)NRxRy, -NHC(=O)NRxRy, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NRxRy
(wherein Rx and Ry are the same as defined earlier), nitro, -S(O)nR3 (wherein n and RS are the
same as defined earlier). Unless otherwise constrained by the definition, all substituents may be
further substituted by 1 -3 substituents chosen from alkyl, carboxy, -COOR2 (wherein R2 is the
same as defined earlier), -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy> -NHC(=O)NRxRy (wherein Rx
and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CFa, cyano, and -S(O)nR3
(where R3 and n are the same as defined earlier). Alkylene can also be optionally interrupted by
1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa, where Ra is chosen
from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, acyl, aralkyl, -C(=O)OR2 (wherein R2 is
the same as defined earlier), -S(O)nR3 (where n and RS are the same as defined earlier), -
C(=O)NRxRy (wherein Rx and Ryare as defined earlier) -CONH-, -C=O or -ONOH.
The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or
geminal geometry. In the event that alkenyl is attached to a heteroatom, the double bond cannot
be alpha to the heteroatom. Alkenyl groups may be substituted further with one or more
substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,
acyloxy, -NHC (=O)Rf, -NR,Rq, -C(=O)NRfRq, -NHC(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf
and Rq are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy,
oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl,
heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino,
alkoxyamino, nitro, or SO2R6 (wherein R& are is same as defined earlier). Unless otherwise
constrained by the definition, alkenyl substituents optionally may be substituted further by 1 -3
substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CFs, cyano, -NRfRq,
-C(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier) and -SO2R6(
where Re is same as defined earlier).
The term "alkenylene" unless otherwise specified, refers to a diradical of a branched
unbranched unsaturated hydrocarbon group preferably having from 2 to 6 carbon atoms with cis,
trans or geminal geometry. In the event that alkenylene is attached to the heteroatom, the double
bond cannot be alpha to the heteroatom. The alkenylene group can be connected by two bonds to
the rest of the structure of compound of Formula I. Alkenylene may further be substituted with
one or more substituents such as alkyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, -
NHC(=O)RX, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are
the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo,
thiocarbonyl, carboxy, -COOR2 (wherein R2 is the same as defined earlier), arylthio, thiol,
alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl,
aminosulfonyl, alkoxyamino, nitro, -S(O)nR3 (where RS 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, -COOR2 (wherein R2 is the same as
defined earlier), hydroxy, alkoxy, halogen, -CF3, cyano, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy
(wherein Rx and Ry are the same as defined earlier) and -S(O)nR3 (where R3 and n are the same as
defined earlier).
The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated
hydrocarbon, having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a
heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted
further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl,
cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,
oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl,
aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -
NHC(=O)Rf. -NRfRq, -NHC(=O)NRtRq, -C(=O)NRfRq, -O-C(=O)NRfRq (wherein Rt-and Rq are
the same as defined earlier), or -SC^Re (wherein R(, is as defined earlier). Unless otherwise
constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3
substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, -NRfRq, -
C(=O)NRfRq, -NHC(=O)NRfRq, -C(=O)NRfRq (wherein Rf and Rq are the same as defined
earlier), cyano, or -SChRe (where Re is same as defined earlier).
The term "alkynylene" unless otherwise specified, refers to a diradical of a triplyunsaturated
hydrocarbon, preferably having from 2 to 6 carbon atoms. In the event that
alkynylene is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom. The
alkenylene group can be connected by two bonds to the rest of the structure of compound
Formula I. Alkynylene may further be substituted with one or more substituents such as alkyl,
alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy,
aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, -NHC(=O)RX -
NRxRy, -NHC(=O)NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are the same as
defined earlier), -S(O)nR3 (where R3 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, -COOR2 (wherein R2 is the same as defined earlier),
hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRy, -C(=O)NRxRy
(wherein Rx and Ry are the same as defined earlier), cyano, and -S(O)nR3 (where R3 and n are the
same as defined earlier).
The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3
to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally
contain one or more olefinic bonds, unless otherwise constrained by the definition. Such
cycloalkyl groups can include, for example, single ring structures, including cyclopropyl,
cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including
adamantanyl, and bicycle [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group,
for example, indane, and the like. Spiro and fused ring structures can also be included.
Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl,
arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRfRq, -
NHC (=O) NRfRq, -NHC (=O) Rf, -C (=O) NRtRq, -O-C(=O)NRfRq (wherein Rf and Rq are the
same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or
SO2-R6 (wherein Re is same as defined earlier). Unless otherwise constrained by the definition,
cycloalkyl substituents optionally may be substituted further by 1 -3 substituents selected from
alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq, -
OC(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano or -SOaRe (where Re is
same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl
portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined above.
The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for
example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1
substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl,
alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORg (wherein Reis hydrogen, alkyl, alkenyl,
cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -
NHC(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), -S02R6
(wherein R& is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl,
heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a
cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from
O, N or S.The term "aralkyl," unless otherwise specified, refers to alkyl-aryl linked through an alkyl
portion (wherein alkyl is as defined above) and the alkyl portion contains 1 -6 carbon atoms andaryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl and the like.
The term "aralkenyl," unless otherwise specified, refers to alkenyl-aryl linked through
alkenyl (wherein alkenyl is as defined above) portion and the alkenyl portion contains 1 to 6
carbon atoms and aryl is as defined below.
The term "aryloxy" denotes the group O-aryl, wherein aryl is as defined above.
The term "carboxy," as defined herein, refers to -C(=O)OH.
The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure
containing 5 or 6 ring atoms, or a bicyclic aromatic group having from 8 to 10 ring atoms, with
one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to
4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl,
cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRfRq,
CH=NOH, -(CH2)wC(=O)Rg {wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy,ORf, NRfRq, -NHORZ or -NHOH}, -C(=O)NRfRq and -NHC(=O)NRtRq, -SO2R6, -OC(=
O)NRtRq, -O-C(=O)Rf, -O-C(=O)ORf (wherein R6, Rf and Rq are as defined earlier, and Rz is
alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless
otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or
heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl,
indolyl, benzothiazolyl, or benzoxazolyl, and the like.
The term 'heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic
or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are
replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused
heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are
selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl,
alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)Rf, -O-C(=O)ORf,
-C(-O)NRtRq, SO2R6, -O-C(=O)NRfRq, -NHC(=O)NRtRq, -NRfRq (wherein R6, Rf and Rq are as
defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more
double bonds. Unless otherwise constrained by the definition, the substituents are attached to the
ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the
definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples
of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl,
dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-
dione, piperidinyl or piperazinyl.
"Heteroarylalkyl" refers to alkyl-heteroaryl group linked through alkyl portion, wherein
the alkyl and heteroaryl are as defined earlier.
"Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion,
wherein the alkyl and heterocyclyl are as defined earlier.
"Acyl" refers to -C(=O)R" wherein R" is selected from hydrogen, alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
"Alkylcarbonyl" refers to -C(=O)R", wherein R" is selected from alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
"Alkylcarboxy" refers to -O-C(=O)R", wherein R" is selected from alkyl, cycloalkyl,
aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
"Amine," unless otherwise specified, refers to -NH2. "Substituted amine," unless
otherwise specified, refers to -N (Rk)2, wherein each Rk independently is selected from hydrogen
{provided that both Rk groups are not hydrogen (defined as "amino")}, alkyl, alkenyl, alkynyl,
aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, SC^Rb
(wherein R6 is as defined above), -C(=O)NRfRq, NHC(=O)NRfRq, or -NHC(=O)ORf (wherein Rf
and Rq are as defined earlier).
"Amine," unless otherwise specified, refers to -NH2. "Substituted amino" unless
otherwise specified, refers to a group -N(Rk)2 wherein each Rk is independently selected from the
group hydrogen provided that both Rk groups are not hydrogen (defined as "amino"), alkyl,
alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl,
heteroarylalkyl, acyl, S(O)mR6 (wherein m and R6 is the same as defined above), -C(=Rv)NRxRy
(wherein Rv is O or S & Rx and Ry are the same as defined earlier) or NHC(=Rv)NRyRx (wherein
Rv, Ry and Rx are the same as defined earlier). Unless otherwise constrained by the definition, all
amino substituents may optionally be further substituted by 1-3 substituents chosen from alkyl,
aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, -COORy (wherein Ry is the same as
defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, -C(=Rv)NRxRy (wherein Rv is the same as
defined earlier), -O(C=O)NRxRy, -OC(=Rv)NRxRy (wherein Rx, Ry and Rv are the same as
defined earlier), -S(O)mR6 (where R& and m is the same as defined above).
The term "leaving group" generally refers to groups that exhibit the desirable properties of
being labile under the defined synthetic conditions and also, of being easily separated from
synthetic products under defined conditions. Examples of such leaving groups includes but not
limited to halogen (F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals
and the like.
13
The term "protecting groups" refers to moieties that prevent chemical reaction at a
location of a molecule intended to be left unaffected during chemical modification of such
molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy,
amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts,
"Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, New York, N.Y., which
is incorporated herein by reference. The species of the carboxylic protecting groups, amino
protecting groups or hydroxy protecting groups employed are not critical, as long as the
derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be
removed without disrupting the remainder of the molecule.
The compounds of this invention contain one or more asymmetric carbon atoms and thus
can occur as racemates and racemic mixtures, single enantiomers, diastereomieric mixtures and
individual diastereomers. All such isomeric forms of these compounds are expressly included in
the present invention. Each stereogenic carbon may be of the R or S configuration. Although the
specific compounds exemplified in this application may be depicted in a particular stereochemical
configuration, compounds having either the opposite stereochemistry at any given chiral center or
mixture(s) thereof are envisioned as part of the invention. Although amino acids and amino acid
side chains may be depicted in a particular configuration, both natural and unnatural forms are
envisioned as part of the invention.
Detailed Description of the Invention
The compounds of the present invention may be prepared by techniques well known in the
art and familiar to the average synthetic organic chemist. In addition, the compounds of the
present invention may be prepared by the following the reaction Schemes I, II and III
The compounds of Formulae VI and VII may be prepared according to Scheme I. Thus,
the preparation comprises condensing a compound of Formula II (wherein Ar, RI and RS are the
same as defined earlier) with a compound of Formula III (wherein X, R4 and RS are the same as
defined earlier and P is a protecting group for example, aralkyl or acyl) to give a compound of
Formula IV, which can be deprotected to give a compound of Formula V,
Path a: the compound of Formula V is reacted with a compound of Formula L-Y-R6 (wherein L
is a leaving group for example halogen (F, Cl, Br, I), Y is -C(=O), SO2 and R6 is the same as
defined earlier) to give a compound of Formula VI.
Path b: the compound of Formula V is reacted with a compound of Formula
hal-C(=O)OR7 (wherein R7 is the same as defined earlier and hal is halogen (Br, Cl, I)) to give a
compound of Formula VII.
The condensation of a compound of Formula II with a compound of Formula III can be
carried out in the presence of a condensing agent (for example, l-(3-dimethylaminopropyl)-3-
ethyl carbodiimide hydrochloride or dicyclohexylcarbodiimide in an organic base (for example,
l,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, triethylamine, diisopropylethylamine
or pyridine) in an organic solvent (for example, N,N-dimethylformamide, chloroform,
tetrahydrofuran, dioxane, diethylether, benzene or toluene) to give a compound of Formula IV
which on deprotection (for example, hydrogenatically utilizing palladium on carbon under
catalytic hydrogenation transfer conditions of ammonium formate and palladium on carbon) in an
organic solvent (for example, methanol, ethanol, tetrahydrofuran and acetonitrile) gives a
compound of Formula V, which on reaction with a compound of Formula L-Y-R6 (Path a) in the
presence of a base (for example, triethylamine, diisopropylethylamine or pyridine) in an organic
solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride) gives a
compound of Formula VI. The reaction of a compound of Formula V (Path b) with a compound
of Formula hal-C(=O)OR7 can be carried out in the presence of a base (for example,
triethylamine, diisopropylethylamine or pyridine) in an organic solvent (for example,
dichloromethane, dichloroethane, chloroform or carbon tetrachloride) to give a compound of
Formula VII.
Particular illustrative compounds which can be prepared following Scheme I include those
listed below (also shown in Table I and II):
lct, 5a, 6a)-3-(4-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 4),
N-{[(la,5a,6a)-3-Benzenesulfonyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 5),
15
N-{[(la,5a,6a)-3-(3,5-Dinitrobenzoyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 6),
N-{[(la,5a,6a)-3-(2-Benzyloxyacetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 7),
N-{[(la,5a,6a)-3-Benzoyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-
phenyl acetamide (Compound No. 8),
N-{[(la,5a,6a)-3-(3-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide (Compound No. 9),
N-{[(la,5a,6a)-3-(2-Benzo[l,3]dioxol-5-yl-acetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 10),
N-{[(la,5a,6a)-3-(4-Trifluoromethylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 11),
N-{[(la,5a,6a)-3-[2-(3,5-Difluoro-phenyl)-acetyl]-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 13),
N-{[(la,5a,6a)-3-(4-Tert-butylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 14),
N-{[(la, 5a, 6a)-3-(2-Fluorobenzoyl)-3-azabicyclo [3.1.0]hex-6-ylmethyl}]-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 15),
N-{[(la, 5a, 6a)-3-(3,4,5-Trimethoxybenzoyl)-3-azabicyclo [3.1.0]hex-6-yl methyl]}-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 16),
la, 5a, 6a)-3-Phenylacetyl-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 1 8),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid-4-nitro-benzyl ester (Compound No. 19),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid isobutyl ester (Compound No. 20),
ot, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid 4-nitro-phenyl ester (Compound No. 21),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid benzyl ester (Compound No. 22),
N-{[(la, 5a, 6a)-3-(4-Fluorobenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl}]-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 23)
N-{[(la, 5a, 6a)-3-(2,4,6-Trisopropylbenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-
2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 24)
a, 5a, 6a)-3-(3,5-Dimethylbenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-
2-hydroxy-2-phenyl acetamide (Compound No. 27)
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound No. 35)
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3. 1 .0]hexane-3-carboxylic acid butyl ester (Compound No. 36)
la, 5a, 6a)-3-(Methanesulphonyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 37)
16
la, 5a, 6a)-3-(4-Methoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 39)
N-{[(la, 5a, 6a)-3-(3-Benzo[l,3]-dioxol-5-yl-propionyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-
2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.40)
N-{[(la, 5a, 6a)-3-(Dimethylsulfamoyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No.41)
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or
polymorphs.
The compounds of Formulae IX and XI may be prepared according to Scheme II. Thus,
Path a: the compound of Formula VIII (wherein X, R|, RS, Rj and RS are the same as defined
earlier) undergoes N-derivatization to give a compound of Formula IX [wherein PI is halogen (F,
Cl, Br or I), cyano or -C(=O)OR7 (R? is the same as defined earlier)].
Path b: the compound of Formula VIII is reacted with a compound of Formula X (wherein Rx is
the same as defined earlier) to give a compound of Formula XI.
The N-derivatization of a compound of Formula VIII (Path a) (when PI is halogen) can be
carried out with halogenating agent (for example, sodium hypochlorite, sodium hypobromite or
sodium hypoiodite) in an organic solvent (for example, dichloromethane, dichloroethane,
chloroform or carbon tetrachloride) to give a compound of Formula IX. The N-derivatization of a
compound of Formula VIII (when PI is cyano) can be carried out with a nitrilating agent (for
example, cyanogen bromide) in the presence of an organic base (for example, triethylamine,
diisopropylethylamine or pyridine) in an organic solvent (for example, dichloromethane,
dichloroethane, chloroform or carbon tetrachloride) to give a compound of Formula IX. The Nderivatization
of a compound of Formula VIII (when PI is -C(=O)OR7) can be carried out with
anhydrides (for example, ditert-butoxycarbonyl anhydride, dipropoxycarbonyl anhydride,
dimethoxycarbonyl anhydride or diethoxycarbonyl anhydride) in the presence of an organic base
17
(for example, triethylamine, diisopropylethylamine or pyridine) in an organic solvent (for
example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride) to give a
compound of Formula IX. The compound of Formula VIII (Path b) can be reacted with an
isocyanate of Formula X in an organic solvent (for example, dichloroethane, dichloromethane,
chloroform or carbon tetrachloride) to give a substituted urea of Formula XI.
Alternatively, the compound of Formula XI can also be prepared by reacting a compound
of Formula VIII with an appropriate amine in the presence of carbonyldiimidazole (GDI) or with
carbamates such as phenyl carbamate or p-nitrophenyl carbamate.
Particular representative compounds which can be prepared following Scheme II include those
listed below (also listed in Table I):
N- { [( 1 a,5a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid tert-butyl ester (Compound No. 1)
N- { [( 1 a,5a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3. 1 .0]hexane-3-carboxylic acid benzylamide (Compound No. 3)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (4-trifluoromethyl-phenyl)-amide (Compound No. 12)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (4-fluorophenyl)-amide (Compound No. 17)
N- { [( 1 a,5a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid allylamide (Compound No. 25)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (2,4-dimethoxy-phenyl)-amide (Compound No. 26)
N- { [( 1 a,5a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (4-benzyloxy-phenyl)-amide (Compound No. 28)
N-{[(1 a,5a,6a)-3-Chloro-3-azabicyclo [3. 1 .0] hex-6-ylmethyl] }-2-cyclopentyl-2-hydroxy-2-
phenyl acetamide (Compound No. 29)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid amide (Compound No. 30)
N-{[(la, 5a, 6a)-3-Cyano-3-azabicyclo [3.1.0] hex-6-ylmethyl] }-2-cyclopentyl-2-hydroxy-2-
phenyl acetamide (Compound No. 31)
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl] }-2-cyclopentyl-2-hydroxy-2-
phenyl acetamide hydrochloride salts (Compound No. 32)
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl] }-2-cyclohexyl-2-hydroxy-2-
phenyl acetamide (Compound No. 33)
a, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylniethyl]}-2-hydroxy-2-diphenyl
acetamide (Compound No. 34)
N-{[(la,5a,6oc)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (2,4-difluoro-phenyl)-amide (Compound No. 38)
18
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or
polymorphs.
The compound of Formula XIV may be prepared by following Scheme III. The
preparation comprises reacting a compound of Formula XII (where in X, R2, R3, RA and RS are the
same as defined earlier) with trimethyl silyl chloride to give a compound of Formula XIII, which
undergoes O-alkylation to give a compound of Formula XIV (wherein Rt is alkyl).
The reaction of a compound of Formula XII with trimethyl silyl chloride can be carried
out in an organic base (for example, imidazole, triethylamine, N-methylmorpholine,
diisopropylethylamine or pyridine) in an organic solvent (for example, dimethylformamide,
tetrahydrofuran, dioxane or diethylether) to give a compound of Formula XIII which can undergo
O-alkylation in the presence an organic base (for example, sodium hydride or sodium cyanoboro
hydride) in an organic solvent (for example, tetrahydrofuran, dimethylformamide, diethylether or
dioxane) to give a compound of Formula XIV.
Particular representative compounds which may be prepared following Scheme III include those
listed below (also listed in Table I):
N-{[(la, 5a, 6a)-3-Terbutyl-carboxy-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
methoxy-2-phenyl acetamide (Compound No. 2)
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or
polymorphs.
Also, in all the above representative examples wherever amines are specified, one skilled
in an art would optionally convert them to their respective salts, for example amines can be
converted to corresponding hydrochloride salts with ethanolic hydrochloric acid solution in an
19
organic solvent selected from the group consisting of dichloromethane, dichloroethane,
chloroform or carbon tetrachloride.
In the above schemes, where specific bases, solvents, condensing agents, etc. are
mentioned, it is to be understood that other acids, bases, solvents, condensing agents, hydrolyzing
agents, etc, known to those skilled in an art may also be used. Similarly the reaction temperature
and duration of the reactions may be adjusted according to desired needs.
Because of their valuable pharmacological properties, the compounds described herein
may be administered to an animal for treatment orally, or by a parenteral route.
The pharmaceutical compositions described herein can be produced and administered in
dosage units, each unit containing a certain amount of at least one compound described herein
and/or at least one physiologically acceptable addition salt thereof. The dosage may be varied over
extremely wide limits, as the compounds are effective at low dosage levels and relatively free of
toxicity. The compounds may be administered in the low micromolar concentration, which is
therapeutically effective, and the dosage may be increased as desired up to the maximum dosage
tolerated by the patient.
The compounds described herein can be produced and formulated as their enantiomers,
diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as
metabolites having the same type of activity. Pharmaceutical compositions comprising the
molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs,
solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically
acceptable carrier and optionally included excipient can also be produced.
EXAMPLES
Various solvents, such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexanes, and
dichloromethane, were dried using various drying reagents according to procedures described in
literature. IR Spectra were recorded as Nujol Mulls or a thin neat film on a Perkin Elmer Paragon
instrument, Nuclear Magnetic Resonance (NMR) were recorded on Varian XL-300 MHz
instrument using tetramethylsilane as an internal standard.
Synthesis of (la, 5a, 6a)-6-aminomethvl-3-benzyl-3-azabicvclo[3.1.0]hexane
This compound was synthesised following the procedure described in EP 0413455 A2.
Synthesis of 2-hvdroxv-2-cvclopentvl-phenyl acetic acid
Step a: Synthesis of 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid
This was prepared following the procedure described in J. Amer. Chem. Soc., 75,
265(1953).
Step b: Synthesis of (la, 5a, 6a)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane.
The compound was prepared following the procedure described in EP 0 413 455 A2.
Step c: Synthesis of (la, 5a, 6a)-N-(3-benzyl-3-azabicycIo[3.1.0]hex-6-ylmethyl)-2-
cyc!opentyl-2-hydroxy-2-phenyI acetamide.
To a solution of a compound obtained from step b above (29.9 mmole, 6.05 g) in
dimethylformamide (100 ml) was added 2-hydroxy-2-cyclopentyl-2-phenyl acetic acid
(commercially available) (27.2 mmole, 6.0 g) followed by the addition of l-(3-
dimemylaminopropyl)-3 -ethyl carbodiimide and cooled at 0°C. The reaction mixture was treated
with hydroxy benzotriazole (29.9 mmole, 4.04 gm) followed by addition of N-methyl morpholine
(54.4 mmole, 5.2 g) and was stirred at 0°C for Ihour and at room temperature overnight. The
reaction mixture was poured into saturated sodium bicarbonate solution. The organic compound
was extracted with ethyl acetate. The organic layers were washed with water and dried over
anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by
column chromatography to yield the title compound with 95% yield.
The analogs of (la, 5a, 6a)-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-
cyclopentyl-2-hydroxy-2-phenyl-acetamide described below, can be prepared by replacing
appropriate acid in place of 2-hydroxy 2-cyclopentyl phenyl acetic acid.
N-(la, 5a, 6a)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclobutyl-2-hydroxy-2-phenyl
acetamide
, 5a, 6a)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclohexyl-2-hydroxy-2-phenyl
acetamide
N-(la, 5a, 6a)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-phenyl acetamide
Synthesis of N-(la, 5a, 6aV(3-azabicvclo[3.1.0]hex-6-vlmethvl)-2-cvclopentyl-2-hvdroxv-2-
phenyl acetamide.
To a solution of N-(la, 5a, 6a)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (1.0 g, 2.48 mmole) in dry methanol (25.0 ml), was
added palladium on carbon (5%, 0.2 g) under N2 atmosphere followed by the addition of
ammonium formate (0.8 g, 12.38 mmole) under constant stirring. The reaction mixture was
refluxed for half an hour under N2 atmosphere. The reaction mixture was cooled to room
temperature and the reaction mixture was filtered through hyflo bed. The hyflo bed was washed
with methanol (75.0 ml), ethyl acetate (25.0 ml) and water (25.0 ml). The filtrate was
concentrated under vacuum. The residue thus obtained was diluted with water and pH of the
resulting solution was adjusted to pH~14 with sodium hydroxide. The compound was extracted
with ethyl acetate (2x50 ml) and the ethyl acetate layer was washed with water and brine solution.
The layer was dried over anhydrous sodium sulphate and concentrated to give the title compound
with 96.2% yield.
The analogs of N-(la, 5a, 6a)-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-hydroxy-2-
phenyl acetamide described below, can be prepared by deprotection of appropriate amine, as
applicable in each case.
N-(la, 5a, 6a)-(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclobutyl-2-hydroxy-2-phenyl acetamide
N-(la, 5a, 6a)-(3-Azabicyclo[3. 1 .0]hex-6-ylmethyl)-2-cyclohexyl-2-hydroxy-2-phenyl
acetamide
N-(la, 5a, 6a)- (3-Azabicyclo[3.1.0]hex-6-ylmethyl)-2-hydroxy-2,2-diphenyl acetamide
SCHEME I, PATH A PROCEDURE
Example 1: Synthesis of N-|[(la. 5a. 6a)-3-(4-nitrobenzenesulphonvl)-3-azabicyclo[3.1.Q]hex-6-
yl methyl] } -2-cyclopentvl-2-hvdroxv-2-phenyl acetamide (Compound No. 4)
To a solution of N-(loc, 5a, 6a)-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (0.796 mmole) and triethyl amine (1.592 mmol) in dichloromethane
(10.0 ml) at 0°C was added p-nitro phenyl sulphonyl chloride (0.955 mmole). The reaction
mixture was stirred for 1 hour at 0°C and then at room temperature for overnight. The solid thus
separated was filtered, washed thoroughly with dichloromethane and dried to get the title
compound with 60% yield; M.P: 225.3-227.1°C; IR (KBr): 1642.5 cm'1; 'H NMR (DMSO-d6):8
8.39-8.42 (m, 2H), 7.91-7.99 (m, 2H), 7.54-7.56 (m, 2H), 7.22-7.32 (m, 3H), 5.47 (s, 1H), 3.06-
3.09 (m, 3H), 2.90-2.92 (m, 2H), 2.76-2.79 (m, 2H), 1.42-1.47 (m, 9H), 1.25-1.28 (m, 2H), 0.61
(brs, 1H); Mass (m/z): 500 (M++l), 482 (M+-OH).
Analogs of N-{[(la, 5a, 6a)-3-(4-nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-yl
methyl] }-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 4) described below, can
be prepared by replacing appropriate sulfonyl group in place of n-nitro phenyl sulfonyl chloride,
as applicable in each case.
ot, 5a, 6a)-3-Benzenesulfonyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2 -phenyl acetamide (Compound No. 5)
22
N-{[(la,5a,6a)-3-(3-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide (Compound No. 9)
N- {[(1 a,5a,6a)-3 -(4-Trifluoromethylbenzenesulfonyl)-3-azabicyclo [3.1.0] -hex-6-ylmethyl]} -2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 11)
N-{[(la,5a,6a)-3-(4-Tert-butylbenzenesulfonyl)-3-azabicyclo[3.1.0]-hex-6-ylmethyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 14)
N-{[(la, 5a, 6a)-3-(4-Fluorobenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}{-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 23)
N-{[(la, 5a, 6a)-3-(2,4,6-Trisopropylbenzenesulfonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 24)
N-{[(la, 5a, 6a)-3-(Methanesulfonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 37)
N-{[(la, 5a, 6a)-3-(Dimethylsulfamoyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No.41)
Example 2: Synthesis of N-|[(la.5a,6a)-3-[2-(3,5-difluorophenvl)-acetyl]-3-azabicvclo (3.1.0)-
hex-6-ylmethyl}-2-cvclopentvl-2-hvdroxy-2-phenyl acetamide (Compound No. 13)
The compound was prepared following the procedure as described for the synthesis of
Compound No. 4, Example-1 by using 2,4-difluoro phenyl acetyl chloride in place of p-nitro
phenyl sulphonyl chloride with 54% yield; IR (KBr): 1640.9 cm'1; *H NMR (CDC13): 5 7.59-7.61
(m, 2H), 7.19-7.37 (m, 4H), 6.76-6.86 (m, 2H), 6.65 (brs, 1H), 3.73-3.77 (m, 1H), 3.40-3.51 (m,
4H, including -OH), 3.22-3.23 (m, 7H).
Analogs of N-{[(la,5a,6a)-3-[2-(3,5-difluorophenyl)-acetyl]-3-azabicyclo-(3.1.0)-hex-6-
ylmethyl}-2-hydroxy-2-phenyl acetamide (Compound No. 13) described below, can be prepared
by replacing appropriate acyl halide group in place of 2,4-difluoro phenyl acetyl chloride, as
applicable in each case.
N-{[(la,5a,6a)-3-(3,5-Dinitrobenzoyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 6),
N-{[(la,5a,6a)-3-(2-Benzyloxyacetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 7),
N-{[(la,5a,6a)-3-Benzoyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-
phenyl acetamide (Compound No. 8),
N-{[(la,5a,6a)-3-(2-Benzo[l,3]dioxol-5-yl-acetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 10),
N-{[(la, 5a, 6a)-3-(2-Fluorobenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 15),
N-{[(la, 5a, 6a)-3-(3,4,5-Trimethoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 16),
N-{[(la, 5a, 6a)-3-Phenylacetyl-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 18),
23
loc, 5a, 6a)-3-(3,5-Dimethylbenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 27).
Example 3: Synthesis of N-{[(la. 5a, 6a)-3-(4-methoxv-benzoyl)-3-azabicvclo [3.1.0] hex-6-yl
methyl] I -2-cyclopentvl-2-hvdroxy-2-phenyl acetamide (Compound No. 39)
The compound was synthesised following the procedure as described for the synthesis of
compound No. 4, Example- 1 by using 4-methoxy benzoyl chloride in place of p-nitro benzene
sulfonyl chloride with 90% yield; M.P: 58.3-59.6°C; IR (KBr): 1656.3, 1610.3 cm"1; 'HNMR
(CDC13): 8 7.57-7.60 (m, 2H), 7.21-7.41 (m, 5H), 6.87-6.90 (m, 2H), 3.83 (s, 3H), 3.40-3.59 (m,
3H), 3.03-3.10 (m, 4H), 1.42-1.65 (m, 9H), 1.26-1.40 (m, 2H), 0.72-0.74 (m, 1H); Mass (m/z):
449(M++1),431(M+-OH)
Analogs of N-{[(lct, 5a, 6a)-3-(4-methoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-yl
methyl] }-2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 39) described below, can
be prepared by replacing appropriate acyl halide group in place of 4-methoxy benzoyl chloride as
applicable in each case.
N-{[(la, 5a, 6a)-3-(3-Benzo[l,3]-dioxol-5-yl-propionyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-
2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No.40),
SCHEME I, PATH B PROCEDURE
Example 4: Synthesis N- 1 [(la, 5a. 6a)-6-[(2-cvclopentvl-2-hvdroxv-2-phenvl-acetylamino)-
methyl]}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 4-nitro-benzyl ester (Compound No. 19)
The title compound was prepared following the procedure described for the synthesis of
Compound No. 4, Example- 1 by using 4-nitrobenzyl chloroformate in place of 4-methoxy
benzoyl chloride with 46% yield; M.P: 73.1-74.3°C; IR (KBr): 1635.0 cm'1; 'HNMR (CDC13):8
7.59-7.62 (m, 2H), 7.29-7.37 (m, 4H), 6.63-6.74 (m, 2H), 6.59 (brs, 1H), 5.91 (s, 2H), 3.72-3.76
(m, 1H), 3.02-3.37 (m, 6H, including -OH), 2.85 (t, 2H, J=6Hz), 2.42 (t, 2H, J=6Hz), 1.26-1.66
(m, 11H), 0.75 (m, 1H); Mass (m/z): 491 (M++l), 473 (M+-OH).
Analogs of N-{[(la, 5a, 6a)-6-[(2-cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-
aza-bicyclo[3.1.0]hexane-3-carboxylic acid 4-nitro-benzyl ester (Compound no. 19) described
below, can be prepared by replacing appropriate chloroformate in place of 4-nitro benzyl
chloroformate, as applicable in each case.
a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid isobutyl ester (Compound No. 20),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3. 1 .0]hexane-3-carboxylic acid 4-nitro-phenyl ester (Compound No. 21),
24
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid benzyl ester (Compound No. 22),
a, 5a, 6a)-6-{ [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound No. 35),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3. 1 .0]hexane-3-carboxylic acid butyl ester (Compound No. 36),
SCHEME II, PATH A PROCEDURE
Example 5: Synthesis of N-([(la. 5a. 6a)-3-chloro-3-azabicyclo [3.1.0] hex-6-yl methyl]}-2-
cyclopentvl-2-hvdroxy-2-phenyl acetamide (Compound No. 29)
To a solution of N-(la, 5a, 6a)-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide in dichloromethane (10.0 ml), was added sodium hypochlorite (4.0
ml) at room temperature and the reaction mixture was stirred at room temperature for 3 hours.
The reaction mixture was diluted with chloroform and water followed by stirring it for five
minutes. The organic layer was separated, washed thoroughly with water, dried and concentrated
to get the title organic compound with 90% yield; M.P: 130.7-131.9°C; IR (KBr): 1656.8 cm"1;
'H NMR (CDC13):6 7.59-7.61 (m, 2H), 7.30-7.38 (m, 3H), 3.61-3.68 (m, 2H), 3.03-3.17 (m, 4H),
1.49-1.69 (m, 9H), 1.11-1.26 (m, 2H), 0.83 (s, 1H); Mass (m/z): 349 (M++l), 331 (M+-OH).
Analogs of N-{[(lot, 5oc, 6a)-3-chloro-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 29) described below, can be prepared by replacing
appropriate amine in place of (la, 5a, 6a)-N-(3-azabicyclo[3.1.0]hex-6-ylmethyl)-2-cyclopentyl-
2-hydroxy-2-phenyl-acetamide, as applicable in each case.
N-{[(la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclohexyl-2-hydroxy-2-
phenyl acetamide (Compound No. 33),
lot, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-hydroxy-2-diphenyl
acetamide (Compound No. 34).
Example 6: Synthesis of hvdrochloride salt of N-([(la. 5a, 6a)-3-chloro-3-azabicyclo [3.1.0]
hex-6-ylmethyl]l-2-cyclopentvl-2-hvdroxv-2-phenyl acetamide hvdrochloride salt (Compound
No. 32)
To a solution of the compound No. 29 (0.15 g) in dichloromethane (5.0 ml), was added
ethanolic hydrochloric acid solution (3N, 0.5 ml) and stirred the reaction mixture for 10 minutes.
The solvent was evaporated off under reduced pressure and the residue thus obtained was
triturated with diethylether to get the solid. The solid was dried under vacuum to furnish the title
25
compound with 90% yield; 'H NMR (DMSO-d6): 8.02 (t, IH, J=6Hz), 7.56-7.59 (m, 2H), 7.19-
7.32 (m, 3H), 5.55 (s, IH), 2.98-3.16 (m, 4H, including-OH), 2.85-2.94 (m, 3H), 1.24-1.53 (m,
11H), 1.07(t, IH, J=3Hz).
Example 7: Synthesis of M-ITdou 5a. 6a)-3-cvano-3-azabicyclo [3.1.0] hex-6-ylmethyl]l-2-
cyclopentvl-2-hvdroxv-2-phenyl acetamide (Compound No. 31)
To a solution of N-(lot, 5a, 6a)-(3-azabicyclo[3.1.0]hex-l-ylmethyl)-2-cyclopentyl-2-
hydorxy-2-phenyl acetamide (0.25 g) and triethylamine (0.22 ml) in dichloromethane (5.0 ml) at
room temperature, was added cyanogen bromide (0.25 g) and the reaction mixture was stirred at
the same temperature for half on hour. The reaction mixture was cooled to 0°C followed by the
addition of sodium hydroxide (0.5 N) and stirred for 10 minutes. Organic layer was separated,
washed with brine solution, dried and concentrated under reduced pressure. The residue was
purified by column chromatography using ethylacetate in hexane solvent mixture as an eluent to
furnish the title organic compound with 74% yield; M.P: 122.6-123.8°C; IR (KBr): 2213.5,
1648.4 cm'1; 'H NMR (CDC13):8 7.59-7.61 (m, 2H), 7.30-7.38 (m, 3H), 6.65 (brs,lH), 3.32-3.47
(m, 4H, including -OH), 3.09-3.22 (m, 3H), 1.19-1.57 (m, 11H), 0.91 (brs, IH); Mass (m/z): 340
(M++OH), 322 (M+-OH).
Example 8: Synthesis of N-U(la.5a.6a)-6-l[(2-cvclopentvl-2-hydroxv-2-phenvl-acetvlamino)-
methvl]|-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Compound No. 1)
To a cold solution of N-(lot, 5a, 6a)-(3-azabicyclo[3.1.0]hex-l-ylmethyl)-2-cyclopentyl-
2-hydroxy acetamide (5.1 mmole) in dichloromethane, was added triethylamine (10.1 mmole)
followed by the addition of di-tertbutoxy carbonyl anhydride (6.1 mmole). The reaction mixture
was stirred at same temperature for 30 minutes and then at room temperature for 3Y2 hour. The
organic layer was separated and the aqueous layer was extracted with dichloromethane. The
combined organic layer was dried over anhydrous sodium sulphate and concentrated. The crude
organic compound was purified by column chromatography using ethyl acetate in hexane solvent
mixture as eluent to furnish the title compound with 75% yield; 'H NMR (CDC13): 8 7.61-7.59
(2H, m), 7.37-7.28 (3H, m), 6.55 (IH, brs), 3.48-3.45 (2H, m), 3.29-3.26 (2H, m), 3.08-3.03 (3H,
m), 1.69-1.55 (8H, m), 1.42-1.36 (9H, m), 1.23-1.18 (2H, m), 0.74-0.72 (IH, m); Mass (m/z): 414
(M++l).
SCHEME II, PATH B PROCEDURE
Example 9: Synthesis of N-([(la.5a,6a)-6-|[(2-cvclopentyl-2-hvdroxv-2-phenvl-acetylammoV
methvl1l-3-aza-bicyclor3.1.01hexane-3-carboxvlic acid benzylamide (Compound No.3)
26
To a solution of N-( la, 5a, 6a)-(3-azabicyclo[3.1.0]hex-l-ylmethyl)-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (0.8 mmole) in dichloroethane (100 ml), was added benzyl
isocyanate (0.955 mmole) at room temperature and stirred for 1 hour at the same temperature.
The reaction mixture was directly absorbed onto the silica gel and purified by column
chromatography using methanol in chloroform as an eluent with 85% yield; m.p: 76-78°C; IR
(KBr): 1636.4, 1527.7 cm'1; !H NMR (CDC13):6 7.58-7.61 (m, 2H), 7.23-7.36 (m, 8H), 6.62 (brs,
1H), 4.39 (s, 2H), 3.33-3.47 (m, 4H), 3.06-3.16 (m, 4H), 1.45-1.70 (m, 9H), 1.25 (brs, 2H), 0.79
(t, 1H, J=6Hz); Mass (m/z): 448 (M++l), 430 (M+-OH).
The analogs of N- { [( 1 a,5a,6a)-6- { [(2-cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -
3-aza-bicyclo[3. 1 .0]hexane-3-carboxylic acid benzylamide (Compound No. 3)
described below, can be prepared by replacing appropriate isocyanate in place of benzyl
isocyanate, as applicable in each case.
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid-(4-trifluoromethyl-phenyl)-amide (Compound No. 12)
N- { [( 1 a,5 a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid-(4-fluoro-phenyl)-amide (Compound No. 17)
N- { [( 1 a,5 a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid allylamide (Compound No. 25)
N- { [( 1 ot,5 a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid-(2,4-dimethoxy-phenyl)-amide (Compound No. 26)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid-(4-benzyloxy-phenyl)-amide (Compound No. 28)
N-{[(la,5a,6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid amide (Compound No. 30)
N- { [( 1 a,5 a,6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid-(2,4-difluoro-phenyl)-amide (Compound No. 38)
SCHEME HI PROCEDURE
Example 10: Synthesis of //-([(la. 5a, 6a)-3-terbutvl-carboxy-3-azabicyclo [3.1.01 hex-6-yl
methyl] }-2-cvclopentyl-2-methoxy-2-phenyl acetamide (Compound No. 2)
Step a: Synthesis of 4-[(2-cyclopentyl-2-hydroxy-2-phenyI acetamide)-methyl]-3-methyl
piperidine-1-carboxylic acid tert-butyl ester
To a solution of (la, 5a, 6a)-N-(3-azabicyclo[3.1.0]hex-l-ylmethyl)-2-cyclopentyl-2-hydroxy-2-
phenyl acetamide (0.3 g, 1 mmole) in dichloromethane was added trimethyl amine at 0°C
followed by the addition of ditert-butoxy carboxyl anhydride (0.261 g, 1.2 mmole) in
dichloromethane. Reaction mixture was stirred at 0°C for 30 minutes then at room temperature
for 3'/2 hours. The reaction mixture was poured into water and the layers were separated. The
27
aqueous layer was extracted with dichloromethane. The combined organic layer was dried over
anhydrous was purified by column chromatography to give the title compound.
Step b: Synthesis of 4-[(2-cyclopentyl-2-phenyl-2-trimethylaryloxy-acetylamino)-methyl]-3-
methyl-piperidine-1-carboxylic acid tert-butyl ester
To a solution of a compound obtained form step a above (0.414 g, 1 mmole) in
dimethylformamide, was added imidazole (0.251 g, 3.7 mmole) followed by the addition of
trimethyl silyl chloride (0.293 g, 2.7 mmole) at room temperature and stirred at same temperature
for 2 hours. Reaction mixture was poured into water and extracted with diethylether. The organic
layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced
pressure crude organic compound was purified by column chromatography.
Step c: Synthesis of N-{[(la, 5a, 6a)-3-terbutyl-carboxy-3-azabicyclo [3.1.0] hex-6-yl
methyl] }-2-cycIopentyI-2-methoxy-2-phenyl acetamide (Compound No. 2)
To a solution of a compound obtained from step b above (0.486 g, 1 mmole) in dry
tetrahydrofuran at 0°C, was added sodium hydride (0.080 g, 2 mmole, 60% suspension in mineral
oil) followed by the addition of tetra n-butyl ammonium iodide (0.025 g, 0.07 mmole). The
reaction mixture was stirred at same temperature for 30 minutes and then at room temperature for
1 hour followed by cooling the reaction mixture at 0°C.
To the reaction mixture iodomethane (1.28 g, 9 mmole) was added. The reaction mixture
was allowed to warm at room temperature and then stirred overnight. The reaction mixture was
quenched with ammonium chloride solution and the organic compound was extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under
reduced pressure. The crude organic compound was purified by column chromatography to
furnish the title compound with 34% yield; iR (KBr): 1657.8 cm"1; !H NMR (CDC13): 5 7.26-7.46
(m, 5Ar-H), 6.99 (s, 1H), 3.17-3.25 (m, 2H), 3.15 (s, 3H), 2.87-3.00 (m, 6H), 1.67-1.85 (m, 8H),
0.86-0.88 (m, 2H); Mass (m/z): 428 (M++l).
Biological Activity
Radioligand Binding Assays:
The affinity of test compounds for M2 and MT, 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, Ma,
M4 and M$ receptors. Selectivities were calculated from the Ki values obtained on these human
cloned membranes.
28
Membrane preparation: Submandibular glands and heart were isolated and placed in ice
cold homogenising buffer (HEPES 20mM, lOmM EDTA, pH 7.4) immediately after sacrifice.
The tissues were homogenised in 10 volumes of homogenising buffer and the homogenate was
filtered through two layers of wet gauze and filtrate was centrifuged at 500g for lOmin. The
supernatant was subsequently centrifuged at 40,000g for 20 min. The pellet thus obtained was
resuspended in assay buffer (HEPES 20 mM, EDTA 5mM, pH 7.4) and were stored at -70°C until
the time of assay.
Ligand binding assay: The compounds were dissolved and diluted in DMSO. The
membrane homogenates (150-250 ug protein) were incubated in 250 |^1 of assay volume (HEPES
20 mM, pH 7.4) at 24-25°C for 3h. Non-specific binding was determined in the presence of 1 uM
atropine. The incubation was terminated by vacuum filtration over GF/B fiber filters (Wallac).
The filters were then washed with ice-cold 50mM Tris HC1 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 Ki 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
of [-*H]NMS used in the particular experiment, pki is -log [Ki].
Functional Experiments using isolated rat bladder: Methodology:
Animals were euthanized by overdose of thiopentone and whole bladder was isolated and
removed rapidly and placed in ice cold Tyrode buffer with the following composition (mMol/L)
NaCl 137;KC12.7;CaCl2 1.8; MgCl2 0.1; NaHCO3 11.9; NaH2PO4 0.4; Glucose 5.55 and
continuously gassed with 95% O2 and 5 % CO2.
The bladder was cut into longitudinal strips (3mm wide and 5-6 mm long) and mounted in
10 ml organ baths at 30° C, with one end connected to the base of the tissue holder and the other
end connected through a force displacement transducer. Each tissue was maintained at a constant
basal tension of 1 g and allowed to equilibrate for 11/2 hour during which the Tyrode buffer was
changed every 15-20 min. At the end of equilibration period the stabilization of the tissue
contractile response was assessed with Ijamol/L of Carbachol till a reproducible response is
obtained. Subsequently a cumulative concentration response curve to carbachol (10~9 mol/L to 3
X 10"4 mol/L) was obtained. After several washes, once the baseline was achieved, cumulative
concentration response curve was obtained in presence of NCE (NCE added 20 min. prior to the
second cumulative response curve.
The contractile results were expressed as % of control E max. EDjo values were calculated
by fitting a non-linear regression curve (Graph Pad Prism). pKb values were calculated by the
formula pKb = - log [ (molar concentration of antagonist/ (dose ratio-1))]
where, dose ratio = EDso in the presence of antagonist/ED in the absence of antagonist. The
results of in-vitro tests are found to be < 10.
The particular compounds specified herein exhibited Kj values for Ma receptors of from
about 10,000 nM to about 7.8 nM, for example from about 1000 nM to about 7.8 nM, or from
about 60 nM to about 7.8 nM, or from about 9.0 to about 7.8 nM. The particular compounds
specified herein exhibited Kj values for Mj receptors of from about 1000 nM to about 0.5 nM, for
example from about 500 nM to about 0.5 nM, or from about 30 nM to about 0.5 nM, or from
about 0.7 to about 0.5 nM.
While the present invention has been described in terms of its specific embodiments,
certain modification and equivalents will be apparent to those skilled in the art and are intended to
be included within the scope of the present invention.

WE CLAIM:
1. Compounds having the structure of Formula I
Formula
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers orpolymorphs, wherein
R, is hydrogen, lower (C2-C6) alkyl, lower (C2-C7) alkenyl, lower (C2-C7) alkynyl,
cycloalkyl, amino, substituted amino, -ORZ {wherein Hz is selected from hydrogen, - lower (Ci-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C6) alkynyl, cycloalkyl, aryl, and -
C(=O)NHRr (wherein Rr is selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-C6) alkenyl,
lower (C2-C6) alkynyl, aryl, and cycloalkyl)};
R2 is carboxy, -SO2R6 {wherein R6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -
NRpRq (wherein Rp and Rq are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, and heteroarylalkyl), aryl, aralkyl, heteroaryl,
heterocyclyl, heterocyclylalkyl, and heteroarylalkyl, or Rp and Rq may also together join to form a
heterocyclyl ring}, -C(=O)OR7 (wherein R7 is selected from alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, and aralkyl), -C(=O)NRxRy (wherein Rx and Ry are each independently selected from
hydrogen, hydroxy (as restricted by the definition that both Rx and Ry cannot be hydroxy at the
same time), alkyl, alkenyl, alkynyl, aryl, aralkyl, S(O)2R6 wherein Re is the same as defined
above, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl, or Rx and Ry may also
together join to form a heterocyclyl ring), acyl, halogen (F, Cl, Br, I), cyano, -NRxRy, wherein Rx
and Ry are the same as defined above), or -C(=O)CH2ORX (wherein Rx is the same as defined
above);
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl;
R4 and R5 are independently selected from hydrogen, lower alkyl, lower (C2-C7)
alkenyl, and lower (C2-C7) alkynyl;
X is oxygen, -NR7 (wherein R7 is selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-
C7) alkenyl, lower (C2-C7) alkynyl, aralkyl, and aryl; and
Ar is aryl, heteroaryl, and heterocyclyl.
2. A compound selected from
1 a, 5a, 6a)-6-{ [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid tert-butyl ester (Compound No. 1),
N-{[(la, 5a, 6a)-3-Terbutyl-carboxy-3-azabicyclo [3.1.0] hex-6-ylmethyl] }-2-cyclopentyl-2-
methoxy-2-phenyl acetamide (Compound No. 2),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acety lamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid benzylamide (Compound No. 3),
a, 5a, 6a)-3-(4-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 4),
N- { [( 1 a, 5a, 6a)-3-Benzenesulfonyl-3 -azabicyclo [3.1.0] hex-6-ylmethyl] } -2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 5),
N-{[(la,5a,6a)-3-(3,5-Dinitrobenzoyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 6),
N-{[(la,5a,6a)-3-(2-Benzyloxyacetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 7),
N-{[(la,5a,6a)-3-Benzoyl-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-cyclopentyl-2-
phenyl acetamide (Compound No. 8),
N-{[(la,5a,6a)-3-(3-Nitrobenzenesulphonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-hydroxy-2-
cyclopentyl-2-phenyl acetamide (Compound No. 9),
N-{[(la,5a,6a)-3-(2-Benzo[l,3]dioxol-5-yl-acetyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 10),
N-{[(la,5a,6a)-3-(4-Trifluoromethylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 11),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (4-trifluoromethyl-phenyl)-amide (Compound No. 12),
N-{[(la,5a,6a)-3-[2-(3,5-Difluoro-phenyl)-acetyl]-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-2-
hydroxy-2-cyclopentyl-2-phenyl acetamide (Compound No. 13),
N-{[(la,5a,6a)-3-(4-Tert-butylbenzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-ylmethyl]}-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 14),
la, 5a, 6a)-3-(2-Fluorobenzoyl)-3-azabicyclo [3.1.0]hex-6-ylmethyl}]-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 15),
la, 5a, 6a)-3-(3,4,5-Trimethoxybenzoyl)-3-azabicyclo [3.1.0]hex-6-yl methyl]}-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 16),
la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (4-fluorophenyl)-amide (Compound No. 17),
N-{[(lct, 5a, 6a)-3-Phenylacetyl-3-azabicyclo [3.1.0] hex-6-ylmethyl] }-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 18),
la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid-4-nitro-benzyl ester (Compound No. 19),
la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid isobutyl ester (Compound No. 20),
32
la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid 4-nitro-phenyl ester (Compound No. 21),
N-{[(1 a, 5a, 6a)-6-{ [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] }-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid benzyl ester (Compound No. 22),
N-{[(la, 5a, 6a)-3-(4-Fluorobenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl}]-2-
cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 23),
N-{[(lct, 5a, 6a)-3-(2,4,6-Trisopropylbenzenesulphonyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-
2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 24),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid allylamide (Compound No.25),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (2,4-dimethoxy-phenyl)-amide (Compound No.26),
N-{[(lct, 5a, 6a)-3-(3,5-Dimethylbenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-
2-hydroxy-2-phenyl acetamide (Compound No. 27),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (4-benzyloxy-phenyl)-amide (Compound No. 28),
a, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-
phenyl acetamide (Compound No. 29),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0] hexane-3-carboxylic acid amide (Compound No. 30),
a, 5a, 6a)-3-Cyano-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-2-
phenyl acetamide (Compound No. 31),
la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-hydroxy-
phenyl acetamide hydrochloride salts (Compound No. 32),
a, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclohexyl-2-hydroxy-2-
phenyl acetamide (Compound No. 33),la, 5a, 6a)-3-Chloro-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-hydroxy-2-diphenyl
acetamide (Compound No. 34),
N- { [( 1 a, 5a, 6a)-6- { [(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl] } -3-azabicyclo[
3.1.0]hexane-3-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound No.35),
lct, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0]hexane-3-carboxylic acid butyl ester (Compound No. 36),
la, 5a, 6a)-3-(Methanesulphonyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 37),
la, 5a, 6a)-6-{[(2-Cyclopentyl-2-hydroxy-2-phenyl-acetylamino)-methyl]}-3-azabicyclo[
3.1.0] hexane-3-carboxylic acid (2,4-difluoro-phenyl)-amide (Compound No.38),
la, 5a, 6a)-3-(4-Methoxybenzoyl)-3-azabicyclo [3.1.0] hex-6-ylmethyl]}-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No. 39),
N-{[(la, 5a, 6a)-3-(3-Benzo[l,3]-dioxol-5-yl-propionyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-
2-cyclopentyl-2-hydroxy-2-phenyl acetamide (Compound No. 40),
N-{[(la, 5a, 6a)-3-(Dimethylsulfamoyl)-3-azabicyclo [3.1.0] hex-6-yl methyl] }-2-cyclopentyl-2-
hydroxy-2-phenyl acetamide (Compound No.41).
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or
polymorphs.
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. A method for treatment or prophylaxis of an animal or a human suffering from a disease or
disorder of the respiratory, urinary and gastrointestinal systems, wherein the disease or disorder is
mediated through muscarinic receptors, comprising administering to said animal or human, a
therapeutically effective amount of a compound having the structure of Formula I of claim 1 or 2.
5. The method according to claim 4, wherein the disease or disorder is urinary incontinence,
lower urinary tract symptoms (LUTS), bronchial asthma, chronic obstructive pulmonary disorders
(COPD), pulmonary fibrosis, irritable bowel syndrome, obesity, diabetes or gastrointestinal
hyperkinesis.
6. The method for treatment or prophylaxis of an animal or a human suffering from a disease
or disorder of the respiratory, urinary and gastrointestinal systems, wherein the disease or disorder
is mediated through muscarinic receptors, comprising administering to said animal or human, a
therapeutically effective amount of the pharmaceutical composition according to claim 3.
7. A process of preparing a compound of Formula VI
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or
polymorphs,
wherein
RI is hydrogen, lower (C2-C6) alkyl, lower (C2-C7) alkenyl, lower (C2-C7) alkynyl,
cycloalkyl, amino, substituted amino, -ORZ {wherein Rz is selected from hydrogen, -Si(CH3)3,
lower (Ci-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C6) alkynyl, cycloalkyl, aryl, and
-C(=O)NHRr (wherein Rr is selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-C6) alkenyl,
lower (C2-C6) alkynyl, aryl, and cycloalkyl)};
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl;
RI and R5 are independently selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-
alkenyl, and lower (C2-Cj) alkynyl;
R6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq (wherein Rp and Rq are
selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,
and heteroarylalkyl, or Rp and Rq may also together join to form a heterocyclyl ring;
X is oxygen, -NR? (wherein R? is selected from hydrogen, lower (Ci-C6) alkyl, lower
Cy) alkenyl, lower lkynyl, aralkyl, and aryl; and
Ar is aryl, heteroaryl, and heterocyclyl,
the process comprising:
a) condensing a compound of Formula II (wherein Ar, RI and RS are the same as defined earlier)
with a compound of Formula III (wherein X, R4 and RS are the same as defined earlier and P i s a
protecting group) to give a compound of Formula IV,
b) deprotecting the compound of Formula IV to give a compound of Formula V, and
c) reacting the compound of Formula V with a compound of Formula L-Y-R6 leaving group, Y is -C(=O), SO2 and R6 is the same as defined earlier) to give a compound of
Formula VI.
8. A process of preparing a compound of Formula VII
N—C(=0)OR7
Formula VII
wherein
RI is hydrogen, lower (C|-C6) alkyl, lower (C2-C7) alkenyl, lower (C2-C7) alkynyl,
cycloalkyl, amino, substituted amino, -ORZ {wherein Rz is selected from hydrogen, -Si(CH3)3,
lower (Ci-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C6) alkynyl, cycloalkyl, aryl,
-C(=O)NHRr (wherein Rr is selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-C6) alkenyl,
lower (C2-C6) alkynyl, aryl, and cycloalkyl)};
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl;
R4 and R5 are independently selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-C7)
alkenyl, and lower (C2-C7) alkynyl;
R6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq (wherein Rpand Rq are
selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,
and heteroarylalkyl, or Rp and Rq may also together join to form a heterocyclyl ring;
R7 is selected from hydrogen, lower (C\-Ce) alkyl, lower (C2-C7) alkenyl, lower (C2-
alkynyl, aralkyl, and aryl;
X is oxygen, -NR7 (wherein R7 is as defined above); and
Ar is aryl, heteroaryl, and heterocyclyl,
the process comprising:
a) condensing a compound of Formula II (wherein Ar, RI and R3 are the same as defined earlier)
with a compound of Formula III (wherein X, R4 and R5 are the same as defined earlier and P is a
protecting group) to give a compound of Formula IV,
b) deprotecting the compound of Formula IV to give a compound of Formula V, and
reacting the compound of Formula V with a compound of Formula
36
hal-C(=O)OR7 (wherein R7 is the same as defined earlier and hal is halogen) to give a compound
9. A process of preparing a compound of Formula IX
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or
polymorphs, wherein
RI is hydrogen, lower (C1-C6) alkyl, lower (C2-C7) alkenyl, lower (C2-C7) alkynyl,
cycloalkyl, amino, substituted amino, -ORZ {wherein Rz is selected from hydrogen, -Si(CH3)3,
lower (1i-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C6) alkynyl, cycloalkyl, aryl, and
-C(=O)NHRr (wherein Rr is selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-C6) alkenyl,
lower (C2-C6) alkynyl, aryl, and cycloalkyl)};
RB is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl;
R4 and RS are independently selected from hydrogen, lower (C\-C(,) alkyl, lower (C2-C7)
alkenyl, and lower (C2-C7) alkynyl;
R7 is selected from hydrogen, lower (C1-C6) alkyl, lower (C2-C7) alkenyl, lower (C2-C7)
alkynyl, aralkyl, and aryl;
X is oxygen, or -NR7 (wherein R7 is as defined above); and
PI is halogen (F, Cl, Br or I), cyano or -C(=O)OR7 (R7 is the same as defined earlier)
the process comprising:
N-protecting the compound of Formula VIII to give a compound of Formula IX
[wherein P, is halogen (F, Cl, Br or I), cyano or -C(=O)OR7 (R7 is the same as defined earlier)].
10. A process of preparing a compound of Formula XI
wherein,
Ri is hydrogen, lower (C2-C6) alkyl, lower (C2-C7) alkenyl, lower (C2-C7) alkynyl,
cycloalkyl, amino, substituted amino, -ORZ {wherein Rz is selected from hydrogen, -Si(CH3)3,
lower (C2-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C6) alkynyl, cycloalkyl, aryl, and
-C(=O)NHRr (wherein Rr is selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-C6) lower (C2-C6) alkynyl, aryl, and cycloalkyl)};
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl;
R4 and RS are independently selected from hydrogen, lower (C1-C6) alkyl, lower (C2-C7)
alkenyl, and lower (C2-C7) alkynyl;
X is oxygen, or -NR7 (wherein R7 is as defined above); and
Rx is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, aralkyl, S(O)2R6 {wherein Re is Re
is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq (wherein Rp and Rq are selected from
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,
and heteroarylalkyl, or Rp and Rq may also together join to form a heterocyclyl ring}, heteroaryl,
heterocyclyl, heteroarylalkyl, and heterocyclylalkyl,
the process comprising
reacting a compound of Formula VIII with a compound of Formula X
(wherein Rx is the same as defined earlier) to give a compound of Formula XI.
11. A process of preparing a compound of Formula XIV
and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or
polymorphs, wherein,
R2 is carboxy, -SO2R6 (wherein R6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -
NRpRq (wherein Rp and Rq are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, and heteroarylalkyl), aryl, aralkyl, heteroaryl,
heterocyclyl, heterocyclylalkyl, and heteroarylalkyl, or Rp and Rq may also together join to form a
heterocyclyl ring}, -C(=O)OR7 (wherein R7 is selected from alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, and aralkyl), -C(=O)NRxRy (wherein Rx and Ry are each independently selected from
hydrogen, hydroxy (as restricted by the definition that both Rx and Ry cannot be hydroxy at the
same time), alkyl, alkenyl, alkynyl, aryl, aralkyl, S(O)2R6 wherein R& is the same as defined
above, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl, or Rx and Ry may also
together join to form a heterocyclyl ring), acyl, halogen (F, Cl, Br, I), cyano, -NRxRy, wherein Rx
and Ry are the same as defined above), or -C(=0)CH2ORX (wherein Rx is the same as defined
above);
RS is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heterocyclylalkyl, and heteroarylalkyl;
R4 and RS are independently selected from hydrogen, lower (Q-Ce) alkyl, lower (€2-07)
alkenyl, and lower (C2-C7) alkynyl;
Rt is alkyl;
X is oxygen, -NR7 (wherein R7 is selected from hydrogen, lower (Ci-C6) alkyl, lower (C2-
C7) alkenyl, lower (C2-C7) alkynyl, aralkyl, and aryl; and
Ar is aryl, heteroaryl, and heterocyclyl
which comprises:
a) reacting a compound of Formula XII with trimethyl silyl chloride to give a compound
b) O-alkylating the compound of Formula XIII to give a compound of Formula XIV.