Specification
Field of the Invention
This present invention generally relates to muscarinic receptor antagonists which are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. The invention also relates to the process for the prepration of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and the methods for treating diseases mediated through muscarinic receptors.
Background of the Invention
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 superfarnily of G-protein coupled receptors and five molecularly distinct subtypes are known to exist (Mi, MZ, MB, M4 and MS).
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 M: 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. Chetn. 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 MI and MS receptors. Although the Ma- receptors are the predominant cholinoreceptors, the smaller population of Ma-receptors appears to be the most functionally important as they mediate the direct contraction of these 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 inuscarinic receptor antagonists that demonstrate target organ selectivity.
Compounds having antagonistic activity against muscarinic receptors have been described in Japanese patent application Laid Open Number 92921/1994 and 135958/1994; WO 93/16048; United States 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, United States Patent Nos. 6,174,900, 6,130,232 and 5,948,792; WO 97/45414 are related to 1,4-disubstituted piperidine derivatives; WO 98/05641 describes fluorinated, 1,4-disubstitued piperidine derivatives; WO 93/16018 and WO96/33973 are other references of interest. United States Patent No. 5,397,800 discloses l-azabicyclo[2.2.1]heptanes. United States Patent No.5, 001,160 describes 1 -ary 1-1 -hydroxy-1 -substituted-3-(4-substituted-1 -piperaziny l)-2-propanones. WO 01/42213 describes 2-biphenyl-4-piperidinyl ureas. WO 01/42212 describes carbamate derivatives. WO 01/90081 describes amino alkyl lactam. WO 02/53564 describes quinuclidine derivatives. WO 02/00652 describes carbamates derived from arylalkyl amines. WO 02/06241 describes l,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives. United States application No. 20030105071 describes thiazole and other heterocyclic ligands as useful for mammalian dopamine, muscarinic and serotonic receptors and transporters, and method of use thereof. WO 04/005252 discloses azabicyclo derivatives described as musacrinic receptor antagonists. WO 04/004629 discloses 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives described as useful muscarinic receptor antagonists. WO 01/47893 describes azabicycloctane derivatives said to be useful in the treatment of cardiac arrhythmias. WO 99/43657 describes 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives reportedly as muscarinic receptor antagonists. WO 01/090082 describes substituted 1-amino-alkyl lactams and their apparent use as muscarinic receptor antagonists. WO 03/033495 describes quinuclidine derivatives and their putative use as M2 and/or M3 muscarinic receptor antagonists. United States application 2003 0171362 describes amino-tetralin derivatives said to be muscarinic receptor antagonists. United States application 20030162780 describes 4-piperidinyl alkyl amine derivatives as muscarinic receptor antagonists. WO 04/014853 and WO 04/014363 disclose derivatives of 3,6-disubstituted azabicyclohexane said to be useful as muscarinic receptor antagonists.
WO 04/052857 and WO 04/067510 disclose 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives described as useful muscarinic receptor antagonists. WO 04/056811 discloses flaxavate derivatives as muscarinic receptor antagonists. WO 04/056810 discloses xanthene derivatives as muscarinic receptor antagonists. WO 04/056767 discloses l-substituted-3-
pyrrolidine derivatives as muscarinic receptor antagonists. WO 04/089363, WO 04/089898, WO 04/069835, WO 04/089900 and WO 04/089364 disclose substituted azabicyclohexane derivatives as muscarinic receptor antagonists.
,/. Med. Chem., 44, p. 984 (2002), describes cyclohexylmethylpiperidinyl-triphenylpropioamide derivatives as selective M3 antagonist discriminating against the other receptor subtypes. J. Med. Chem., 36, p. 610 (1993), describes the synthesis and antimuscarinic activity of some l-cycloalkyl-l-hydroxy-l-phenyl-3-(4-substituted piperazinyl)-2-propanones and related compounds. ./. 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-Org. Med. Chem. Lett., 15, 2093 (2005) describes the synthesis and activity of analogues of oxybutynin and tolterodine.
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 Formula I
represents an optional double bond;
(Figure Removed)
W can representheteroaryl, or heterocyclyl, where 'AIWVW represents a point of
attachment.
R1 can be aryl, heteroaryl, heterocyclyl, or cycloalkyl.
R2 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl.
R3 can be hydrogen, lower alkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, halogen, or amino.
X can be oxygen, sulphur, or alkylene wherein the alkylene group may be interrupted by 1 -5 oxygen, sulfur and -NRa (where Ra can be hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl) groups.
R4 can be hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl; carboxy; halogen; aryl; aralkyl; acyl; heteroaryl; heterocyclyl; SO2R5 [wherein R5 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, or heteroarylalkyl, or Rp and RC| may also together join to form a heterocyclyl ring), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, or heteroarylalkyl]; -COOR6 (wherein R6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl); -(C=O)NRxRy [wherein Rx and Ry are 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, -SO2R5 (wherein RS is the same as defined above), heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl, or Rx and Ry may also together join to form a heterocyclyl ring]; -NRxRy wherein Rx and Ry are the same as defined above; and -OC(=O)NRxRy (wherein Rx and Ry are the same as defined above).
G can be -OR (wherein R represents hydrogen or unsubstituted lower (C\-C(,) alkyl); -
NOR (wherein R is the same as defined above); -NHYR (wherein R is hydrogen, alkyl or aryl
and Y is -C(=O), SO, SO2); or oxygen. The compounds of Formula 1 are also restricted by the definition that when X is oxygen or sulphur, then G can not be OR (wherein R is the same as defined above).
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 is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl may further be substituted with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbcmylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -
COOR6 (wherein R6 is as defined earlier), arylthio, thiol, alkylthio, aryloxy, aminosulfonyl, aminocarbonylamino, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ryare as defined earlier), nitro, -S(O)nR5 (wherein R$ is the same as defined earlier and n is 0, 1 or 2). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COORe (wherein R6 is as defined earlier), -NRxRy, -C(=0)NRxRy, -OC(=O)NRXRY (wherein Rx and Ry are as defined earlier), hydroxy, alkoxy, halogen, -CF3, cyano, and -S(O)nR5 (where n and R5 are as defined earlier).
Alkyl groups may also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa (where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR6 (wherein R6 is as defined earlier), -NRxRy, -C(=0)NRXRV, -OC(=O)NRxRy (wherein Rx and Ry are as defined earlier), hydroxy, alkoxy, halogen, CF3 cyano, and -S(O)nRs (where n and R5 are as defined earlier).
The term "alkylene," unless otherwise specified, refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms. This term can be exemplified by groups such as methylene, ethylene, propylene isomers and the like.
Alkylene may further be substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, heteroaryloxy, aminosulfonyl, -COOR6 (wherein R6 is as defined earlier), -NHC(=O)RX, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRy, -C(=O)heteroaryl, -C(=O)heterocyclyl, -OC(=O)NRxRy (wherein Rx and Ry are as defined earlier), nitro, -S(O)nR5 (wherein n and RS are as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR6 (wherein R& is as defined earlier), -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy, -NHC(=O)NRxRy (wherein Rx and Ry arc as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)mRs (where R$ and n are as defined earlier).
Alkylene groups may also be interrupted by 1-5 atoms chosen from oxygen, sulfur and -NRa (where RH is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR6 (wherein Re is as defined earlier), -NRxRy, -C(=O)NR.vRy, -O-C( O)NRxRy (wherein Rx and Ry are as defined earlier), hydroxy, alkoxy, halogen, CFj, cyano, and -S(O)nR5 (where n and RS are as defined earlier).
The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with
cis or trans geometry. Particular alkenyl groups include ethenyl or vinyl, 1-propylene or allyl, iso-propylene, bicyclo[2.2.1 jheptene, and the like. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl may further be substituted with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, -NRxRy, -C(=0)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR6 (wherein Ra is as defined earlier), arylthio, thiol, alkylthio, aryl, alkaryl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, nitro, -S(O)nR5 (wherein RS is as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, -COORe (wherein R6 is as defined earlier), hydroxy, alkoxy. halogen, -CF3, cyano, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and RS are as defined earlier) and -S(O)nRs (where RS and n are as defined earlier).
The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms. Particular 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. Alkynyl may further be substituted with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR*, (wherein R^ is as defined earlier), arylthio, thiol, alkylthio, aryl, alkaryl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NRxRy,-C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are as defined earlier), -S(O)nR.
Documents
Application Documents
| # |
Name |
Date |
| 1 |
3038-delnp-2007-abstract.pdf |
2011-08-21 |
| 1 |
abstract.jpg |
2011-08-21 |
| 2 |
3038-delnp-2007-claims.pdf |
2011-08-21 |
| 2 |
3038-delnp-2007-form-2.pdf |
2011-08-21 |
| 3 |
3038-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 3 |
3038-delnp-2007-form-1.pdf |
2011-08-21 |
| 4 |
3038-delnp-2007-description (complete).pdf |
2011-08-21 |
| 5 |
3038-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 5 |
3038-delnp-2007-form-1.pdf |
2011-08-21 |
| 6 |
3038-delnp-2007-claims.pdf |
2011-08-21 |
| 6 |
3038-delnp-2007-form-2.pdf |
2011-08-21 |
| 7 |
3038-delnp-2007-abstract.pdf |
2011-08-21 |
| 7 |
abstract.jpg |
2011-08-21 |