Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-22
2003-04-22
Kifle, Bruce (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S112000
Reexamination Certificate
active
06552036
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to compounds useful as delta-opioid and mu-opioid receptor modulators. More particularly, the present invention is directed to 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives useful as delta-opioid or mu-opioid receptor modulators.
BACKGROUND OF THE INVENTION
WO 97/23466 describes compounds as having an analgesic effect of a general and one preferred formula:
WO 98/28270 describes compounds as having an analgesic effect of a general and one preferred formula:
WO 98/28275 describes compounds as having an analgesic effect of a general and one preferred formula:
Amide derivatives of 3-aminotropane have been prepared and described as having potential pharmacological activity (Gutkowska, B., et al.,
Acta Pol. Pharm.,
1984, 41(6), 613-617), of the formula:
WO 93/15062 describes compounds as delta-opioid (&dgr;-opioid) and mu-opioid (&mgr;-opioid) receptor agonists of (approximately) the general formula:
The synthesis and binding affinities for 4-Diarylaminotropane compounds as &dgr;-opioid agonists have been described (Boyd, R. E., Carson, J. R., Codd, E. E., Gauthier, A. D., Neilson, L. A and Zhang, S-P.,
Biorg. Med. Chem. Lett.,
2000, 10: 1109-1111) of the general formula:
wherein R is hydrogen, methyl, propyl, hexyl, 2-ethylbutyl, allyl, 3,3-dimethallyl, cyclohexylmethyl, phenethyl, phenylpropyl, 2,2-diphenylethyl, 3,4-dimethoxyphenethyl, 4-fluorophenethyl, 2-furylmethyl, 3,4-methylenedioxybenzyl, cyano and X is N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-phenylamino, N-ethyl-N-(4-methyl)benzylamino, N-butyl-N-ethylamino, N-butyl-N-propylamino, [N-ethyl-N-(2-methyl)allyl]amino, hydroxy, O-t-butyl and 1-pyrrolidinyl; and, Y is hydrogen, methoxy and methylthio.
Other selective 4-[(8-alkyl-8-azabicyclo[3.2.1] octyl-3-yl)-3-arylanilino]-N,N-diethylbenzamide &dgr;-opioid ligands have also been described (Thomas, J. B., Atkinson, R. N., Rothman, R. B., Burgess, J. P., Mascarella, S. W., Dersch, C. M., Xu, H. and Carroll, F. I.,
Biorg. Med. Chem. Lett.,
2000, 10: 1281-1284).
The present invention is directed to compounds useful as delta-opioid and mu-opioid receptor modulators. More particularly, the present invention is directed to delta-opioid and mu-opioid receptor modulators.
It is an object of the present invention to provide 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives useful as &dgr;-opioid or &mgr;-opioid receptor modulators. It is also an object of the present invention to provide &dgr;-opioid and &mgr;-opioid receptor selective agonists as analgesics having reduced side-effects. It is another object of the present invention to provide &dgr;-opioid and &mgr;-opioid receptor selective antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, having reduced side-effects. It is also another object of the present invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as a &dgr;-opioid or &mgr;-opioid receptor modulator. It is a further object of the present invention to provide a useful pharmaceutical composition comprising a &dgr;-opioid or &mgr;-opioid receptor modulator compound of Formula (I) in combination with a &mgr;-opioid receptor modulator or a &dgr;-opioid or &mgr;-opioid receptor modulator compound of Formula (I) wherein the combination has a synergistic therapeutic effect.
SUMMARY OF THE INVENTION
The present invention provides an opioid receptor modulator compound selected from the group consisting of a &dgr;-opioid and a &mgr;-opioid receptor modulator compound of Formula (I):
wherein:
R
1
is selected from the group consisting of hydrogen, C
1-8
alkyl, halo
1-3
(C
1-8
)alkyl, C
2-8
alkenyl, C
1-8
alkoxy(C
2-8
)alkenyl, C
2-8
alkynyl, C
1-8
alkoxy(C
2-8
)alkynyl, cycloalkyl, cycloalkyl(C
1-8
)alkyl, cycloalkylcarbonyl(C
1-8
)alkyl, cycloalkyl(C
2-8
)alkenyl, cycloalkyl(C
2-8
)alkynyl, heterocyclyl, heterocyclyl(C
1-8
)alkyl, heterocyclylcarbonyl (C
1-8
)alkyl, heterocyclyl(C
2-8
)alkenyl, heterocyclyl(C
2-8
)alkynyl, aryl, aryl(C
1-8
)alkyl, arylcarbonyl(C
1-8
)alkyl, aryl(C
2-8
)alkenyl, aryl(C
2-8
)alkynyl, arylaminocarbonyl(C
1-8
)alkyl, heteroaryl(C
1-8
)alkyl, heteroarylcarbonyl(C
1-8
)alkyl, heteroaryl(C
2-8
)alkenyl, heteroaryl(C
2-8
)alkynyl, heteroarylaminocarbonyl(C
1-8
)alkyl, (R
1a
)
2
—N—(C
1-8
)alkyl, R
1a
—O—(C
1-8
)alkyl, R
1a
—S—(C
1-8
)alkyl, R
1a
—SO—(C
1-8
)alkyl and R
1a
—SO
2
—(C
1-8
)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, C
1-6
alkylcarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkylcarbonylamino, C
1-6
alkylthio, C
1-6
alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, C
1-6
alkylcarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkylcarbonylamino, C
1-6
alkylthio, C
1-6
alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
R
1a
is independently selected from the group consisting of hydrogen, C
1-8
alkyl, C
1-8
alkoxy(C
1-8
)alkyl, hydroxy(C
1-8
)alkyl, halo
1-3
(C
1-8
)alkyl, halo
1-3
(C
1-8
)alkoxy(C
1-8
)alkyl, C
2-8
alkenyl, C
2-8
alkynyl, cycloalkyl, cycloalkyl(C
1-8
)alkyl, heterocyclyl, heterocyclyl(C
1-8
)alkyl, heterocyclyl(C
1-8
)alkenyl, heterocyclyl(C
1-8
)alkynyl, aryl, aryl(C
1-8
)alkyl, aryl(C
1-8
)alkenyl, aryl(C
1-8
)alkynyl, arylcarbonyl(C
1-8
)alkyl, heteroaryl, heteroaryl(C
1-8
)alkyl, heteroaryl(C
1-8
)alkenyl, heteroaryl(C
1-8
)alkynyl and heteroarylcarbonyl(C
1-8
)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, C
1-6
alkylcarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkylcarbonylamino, C
1-6
alkylthio, C
1-6
alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, C
1-6
alkylcarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkylcarbonylamino, C
1-6
alkylthio, C
1-6
alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;
R
2
is selected from the group consisting of aryl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, C
1-6
alkylcarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkyloxycarbonyl, C
1-6
alkylaminocarbonyl, C
1-6
alkylcarbonylamino, C
1-6
alkylthio, C
1-6
alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of —(CH
2
)
3-5
— and —O(CH
2
)
1-3
O—;
R
3
is selected from the group consisting of aryl and heteroaryl optionally substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, amino, C
1-6
alkylamino, di(C
1-6
alkyl)amino, C
1-6
alkylcarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkyloxycarbonyl, C
1-6
alkylaminocarbonyl, C
1-6
Boyd Robert E.
Carson John R.
Coats Steven J.
Neilson Lou Anne
Pitis Philip M
Kifle Bruce
Ortho-McNeil Pharmaceutical , Inc.
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