-143-
What is Claimed is:
1. A method of treadng a human being suffering from drug
abuse, gastrointesdnal disorder or depression, which comprises
administering to said human a therapeudcally effective amount of a
compound of the formula:
<IMG>
wherein:
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano. C3-C15 dialkylaminoalkyl. carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl;
R is hydrogen or C1-C6 alkyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl,
C1-C6 alkoxy, fluoro, chloro, bromo and =O; or
R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
WO 93/00313 PCT/US92/05330
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W is -(CH2)p- or -H H-, wherein p is 1-3;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C ? C-(CH2)r-,
-(CH2)r-CH=CH(CH2)r-;
<IMG> ;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is hydrogen, cycloalkyl, aryl, an aryl-substituted carboxylic acid group,
or heteroaryl wherein Z may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or an ortho methylene-dioxy group;
wherein said compound exhibits high binding activity with respect
to the sigma receptor.
2. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound of the formula:
WO 93/00313 PCT/US92/05330
-145-
<IMG>
wherein:
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroary, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl;
R is hydrogen or C1-C6 alkyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl,
C1-C6 alkoxy, fluoro, chloro, bromo and =O; or
R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
W is -(CH2)p- or -H H-, wherein p is 1-3;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-;
WO 93/00313 PCT/US92/05330
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<IMG> ;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl or an aryl-substituted carboxylic acid group, wherein Z may
be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6
dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy,
carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6
cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio,
C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-
C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15
N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or an ortho
methylene-dioxy group;
wherein said compound exhibits high binding activity with respect
to the sigma receptor.
3. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder or depression, which comprises
administering to said human a therapeutically effective amount of a
compound of the formula:
<IMG>
wherein:
R is hydrogen or C1-C6 alkyl;
WO 93/00313 PCT/US92/05330
-147-
T is aryl, heteroaryl, substituted aryl, substituted heteroaryl, or
cycloalkyl, wherein said substituent is selected from the group consisting of
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 helerocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C1-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl, and an ortho methylenedioxy group;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6
alkoxy, fluoro, bromo, chloro, iodo and =O; or
R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is hydrogen, cycloalkyl, aryl, an aryl-substituted carboxylic acid group,
or aryl wherein Z may be substituted by chloro, fluoro, bromo, iodo, CF3,
C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
WO 93/00313 PCT/US92/05330
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C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl, or an ortho methylene-dioxy group;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
4. The method of claim 3, wherein said compound is selected
from the group consisting of N-phenethyl-1-phenylisopropylamine, N-(3-
phenylpropyl)-1-phenyl-isopropylamine, N-(2-phenoxy)ethyl-1-
phenylisopropylamine, N-(3-phenyl-3-propanon-1-yl)-1-
phenylisopropyhminc, N-(4-phenylbutyl)-1-phcnylisopropylamine, N-(3-(1-
naphthyl)propyl)-1-phenyl-isopropylamine, N-(3-(2-naphthyl)propyl-1-
phenylisopropylamine, N-methyl-N-(3-(2-naphthyl)propyl)-1-
phenylisopropylamine, N-(3-phenyl-2-propyn-1-yl)-1-phenyl-
isopropylamine, N-(3-phenyl-propyl)-1-(4-hydroxyphenyl)isopropylamine,
N-(3-phenylpropyl)-1-(4-methoxyphenyl)isopropylamine, N-(3-
phenylpropyl)-1-(3-bromophenyl)isopropylamine, N-(3-phenylpropyl)-1-(4-
bromophenyl)isopropylamine, N-(3-phenylpropyl)-1-(3,4-dichloro-
phenyl)isopropylamine, N-(3-phenylpropyl)-1-(4-iodophenyl-isopropyl)-
amine, N-(3-phenylpropyl)-1-(3-trifluoromethyl-phenyl)isopropylamine, N-
(2-phencthyl)-N-methyl-1-phenyl-isopropylamine, N-(3-phenylprowl)-1-
phenylpropan-1-one-2-amine, N-(2-indanyl)-3-phenylpropylamine, N,N-di-
(3-phenylpropyl)amine, N-(2-(1-naphthyl)ethyl)-1-phenylisopropylamine, N-
(2-(2-naphthyl)ethyl)-1-phenylisopropylamine, N-(2-(1-naphthyl)propyl)-1-
phenylisopropylamine, N-(2-(2-naphthyl)propyl)-1-phenyliso-propylamine,
N-(4-phenylbutyl)-1-(2,5-dimethoxyphenyl)iso-propylamine, N-(4-
phenylbutyl)-1-(4-bromo-2,5-dimethoxyphenyl)-isopropylamine, N-methyl-
N-(4-phenylbutyl)-1-phenylisopropyl-amine, N-methyl-N-(5-phenylpentyl)-1-
phenylisopropylamine, N-(3-phenylpropyl)-1-(4-ethoxyphenyl)isopropyl-
amine, N-(3-phenyl-propyl)-1-(4-propylphenyl)isopropylamine, N-(3-
phenylpropyl-1-(4-benzoxyphenyl)isopropylamine, N-methyl-N-(3-
WO 93/00313 PCT/US92/05330
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phenylpropyl)-1-(4-propylphenyl)isopropylamine, N-(3-phenylpropyl)-1-
phenyl-2-pentylamine, N-(4-phenylbutyl)-1-phenyl-2-pentylamine, N,N-di-
(2-ethylphenyl)methylamine, N,N-dibenzylamine, N-(3-phenylpropyl)-N-(6-
phenylhexyl)amine, N-(3-phenylpropyl)-N-(5-phenylpentyl)amine, N-propyl-
N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenyl-propyl)-1-
phenylisopropylamine, N-methyl-N-(3-methyl-2-butenyl)-1-phenyliso-
propylamine, N-methyl-N-(3-methylbutyl-1-phenyl-isopropylamine, N-
methyl-N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-methyl-N-(3-
methylbutyl)-1-isopropylamine, N-methyl-N-(3-phenylbutyl)-1-phenyl-2-
pentylamine, N-propyl-N-(3-phenyl)propyl-1-phenyl-2-propylamine, N-
benzyl-N-(3-phenyl)-propyl)-1-phenyl-2-propylamine, N-phenyl-(5-
phenyl)pentylamine, N-methyl-N-(3-phenyl)propyl-5-phenylpentylamine, N-
(2-(o-methyl-phenyl)ethyl-5-phenylpentylamine, N-(2-(m-
methylphenyl)ethyl)-5-phenylpentylamine, N-(2-(p-methylphenyl)ethyl-5-
phenylpentylamine, N-benzyl-5-phenylpentylamine, N-benzyl-N-methyl-5-
phenyl-pentylamine, N-(2-(3-hydroxyphenyl)ethyl)-5-phenylpentylamine, N-
(2-(2-hydroxyphenyl)ethyl)-5-phenylpentylamine, N,N'-diethyl-2-
(diphenylacetoxy)ethylamine, N,N'-diethyl-2-(9-fluorenecarboxy)-
ethylamine, N,N-Dimethyl-5-phenylpentylamine, N-Benzyl-N-(3-
phenylpropyl)-1-phenyl-2-propylamine, N-Benzyl-N-methyl-5-
phenylpentylamine, N-Benzyl-5-phenylpentylamine, and N-(2-phenethyl)-N-
methylpentylamine.
5. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound of the formula:
<IMG>
wherein:
WO 93/00313 PCT/US92/05330
-150-
R is hydrogen or C1-C6 alkyl;
T is aryl, heteroaryl, substituted aryl, substituted heteroaryl, or
cycloalkyl. wherein said substituent is selected from the group consisting of
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substitutcd aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl, and an ortho methylenedioxy group;
R1 is selected from the group consisting of hydrogcn, C1-C6 alkyl, C1-C6
alkoxy, fluoro, bromo, chloro, iodo and =O; or
R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 0-5;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl or an aryl-substituted carboxylic acid group, wherein Z may
be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6
dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy,
carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6
cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio,
C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
WO 93/00313 PCT/US92/05330
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haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-
C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15
N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl, or an ortho
methylene-dioxy group; wherein said compound exhibits high binding
activity with respect to the sigma receptor.
6. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound selecled from the group
consisting of N-(3-phenyl-propyl)-1-(4-propylphenyl)isopropylamine, N-(3-
phenylpropyl)-1-(4-benzoxyphenyl)isopropylamine, N-methyl-N-(3-
phenylpropyl)-1-(4-propylphenyl)isopropylamine, N-(3-phenylpropyl)-1-
phenyl-2-pentylamine,N-(4-phenylbutyl)-1-phenyl-2-pentylamine,N,N-di-(2-
ethylphenyl)methylamine,N,N-dibenzylamine,N-(3-phenylpropyl)N-(6-
phenylhexyl)amine, N-(3-phenylpropyl)N-(5-phenylpentyl)amine, N-propyl-
N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenylpropyl)-1-
phenylisopropylamine,N-methyl-N-(3-methyl-2-butenyl)-1-phenyliso-
propylamine, N-methyl-N-(3-methylbutyl)-1-phenylisopropylamine, N-
methyl-N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-methyl-N-(3-
phenylpropyl)-1-phenyl-2-pentylamine, N-methyl-N-(3-methylbutyl)-1-
isopropylamine, N-methyl-N-(3-phenylbutyl)-1-phenyl-2-pentylamine, N-
propyl-N-(3-phenyl)propyl)-1-phenyl-2-propylamine, N-benzyl-N-(3-
phenyl)-propyl)-1-phenyl-2-propylamine, N-phenyl-(5-phenyl)pentylamine,
N-methyl-N-(3-phenyl)propyl-5-phenylpentylamine, N-(2-(o-
methylphenyl)ethyl)-5-phenylpentylamine, N-(2-(m-methylphenyl)ethyl)-5-
phenylpentylamine, N-(2-(p-methylphenyl)ethyl)-5-phenylpentylamine, N-
benzyl-5-phenylpentylamine, N-benzyl-N-methyl-5-phenylpentylamine, N-
(2-(3-hydroxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(2-
hydroxyphenyl)ethyl)-5-phenylpentylamine, N,N'-diethyl-2-
(diphenylacetoxy)ethylamine,N ,N'-diethyl-2-(9-fluorenecarboxy)-
ethylamine, N,N-Dimethyl-5-phenylpentylamine, N-Benzyl-N-(3-
WO 93/00313 PCT/US92/05330
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phenylpropyl-1-phenyl-2-propylamine, N-Benzyl-N-methyl-5-
phenylpentylamine, N-Benzy1-5-phenylpentylamine, N-(2-phenethyl)-N-
methylpentylamine, N-(5-phenylpentyl)-4-benzylpiperidine and N-(5-
phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
7. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder, or depression, which comprises
administering to said human a therapeutically effective amount of a
compound of the formula:
<IMG>
wherein:
R is hydrogen or C1-C6 alkyl;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, X1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl;
WO 93/00313 PCT/US92/05330
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R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6
alkoxy, fluoro, chloro, bromo and =O; or
R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 1-3;
p is 1-3;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-,
-(CH2r-CH=CH-(CH2)r-;
-(CH2)r-?-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl;
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted
by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl,
C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aryl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkyl-
sulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits high binding activity with respect
to the sigma receptor.
8. The method of claim 7, wherein said compound is selected
from the group consisting of N-(2-indanyl)-1-phenylisopropylamine, N-(2-
indanyl)-3-phenylpropylamine, N-(4,5-benzocycloheptyl)-1-
phenylisopropylamine, N-(3,4-benzocyclo-heptyl)-3-(phenyl)propylamine,
WO 93/00313 PCT/US92/05330
-154-
N-(4,5-benzocycloheptyl)-3-phenylpropylamine, N-(3,4-benzocyclohexyl)-1-
phenylisopropylamine and N-3,4-benzocyclohexyl-3-phenylpropylamine.
9. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound of the formula:
<IMG>
wherein:
R is hydrogen or C1-C6 alkyl;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
and C2-C15 dialkylsulfamoyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6
alkoxy, fluoro, chloro, bromo and =O; or
WO 93/00313 PCT/US92/05330
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R and R1 together form a morpholino, piperazinyl or piperidinyl ring;
n is 1-3;
p is 1-3;
X is-(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-.
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits high binding activity with respect
to the sigma receptor.
10. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder, or depression, which comprises
administering to said human a therapeutically effective amount of a
compound of the formula:
WO 93/00313 PCT/US92/05330
-156-
<IMG>
wherein:
R2 is selected from the group consisting of hydrogen, chloro, fluoro,
bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano,
C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1l-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkyl-
sulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 halo-
alkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
X is-(CH2)-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-.
-(CH2)r-CH=CH-(CH2)r-,
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl. aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
WO 93/00313 PCT/US92/05330
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substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy,
hydroxy, fluoro, chloro, bromo or represents one half of a double bond
with a neighboring endocyclic carbon;
wherein said compound exhibits a high binding activity with respect
to the sigma receptor.
11. The method of claim 10, wherein V is N, said compound
having the formula
<IMG>
12. The method of claim 11, wherein said compound is selected
from the group consisting of N-(3-trifluoromethyl-phenyl)-N'-
phenethylpiperazine, N-(3-trifluoromethylphenyl)-N'-(4-
phenylbutyl)piperazine, N-(3-chlorophenyl)-N'-benzylpiperazine, N-(3-
chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-(3-chlorophenyl)-N'-
phenethylpiperazine, N-phenyl-N'-(3-phenyl-propyl)piperazine, N-phenyl-
N'-(3-phenylbutyl)piperazine, N-(2-naphthyl)-N'-(3-phenylpropyl)-
piperazine, N-phenyl-N'-(3-(2-naphthyl)propyl)-piperazine, N-phenyl-N'-
propylpiperazine, N-(4-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-
benzyl-N'-(4-phenylbutyl)-piperazine, N-phenyl-N'-(4-phthalimidobutyl)-
piperazine, and N-phenyl-N'-(5-phthalimidopentyl)piperazine.
WO 93/00313 PCT/US92/05330
-158-
13. The method of claim 11, wherein V is CM, said compound
having the formula
<IMG>
14. The method of claim 13, wherein said compound is selected
from the group consisting of N-phenethyl-4-phenylpiperidine, N-phenethyl-
4-phenyl 4 hydroxypiperidine, N-(3-phenylpropyl)-4-phenylpiperidine, N-
(3-phenylpropyl)-4-phenyl-4-hydroxypiperidine, N-(5-phenylpentyl)-4-
phenylpiperidine, N-(4-phenylbutyl)-4-phenylpiperidine, N-(3-
phenylpropyl)-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine, N-(4-
phenylbutyl)-4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine, N-(5-
phenylpentyl)-4-benzylpiperidine and N-(5-phenylpentyl)-4-benzyl-4-
hydroxy-piperidine.
15. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound of the formula:
<IMG>
wherein:
R2 is selected from the group consisting of hydrogen, chloro, fluoro,
bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano,
C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
WO 93/00313 PCT/US92/05330
-159-
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl; C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
and C2-C15 dialkylsulfamoyl;
X is -(CH2)-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2),-CH=CH-(CH2)r-,
<IMG>;
-(CH2)r-C-(CH2)r-;
-(CH2),-Y-(CH,)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy,
hydroxy, fluoro, chloro, bromo or represents one half of a double bond
with a neighboring endocyclic carbon;
WO 93/00313 PCT/US92/05330
-160-
wherein said compound exhibits a high binding activity with respect
to the sigma receptor.
16. The method of claim 15, wherein V is N, said compound
having the formula
<IMG>
17. The method of claim 15, wherein V is CM, said compound
having the formula
<IMG>
18. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder, or depression, which comprises
administering to said human a therapeutically effective amount of a
compound of the formula:
<IMG>
wherein:
R3 is selected from the group consisting of C1-C6 alkyl, C1-C6
alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6
WO 93/00313 PCT/US92/05330
-161-
cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG> ;
-(CH2)r-C-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy,
hydroxy, fluoro, chloro, bromo or represents one half of a double bond
with a neighboring endocyclic carbon;
wherein said compound exhibits a high binding activity with respect
to the sigma receptor.
19. The method of claim 18, wherein said compound is selected
from the group consisting of N-methyl-N'-(4-phenyl-3-(E)butenyl)pipera-
zine, N-methyl-N'-(4-phenyl-3-(Z)butenyl)-piprrazine, N-methyl-N'-(4-(3-
WO 93/00313 PCT/US92/05330
-162-
trifuoromethylphenyl)-3-(Z)butenyl)piperazine, N-methyl-N'-(4-
phenylbutyl)piperazine, N-benzyl-N-(4-phthalimidobutyl)piperazine, N-(2-
methoxyphenyl)-N'-(4-phthalimidobutyl)piperazine, N-(5-phenylpentyl)-4-
benzyl-piperidine, and N-(5-phenylpentyl)4 benzyl-4-hydroxy-piperidine.
20. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound of the formula:
<IMG>
wherein:
R3 is selected from the group consisting of C1-C6 alkyl, C1-C6
alkenyl. C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6
cycloalkyl, aroyl, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl;
X is-(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG>;
-(CH2)r-C-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
WO 93/00313 PCT/US92/05330
-163-
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C13 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy,
hydroxy, fluoro, chloro, bromo or represents one half of a double bond
with a neighboring endocyclic carbon;
wherein said compound exhibits a high binding activity with respect
to the sigma receptor.
21. A method of treating a human being suffering from a central
nervous system disorder, drug abuse, gastrointestinal disorder, or
depression, which comprises administering to said human a therapeutically
effective amount of a compound of the formula:
<IMG>
wherein:
R4 is hydrogen or an aryl group substituted with a group selected
from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxy-
methyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6
acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl;
R5 is hydrogen or hydroxy;
X is -(CH2)q-, wherein q is 1-6,
WO 93/00313 PCT/US92/05330
-164-
-(CH)2r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG>;
-(CH2)r-C-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
floro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalky, carboxy, carboxamindo, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsufinyl, arylthio, C1-C6 haloalkoxy, amino C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
22. The method of claim 21, wherein said compound is selected
from the group consisting of N-(5-phenylpentyl)-piperidine, N-(8-
phenylheptyl)piperidine, N-(5-(4-methoxyphenyl)pentyl)piperidine, N-(3-
phenylpropyl)piperidine, N-(5-cyclohexyl)pentylpiperidine, N-
benzylpiperidine, N-(2-phenethyl)-4-hydroxy-4-phenylpiperidine, N-(2-
phenethyl)-4-hydroxy-4-t-butylpiperidine, N-(5-(4-chlorophenyl)-5-pentanon-
1-yl)piperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-phenyl-piperidine,
N-(5-(4-methoxyphenyl)-5-pentanon-1-yl)piperidine, N-(5-(4-
methoxyphenyl)-5-pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-
WO 93/00313 PCT/US92/05330
-165-
methoxyphenyl)pentyl)-4-phenylpiperidine, N-(5-phenyl-5-pentanon-1-yl)-4-
phenylpiperidine, N-(5-(4-chlorophenyl)-pentyl)-4-phenylpiperidine, N-(5-
(3-methoxyphenyl)-5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-5-
pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-5-pentanon-1-yl) 4-
phenylpiperidine, N-(5-(3-methoxphenyl)-5-pentanon-1-yl)-4-
phenylpiperidine, N-(4-(4-fluorophenyl)-4-butanon-1-yl)piperidine, N-(5-(4-
fluorophenyl)-5-pentanon-1-yl)piperidine, N-(5-(4-fluorophenyl)-5-pentanon-
1-yl)-4-phenylpiperidine, N-(5-(4-fluorophenyl)-5-pentanon-1-yl)-4-(3-
chlorophenyl)-4-hydroxypiperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-
4-(4-fluorophenyl)-1,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl)-5-
pentanon-1-yl)-4-(4-fluorophenyl)-piperidine, N-(5-(4-chlorophenyl)-5-
pentanon-1-yl)-4-(4-fluorophenyl)-1,2,3,6-terahydropyridine, N-(5-(4-
chlorophenyl)-5-pentanon-1-yl)-4-(4-fluorophenyl)-piperidine, N-(5-(4-
chlorophenyl)-5-pentanon-1-yl)-4-(chlorophenyl)-1,2,3,6-terahydropyridine,
N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-4-(chlorophenyl)piperidine, N-(5-
(3,4-dichlorophenyl)-5-pentanon-1-yl)-4-(chlorophenyl)-piperidine, N-(5-
cyclopentylpentan-5-on-1-yl)piperidine and N-(5-(3,4-
methylenedioxyphenyl)penta-2,4-dienyl)piperidine.
23. A method of treating a human being suffering from a central
nervous system disorder, drug abuse, gastrointestinal disorder, or
depression, which comprises administering to said human a therapeutically
effective amount of a compound having the formula:
<IMG>
wherein,
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
WO 93/00313 PCT/US92/05330
-166-
<IMG> ;
-(CH2)r-C-(CH2)r-,
-(CH2)r-Y-(CH2r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (herein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, ido, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acarboxylic acyl, aryl, substituted aryl, heteraryl,
substitued heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamyol or methylenedioxy;
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
24. The method of claim 23, wherein said compound is N-(5-
phenyl)pentyl-3-azabcyclo[3.2.2]nonane.
25. A method of treating a human being suffering from a central
nervous system disorder, drug abuse, gastrointestinal disorder, or
depression, which comprises administering to said human a therapeutically
effective amount of a tropane derivative having the formula:
<IMG>
WO 93/00313 PCT/US92/05330
-167-
wherein,
R4 is hydrogen or an aryl group substituted with a group selected
from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxy-
methyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6
acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl;
R5 is hydrogen or hydroxy;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG>
-(CH2)r-C-(CH2)r-,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
WO 93/00313 PCT/US92/05330
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26. The method of claim 25, wherein said compound is N-(5-
phenyl)pentyl-4-phenyltropan-4-ol.
27. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder, or depression, which comprises
administering to said human a therapeutically effective amount of a
compound of the formula:
<IMG>
wherein
a is 1-8;
b is 1-8;
R is hydrogen or C1-C6 alkyl;
R2 is independently selected from the group consisting of hydrogen,
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
WO 93/00313 PCT/US92/05330
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28. The method of claim 27 wherein said compound is selected
from the group consisting of N-(4-phenylbutyl)phenethyl-amine, N-(4-
phenylbutyl)-3-phenylpropylamine, N-(4-phenylbutyl)-4-phenylbutylamine,
N-(4-phenylbutyl)benzylamine, N-(4-phenylbutyl)-5-phenylpentylamine, N-
(5-phenylpentyl)benzylamine, N-(3-phenylpropyl)phenethylamine, N-(5-
phenylpentyl)phenethyl-amine, N-(7-phenylheptyl)benzylamine, N-(7-
phenylheptyl)-phenethylamine, N-methyl-N-(2-phenethyl)-1-
phenylisopropylamine, N-methyl-N-(5-phenylpentyl)-1-
phenylisopropylamine, N-methyl-N-(3-phenylpropyl)-1-(4-
propylphenyl)isopropylamine, N-phenyl-(5-phenyl)pentylamine, N-methyl-
N-(3-phenylpropyl)-5-phenylpentyl-amine, N-benzyl-N-methyl-5-
phenylpentylamine, N-(2-(o-methoxyphenyl)ethyl)-5-phenylpentylamine, N-
(2-(m-methoxy-phenyl)ethyl)-5-phenylpentylamine, N-(2-(p-
methoxyphenyl)ethyl)-5-phenylpentylamine, N-benzyl-5-phenylpentylamine,
N-(2-m-hydroxyphenyl)ethyl)-5-phenylpentylamine, and N-(2-(o-
hydroxyphenyl)ethyl)-5-phenylpentylamine.
29. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder, or depression, which comprises
administering to said human a therapeutically effective amount of a
compound having the Formula:
<IMG>
wherein
a is 1-8;
b is 1-8;
R is hydrogen or C1-C6 alkyl;
WO 93/00313 PCT/US92/05330
-17-
R2 is independently selected from the group consisting of hydrogen,
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C3-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl; and
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
30. The method of claim 29, wherein said compound is N-(3-
phenylpropyl)-2-(2-naphthyl)ethylamine.
31. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder or depression, which comprises
administering to said human a therapeutically effective amount of a
compound having the formula:
<IMG>
wherein;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
WO 93/00313 PCT/US92/05330
-171-
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-?-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl;
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted
by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl,
C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkyl-
sulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
32. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound having the formula:
WO 93/00313 PCT/US92/05330
-172-
<IMG>
wherein;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
-(CH2)r-?-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
Wo 93/00313 PCT/US92/05330
-173-
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits high binding activity with respect
to the sigma receptor.
33. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder, or depression, which comprises
administering to said human a therapeutically effective amount of a
compound having the formula:
<IMG>
wherein n is 0-5;
Cy is C3-C8 cycloalkyl;
R is hydrogen or C1-C6 alkyl;
R1 is independently selected from the group consisting of hydrogen,
C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =O;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-?-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted
by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl,
WO 93/00313 PCT/US92/05330
-174-
C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkyl-
sulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
34. The method of claim 33, wherein said compound is selected
from the group consisting of N-(3-cyclohexylpropyl)-3-phenylpropylamine,
N-cyclohexylmethyl-3-phenylpropylamine, N-(5-
cyclohexylpentyl)benzylamine, 5-cyclohexylpentylamine, N-methyl-5-
cyclohexylpentylamine, N,N-Dimethyl-5-cyclohexylpentylamine, N-
cyclohexylmethyl-5-cyclohexyl-n-pentylamine, and N-cyclohexylmethyl-N-
methyl-5-cyclohexyl-n-pentylamine.
35. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound having the formula:
<IMG>
wherein n is 0-5;
Cy is C3-C8 cycloalkyl;
R is hydrogen or C1-C6 alkyl;
R1 is independently selected from the group consisting of hydrogen,
C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =O;
WO 93/00313 PCT/US92/05330
-175-
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-?-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carobxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
36. A method of treating a human being suffering from drug
abuse, gastrointestinal disorder or depression, which comprises
administering to said human a therapeutically effective amount of a
compound having the formula:
<IMG>
WO 93/00313 PCT/US92/05330
-176-
wherein X1 is -(CH2)r-C?C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-?-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
R2 is independently selected from the group consisting of hydrogen,
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro and C2-C15 dialklsulfamoyl;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro,
chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with
the neighboring endocyclic carbon;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
-(CH2)r-?-(CH2)r-;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is hydrogen, cycloalkyl, aryl or heteroaryl wherein Z may be substituted
by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl,
C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
WO 93/00313 PCT/US92/05330
-177-
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkyl-
sulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15
dialblamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialkylcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
37. A method of treating a human being suffering from a central
nervous system disorder, which comprises administering to said human a
therapeutically effective amount of a compound having the formula:
<IMG>
wherein X1 is -(CH2)r-C?C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
R2 is independently selected from the group consisting of hydrogen,
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
WO 93/00313 PCT/US92/05330
-178-
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro,
chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with
the neighboring endocyclic carbon;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
38. A method of treating a human being suffering from a central
nervous system disorder, drug abuse, gastrointestinal disorder or
depression, which comprises administering to said human a therapeutically
effective amount of a compound having the formula:
WO 93/00313 PCT/US92/05330
-179-
<IMG>
wherein R5 and R6 are independently a C1-8 alkyl group;
R7 is hydrogen or a C1-8 alkyl group substituted by an arylacetoxy or
arylcarboxy group; and
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>
-(CH2)r-Y-(CH2)r, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein R7 is hydrogen);
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
39. The method of claim 38, wherein said compound is selected
from the group consisting of N,N-dimethyl-n-hexylamine, N-methyl-N-
propylhexylamine, N,N'diethyl-2-(diphenylacetoxy)ethylamine, and N,N'-
diethyl-2-(9-fluoreneboxy)ethylamine.
40. A method of treating or preventing a central nervous system
disorder, angina, migrane or hypertension, comprising administering to an
animal an effective amount of a compound selected from the group
consisting of N-phenyl-N'-(3-(1-phthalimido)propyl)piperazine, N-(4-(1-
phthalimido)butyl)-N'-(o-methoxylphenyl)piperazine, and N-phenyl-N'-(4-
(1-phthalimido)butyl)piperazine.
WO 93/00313 PCT/US92/05330
-180-
41. The method of any one of claims 1-3, 5-10, 15, 18, 20, 23,
25, 27, 29, 31, 32, 33, 35-38 and 40 wherein said compound is
administered as part of a pharmaceutical composition comprising a
pharmaceutically acceptable carrier.
42. A compound of the formula
<IMG>
wherein:
R is hydrogen or methyl;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio. allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6
alkoxy, fluoro, chloro, bromo, iodo and =O; or
R and R1 together form a morpholino ring;
n is 0-5;
WO 93/00313 PCT/US92/05330
-181-
W is -(CH2)p- or -H H-, wherein p is 1-3;
X is -(CH2)q-, wherein q is 3-6;
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-;
<IMG>; or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
with the proviso that when W is -H H-, R and R1 are hydrogen and
n is 0-2, then q is 4-6;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
43. A compound of the formula:
<IMG>
wherein:
R is hydrogen or C1-C6 alkyl;
WO 93/00313 PCT/US92/05330
-182-
T is cycloalkyl, aryl, heteroaryl, substituted aryl, or substituted
heteroaryl, wherein said substituent is selected from the group consisting of
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfiunoyl;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6
alkoxy, fluoro, chloro, bromo, iodo and =O;
n is 0-5;
X is -(CH2)q, wherein q is 3-6;
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-;
<IMG>; or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S;
Z is cycloalkyl, an arylcarboxy, or an arylacetoxy group, wherein Z may
be substituted by chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6
dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy,
carboxamido, C1-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6
cycloalkyl, aroyl, aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio,
C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-
C15 dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15
N,N-dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylene dioxy;
WO 93/00313 PCT/US92/05330
-183-
with the proviso that when R and R1 are hydrogen and n is 0-2, then
q is 4-6;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
44. A compound selected from the group consisting of N-(3-
phenylpropyl)-1-(4-propyl-phenyl)-isopropylamine, N-(3-phenylpropyl)-1-(4-
benzoxyphenyl)-isopropyhmine, N-methyl-N-(3-phenylpropyl)-1-(4-
propylphenyl)-isopropylamine, N-(3-phenylpropyl)-1-phenyl-2-pentylamine,
N-(4-phenylbutyl)-1-phenyl-2-pentylamine, N-(3-phenylpropyl)-N-(6-
phenylhexyl)amine, N-(3-phenylpropyl)-N-(5-phenylpentyl)amine, N-propyl-
N-methyl-5-phenylpentylamine, N-methyl-N-(3-phenylpropyl)-1-
phenylisopropylamine, N-methyl-N-(3-methyl-2-butenyl)-1-
phenylisopropylamine, N-methyl-N-(3-methylbutyl)-1-phenyl-
isopropylamine, N-methyl-N-(3-phenylpropyl)-1-phenyl-2-pentylamine, N-
methyl-N-(3-methylbutyl)-1-isopropylamine, N-methyl-N-(3-phenylbutyl)-1-
phenyl-2-pentylamine, N-propyl-N-(3-phenyl)propyl)-1-phenyl-2-
propylamine, N-benzyl-N-(3-phenyl)-propyl)-1-phenyl-2-propylamine, N-
phenyl-(5-phenyl)pentylamine, N-methyl-N-(3-phenyl)propyl-5-
phenylpentylamine, N-(2-(o-methyl-phenyl)ethyl)-5-phenylpentylamine, N-
(2-(m-methylphenylkthyl)-5-phenylpentylamine, N-(2-(p-
methylphenyl)ethyl)-5-phenylpentyl-amine, N-benzyl-5-phenylpentylamine,
N-benzyl-N-methyl-5-phenylpentylamine, N-(2-(3-hydroxyphenyl)ethyl)-5-
phenyl-pentylamine, N-(2-(2-hydroxyphenyl)ethyl)-5-phenylpentylamine,
N,N'-diethyl-2-(diphenylacetoxy)ethylamine, N,N'-diethyl-2-(9-
fluorenecarboxy)ethylamine, N,N-Dimethyl-5-phenylpentylamine, N-
Benzyl-N-(3-phenylpropyl)-1-phenyl-2-propylamine, N-Benzyl-N-methyl-5-
phenylpentylamine, N-Benzyl-5-phenylpentylamine, and N-(2-phenethyl)-N-
methylpentylamine.
WO 93/00313 PCT/US92/05330
-184-
45. A compound of the formula:
<IMG>
wherein:
R is hydrogen or methyl;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl. substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6
alkoxy, fluoro, chloro, bromo, iodo and =O; or
R and R1 together form a morpholino ring;
n is 1-3;
p is 1-3;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
WO 93/00313 PCT/US92/05330
-185-
<IMG>; or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-1 and wherein Y
is O or S;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
46. A compound of the formula:
<IMG>
wherein:
R2 is selected from the group consisting of hydrogen, chloro, fluoro,
bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano,
C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 haloalkyl-
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sulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 halo-
alkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
X is -(CH2)-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy,
hydroxy, fluoro, chloro, bromo or represents one half of a double bond
with a neighboring endocyclic carbon;
wherein said compound exhibits a high binding activity with respect
to the sigma receptor.
47. The compound claim 46, wherein V is N, said compound
having the formula
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<IMG>
48. A compound selected from the group consisting of N-(3-
trifluoromethylphenyl-N'-(4-phenylbutyl)piperazine, N-(3-chlorophenyl)-
N--benzylpiperazine, N-(3-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-
phenyl-N'-(3-phenylpropyl)piperazine, N-phenyl-N'-(3-
phenylbutyl)piperazine, N-(2-naphthyl-N'-(3-phenylpropyl)-piperazine, N-
phenyl-N'-(3-(2-naphthyl)propyl)pipelazine, N-phenyl-N'-propylpiperazine,
N-(4-chlorophenyl)-N'-(3-phenylpropyl)piperazine, N-benzyl-N'-(4-
phenylbutyl)piperazine, N-phenyl-N'-(4-phthalimidobutyl)piperazine, N-
phenyl-N'-(5-phthalimidopentyl)piperazine, N-(5-phenylpentyl)-4-
benzylpiperidine and N-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
49. The compound of claim 46, wherein V is CM, said
compound having the formula
<IMG>
50. A compound of the formula:
<IMG>
wherein:
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R3 is selected from the group consisting of C1-C6 alkyl, C1-C6
alkenyl, C2-C6 dialkoxymethyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6
cycloalkyl, aroyl, C2-C6 acyl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG>
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy,
hydroxy, fluoro, chloro, bromo or represents one half of a double bond
with a neighboring endocyclic carbon;
wherein said compound exhibits a high binding activity with respect
to the sigma receptor.
51. The compound of claim 50 selected from the group
consisting of N-methyl-N'-(4-phenyl-3-(E)butenyl)pipera-zine, N-methyl-N'-
(4-phenyl-3-(Z)butenyl)-piperazine, N-methyl-N'-(4-(3-
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trifuoromethylphenyl)-3-(Z)butenyl)piperazine, N-methyl-N'-(4-
phenylbutyl)piperazine, N-benzyl-N'-(4-phthalimidobutyl)-piperazine, N-(2-
methoxyphenyl)-N'-(4-phthalimidobutyl)-piperazine, N-(5-phenylpentyl)-4-
benzylpiperidine, and N-(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
52. A compound selected from the group consisdng of N-(3-
trifluoromethylphenyl)-N'-phenylbutyl)piperazine, N-(3-chlorophenyl)-N'-
(3-phenylpropyl)piperazine, N-phenyl-N'-(3-phenylpropy)piperazine, N-
phenyl-N'-(3-phenylbutyl)piperazine, N-naphthyl-N'-(3-phenylpropyl)-
piperazine, N-phenyl-N'-propylpiperazine, N-(4-chlorophenyl)-N'-(3-
phenylpropyl)piperazine, N-benzyl-N'-(4-phenylbutyl)-piperazine, N-phenyl-
N'-(4-phthalimidobutyl)piperazine, N-phenyl-N'-(5-
phthalimidopentyl)piperazine, N-(5-phenylpentyl)-4-benzylpiperidine and N-
(5-phenylpentyl)-4-benzyl-4-hydroxy-piperidine.
53. A compound having the formula
<IMG>
wherein
R2 is selected from the group consisting of hydrogen, chloro, fluoro,
bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano,
C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6 acyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl, C1-C6 alkylthio, C1-C6, alkylsulfonyl, C1-C6 haloalkyl-
sulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-C6 halo-
alkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl;
X is -(CH2)r-C?C-(CH2)r-,
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-(CH2)r-CH=CH-(CH2)r-,
<IMG>, or
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and Y is O or
S;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkyl-amino, dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialklcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect
to the sigma receptor.
54. A compound of the formula:
<IMG>
wherein:
R4 is hydrogen or an aryl group substituted with a group selected
from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxy-
methyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6
acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl;
R5 is hydrogen or hydroxy;
X is -(CH2)q-, wherein q is 1-6,
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-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG>,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C1-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialkylcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
55. The compound of claim 54 selected from the group
consisting of N-(5-phenylpentyl)piperidine, N-(8-phenylheptyl)-piperidine,
N-(5-(4-methoxyphenyl)pentyl)piperidine, N-(3-phenylpropyl)piperidine, N-
(5-cyclohexyl)pentylpiperidine, N-benzylpiperidine, N-(2-phenethyl)-4-
hydroxy-4-phenylpiperidine, N-(2-phenethyl)-4-hydroxy-4-t-butylpiperidine,
N-(5-(4-chlorophenyl)-5-pentanon-1-yl)piperidine, N-(5-(4-chlorophenyl)-5-
pentanon-1-yl)-4-phenylpiperidine, N-(5-(4-methoxyphenyl)-5-pentanon-1-
yl)piperidine, N-(5-(4-methoxyphenyl)-5-pentanon-1-yl)-4-phenylpiperidine,
N-(5-(4-methoxyphenyl)pentyl)-4-phenylpiperidine, N-(5-phenyl-5-pentanon-
1-yl)-4-phenylpiperidine, N-(5-(4-chlorophenyl)pentyl)-4-phenylpiperidine,
N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-
WO 93/00313 PCT/US92/05330
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5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-5-pentanon-1-yl)-4-
phenylpiperidine, N-(5-(3-methoxyphenyl)-5-pentanon-1-yl)-4-
phenylpiperidine, N-(4-(4-fluorophenyl)-4-butanon-1-yl)piperidine, N-(5-(4-
fluorophenyl)-5-pentanon-1-yl)piperidine, N-(5-(4-fluorophenyl)-5-pentanon-
1-yl)-4-phenylpiperidine, N-(5-(4-fluorophenyl)-5-pentanon-1-yl)4-(3-
chlorophenyl)-4-hydroxypiperidine, N-(5-(4-chlorophenyl)-5-pentanon-1-yl)-
4-(4-fluorophenyl)-1,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl)-5-
pentanon-1-yl)-4-(4-fluorophenyl)piperidine, N-(5-(4-chloro-phenyl)-5-
pentanon-1-yl)-4-(4-fluorophenyl)-1,2,3,6-terahydro-pyridine, N-(5-(4-
chlorophenyl)-5-pentanon-1-yl)-4-(4-fluo-phenyl)-piperidine, N-(5-(4-
chlorophenyl)-5-pentanon-1-yl)-4-(chlorophenyl)-1,2,3,6-terahydropyridine,
N-(5-(4-chlorophenyl)-5-pentanon-1-yl)4-(chlorophenyl)piperidine, N-(5-
(3,4-dichloro phenyl)-5-pentanon-1-yl)4-(chlorophenyl)-piperidine, N-(5-
cyclopentylpentan-5-on-1-yl)piperidine, N-(5-(3,4-methylene-
dioxyphenyl)penta-2,4-dienyl)piperidine, N-phenyl-(5-phenyl)pentylamine,
N-methyl-N-(3-phenylpropyl)-5-phenylpentylamine, N-benzyl-N-methyl-5-
phenylpentylamine, N-(2-(o-methoxyphenyl)ethyl)-5-phenylpentylamine, N-
(2-(m-methoxyphenyl)ethyl)-5-phenylpentylamine, N-(2-(p-
methoxyphenyl)ethyl)-5-phenylpentylamine, N-benzyl-5-phenylpentylamine,
N-(2-(m-hydroxyphenyl)ethyl)-5-phenylpentylamine, and N-(2-(o-
hydroxyphenyl)ethyl)-5-phenylpentylamine.
56. A compound having the formula:
<IMG>
wherein,
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
WO 93/00313 PCT/US92/05330
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-(CH2)r-CH=CH-(CH2)r-,
<IMG>,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6, cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
57. N-(5-phenyl)pentyl-3-azabicyclo[3.2.2]nonane, a compound
of claim 56.
58. A tropane derivative having the formula:
<IMG>
wherein,
R4 is hydrogen or an aryl group substituted with a group selected
from the group consisting of C1-C6 alkyl, C1-C6 alkenyl, C2-C6 dialkoxy-
methyl, C3-C15 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6.
WO 93/00313 PCT/US92/05330
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acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C6
heterocycloalkyl;
R5 is hydrogen or hydroxy;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2),-,
-(CH2)r-CH=CH-(CH)r-,
<IMG>,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
Z is cycloalkyl, aryl or heteroaryl wherein Z may be substituted by chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro, C2-C15 dialkylsulfamoyl or methylenedioxy;
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
59. N-(5-phenyl)pentyl-4-phenyltropan-4-ol, a compound of claim
58.
60. A compound having the formula:
WO 93/00313 PCT/US92/05330
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<IMG>
wherein;
Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,
wherein the substituent is selected from the group consisting of chloro,
fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 acyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-
C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio,
C1-C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C1s dialkylsulfamoyl;
X is -(CH2)q-, wherein q is 1-6,
-(CH2)r-C?C-(CH2)r-,
-(CH2)r-CH=CH-(CH2)r-,
<IMG>,
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl;
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
WO 93/00313 PCT/US92/05330
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C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro or
C2-C15 dialkylsulfamoyl;
wherein said compound exhibits high binding activity with respect to
the sigma receptor.
61. A compound of the formula
<IMG>
wherein n is 0-5;
Cy is C3-C15 cycloalkyl; and
R1 is independently selected from the group consisting of hydrogen,
C1-C6 alkyl, C1-C6 alkoxy, fluoro, chloro, bromo, iodo and =O;
R is hydrogen or C1-C6 alkyl;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
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haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl. aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro,
C2-C15 dialkylsulfamoyl or methylenedioxy.
62. A compound selected from the group consisting of N-
cyclohcxylmethyl-3-phenylpropylamine, N-(5-
cyclohexylpentyl)benzylamine, 5-cyclohcxylpentylamine, 5-
cyclohcxylpentylamine, N-mctbyl-5-cyclohcxylpentylamine, N,N-Dimethyl-
5-cyclohcxylpentylamine, N-cyclohcxylmethyl-5-cyclohexyl-n-pentylamine,
and N-cyclohexylmethyl-N-methyl-5-cyclohexyl-n-pentylamine.
63. A compound of the formula
<IMG>
wherein X1 is -(CH2)r-C?C-(CH2)r-, wherein each r is 0-3 independently;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein Y is O or S; or
C1-C6 alkyl (wherein Z is hydrogen);
R1 is independently selected from the group consisting of hydrogen,
chloro, fluoro, bromo, iodo, CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-
C6 alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C1-C6
WO 93/00313 PCT/US92/05330
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haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkyl-
sulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6
haloalkylsulfinyl, arylthio, C1-C6 haloalkoxy, amino, C1-C6 alkyl-amino,
dialkylamino, hydroxy, carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-
dialklcarbamoyl, nitro and C2-C15 dialkylsulfamoyl;
V is N or CM, wherein M is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, fluoro,
chloro, bromo, trifluoromethyl, hydroxy or one half of a double bond with
the neighboring endocyclic carbon;
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein Z is hydrogen); and
Z is cycloalkyl which may be substituted by chloro, fluoro, bromo, iodo,
CF3, C1-C6 alkoxy, C2-C6 dialkoxymethyl, C1-C6 alkyl, cyano, C3-C15
dialkylaminoalkyl, carboxy, carboxamido, C1-C6 haloalkyl, C1-C6
haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
carboxylic acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6
haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, arylthio, C1-
C6 haloalkoxy, amino, C1-C6 alkylamino, C2-C15 dialkylamino, hydroxy,
carbamoyl, C1-C6 N-alkylcarbamoyl, C2-C15 N,N-dialkylcarbamoyl, nitro
and C2-C15 dialkylsulfamoyl.
64. A compound having the formula:
WO 93/00313 PCT/US92/05330
-199-
<IMG>
wherein R5 and R6 are independently a C1-8 alkyl group;
R7 is hydrogen or a C1-8 alkyl group substituted by an arylacetoxy or
arylcarboxy group; and
X is -(CH2)q-, wherein q is 1-6;
-(CH2)r-C?C-(CH2)r-, wherein r is 0-3;
-(CH2)r-CH=CH-(CH2)r-;
<IMG>;
-(CH2)r-Y-(CH2)r-, wherein each r is independently 0-3 and wherein Y
is O or S; or
C1-C6 alkyl (wherein R7 is hydrogen);
wherein said compound exhibits a high binding activity with respect
to the sigma receptors.
65. The compound claim 64 selected from the group consisting
of N,N-dimethyl-n-hexylamine, N-methyl-N-propylhexylamine, N,N'-
diethyl-2-(diphenylacetoxy)ethylamine, and N,N'-diethyl-2-(9-
fluorenecarboxy)ethylamine.
66. A compound selected from the group consisting of N-phenyl-
N'-(3-(1-phthalimido)propyl)piperazine, N-(4-(1-phthalimido)butyl)-N'-(o-
methoxylphenyl)piperazine, and N-phenyl-N'-(4-(1-
phthalimido)butyl)piperazine.
WO 93/00313 PCT/US92/05330
-200-
67. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of any one of claims 42-46, 48, 52-54,
56, 58 and 60-66 and a pharmaceutically acceptable carrier.
