SIGMA RECEPTOR LIGANDS AND THE USE THEREOF

LIGANDS DU RECEPTEUR SIGMA ET UTILISATION CORRESPONDANTE

English Abstract

2111957 9300313 PCTABS00019
The invention relates to methods for the treatment of central
nervous system disorders, gastrointestinal disorders, drug abuse,
angina, migraine, hypertension and depression by administering a
pharmaceutical composition comprising an effective amount of
certain sigma receptor ligands to a patient in need of such treatment.
The invention further relates to novel sigma receptor ligands
having high binding to the sigma receptor and pharmaceutical
compositions thereof. Unexpectedly, certain of the sigma receptor
ligands of the present invention have selectivity for the sigma
receptor over the DA, PCP and 5-HT1A receptors.

Claims

-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;

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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
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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, 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-;

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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;

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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-

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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;

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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,

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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
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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
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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-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
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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-,

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<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)-

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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-,

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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.

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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,

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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

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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.

Description

WO93~00313 _1_ Pcr/us92/05330
2111957
Title of the Invention
SIGMA RECEPTOR LIGANDS
AND l~IE USE I~IEREOF
.
~kld of the In~cntwn
S The invendon is in the field of medicinal chemistry. In particular, the
invcndon relaites to new compounds having high binding to the sigma receptor
and pharmaceudcal composidons thereof. These compounds are useful for the
treatment of cent~l nervous system disorders and other conditions.
, . . . , ~ . ,
Bacl~ground of thc In~cntJ'on ~ -
Brain sigma receptors are the subject of intense investigation in light
of the fact that sigma receptors bind many psychotropic drugs (Sonders a al.,
Trcnds Nc~rosa. 11:3740 (1988. Moreover, certain sigma rec.,ptor ligands
have andpsychodc activity which suggests that sigma receptor acdve
compounds may be used for the treatment of schizophrenia (Largent e~ al.,
E~r. J. Pharmacol. 11:345-347 (1988). ;
Certain neuroleptic (i.e., antipsychodc) agents bind with very high
affinity at sigma sites. Su, T., J. Pharmacol. E~p Ther. 223:284 (1982); ~;
Tam, S.W., Proc. Nat. Acad. Sci (USAJ 80:6703 (1983). One agent with
very high affinity for sigma sites (Ki _a 1 nM; i.e., approximately 100 fold
higher affinity than N-allyl normetrazocine (NANM)) is the neuroleptic agent
haloperidol. Tam, S.W., et al., Proc. Na~. Acad. Sci (USA) 81:5618 (1984).
Sigma-opiates, such as NANM, bind with low affinity at typical opiate
receptors but bind widl significant affinity at PCP receptors.
Current neuroleptic agents are thought to produce their effects via a
dopaminergic (DA) mechanism; they display very high affinities for DA
binding sites. However, not all of the potent neuroleptic agents bind at
l3H]NANM-labelled sigma sites, nor do the sigma-opiates bind at DA sites.
This has led to the suggcstion that the sites labelled by ~3H]NANM be termed
sigma-sites and not sigma-opiate sites (i~e., it may simply be coincidental thatthe sigma opiates possess an opiate-like chemical structure). In addition, there
SUBSrITUTE SHEET

W O 93/00313 PC~r~US92/05330
21119~7 -2-
has becn speculadon that agents with high affinity for sigma SitCS may cithcr
(a) produce psychodc cffccts (if they behave as agonists), or (b) produce
antipsychodc cffccts (if they behave as antagonists). It has further bccn
speculated that certain neurolepdc agents, such as halopcridol, producc their
antipsychodc effects by both a sigma and DA mechanism. Tam, S.W. and
Cook, L., Proc. Nat. ~tcad. Sci. (US~l) U:5618 (1984). In fact,
pHplaloperidol, in combinadon with spiperone (an agent with high affinity for
DA sites and essen~ally no affinity for sigma sites) is now commonly usçd to
label sigma sitcs in radioligand binding studies.
A number of researchers have studied the structure-activity relationship
of sigma ligands. For cxample, Manallack, D.T., ct al., Eur. J. Pha~ol.
144:231-235 (1987), disclose a receptor model for the phencydidine and
sigma binding sites. Manallack ct al. disclose that in a recent SAR study
(Largent a al., in press), sigma site affinity was shown to be cnhanced by
large N-alkyl substituents, e.g., benzyl or phenethyl.
Largent, B.L., ct al., A~ol. Phannacol. 32:772-784 (1987), disclose a ;
study of the structuIal determinants of sigma receptor affinity. In pardcular,
L~rgent et al. teach that several piperidine and piperazine derivadves have
sigma receptor activity. Largent et al. also disclose that affinity for the sigma
receptor is markedly influenced by the N-alkyl substituents, with more
lipophilic substituents affording greater affinity for the sigma receptor binding
sites.
Sharkey, J., etal., Eur. J. Pharmacol. 149:171-174 (1988), studiedthe
sigma receptor binding activity of cocaine-related compounds.
The literature contains a number of suggestions that the sigma receptor
is not a single, homogeneous binding site. Bowen, W.D. et al., Eur. J.
Phann. 163:309-318 (1989), disclose that the effect of U.V. radiation on
sigma receptor binding depended on the radioligand used to assay for it. It r`was also demonstrated that the binding characteristics of several sigma hgands
were different in membranes from certain cell lines than in guinea pig brain
membranes. (Hellcwell, S.B. and Bowen, W.D., Brain Res. 527:224-253

wo 93~00313 Pcr/uS92/os33o
`''`'`" 2111gS7
-3~
(1990); Wu, X.-Z. ct al., J. Pharnwcol. E~p. Thcr. 257:351-359 (1991)). At
least two groups have reported significantly differcnt pharmacology for "sigma
receptors" whcn using different radioligands to label these sites.; (Itzhak, Y.,ctal., J. Phannacol. E~p. Ther. 257:141-148 (1991); Karbon, E.W., ctal.,
S E~r. J. Pharm. 93:2i 27 (1991)). In addition, pHlDTG binding was found
to have t~vo componcnts in guinea pig memb~ancs (Rothman, R.B. ct al., Uol.
Phann. 39 222-232 (1991)). An overlap of sigma sites with some of the
multiple sites labcled by pH~da~tromethorphan has also becn described
(Musacchio, J.M., ct al., L~fc Sa. 45:1721-1732 (1989.
Hcllewell and Bowen, Brain Rcs. 527:224-253 (1990), were the first
to define thc charactcristics of the t vo putativc sigma receptor substypes,
named sigma-l and sigma-2. The primary pharmacological distinction
between thesc tow sites is thc affinity of the (+) isomers of thc bcnzomorphan
opiates for the binding sitcs. Thcse compounds, such as (+)SKF 10,047 and
(+)pentazocinc show nearly t~vo orders of magnitude higher affinity for the
sigma-l site compared to the sigma-2 site. The (-) isomers of the
benzomethorphans show little selectivity between these two sites. Other
distinctions noted bctween the two sites are a preponderance of the sigma-2
sites in cell lines such as NCB-20, PC12 and NG108-15 cells (Hellewell, S.B
and Bowen, W.D., Brain Res. 527:224-253 (1990); Wu, X.-Z., et al
J. Pharmacol. E~p. Ther. 257:351-359 (1991); Georg, A. and Friedl, A.,
J. Pharrnacol. Exp. Ther. 259:479483 (1991); Quirion, R., et al., Tr~nds in
Pharmacological Sciences 13:85-86 (1992)).
There has been considerable research on amphetamine and
amphetamine derivatives. For example, Aldous, F.A.B., J. Med. Chcm.
17:1100~1111 (1974), disclosesastructure-activity studyofpsychotomimctic
phenylalkylamines. Aldous et al. also disclose a number of halo, methyl, and
methoxy substituted amphetamines.
Fuller, R.W. e~ al., J. Med. Chem. 14:322-325 (1971), disclose
amphetamine derivatives substituted on the 3- and 4-positions of the aromatic

wo 93/00313 Pcr/uS92/o~33o
,~ . . .. . . . .
4-
2111957
ring with one or more chloro, fluoro, alkyl, phenoxy, alkoxy and hydroxy
substitucnts.
Foye, W.O. ct al., J. Pharm. Sa. 68:591-595 (1979), disclose
heterocyclic analogucs of amphetamine having 2-furyl, 2-thicnyl, 3-methyl-2-
5 - phenol, 3-pyridyl, ~methyl-2-pyridyl, ~chlorophenyl, and 1-naphthyl rings.
Boissier, J.R. a al., Chan. ~bstr. 66:46195h (1967), disclose
N~enzyl amphetamine derivatives of the Formuh (1):
Clt2-C-- I CH2 ~/ ~;;;
(I) :. :'
wherein X is methyl, CF3, methoxy, or a halogen and R is hydrogen or
methyl. These compounds reportedly have anoretic activity and low toxicity.
Particular compounds disclosed by Boissier ct al. include N-(l-phenyl-2-
propyl)-4-chlorobenzylamine, N-(l-phenyl-2-propyl)4-methylbenzyl-amine,
and N-(l-phenyl-2-propyl)-4-methoxybenzylamine.
Boissier, J.R. et al., ~cm. Abstr. 67:21527a (1967), disclose
15 ' amphetamine derivatives of the Pormula (11):
CH3
~ CHz-!U-NH-CH2-R2
(Il)
~Er

WO 93/00313 Pcr/us92/os33o
.~ 21119~i7
. . , 5
~ ~ . J r ~ ~ ~
whcrein R' is hydrogen, ~CI, 3-CI, or 3-CF3 and R2 is 2-chlorophenyl,
4 chlorophenyl, 4-bromophenyl, 3-CP3-phenyl, 4-tolyl, 4-methoxyphenyl,
phenyl, 2-furyl, 2-tetrahydrofuryl, 2-thienyl, or 3-thienyl. Reportedly, these
compounds were tested for anore~cigenic activity in rats and dogs.
Osbond, J.M. ctal., Chcm. Abstr. 69:51816c (1968), disclose N,N-bis-
(omega-phenylalkyl)amines having the Fonnula (Ill): ;
R l l? R R
R2 ~CH2-C -~H-CI~-c~2
(111) ,`.~` ~' ~
" ~ ,, .
wherein R', R2, and R3 are hydrogen, chloro, CF3, or methoxy. -
Gosztonyi, T. ct al., J. L~el. Comp. Ra~l~opharm. 8:293-303 (1977),
disclose the preparation of N-subsdtuted omega-haloalkyl derivatives of
~chloro amphetamine. Also disclosed. is the corresponding omega-
hydroxyalkyl amine.
Coutts, R.T. et al., Can. J. Microbiol. 26:844-848 (1980), disclose N-
subsdtuted ~-chloro amphetamines having the following Formula (IV):
. ~ .
CH3
C 1~ CH2-CH-NH-Rl
(IV)
su~#~

Wo 93/00313 Pcr~us92/os33o
2111957
whercin R' is 2-butanonc-3-yl, 2-hydroxybutane-3-yl, 1-hydroxybutane-3-yl,
or acctatc.
Fuller, R.W. ctal.,J. Pha~m. Phannacol. 25:828-829(1973~,disclosc
lipid-soluble derivadves of amphetamine comprising 2-chloro, 3-chloro, 4-
chloro, and bcta, bcta-difluoroamphctamine, and the effect thereof on
amphetaminc levels in the brain. - ~:
Fuller, R.W. ct al., Ncurophannacology 14:739-746 (197S~, disclosc
4chloroamphctamine, 4-bromoamphe~mine, and 4-fluoroamphetamine and ~c
cffect thereof on serotonin metabolism. ; -~
Conde, S. ctal.. J. Ucd. Chan. 21:978-981 (1978), disclosethiophene
analogues of chloroamphetaminc having the following Formula (V):
Y Z
-/ CH~
X CH2-CH-UH2
(V)
wherdn X, Y, and Z are chloro or hydrogen, and the effect thereof on
serotonin levels in the brain.
' Lukovits, 1., Inl. J. Quan~um. Chem. 20:429~38 (1981), discloses
various halo, methyl, and methoxy ring-subsdtuted amphetamines, and the
inhibitory potencies thereof on phenylethanolamine-N-methyl transferase.
Law, B., J. Ghroma~og. 407:1-18 (1987), discloses amphetamine
analoguescomprising 1-methyl-2-(2'-naphthyl)ethylamine, N-isopropyl-2-(2'-
naphthyl)ethylamine, and N-isopropyl-2-phenylethylamine.
Johansson, A.M. c~ al., J. Med. Chem. 30:602-611 (1987), disclose
N-substituted 2-aminotetralins of the Formula (Vl):

WO 93/003t3 `~ PCI/US92/05330
7 21119~i7
~ I t
R~
NR2R3
(Vl)
', "
whercin Rl is OH or OMc and R2 nd R3 arc H or C~-c4 lowcr alkyl. Thesc
compounds wcrc tcstcd for dopaminc receptor agonist and antagonist acd~ridcs.
Hackscll, U. a al., J. Mcd. ~an. æ:l469-1475 (lg79), disclose ~-~
N-alkyb~ed-2-aminotetralins of dlc Formuh (Vll):
R~
NRZR3
(Vll) i
~ ...
wherein R' is OH or OMe, R2 is lower alkyl, and R3 is lower alkyl or
phene~yl. In particular, Hacksell et al. disclose two aminotetralins of the
Formulae (Vlll) and (IX):
OCH3 OH
1~ /n-Pr ~ /n-~r
( CH3 )2 Ph ( CH2 )3- P~ -
(~JIII) (IX)

wO 93/00313 ` rcr/us92/os33o,
2ill957 ;~
These compounds reportedly have dopamine-receptor stimulating
activity.
McDermed, J.D. c~ al., J. Mod. ~cm. 18:362-367 (1975), disclose ~ ~
N-alkyl aminotetralins of the Pormula (X): ~- -
;~
NR lR2 ~;
` - , ~ . ... . ~,
j (X)
. . ,
wherein Rl and R2 is one of a large number or alkyl, heteroalkyl, and alkaryl
groups. ln particular, McDermed ct al. disclose two o~mpounds of the
Pormula (Xl) and (Xll):
OH OCH3
HC ~\NH-CH2- h ~\NH-CH2-Ph
(XI) (XII)
These compounds are reportedly dopamine receptor agonists.
Glennon, R.A. etal., Phannacol. Biochcm. Behav. 21:895-901(1984),
disclose that 2-aminotetralin is a confonnationally restricted analog of
amphetamine which is about on~-half as effecdve as racemic amphetamine.
Beaulieu, M. et al., Eur. J. Pharmacol. 10~:15-21 (1984), disclose
N,N-disubstituted 2-aminotetralins of the Formula (Xlll):
8UBSTITUTE SHEEr
.;, ~

W O 93~00313'` P~r/US92/05330 : : -
~`` 2111957 ~;
.. . ..
5-OH H H ~
5-OH C3H7 ~`
5-OH CH3~7 C3H7 `;~:
S-OH CH3H7 CH2 CH2 ~
5-OH CH3H7 CH2-CH2~ ~ --
5-H CH3H7 C3H7 ::
5-H CH3H7 2 CH2
5,6 OH H H
5,6 OH CH3H7 C3H7 ...
These compounds are reportedly potent D-2 dopamine receptor -
agonists. -
Naiman, N. et al., J. Mcd. Chan. 32:253-256 (1989), disclose
2-(alkylamino)tetralin dcrivatives of the Formula (XIV):
R NRlRZ
(XIV)
wherein R is H, OMe, or OBz; R' is H, Me, or n-Pr; and R2 is H, n-propyl,
benzyl, phenethyl, or phcnpropyl. Thesc compounds reportcdly bind to the ;
5-HT,A receptor dtc.
~Er ' ; ~

WO 93/00313 Pcr/uss2/0s330 ~ ~
,; . ,. .. , ~ .
2 1 1 1 9 S 7
Beecroft, R.A. ctal., Tctrahedron41:3853-3865 (1985), disclose N,N-
disubstitutcd pipe~azines having the Pormulae (XV)-(XVIII): :~ :
CH2CH2 N3 11e
~ txu) ~ ~ ~
1 -Np ~ CH2 )2 N~N CH2CH2 N~ ~ KUI )
H2)2N~NcH2cH2N3 ~XUII)
2 ~
Irl)
~here ~r ~ 1.2-NaPthyl ~r
9-P~nthr!~ I
~nd Z = t~ ,2-Olle or
~l-011e
Fuller, R.W., et al., J. Phannacol. Exp. Therapeut. 218:63~641
(1981), disclose substituted piperazines having the following Formulae (XlX)
and (XX):
SUBSTITUTE SHEET
. ,.
.

WO 93/00313 P(~/US92/0533t~ ` :
` 21119S~ : ~
~ . .
CF3
~NH ~--~H
(XIX) (XX) ~
which reportedly act as serotonin agonists and inhibit scrotonin uptakc or ~-
scrotonin o~cidation.
Fuller, R.W. ct al., Rcs. ~mmun. ~an. Pad~l. ~macol. ~ ~
2~.201-204 (1980), disclose ~c comparadve effects on S-hydto~yindole -
concentration in ~at brain by ~chloroamphetamine ~ and ~-; 1-~ - ~;
chlorophcnol)pipe~azine having the following Formulae (~1) and (XXII): -
CU3 - ~` ~-
CI ~C112-Cll-NU2 Cl~IGN~ ~
~: .
(XXI) (XXII) ~`
Boissier, J. ct al., Ch~m. Abstr. 61:10691c, disclose disubstituted
piperazines having the Fonnula (XXIII): -
A 2 ~`
R -X-N~ N-R
wherein R' and R2 are aryl and X is a straight or branched chain alkylcne of
C,-C3. The compounds are reportedly ad~enolytics, hypotensors, potcntiators
of barbiturates, and depressants of dle central nervous system.
Rocsslcr, ChanAbstr. 61:13328g, disclosepipe~azinederivadvesofthe
Formula (XXIV):
.,~

wo 93/~0313 PCr/US92/OSi330
21119S7 -12-
CH3
R CHz-CH- N~N-R
(XXIV)
whcrcin R = H or mctho~y and R' = H, ~cthylphenyl, or ~chlorophenyl.
Ruschig, H., c al., Chan. ~bstr. S3:3253e, disclose a largc series of
N,N-disubsdtuted pipcr zincs including l-benzyl-4-(3-chloro-4-
5mcthylphcnyl)piperazine.
Shvcdov, V l., ct al., ~ bstr. 73:11806q (1970), disclosc~(R2CH2-CH2 substituted)-l-phcnyl-pipNazines whcrcin R2 is phenyl,
2-naphthyloxy, 3-indolyl, 2-methyl-3-indolyl or 2bcnzimidazolyl.
Popov, D., a~ bstr. 67:541û2m (1967), disclose disubsdtuted
piperazines ofthe Formula (XXV):
R-N N-Ph
:,.`,
(XXV) :;,,
wherein R is tolyl, ~methoxyphenyl, m-ethoxyphenyl, beta-naphthyl, m-or ~- ;
carboxylphenyl, 3,~dimethoxyphenyl, 5-hydrindenyl, p-chloro-phenyl,
bromopheny1, ~iodophenyl, 3,~dichlorophenyl, and m- or P-ni,t~ophenyl.
15Glennon, R.A et al., J. A~ed. Chcm. 31:1968-1971 (1988), disclose
various N,N-disubsdtuted piperazines having the Formulae (XXVI)-(XXIX): `
.`:' .
SUBSTITUTE SHEET

WO 93/00313 PCI~/US92/05330
-13- 2111957
'~ ~ f t
f ~N~QtF3
XXUI)
J~N
~12N ~ ~
N~ (XXIJII) ~
~Go ~ ~ -
O ~NJ~
~~N~J ( X X U I I I ) ~;
~J~o ~:~
N~ ( XXI X )
oz
SUBSTITUTE SHEEr ` `

Wo 93/003t3 Pcr/us92/0533o
; ~ l - I 4-
2111957
These compounds reportedly have high affinity for the 5-HT,~
serotonin binding site. ~
P~ssad, R.N aal., J. Mcd. Chan. 11:1144-l lS0 (1968), disclose N,N-
disubstituted piperazincs of the Formula (~):
Rl-N~N-CUz-R2
~ ~ :
wherein R' is phenyl ~r ~mctho%yphenyl and R2 is 2,4-dichlorophenyl, ~, m-
or~ methoxyphcnyl, 3,4-dimctho%yphenyl, or m-tolyl. Thesecompoundsare
reported to be andhypcrtcnsive agents. -
Despite thc dcvelopment of the above-mendoned derivatives, a need
condnues to adst for ncw sigma reccptor ligands and for mcthods for the
trea~nent of central ncrvous system disorders. -,
.,~
Summ~ of ~e In~cn~on :~
The invendon relates to the discovery that certain phenylalkyl-amine, ` ;
aminotetralin, piperazine, piperidine and related derivadves have high binding ~ ;
to the sigma receptor and, une~pectedly, low binding for the PCP, DA and 5-
HTI~ receptors. Thus, the sigma receptor ligands of the present invention can
be used for the treatment of ccntral nervous system disorders and drug abuse 9 `
without the side effects of traditional neuroleptic agents which also bind to the
DA and 5-HT,A receptors.
The invendon also relates to ~e discovery that certain phenylalkyl-
amines, aminotetralins, pipe~zines, piperidines and related derivatives have
selecdve binding for the sigma-l binding site while others have selective
binding to the sigma-2 binding site. Compounds which bind to dle sigma-l
binding site are useful in treadng gastrointesdnal disorders, and are not
associated with dystonic effects which are associated with binding to the
sigma-2 binding site. In cont~ast, compouds which selectively bind to the
sigma-2 binding sitc may block calcium channels. Thus, such calcium channel
~mUlE~Er

WO 93/00313 ~ ~ PCr/US92/0533~
- ! 211195 1
-15- ` ;,.,~,,
: .` .
blocking sigma-2 receptor ligands may be used to treat psychosis, angina,
migrane and hypcrtcnsion.
The sigma reccptor ligands of the present invendon may also be
cmployed in mcthods of treating or prcvendng deprcssion.
S In particular, thc invendon rclates to methods of trcating a human bcing
suffcring from ccntral nervous systcm disordcrs, drug abuse, gas~ointcsdnal
disordcrs, hypcrtension, migrane, angina and dcpression, which compnses
administcring to said human a thc~apcudcally effecdvc amount of a compound
selectcd from thc Formulae (X~KI) and (~11)~
, I
/ ~ C H~
/ \
~r~ "CI ~ 2
~U~
(XXXI) ~';
~ X-Z
(XXXII)
wherein said compound exhibits high binding activity with respect to the sigma
receptor.
The invention also relates to certain novel sigma receptor ligands
lS defined by Formulae (XXXI) and (XXXII) as well as pharmaceutical
compositions comprising these novel sigma receptor ligands.
Surprisingly. the present inventor has discovered that certain
N-substituted phenylalkylamines, although seemingly related to amphetamine,

Wo 93/00313 Pcr/uss2/os33~
2 1 1 1 9 S 7
.
have activities which are, in fact, very much unlike amphetamine. Instead, the
N-subsdtuted phenylalkylamincs have high affinity to thc sigma rcceptors and
low affnity to the DA and PCP receptors. In addition, cerlain of the sigma
rcceptor ligands of thepresent invendon have une~cpectedly low affinity for the
5-HT,~ rcceptor. In addidon, certain of the sigma receptor ligands of the
prcscnt invendon are highly sclective for thc sigma-l binding site over the
sigma-2 binding sitc. The discovery of wch ligands having high affinity for
thc sigma rcceptors, in pardcubr thc sigma-l roceptor, and low affinity for
othcr such rcceptors allows for the treatmcnt of psychosis, drug abuse,
gastrointesdnal disorders, and depression, and other conditions without
untoward side effects. In contrast, compounds which are selectivc for the
sigma-2 receptor arc useful for the treatment of psychosis, hypcrtcnsion,
migrane and angina.
D~scnpt~on of ~hc Pr~fcmd EmbodiJnen~s
}S The invcndon relatcs to a mcthod of treating a human being suffering
from cc.ltral ncrvous systcm disorders, drug abuse, gastrointestinal disorders,
hypertension, migrane, angina and deprcssion, which comprises administering
to said human a therapeutically effecdve amount of a compound having d~e
Formula (XXXI):
R
/ ( C H~
f~r~ "CH-N-X-Z
( XXX I )
~ "
~ u
SUBSTITUTE SHEET

WO 93/00313 2 1 1 1 9 s 7 PCr/U592/05330
-17- . ~.
whcrcin:
Ar is aryl or heteroaryl wherein aryl or heteroaryl can be substituted
by hydrogen, halogcn such as chloro, fluoro, bromo, iodo, CF3, C,-C6 alkoxy,
C2-C6dialkoxymethyl, Cl-C6 alkyl, cyano, C3-C,s dialkylaminoalkyl, carboxy,
S carboxamido, C,-C6 haloalkyl, C1-C6 haloalkylthio, allyl, aralkyl, C3-C6 cyclo-
alkyl, aroyl, a~alkoxy, C2-C6acyl, a~yl, subsdtutedaryl, hctcroaryl, substitutedhctcroaryl, an aryl ring fuscd to a substitutcd bcnzenc ring, a subsdtutcd aryl
ring fused to a bcn~nc ring, a heteroaryl ring fused to a benzcnc ring, a
substituted hctcroaryl ring fuscd to a bcnzenc ring, C3-C6 heterocycloalkyl, a :
C3-C6 hctcrocycloalkyl ring fuscd to a bcnzcne ring, C,-C6 alkylthioj C,-C6
alkylsulfonyl, C,-C6 haloalkylsulfonyl, C,-C6 alkylsulfinyl, C,-C6 haloalkyl-
sulffnyl, arylthio, C,-C6 haloalkoxy, amino, C,-C6 alkylamino, C2-C,5 dialkyl- ~;~
amino, hydroxy, carbamoyl, C~-C6 N-alkylcarbamoyl, C2-C,5 N,N~ialkyl- :
carbamoyl, nitro and C2-C,5 dialkylsulfamoyl; :
R is hydrogen or C,-C6 alkyl; ::
R' is independently sclectcd from the group consisting of hydrogcn, C,-
C6 alkyl, hydroxy, ami. Cl-C6 alkylami or =O (a double bonded o~ygen); ~-~
or
R and R' together form a morpholino ring;
n is ~S;
W is-(CH2)p- or -H H-, wherein p is 1-3;
X is-(CH2)q-, wherein q is 1-6;
-(CH2);C~C-(CH2),-, wherein each r is ~3 independently;
-(CH2);~H =~ ~2J;-
O
Il
~(CH2)r~C~(CH2)~~~
-(CH~);Y-(CH2);. whereiin Y is O or S; or
C,-C6 alkyl (wherein Z is hydrogen);
Z is hydrogen, aryl, an aryl-substituted carboxylic acid group, heteroaryl or
cycloalkyl, wherein aryl, hetcroaryl and cycloalkyl can be substituted by
hydrogen, halogen such as chloro, fluoro-, bromo, iodo; CF3, C,-C~ alkoxy,
SUBSTITUTE SHEET

WO 93/00313 ` Pcr/uS92/os33o
! ' . .,
2111957 ~ 18-
.
C2-C6 dialkoxymethyl, C,-C6 alkyl, cyano, C3-cl5 dialkylaminoalkyl, carboxy,
carboxamido, C,-C6 haloalkyl, Cl-C6 haloalkylthio, allyl, aralkyl, C3-C6 cyclo-
alkyl, aroyl, aralkoxy, C2-C6carboxylic acyl, aryl, substituted aryl, hetcroa~
substituted heteroaryl, C3-C6 heterocycloalkyl, C,-C6 alkylthio, C,-C6 alkyl- .
sulfonyl, C,-C6 haloalkylsulfonyl, C,-C6alkylsulfinyl, C,-C6 haloalkylsulfinyl,
arylthio, C,-C6 haloalkoxy, amino, Cl-C6 alkylamino, C2-C,5 dialkylamino,
hydro~cy, carbamoyl, C,-C6 N-alkylcarbamoyl, C2-C,5 N,N-dialkylcarbamoyl, ~
nitro, C2-C,5 dialkylsulfamoyl or an ortho mcthylene dioxy group; `
wherein said compound exhibits high binding activity with respcct to
the sigma receptors.
The invention also relates to methods of trcating central ncrvous systcm -
disorders, drug abuse, gastrointestinal disorders, hypertension, migrane,
angina and dcpression, using compounds having the Formula (~III): ~
Rl R `
I
T--~CH )n~N -X-2
~111)
wherein T is a cycloalkyl group or Ar as described above, n, R, and R', X :
and Z are defined above;
wherein said compound exhibits high binding activity with respect to
the sigma receptors.
Especially preferred compounds within the scope of Formula (XXXIII)
include N-phenethyl- I -phenyl-isopropylamine, N-phcnylpropyl-
l-phenylisopropylamine, N-(2-phenoxyethyl)-1-phenylisopropylamine, N-(3-
phenyl-3-propanon- 1 -yl)- 1 -phenylisopropylamine, N-(4-phenylbutyl)-
1-phenylisopropylamine, N-(3-(1-naphthyl)propyl)-1-phenylisopropylamine,
N-(3-(2-naphthyl)propyl)-1-phenylisopropylan~ine, N-(3-phenyl-2-propyn-1-yl)-
1-phenylisopropylamine, N-(3-phenylpropyl)-3-(4-hydroxyphenyl)
isopropylamine, N-(3-phenylpropyl~3-(~methoxyphenyl)isopropylamine, N-(3-
. phenylpropyl)-3-(3-bromophenyl)isopropylamine, N-(3-phenylpropyl)-3-

WO 93/00313 - Pcr/uS92/o~33o
-19- 2 11 19 5 1 ~ ; `
(4-bromophenyl)isopropylamine, N-(3-phenylpropyl)-3-(3,4-dichlor~
phenyl)isoprowlamine, N-(3-phcnylpropyl)-3-(4-iodophenyl)isopropylamine,
N-(3-phenylpropyl)-3-(3-trifluoromethyl-phenyl)isopropylamine, N-(2-
phenethyl)-N-methyl-l-phenylisopropyl-amine, N-(3-phenylpropyl)-1-
5 phenylpropan-1-one-2-amine, N-(2-indane)-3-phenylisopropylamine, N-(2-
indane)-3-phenylpropylamine, N,N-di-((3-phenyl)propyl)amine, N-(2-(1-
naph~hyl)cthyl)-l-phenylisopropylamine, N-(2-(2-naphthyl)etbyl)-1-
phenylisopropylamine, N-(2~1-naphthyl)propyl~l-phcnylisopropybmine, N~2-
(2-naphthyl)propyl)-1-phenylisopropylamine,N-(3-phcnylpropyl)-1-phcnyl-2-
pcntylamine, N-(3-phcnylbu~yl~l-phcnyl-2-butyhmine, N,N~i-(2~thyl-
phenyl)methylamine, N,N-dibenzylamine, N-(3-phenylpropyl)-N-(~
phenylbexyl)amine, N~3-phenylpropyl)-N-(5-phenylpcntyl)amine, N-pr~pyl-N-
methyl-S-phenylpentylamine~-methyl-N-(3-phenylpropyl~l- isopropylamine,
N-methyl-N-(3-mcthyl-2-butenyl)-1-isopropylamine, N-methyl-N-(3-
IS methylbutyl)-l-isopropylamine, N-methyl-N-(3-phenylbutyl~l-phenyl-2-
pentyhmine, N-propyl-N-(3-phenyl)propyl~l-phenyl-2-propylamine, Nbcnzyl~
N-(3-phenyl)propyl)-1-phenyl-2-propylamine, N-phenyl-(S-phcnylkentylamine,
N-methyl-N-(3-phenyl)propyl-5-phenylpentylamine, N-(2-(o-
methylphenyl)ethyl)-S-phenylpentylamine, N-(2-(m-metbylphenyl)ethyl)-5-
phenylpentylamine, N-(2-(p-methylphenyl)ethyl)-S-phenylpentylamine, N-
benzyl-5-pbenylpentylamine, N-benzyl-N-methyl-S-phenylpentylamine, N-(2-
(3-hydroxyphenylkthyl)-5-phenylpentylamine, N-(2-(2-hydro~yphenylhthyl~5-
phenylpentylamine, N,N'~iethyl-2-(diphenylacetoxykthylamine, N,N'-diethyl-
2-(fluorenecarboxy)ethylamine, N,N-Dimethyl-5-phenylpentylamine, N-Benzyl-
N-(3-phenylpropyl)- 1-phenyl-2-propyiamine, N-Benzyl-N-methyl-5-
phenylpentylamine, N-Benzyl-5-phenylpentylamine, and N-(2-phenethyl)-
N-methylpentylamine.
The invention also relates to methods of treating central nervous system
disorders, drug abuse, gastrointestinal disorders, hypertension, migrane,
angina and depression, with compounds related to Pormula (XXXII) where W
is -(CH2)~- having the Formula (XXXIV):
;` Sl~!:mUlE~

WO 9i/00313 PCI~/US92/05330
2111957 ~ 2~
:.-...
Rl ' ~
,-,.'
nr/ C~l-X-2 t XXXIU )
;:......
- ' `(CH2 jP ,,,~ ,~
, ., ~
: . . . .
whcrcin Ar, n, p, R, R', X and Z are as defincd abovc; and
whercin said compound exhibits high binding acdvity with rcspect to ~ :~
the sigma~oceptors.
S The invcntion also rclates to mcthods of treating central ncrvous systcm
disordcrs, drug abuse, gast~ointestinal disorders, hypcrtcnsion, migrane, `:
angina and deprcssion, with compounds of thc Pormula (~11): ~ -
~",~U~ Z
~XII)
wherein X and Z are as defined above and V is N or -CM-, wherein M is
10 ' hydrogen, C,-C6 alkyl, C,-C6 alkoxy, hydroxy, fluoro, chloro, bromo,
trifluoromethyl, or represents one half of a double bond (with the ncighboring
endocyclic carbon);
R~ is independently selected from the group consisting of hydrogen,
chlcro, fluoro, bromo, iodo, CF3, C,-C6 alkoxy, C2-C6 dialkoxymethyl, C,-C6
alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, Cl-C6
haloalkyl, Cl-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl,
aralkoxy, C2-C6 carboxylic acyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, C3-C6hetcrocycloalkyl, Cl-C6alkylthio, C,-C6alkylsulfonyl, Cl-C6
haloalkylsulfonyl, C,-C6alkylsulfinyl, Cl-C6 haloalkylsulfinyl, arylthio, C,-C6
~1 ~R~ r. ~

WO 93/00313 Pcr/us92/0s330
. : ~
-21- 2111~7 i ~
haloalkoxy, amino, C,-C6 alkylamino, dialkylamino, hydroxy, carbamoyl, Cl-
C6 N-a!kylcarbamoyl, C2-C,s N,N-dialklcarbamoyl, nitro and C2-C,5
dialkylsulfamoyl; and
wherein said compound exhibits high binding activity with respect to -~
S thc sigma receptors. ~ -
P~eferably, thc invention relates to the treatment of central nervous
system disorders, drug abuse, gastrointesdnal disorders, hypertension, :
migrane, angina and depression, witn a piperidine derivative having Formula :
~ x-z
a~xv)
wherein R2, X and Z are as defined above.
The invention also relates to the treatment of central nervous system
disorders, drug abuse, gastrointestinal disorders, hypertension, migrane,
angina and depression, with compounds having the rormula (XXXIX):
R~C~N-~
(XXXIX)
wherein R2. M, X and Z are as defined abov~;
U is selected from the group consisting of hydrogen, halogen such as chloro,
fluoro, bromo, iodo; CF3, C,-C6 alkoxy, C2-C~, dialkoxymethyl, C,-C6 alkyl,
cyano, C3-C,5 dialkylaminoalkyl, carboxy, carboxamido, Cl-C`~, haloalkyl,
C,-C6 haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, an aryl ring
fused to a substituted benzene ring, a substituted aryl ring fused to a benzene

WO 93/00313 PCr/US92/053
21119~7 .~ 22^
, ,.: .:
ring, a heteroaryl ring fused to a benzene ring, a substitutcd heteroaryl ring
fused to a bcnzene nng, C3-C6 hctcrocycloaJkyl, a C3-C6 heterocycloalkyl ring
fussd to a benzene ring, C,-C6 alkylthio, C,-C6 alkylsulfonyl, C,-C6 haloalkyl-
sulfonyl, Cl-C6 alkylsulfinyl, C,-C6 haloalkylsulfinyl, arylthio, Cl-C6 halo-
S ~ alkoxy, amino, Cl-C6 alkylamino, C2-C,5 dialkylamino, hydroxy, ca~bamoyl,
Cl-C6 N-alkylcarbamoyl, C2-CI5 N,N-dialkylcarbamoyl, nitro and C2-C~5 dial-
kylsulfamoyl;
whercin said compoind cxhibits high binding acdvity with respect to thc sigma
receptors. -
Thc invcndon also relatcs to` a method of trcating a human bcing
suffcring from ccntral ncrvous systcm disorders, drug abuse, gastrointcstinaJ
disorders, hypertension, migranc, angina and dcprcssion, which compriscs
administering to said hwnan a therapeutically effectivc amount of a compound
of thc Pormula (XXXVa):
,r~ ....
R3 U N-X-Z
(XXXVa)
wherein:
R3 is selected from the group consisting of C,-C6 alkyl, C,-C6 alkenyl,
C2-C6 dialkoxymethyl, C3-C,s dialkylaminoalkyl, aralkyl, C3-C6.cycloalkyl,
aroyl, C2-C6 acyl, aryl, substituted aryl, hetcroaryl, substituted heteroaryl,
C3-C6 heterocycloalkyl; and X, Y and Z are defined above,
wherein said compound exhibits a high binding activity with respect to
the sigma reccptors.
Especially preferred compounds within the scope of Formula (XXXVa)
include N-mcthyl-N'-(4-phenyl-3-(E)butenyl)piperazine, N-methyl-N'-
(4-phenyl-3-(Z)butcnyl)-pipcrazine~-mcthyl-N'-~4-(3-trifuoromethylphenyl)-
~(Z)butcnyl)pipcrazine, N-mcthyl-N'-(4-phenylbutyl)pipcrazine, N-benzyl-N'-

WO 93/00313 PCr/US92/05330
-23- 2111957
(~phthalimidobutyl~piperazine, N-(2-methoxyphenyl)-N'-(~phthalimidobutyl~
pipcrazine, N-(5-phcnylpentyl)4 bcnzylpiperidine, N-(S-phenylpcntyl~
~bcnzyl~hydroxy-pipcridinc, N-bcnzyl-N'-(5-phcnyl)pentylpipclazinc and
N,N--di-(S-phenyl)pcntylpipe~azine. ~ ~;
Thc invcndon also rclates to a mcthod of treadng a human bcing
suffcring from ccntral ncrvous systcm disordcrs, drug abuse, gastrointcstinal
disordcrs, hypcrtcnsion, migranc, angina and depression, which comprises
administcring to said human a thcrapcudcally cffecdYc amount of a compound
of the Fonnula (XXXVb)~
0 R47~;~ N-X-2
~5 /
(XXXVb)
wherein:
R' is hydrogcn or an aryl group substituted with a group sclccted from ~-
the group consisting of C,-C6 alkyl, C,-C6 alkenyl, C2-C6 dialkoxymethyl, C3-
C~s dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl, aroyl, C2-C6 acyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 hctcrocycloalkyl; -~
R5 is hydrogen or hydroxy; and
X, Y and Z are defined above, -
wherein said compound exhibits a high binding activity with respect to
the sigma receptors.
Examples of compounds having Pormula (XXXVb) include but are not
limited to N-(5-phenylpentyl)piperidine, N-(8-phenylheptyl)pipcridine, 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-bu~lpiperidine, N-(5-
(4-chlorophenyl~5-penlanon-1-yl)piperidine, N-(5-(~chlorophenyl)-S-pentanon-
I-yl)~-pbenylpiperidinel~-(5-(4-methoxyphenyl)-S-pentanon-l-yl)piperidine,
N-(5-!4-methoxyphenyl)-S-pentanon- I -yl)-4-phenylpiperidine, N-(S-
SllBSllllllE8~ ~`

WO 93/00313 Pcr/US92/o533o
2111957 ~ 24-
. .; ... .
(4-methoxyphenyl)pentyl)-4-phenylpiperidine, N-(S-phenyl-5-pentanon-1-yl)-
4-phenylpiperidine N-(S-(4-chlorophenyl)pentyl)-4-phenylpipcridine, N-(S-
(3-mcthoxyphenyl)-5-pentanon-1-yl)piperidine, N-(5-(3-chlorophenyl)-
S-pentanon- 1 -yl)piperidine, N-(5-(3-chlorophenyl)-S-pentanon- 1 -yl)-
S 4-phenylpiperidine, N-(5-(3-methoxyphenyl)-S-pentanon-l-yl)-
4-phenylpiperidine, N-(4-(4-fluoropheny!)~butanon-1-yl)piperidine, N-(5-
(4-fluorophenyl~S-pelnanon-l-yl)pipcridine N-(5~4-fluorophenyl~S-pentanon-
I -yl)-4-phenylpipcridine, N-(5-(4-fluorophenyl)-S-pentanon- 1 -yl)~-
(3 chlorophcnyl)~hydroxypipcridine, N~5~4-chlorophcnyl~S~c nanon-l-yl~
4-(4-fluorophenyl)-1,2,3,6-terahydropyridine, N-(5-(4-chlorophenyl)-
S-pentanon-l-yl)-4-(4-fluorophenyl)piperidine, N-(5-(4-chlorophenyl)-
S-pentanon-l-yl)-4-(4-fluorophenyl)-1,2,3,6-terahydropyridine, N-(5-(4-
chlorophenyl)-S-pentanon- I -yl)-4-(4-fluorophenyl)-piperidine, N-(S-
(4-chlorophcnyl)-S-pentanon-l-yl)~(chlorophenyl~1,2,3,6-terahydropyridine,
N-(5-(4-chlorophenyl)-S-pentanon-l-yl)~(chlorophenyl)piperidine N-(5-
(3 ,4-dichlorophenyl)-S-pentanon- I -yl)-4-(chlorophenyl)-piperidine,
N-(S-cyclopentylpentan-S-or.-l-yl)piperidine and
N-(5-(3 ,4-methylenedioxyphenyl)penta-2,4-dienyl)piperidine .
The invention also relates to a method of treating a human being
suffering from central nervous system disorders, drug abuse, gastrointestinal
disorders, hypertension, migrane, angina and depression, which comprises
administering to said human a therapeutically effective amount of a compound
of the Formula (XXXVc):
~J h--X--Z
(XXXVc) : ,.
wherein X and Z are defined above, -:
wherein said compound exhibits a high binding activity with respect to
the sigma receptors.
':'
SUBSTITUTE SHEET

WO 93/00313 Pcr/us92/os33o
-25- 2 1 1 1 9 S 7 ~
An e~ample of a compound having Formula XXXVc is N-(5-
phenyl)pentyl-3-azabicyclol3.2.ynonane.
The invendon also relates to a me~hod of treadng a human being
suffering from central nervous system disorders, drug abuse, gastrointesdnal
S disorders, hypertension, migrane, angina and depression, which comprises
administering to said human a therapeudcally effective amount of a tropane
derivadve of the Pormula (XXXVd): - -
R4 f ~N-X-Z
R5 (XXXUd)
wherein R4, R5, X and Z are deflned above, and
wherein said compound exhibits a high binding acdvity with respect to -
the sigma receptors.
An example of compounds having Formula (~Nd) include N-(5-
phenyl)pentyl4-phenyltropan4-ol .
The invendon also relates to the treatment of central nervous system
lS disorders, drug abuse, gastrointesdnal disorders, hypertension, migrane,
angina and depression, by administering a compound related to those of
Formula X~lll and having the Formula (XXXVI):
~(CU2~a-NH-(CH2)b (~
R2 R2
( XXX~I )
wherein
a is 1-8;
b is 1-8;
SUBSTITUTE SHEET

WO 93/00313 Pcr/US92/o533o
21119S7 - -2~
,.. ~ ~ .
R is as defined above;
wherein said compound e~hibits high binding activity with respect to
the sigma reoeptors.
Preferably, compounds which are useful for the trcatment of ccntral
5 - nervous system disordcrs, drug abuse, gastrointesdnal disorders, hypenension,
migranc, angina and deprcssion, and which are within the scopc of Formula
(XXXI) are naphthyl derivatives having Formula (XXXVII):
R2 ~CUz~-N~ CHz)l~ 2
( XXXUII)
wherein R, R2, a and b, as dofincd above, may be the same or diffcrent;
wherein said compound exhibits high binding activity with respcct to
the sigma receptors.
O~her compounds useful for the treatment of central nervous system
disorders, drug abuse, gastrointestinal disorders, hypertension, migrane,
angina and depression, include morpholino derivatives having Formula ~;
(XXXVIII):
CH2 : .-
/ \ ` .
O I H2
~9r -CIl-CH2-N-X-Z . . .
( XXX~J I II )
wherein Ar, X and Z are defined above; ~ -
wherein said compound exhibits high binding activity with respect to
the sigma receptors.

wo 93/00313 Pcr/us92/o533o
-27- ~ 5 7
Othcr compounds useful for the treatment of central nervous system
disorders, drug abuse, gastrointesdnal disorders, hypertcnsion, migrane,
angina and depression, include cycloalkyl derivadves having Formula (Lll)
R l R
Cy-- ( CH) n--N-X -Z
'` , :, (`. ) ,
wherein Cy is C3-C~ cycloalkyl and Ar, R', n, R, X, and Z are defined as
above. E~nples of compounds having Formula Lll include `
t - -. ....................................... . . ...
5-cyclohexylpcntylamine,N-mcthyl-5-cydohexylpentylamine,N,N-Dimethyl-
S-cyclohe%ylpentylamine, N-cyclohexylmethyl-S~yclohexyl-n-pentylamine, and
N-cyclohe~ylmethyl-N-methyl-5-cyclohexyl-n-pentylamine.
, . .
Other compounds uscful for the treatment of central nervous system
disorders, drug abuse, gastrointestinal disorders, hypertension, migrane,
angina and depression, includes compounds of the Formula (Llll)
,~ Xl U~ -X-Z
(Llll)
wherein X' is -(CH2)r-C ~C-(CH2)r-, wherein each r is ~3 independently;
-(CH2)r~CH=CH~(CH2)r~;
O
-(cH2)r-c-(cH2);;
-(CH2);Y-(CH2);, wherein Y is O or S; or
C,-C6 alkyl (whcrein Z is hydrogen);
and R2, V, X, and Z are defined as above.

wo 93/00313 Pcr/uss2/o533o
2111957 -28-
: ,; !` `.
.. .
Other compounds useful for the treatment of central nervous systcm
disorders, drug abuse, gastrointcstinal disorders, hypertensiorl, migrane,
angina and deprcssion, includes compounds of the Formula (LIV):
R6
",
R5-N-X-R7
(LI~))
whercin R5 and R6 are independently a C,., alkyl group, R' is hydrogcn or a
... . ..
SC,., alkyl group substituted by an arylacetoxy group, and X is as defined!
- , ,
above. E~les of sucb compounds include but are not limited to N,N'-
diethyl-2-(diphenylaceto~y)ethylamine and N,N'-diethyl-2-
.
(9-fluorcnylcarboxy)ethylamine.
10The invention is also related to the discovery that the aryl rings of ;
compounds having Pormula (LIV) may b missing, and that the compounds ;
still retain high binding to the sigma receptor (Formula (IIV), R' =
hydrogen). Such compounds include N,N-dimethyl-n-hexylamine and N- -;
methyl-N-propylhcxyl-amine. - `
15The sigma rcceptor ligands of the present invention may exist in
racemic form or in the optically active stereoisomeric form. Most preferably,
the compounds exist in the S-(+) form.
The invendon also relates to certain novel sigma receptor ligands and
pharmaceudcal compositions comprising the novel sigma receptor ligands. In
20particular, the invention relates to compounds having the Formula (~XI):
Rl :
..
(CH)n
\
flr ~ ,~CH-N-X -Z
",~' (xxxr) ~';
" .
SlJBS111UrE S~

WO 93/00313 ~ Pcr/uS92/o533o
-29- 2111~57
whercin Ar n, R, R', W and Z are as defined above and
X is -(CH2)q-, whercin q is 3-6;
-(CH2)r-C~C-(CH~;, wherein cach r is 0-3 independently;
-(CH2)r-CH =CH-(CH2);;
S O ~.
Il .
-(CH2),-C-(CH2).-;
-(CH2)r-Y-(CH2);, wherein Y is O or S; or
C,-C6 alkyl (wherein Z is hydrogcn);
wherein said compound exhibits high binding activity with respect to the sigma
reocptors.
Sigma receptor ligands having tnc above Porrnula (~1) wherein q - ~-
is 3-6 have unexpectedly high binding to the sigma receptors (see Example 2,
below). Preferably, q is5.
The invention also relates to sigma receptor ligands having the Pormula
(XXXIII): ,~, ";,,
Rl R
,.
T--(Cll)n-N-X-Z .
(XXXIII) ~`
wherein T, n, R, R', and Z are defined above, and
X is ~(CH2)q~~ wherein q is 3-6;
-(CH~);C--C-(CH2)r-, wherein each r is ~3 independently;
-(CH2)r-CH =CH~(CH2)r~;
O
Il
-(CH2)r~C~(CH2)r~;
-(CH2),-Y-(CH2);, wherein Y is O or S; or
C,-C6 alkyl (wherein Z is hydrogen);
whcrcin said compound exhibits high binding activity with respect to the sigma
receptors.

WO 93/00313 PCr/US92/OS330
3~
2 111957 , ~;,
Sigma receptor ligands having the above Formula (~ V) wherein q
is 3-6 also have une~pectedly high binding to the sigma receptors (see
E~ample 2). Most prefcrably, q is 5.
The invcntion also relates to compounds of the Formula (~11):
Rf ~UV-~-z
(XXXII) ` ~i
wherein R2, V and Z arc as defined abow; ; ` :
X is -(CH2)r-C~C-(CH2)~-, wherein r is ~3;
-(CH2)r-CH =CH-(CH2);; ` . `
O ~`.', . ~-, .
11 .,,,, ~
-(CH2),-C-(CH~,-; .. `~ .:~ .
-(CH2)r-Y-(CH~)r-, wherein Y is O or S; or
C,-C6 alkyl (wherein Z is hydrogen);
wherein said compound exhibits high binding activity with respect to the sigma
receptors. ~:
Sigma receptor ligands having the above Formula (XXXII) wherein q~ ~ ~
is 3-6 also have unexpectedly high binding to the sigma receptors (see :.
Example 2).
The invention also relates to compounds of the Formula (XXXV):
RZ ~ U-X - 2
(XXXV)
wherein R2 and Z are as defined above;
X is -(CH2)r-C~C-(CH2)r-, wherein each r is ~3 independently;
-(CH2),-CH=CH-(CH2),-;
'

WO 93/00313 i Pcr/us92/~s330
.
-31- 2111957
-(CH2)t-C-(CH2);;
-(CH~)r-Y-(CH2),-, wherein Y is O or S; or
S Ct-C6 alkyl (wherein Z is hydrogen);
wherein said compound cxhibits high binding acdvity with respect to the sigma
receptors.
Sigma receptor ligands having the above Pormula (XXXV) also have
unexpectcdly high binding to the sigma receptors (see E~amplc 2).
The invendon also relates to compounds which are relatod to the
Pormula XXXII and having d~e Pormula (~XIX): ~-
.
~ X_~ ~
~lX)
wherein R2, M, X and Z are as dcfined abovc;
U is selected from the group consisting of hydrogen, halogen such as chloro,
fluoro, bromo, iodo; CF3, C,-C6 alkoxy, C2-C6 dialkoxymethyl, Cl-C6 alkyl,
cyano, C3-CI5 dialkylaminoalkyl, carboxy, carboxamido, C,-C6 haloalkyl,
Cl-C, haloalkylthio, allyl, aralkyl, C3-C6 cycloalkyl, aroyl, aralkoxy, C2-C6
acyl, aryl, substituted aryl, heteroatyl, substituted heteroaryl, an aryl ring
fused to a substituted benzene ring, a substituted aryl ring fused to a benzcne
ring, a heteroaryl ring fused to a benzene ring, a substituted heteroaryl ring
fused to a benzene ring, C3-C6 heterocycloalkyl, a C3-C6 heterocycloalkyl ring
fussd to a benzene ring, Cl-C6 alkylthio, C,-C6 alkylsulfonyl, C,-C6 haloalkyl-
sulfonyl, Cl-C6 alkylsulfinyl, C,-C6 haloalkylsulfinyl, arylthio, C,-C6 halo-
alkoxy, amino, Cl-C6 alkylamino, C2-CIs dialkylamino, hydroxy, carbamoyl,
C,-C6 N-alkylcarbamoyl, C2-CI5 N,N-dialkylcarbamoyl, nitro and C2-CI~ dial-
kylsulfamoyl;
~S~r

WO 93~00313 PCr/USg2/0533~
2111957 ~ -32-
wherein said compound exhibits high binding activity with respect to the sigma
receptors.
The invcntion also relates to a compound of the Formula (XXXVa):
,~r~ ,
R3 U N-X-Z ~
\_/ ' , ''"'''.,,''
(XXXVa)
wherein:
R3 is selected from the group consisting of C,-C6 alkyl, Cl-C6 alkenyl,
C2-C6 dialkoxymethyl, C3-C,5 dialkylaminoalkyl, aralkyl, C3-C6 cycloalkyl,
aroyl, C2-C6 acyl, aryl, substituted aryl, alkaryl, substituted alkaryl, a alkyl,
substitutcd aralkyl, heteroaryl, subsdtuted hetcroaryl, C3-C6 heterocycloalkyl;
and X, Y and Z are defined above,
wherein said compound exhibits a high binding activity with respect to
the sigma receptors. .
The invention also relates to a compound of the Formula (XXXVb):
~ `'.,', .
R47~ N-X-Z ~ ~
(XXXVb)
wherein:
R~ is hydrogen or an aryl group substituted with a group selected from ` ``~
the group consisting of C,-C6 alkyl, C,-C6 alkenyl, C2-C6 dialkoxymethyl, C3-
C.s dialkylaminoalkyl, aralkyl, C3-C6 cycloa!kyl, aroyl, C2-C6 acyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, C3-C6 heterocycloalkyl;
R5 is hydrogen or hydroxy; and
X, Y and Z are defined above, ;

WO 93~00313 PCr/US92/0~33~
~33~ 2 1 1 1 9 ~ 7 `~
wherein said compound e~thibits a high binding activity with respcct to - -
the sigma receptors.
The invention also rclates to a compound of the Pormuh (XXXVc): ~
: ",;
N - X - Z ~:
(X~Vc)
whcrcin X and Y are dcfined above,
whcrcin said compound cxhibits a high binding acdvity wid~ respect to
: . .
thc sigma receptors.
The invention also rclates to a tropano derivative of the Formula
(XXXVd):
.
R4 7~ N - X -Z
R5 ( XXXUd )
; '
wherein R4, R5, X and Z are defined above, and
wherein said compound exhibits a high binding acdvity with respect tO
the sigma receptors.
The invention also relates n~ a compound of the FonTlula (XXXVl):
~ ~ CH2 ) ~- NH - ( CH2 ) b <~ 2
R2 R
( XXX~JI )

WO93/00313 ~ Pcr/US92/os330
2 1119 5 ~
wherein ~:
a is 1-8;
b is 1-8; ~ :
R is hydrogen or C,-C6 alkyl;
S R2 is independendy selected from the group consisting of hydrogen, ~ :~
chloro, fluoro, bromo, iodo, CF3, C,-C6 alkoxy, C2-C6dialko~tymethyl, C,-C6 ;:;
alkyl, cyano, C3-C,5 dialkylaminoaJkyl, carboxy, carbo~camido, C,-C
haloalkyl. C1-C6 haloalkylthio, allyl, aralbl, C3-C6 cycloalkyl, atoyl,
a~alkoxy, C2-C6 carbo~cylic acyl, aryl, subsdtutcd aryl, he~aryl, subsdtuted
heteroalryl, C3-C,heterocycloaikyi, C,-C6alkylthio, C~-C6alkylsulfionyl, C,-C6 ~ -:
haloalkylsulfonyl, C,-C6alkylsulfinyl, C,-C6 haloo~kylsulfinyl, arylthio, C,-C6
haloalkoxy, amino, C,-C6alkyl-amino, dialkylamino, hydro~y, carbamoyl, C,~
C6 N-alkylcarbamoyl, C2~,5 N,N-dialklcarbamoyl, nitro and C2-CI5
dialkylsulfamoyl; -::
wherein said compound exhibits high binding acdvity with respect to
the sigma receptors. ~- -
The invendon also relates to naphthyl derivatives within the scope of
Fonnula (~XI) having Fonnula (XXXVII):
R~ ~Cn2)~~NH~~CH2)b~ R2 ~;~
t XXXUII~
wherein R, R', a and b, as defined above, may be the same or different;
wherein said compound exhibits high binding activity with respect to
the sigma receptors.
The invention also relates to morpholino derivatives having Formula
(XXXVIII):

WO 93/00313 - PCI~/USg2/05330
` ` ~35~ 21119~7 -~ '
...
CH
O CH2
' ;'
~r-CH-CH2-N-X-Z
(XXXVIII)
wherein Ar, X and Z are defined above; -
wherein said compound e~chibits high binding activity with respect to
the sigma receptors.
Also as derivatives of compound X~lll, this invcntior~ is concerned ~ -
with a compound hving the Ponnula (Lll) ` ~;
- R 1 R
C~ (CH)n--N-X-Z
wherein Cy is C3-CII cycloalkyl and Ar, R', n, R, X, and ;Z are defined as
abovc.
Compounds derived from th~ Formula XXXII are also an aspect of the
present invention. These compounds include a compound of the Formula
(Llll)
~, x l U9 x z
(Llll)
wherein Xl is -(CH2)r-C~C-(CH2)r-, whercin each r is 0-3 independently;
-(CH2);CH=CH~(CH2)r~; . ~ .O `~ ''
-~CH2)t-C-(CH2`).-; ~
" ;~`
`'' S~nME~Er `,

Wo93/0~313` ~ PCI/US92/05330 ;~
2111957 -3~ j
.
-(CH2),-Y-(CH~)r-, wherein Y is O or S; or
C,-C6 alkyl (whcrcin Z is hydrogen);
and R2, V, X, and Z arc dcfined as abovc. ~ ;
The invcndon also rclatcs to compounds having the Pormula (UV)~
~ ,..
115-!-X-R7 ~ ~
5- J~ r~
whcrcin Rs and R6 are indcpcndendy a C,.~, alkyl group, R' is hydrogen or a
C,~ alkyl subsdtuted by an arylacctoxy or arylcarboxy group, and X is as
dcfined above. Examples of compounds having Formula LIV includc N,N-
dimethyl-n-he%ylamine, N-methyl-N-propylhexylaminc, N,N'-diethyl-
2-(diphenylacetoxy)cthylamine, N,N'-diethyl-2-(fluorenecarboxy)ethylamine,
N,N-diethyl-2-(diphcnylacetoxy)cthylamine and N,N-diethyl-2-
(~fluorenylcarboxy)ethylaminc.
The compounds of the invendon havc high binding to thc sigma
reccptors. The sigma reccptors include both the sigma-1 and sigma-2
subtypes. Scc Hell~well, S.B. and Bowcn, W.D., Brain Rcs. 527:224-253
~1990); and Wu, X.-Z. ct al., J. Phannacol. ~p. Ther. 257:351-359 ~1991).
A sigma receptor binding assay which quandtates the binding affinity of a
putative ligand for both sigma sites (against 3H-DTG, which labels both sites
with about equal affinity) is disclosed by Weber et al., Proc. Natl. Acad. Sci
' (USA) 83:8784-8788 (1986). Alternatively, [3H]pentowcine may be used to
selectively label the sigma-l binding site in a binding assay. A mixturs of
l3H]DTG and unlabeled (+)pentazocine is ussd to selectively label the sigma-2
site in a binding assay. The present invention is also directed to certain
ligands which are selective for the sigma-l and sigma-2 recèptors. The
discovery of such ligands which are selective for one of the ~NO sigma
receptor subtypes may be an important factor in identifying compounds which
are efficacious in treating central nervous system disorders with minimal side
cffects.

WO 93/00313 `i ` PCr/US92/05330
"` 2111~57 ~ ~
-37-
`: ' ~'`.
Typieal C,-C6 alkyl groups inelude methyl, ethyl, n-propyl, i-propyl,
n-butyl, t-butyl, i-butyl, pentyl and hexyl groups.
Typicat C3 " eyeloakyl groups include cyelopropyl, cyclobutyl,
eyelopentyl, eyelohexyl, cycloheptyl, and eydocctyl groups.
S Typieal C2-C~, earboxylie acyl groups include acetyl, propanoyl,
i-propanoyl, butanoyl, s-butanoyl, pentanoyl and hexanoyl groups.
Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl
and fluorene groups. - - -
Typicat aryl-subsdtuted earboxylic aeid groups include the above-
mentioned carboxylie aeyl groups substituted by one or more aryl groups,
e.g., diphenylacetoxy and fluorcnecarboxy groups.
Typieal alkaryl groups inelude the above-listed aryl groups subsdtuted
by one or more C,-C~ alkyl groups. ~ -
Typieal a~alkyl groups include a C,-C6 alkyl group substituted by one
of the above-listed aryl groups, e.g.. phenethyl, phenylpropyl, phenylbutyl,
phenylpentyl and phenylhexyl groups as well as the branehed chain isomers
thereof.
Typical Cl-C6 atkoxycarbonyl groups inelude earbonyt subsdtuted by
methoxy, ethoxy, propanoxy, i-propanoxy, n-butanoxy, t-butanoxy,
i-butanoxy, pentanoxy, and hexanoxy groups.
Typieal aralkyl groups inelude the above-listed C,-C6 alkyl groups
subsdtuted by phenyl, naphthyl, phenanthryl, and anthracyl groups.
Typical C2-C6 alkenyl groups include vinyl, allyl, 2-bu~nyl,
2-pentenyl, and 2-hexenyl groups.
Typical C2-C6 alkynyl groups include acetynyl and propargyl groups.
Typical halo groups include fluorine, chlorine, bromine and iodine.
Typical aroyl groups include carbonyl substituted by phenyl, naphthyl,
phenanthryl, and anthracyl groups.
Typical arallcanoyl groups include carbonyl substituted by the above-
listed aralkyl groups.
:;.

WO 93/00313 PCr/USg~/05330
21119S7 `` -38- `
~
Typical aralkoxy groups include the above listed Cl-C6 alkoxy groups
subsdtuted by phenyl, naphthyl, phenanthyl, and anthracyl groups.
Typical substituted aryl groups include the above-listed uyl groups
substituted by halo, hydroxy, C,-C6 alkoxy, amino, and the like.
Typical heteroaryl groups include furyl, thienyl, pyrrolyl, thiazolyl,
pyridyl, pyrimidinyl, pyrizinyl, o~cazolyl and phthalimido groups which may
be fused to a benzenc ring.
Typical substituted heteroaryl groups includc the above-listed heteroaryl
groups subsdtutcd by halo, Cl-C6 alkyl and the like. ; ;
Typical C5-C6 heterocycloalkyl groups include tetrahydro&ranyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrolidinyl
groups.
Under the binding acdvity studies, an IC~D value of at most about I00
nM, preferably at most about 25 nM, more preferably at most I0 nM, most
preferably at most I nM indicates a high binding affinity with respect to the
sigma receptor binding sites. In the present applicadon, the term "high af-
finity" is intend d to mean a compound which exhibits an IC50 of less than 100
nM in a sigma receptor binding assay, preferably against 3H-DTG as disclosed
by Weber et al., Proc. Natl. Acad. Sa (USA) 83:8784-8788 (1986), which
measures the binding affinity of compounds toward both the sigma-l and
sigma-2 sites. Especially preferred dgma ligands e~hibit IC50 values of less
than about 25 nM, more preferably less than about 10 nM, most preferably
less than about 1 nM against 3H-DTG.
The inventor has unexpectedly discovered that certain of the sigma
receptor ligand of the present invention e~chibit enhanced selectivity to the
sigma-l binding site while other of the sigma receptor ligands exhibit enhanced
selecdvity to the sigma-2 binding site. Selecdve binding to the sigma-l
binding site is associated with various gastrointestinal effects, inhibition of
contracdon of the guinea pig ileum, and inhibition of acetylcholine-induced
phosphoinositide response. In contrast, compounds which exhibit selecdve
binding to the sigma-2 reccptor are associated with dystonia and may block
S~T~ SHE~

Wo 93/00313 - Pcr/US92/o533o
39 2111~.i7
calcium channels. Sec Quiron ct al., Trcnds P)larm. Sci. 13:85-86 (19~2);
Rothman ct al., Mol. Pharmacol. 39:222-232 (1991). Thus, the compounds
of thc present invendon which are selecd~ve for the sigma-l receptor may be
used for, in addition to the treament of psychosis, the treatment or prevendon
of gastrointesdnal disorders such as cmesis, colids and the like, without any
untowud dystonia. In addidon, the compounds of the present invendon which
are sclective for the sigma-2 rcccptor may be used for trcadng psychosis and
condidons which are amcliorated by calcium channel blockers, e.g.
hypertension, migranc and angina. Compounds which are selective for the
sigma-2 rcccptor are known to produce dystonia. However, antagonists of the
sigma-2 rcccptor arc e~pected to be effective in trcating hypcrtension, migrane
and angina without dystonic side effects.
Prefelably, compounds which are sdecdve for the sigma-l receptor
comparcd to the sigma-2 receptor have an IC5D rado of sigma-l/sigma-2 of less
than about 0.1 (scc Table 10). Such compounds include, but are not limited
to( ~)N-(l-phenyl-2-propyl)-4-phenylbutylamine,R(-)N-(l-phenyl-2-propyl)-
3-(2-naphthyl)propylamine, ( ~) N-l1-(1'-Naphthyl)-2-propyll-
3-phenylpropylamine, 4-Hydroxy~phcnyl-1-(3-phenylpropyl)piperidine,
N-(4-phenylbutyl)phenethylamine, Di-N-13-(2'-naphthyl)propyl-N-
methylamine, N-(4-phenylbutyl)-benzylamine, N-(5-phenylpentyl)-
(4-phenyl)butylamine, N-(5-phenylpentyl)benzylamine, N-(4-phenylbutyl)-N '-
benzylpiperazine, N-4(4-phenylbutyl)-N'-benzoylpiperazine, N-
(3-phenylpropyl)-1-(p-ethoxyphenyl)-2-propylamine, N-(5-phenylpentyl)
phenethylamine, N-(7-phenylheptyl)benzylamine, N-(7-phenylhep~yl)
phenethylamine, N-(5-cyclohexylpentyl)benzylamine, N-(4-phenylbutyl)-1-
phenyl-2-butylamine, N-(4-phenyl-3(E)-butenyl)-N'-methylpiperazine, N-(4-
phenyl-3(Z)-butcnyl)-N'-methylpiperazine, N-(4-(3-trifluoro-methyl)-3-(Z)-
butcnyl)-N-methylpipeJazine, N-(4-phenyl)-N'-methylpiperazine, N-(5-
phenylpentyl)-3-phcnylpropylamine~-methyl-N -propyl-5-phenylpentylamine,
N-Methyl-N-(3-phenylpropyl)-1-phenylisopropylamine, N-(5-phenylpentyl)
piperidine, N,N-Dimethyl-S-phenylpentylamine, 5-cyclohe~ylpcntylamine, N-

WO 93/00313 PcrJuS92/os33o
2111~S7 ` ` ~ ~
methyl-5-cyclohe~ylpentylaminc,N,N-Dimethyl-5-cyclohexylpentylamineand
N-Benzyl-N-methyl-5-phenylpcntylamine.
Preferably, compounds which arc selecdve for the sigma-2 rcccptor
compared to the sigma-l receptor have a ratio of sigma-1/sigma-2 of greatcr
- than about 10 (scc Table 10). Such compounds include, but are not limitcd
to N-phcnyl-N'-(3-(1-phthalimido)propyl)-pipcrazine, and N-(4-
phthalimido)butyl-N'-phenylpiperazinc. N-(5-phthalimido)pentyl-N'-
phcnylpipcrazine is also a~pec~d to bc highly selective for sigma-2.
Surprisingly, the inventor has also disoovcred that the sigma receptor
ligands of the prcsent invention c%hibit low affinity to the DA and PCP
reccptors. ln addition, ccrtain of thc sigrna reccptor ligands of thc present
invention also e~hibit low affinity for thc 5-HT~,~ receptor. Thus, the sigma
receptor ligands of the present in~cntion may bc used for the treatment of
ccntral ncrvous systcm disorders without thc untoward sidc cffects associated
with unwantcd binding at thc DA, PCP and/or 5-HT,A receptors. By thc term
"low affinity" is intended a binding affinity of ~100 nM, morc prefcrably,
> 1000 nM in a DA, PCP or 5-HT,~ binding assay. Especially prcferrcd
sigma receptor ligands have high binding to the sigma receptor and low
binding to tne DA, PCP andlor 5-HTIA receptors, as defined herein.
By the term Ncentral ncrvous system disorder" is intended both
psychiatric and movement dysfunctions. The selective sigma ligands of the
present invention may be used to treat psychiatric disorders including
psychoses, such as schizophrenia and related disorders, mania with psychotic
features, major depression with psychotic features, organic psychotic disorders
and other idiopathic psychotic disorders, in addition to anxiety disorders and
depression. The term "schizophrenia" is intended to include any of a group
of severe emotional disorders, usually of psychotic proportions, characterized
by misinterpretadon and retreat from reality, delusions, hallucinations,
ambivalence, inappropriate affect, and withdrawn, bizarre, or regressive
behavior. See Dorland's Illl~stra~cd Me~ical Dicnonary, 26th edition, W.B.
Saunders Company, Philadelphia, Pa., pp. 1171 (1981). The sigma receptor

WO 93`/00313 PCr/US92/05330
. ~ .
- 2111'~57 ,
ligands of the present invention can also be used in treadng movement
disorders such as Parkinson's disease, tardive dyskinesia, and dystonias. See
J.M. Walker ct al., P)~annacol. Rcv. 42:355402 (1990), d~e disclosurc of
which is fully incorporatcd by refcrencc herein.
The sigma receptor ligands of the present invention are also useful for
the treatmcm of drug abuse. In this aspect of the invendon, the compounds
of the invention are administered to an individual to ameliorate symptoms of
drug withdrawal or t~ reducc craving for the drug, e.g. cocaine, heroin, PCP
and hallucinogens.
As discussed abovc, the sigma receptor ligands of the prcsent invchtion
arc highly selecdve for the sigma reccptor and show low aKmity for the DA
and PCP reccptors. Certain specific sigma reccptor ligands of the present
invendon also bind with low affinity to 5-HT~ eceptors. Thus, in addition
to thc treatment of ccntral nervous system disorders, the sigma selective
ligands of thc prcsent invention may also be used as a pharmasological tool in
an animal model for the scre~ning of potential sigma receptor agents.
The sigma receptor ligands of the present invention may also be
radiolabelled with, for example, 3H, "C, '~C, '~F, '~51 and 1311. In their
radiolabelled for n, the sigma receptor ligands of the present invenion may be
used for audoradiography studies of the sigma receptor sites in tissue,
especially neuronal dssue.
The sigma receptor ligands of the present invention may be prepared
by general methods of synthesis as disclosed in Example I. For e~ample, a
sigma receptor ligand having Formula (X~) may be prepared by reductive
amination of a compound having Formula (XXXXl) with an aldehyde having
Formula (XXXXII) according to Scheme I outlined below.

Wo 93/00313 Pcr/US92~os3~
21119S7 .. ~
Scheme 1
Rl ` .,
~CH>~
\ 1 8 ~ ~
flr ~ . , N-H ~ H- ~ -C- ) -Z
~ "~' ( XXXXI~
- ( XXXXI ) tll
Rl
.: ~ .
~< CH )~
r ~ " N- ~ -CH2 ) ~Z
"~
( X X X X )
~`'`.''~''~
.,
The starting compound having Formula (~1), where W---H H-,
may be prepared by general mcd~ods of organic synthesis. For general
S methods of p~eparing compounds of Formula (X~Xl), reference is made to
Fuller, R.W. etal., J. Med. Chem. 14:322- 325 (1971); Foye, W.O. etal.,
J. Pharm. Sa 68:591-S95 (1979); Bossier, ~.R. et al., Chan. Abstr.
66:46195h and 67:21527a (1967); Aldous, P.A.B., J. Med. Chem. 17:1100
1111 (1974); Fuller, R.W. etal., J. Pharm. Phannacol. 25:828-829 (1973);
Fullcr, R.W. ctal., Ncurophannacology 14:739-746 (1975); Conde, S. aal. .
1. Med. Chcm. 21:978-981 (1978); Lukovits, l. ctal.. Int. J. Quantum Chem.

W~93/003t3 i 2 1 1 1 9 ~ 7 Pcr/US92/os330
.. . .
-43-
20:429-438 (1981); and Law, B., J. C7tromatog. 407:1-18 (1987), the
disclosures of which are incorporated by reference herein in their entirety.
The radiolabelled derivadves having Pormula (XXXX) may be prepared by,
for awnple, using a tritiated reducing agent to perform the reduetive
S aminadon or by utilizing a '~C-labelled starting material.
Alternadvely, where R is H, an N-substituted carbo~amide of Pormula
(XX~III) may be ieduced, for example, with LiAlH, to give the N,N-
disubstituted sigma receptor ligand having the Formula (~), below (see
Scheme 11).
Schome 11
Rl ~ .
~ R 8 ~`
~r~ "-N-~-C->-Z
, ~ ;.
~ "
:. '
(XXXXIII) Rl ~ Lil4lH4
I
C H ) Q
r ~ -CH2 ) -Z
(XXXX) `~
~lllJlE S~lEEl'

Wo 93/00313 ~ ~ Pcr/uss2/o533o
2~9~
,
Alternatively, whcrc~ieistarting compound comprises a carbonyl
group, the compound having the Formula (X~XIV) may bc reduced with,
for e~nple, AIH3, diboranc:methyl su1fide or o~er standard carbonyl
reducing reagent to give the sigma receptor ligand having Formula (~)
S according to Schemelll.
~chemc 111 - -
R~
.- ~
R O ; `
\ I 11
f~r~ "-N-(-C-)-Z
~ "
` W '
~XXXXIU) :
R 1
1~ r / - N - ~ - C H2 ) ~ Z
~ ~ " ~
(XXXXI `~'
8U~T~8~1EEr

WO 93~00313 PCr/US92/05330
.
~5- 21119~ 7
The sigma receptor ligands having Pormula (XXXI) may be prepared
by nucleophilic displaccment of an electrophile (E) by the amino derivadvc
(~OOD~V) as outlined in Schcmc IV. Examples of elcctrophiles which may .;
. -~
be used for this pu~pose includc halides such as Cl, Br, or 1, tosylate or
- 5 mesylate.
, . .
Scheme IV
R~
,:.
\ I ~`
Iqr ~ "-N-H ~ E-X-2 ~ ~
~ "~' " ',
( XXXX U ) 1
~ ~ `
I
~r ~ . - N-K-Z
~ ~ "
( XXXI ) - ~

W0 93/00313 ; ~ ~ ~ rCr~US92/Os330
2111957 4~
Molpholino derivatives having the Formula (XXXXVI) may be
prcpared by rcduction of a compound of the Formula (XXXXVII) with, for
examplc, sodium borohydride to give the ring-closed morpholino derivative
(~ODO~VI) according to Scheme V. :
CH2CH2-OH C"2~
8 ¦ o IH2
Rl-C-CHZ-N-X-Z -'''''''' '''' ~ Rl-CH-CH2-N-X-Z -.
(XXXXUIT) ~XXXXUI)
~`
.
Alternadvely, wherc the sigma receptor ligand comprises a ::
tetrahydropyridine ring (Formula (XXXXVIII)), the tetrahydropyridine ring ~-
may be constructed by reaction of a 2-arylpropene derivative (Formula
(XXXXIX)) with an alkyl amine (Formula (L)) and para-formaldehyde in the
presence of orthophosphoric acid (Scheme Vl).
Scheme Vl
CH3
P~r-C ~ NH2-x-Z ~ (CH2)x ~ P~r-C l~-X-Z
CH2
<XXXXIX ) ( L ) ( XXXXUrII )

WO93~00313 2 1 1 1 9 5 7 rcr/usg2~05330
47~
-
Reduetion of the double bond of the eompound having Fonnula ~-~
(~VIII) with, for example, hydrogen and a hydrogenation eatalyst sueh
as Pd/C or Pt gives ~e eorresponding piperidine having Formula (Ll):
Seheme Vll
lH1 /'--\ "
~r-C ~i-X-Z ~ ~r-C N-X-Z
(XX~aVIII) (U)
, . - . ;
Also ineluded within the seope of the present invendon are the optieal
isomers of the eompounds of the invention. The optieal isomers !may be
sepua~ed by elassieal resoludon techniques by, for e`xample, forma~ion of a
salt of the amino group with an optieally aedve aeid. A partieularly preferred
aeid for ~is pulpose is (~ p-toluoyl-D-tartaric acid. The resulting
diastereoisomeric salt may then be separated by erystallizadon, chromatog-
raphy, or by taking advantage of the differing solubilities of the two
diastereoisomeric salts. The free base may then be isolated by treatment with
a base sueh as aqueous ammonia and extraction with an organic solvent.
Alternatively, the optical isomers may be prepared by resolution of the startingamine used to prepare the sigma ligand.
Also included within the scope of the present invention are the non-
toxic pharmaceutically acceptable salts of the eompounds of the invention.
Acid addition salts are formed by mixing a solution of the sigma ligand of the
invention with a solution of a pharmaeeutiea~ly acceptable non-toxic acid such
as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acedc acid,
citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and thelike.
In the methods of treatment of the present invention, the pharmaceuti-
cal composidons may comprise the sigma receptor ligand at a unit dose level
` ~ `SlJ8SmUTESHE~
.. , _ . . . .... .. . ...... . . ... , . . ~ .. .. . . .

WO g3/00313 ; ~ ; ~ ` PCI`/US92/0~330
21113S7 ~8-
. .
of about 0.01 to about 500 mgikg of body wcight, or an cquivalentamount of
the phannaceutically acccptable salt thereof, on a regimen of 1-4 times per
day. Of course, it is understood that the cxact treatmcnt level will depend
upon thc case history of the animal, e.g., human being, that is treated. The
precise treatment levd can be determined by onc of ordinary skill in the art
without unduc cxpcrimcntadon.
The pharmaceudcal composidons of thc invcndon may bc administered
to any animal which may expericnce the beneficial cffects of thc compounds
of thc invcndon. Poremost among such animals arc humans, although the
invcndon is not intended to be so limitcd.
The phannaceudcal composidons of thc prcsent invendon may be
adminis~red by any mcans that achicvc thcir intended purpose. For example,
. . : .
administradon may be by parentcral, subaluneous, intravenous, int~amuscular,
intraperitoneal, transdermal, or buccal routes. Alternativcly, or concurrently,
administradon may be by the oral route. Thc dosage administcred will bc
dcpcndent upon dle age, health, and wdght of the recipient, kind of
concurrcnt treatment, if any, frequency of treatment, and the nature of the
effect desired.
In addition to the sigma r~ceptor ligands, tne new pharmaceutical
preparations may contain suitable pharmaceutically acceptable carriers
comprising excipients and auxiliaries which facilitate processing of the active
compounds intopreparations which can be used pharmaceutically. Preferably,
the preparations, particularly those preparations which can be administered
orally and which can be used for the preferred type of administradon, such as
tablets, dragees, and capsules, and also preparations which can be
administered rectally, such as suppositories, as well as suitable solutions for
administration by injection or orally, are present at a concentration of from
about 0.01 to 99 percent, together with the excipient.
The phannaceutical preparations of the present invention are
manufactured in a manner which is itself known, for example, by means of
conventional mixing, granulating, dragee-making, dissolving, or Iyophilizing

WO 93/00313 Pcr/uss2/os33o
~9 : ,
57 ` ~``
processes. Thus, phannaceudcal preparations for oral use can be obtained by
combining the sigma ligand with solid excipients, optionally grinding the
resulting mixture and processing the mixture of granules, after adding suitable
auxiliaries, if desircd or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in pardcular, fillers such as saccharides, for
a~ample lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or
calcium phosphates, ror examplc tricalcium phosphate or calcium hydrogen
phosphate, as wdl as bindcrs such as starch paste, using, for e~ample, maize
starch, wheat starch, rice starch, potato starch, gelatin, t~agacanth, mcthyl
cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,
and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added
such as the above-mcntdoncd starches and also carboxymethyl-starch, cross-
lirdced polyvinyl pyrrolidone, agar, or alginic acid or a salt thcreof, such as
sodium alginate. Au~dliaries are, above all, flow-reguladng agcnts and
lubricants, for example, silica, talc, stearic acid or salts thereof, such as
magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee
cores are provided with suitable coatings which, if desired, are resistant ~o
gastric juices. For dlis purpose, concentrated saccharide solutions may ~e
used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable
organic solvents or solvent mixtures. In order to produce coatings resistant
to gastric juices, solutions of suitable cellulose preparations such as acetyl-
cellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye
stuffs or pigments may be added to the tablets or dragee coaidngs, for
example, for identification or in order to cha~acterize combinadons of active
compound doses.
Other pharmaceutical preparations which can be used oraJly include
push-fit capsules made of geladn, as well as soft, sealed capsules made of
gelatin and a plasdcizer such ais glycerol or sorbitol. The push-fit capsules can
contain the active compounds in the form of granules which may be mixed
with fillers such as lactose, binders such as stairches, and/or lubricants such as

WO 93/00313 ' Pcr/us92/os330
2111957 50 `
talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the
active compounds are preferably dissolved or suspended in suitable liquids,
such as fatty oils, or liquid paraffin. In addition, stabilizers may bc added.
Possible pharmaceutical preparations which can bc used rec~lly
include, for e~ample, suppositories, which consist of a combinadon of one or
more of the active compounds with a suppository base. Suitable suppository
bases are, for e%ample, natural or synthedc triglycerides, or paraffin
hydroca~ons. In addition, it is also possible to use gelatin rec~l capsules
which consist of a combinadon of the active compounds with a base. Possible
base materials include, for example, liquid triglycerides, polyethylene glycols,or paraffin hydroca~ons.
Suitable formulations for parenteral administradon include aqueous
soludons of the-sigma ligands in water-soluble form, for example, water-
soluble salts. In addition, suspensions of the activc compounds as appropriate
oily injection suspcnsions may be administered. Suitable lipophilic solvents
or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acidesters. for cxample, ethyl oleate or triglyceridcs. Aqucous injection
suspensions may contain substances which increase the viscosity of the
suspension include, for example, sodium carboxymethyl ccllulose, sorbitol,
andlor dextran. Op~ionally, the suspension may also contain stabilizers.
The fiollowing examples are illustrative, but not limiting, of the method
and compositions of the present invention. Other suitable modifications and
adaptations of d~e sigma receptor ligands as well as the variety of conditions
and parameters normally encountered in clinical therapy and which are
obvious to those skilled in the art are within the spirit and ssope of the
invention.

WO 93iO0313 '`; ' ~ '/US92/053~0 ~
-51- 2111957
EY~mDh~S
EX~MPLE 1 PREPARATION OF SlGMA RECEPI'OR LlGANDS
Thc sigma rcceptor ligands listed in Tables 1, 2 and 3 wcre synthesized
according to one of twclve synthetic procedures (Mcthods A-L) disclosed
immediatelybelow.
., . i . ,
METHODS
M~OD A: R(-~N-(3-Phenylpropyl~l-phenyl-2-aminopropane Hydro
ch!oridë. A mixture of hydrocimlanuldehyde (1.11 g. 8.2 mmol) and R(-)-
amphetainine (0.94 g, 7.0 mmol) in MeOH (20 mL) was hydrogenated over
PtlC 5% (0.2 g) a~ room temperaturc undl thc theoredcal amount of hydrogcn
was absorbed. The methanolic solution of thé base was separated from the
catalyst by filtradon and was treated with 10% HCI undl the mixture was
st~ongly acidic. Thc MeOH and H20 were removed under reduced pressure
with warming to give a crude solid, which was recrystallized several dmes
from MeOH and MEK to give 1.6 g (80%) of colorless crystals, mp 215-
217C.
METHOD B: R(-~N-(Cyclopropylmethyl~l-phenyl-2-aminopropane Malease.
. .
To a suspension of LiAlH4 (1.49 g, 38 mmoL) in anhyd. ether (50 mL) was
added a solution of N~ -methylphenylethyl)-2-cyclopropylcarbo~amide (1.5
g, 74 mmol) in anhyd. Et2O (20 mL). The mi~cture was heated at reflux
ovcrnight, cooled to OC and H20 (2.5 mL) was added in a drop wise
manner. This was followed by the addition of 2N NaOH solution (2.5 mL)
and then H2O (5 mL). After the inorganic precipitate was removed by
filtration, the Et20 solution was dried (anhyd. Na2SO4) and treated with a
solution of maleic acid (1.5 g in absolute EtOH (10 mL). The product was
~,,
~nnnESHEEr ' '

WO 93/00313 - Pcr/uss2/os33o
2111957`` ;.~ 52-
.:
collected by filtration, washed with Et20 and recrystallized from 2-PrOH/Et20
(3x) to afford 1.3 g (59%) of fine crystals: mp 162-163C.
METHOD C: N-(3-Phcnylpropyl~1-(4-bromophenyl~2-aminoprapane Hydro-
chloride. AIH3 was prepared by thc addition of AICI3 (0.07g, 0.5 mmol) to
S a suspension of LiAlH4 (0.064 g, 1.7 mmol) in Et20 (50 mL) at 0C under a
nitrogen atmosphere. A soludon of N-hyd~ocinnamoyl-1-(4-bromophenyl)-2-
aminopropane (100 mg, 0.29 mmol) in dry Et20 (10 mL) was added in a drop
wise manner, to the AIH3 soludon at 0C. Aftcr thc addidon was complctc,
the mixture was allowcd to stir for 0.5 h at the same tcmperature. Exccss
AIH3 was decomposed by the addition of crushed icc (1 g) followed by 15%
NaOH solution (2 mL). The mixture was filtcred and the organic portion was
scparated, washed with H20 (20, 10, 5 mL), dried (anhyd. MgSO,) and
treated with sufficient HCI gas until prccipitation was complete. The
precipi~ate was collected by filtration and recrystallized from EtOH/Et20 (4x)
to give 20 mg (19%) of a finely divided powder: mp 17~178C.
METHOD D: N-(3-Phenylpropyl)-1-(3-trifluoromethylphenyl)-2-amin~
propane Hydrochloride. A mixture of 1 -(3-trifluoromethylphenyl)-2-propanone
(102 mg, 0.50 mmol), 3-phenyl-1-propylamine (86 mg, 0.64 mmol), glacial
acetic acid (8 mg, 0.13 mmol), and MeOH (2 mL) was allowed to stir at room
temperature for 0.5 h. To this mixture was added over a ~h period sodium
borohydride (19 mg, 0.50 mmol) and the mixture was allowed to stir at room
temperature for 20 h. The solvents were removed by warming under reduced
pressure to give a small amount of an oil which was cooled and treated with
10% HCI. The crude product separated as a white solid, 122 mg (68%), mp
135-145C. The crystals were dissolved in H20 and the solution was
extracted with Et2O. The H2O portion was separated, the H2O was
evaporated, and the crystals reformed; recrystallization from acetone gave 66
mg (37%) of colorless crystals, mp 167-169C.
SUBSrITUTE SHEET

Wo 93/00313 ` Pcr/uS92/05330
' 53- 21119S7~ ~J;I 9
METHOD E: R(-)-N-Benzyl-l-phenyl-2-aminopropane Hydrochloride. To
a mixture of R(-)-amphetamine sulfate (0.633 g, 3.4 mmol), benzaldehyde
(0.547 g. 5.2 mmol), MeOH (3 mL), and glacial acedc acid (0.5 g) was addcd
sodium cyanoborohydridc (0.263 g, 4.0 mmol) at room tempcrature ovcr a l-h
period. During this addidon, the pH was maintained at pH 5.5-6.0 by the
addidon of additional glacW acetic acid (0.25 g). After stdrring 20 h at room`
tcmperature, the MeOH was rcmoved by warming under reduced pressurë.
The residue was treated with an a~cess of 10% NaOH and the p~ct
exbac~ed into Et20. Thc prodùct was then ext~actcd into an excess of 10%
HCI soludon; the aqucous layer was decànted and the water was removed by
warming under reduccd pressurc to give the crude product, 0.5 g (56%), mp
.. . , . ~ ,.
170-174C. After several rccrystallizations from MeOH-MEK, the colorless
cryst~ls weighed 0.46 g (51%), mp 173-175C.
METHOD F: R(-)-N-(2-Phenoxyethyl)-l-phenyl-2-aminopropane Hydro-
chloride. In a 5-mL reaction vial was placed R(-)-amphetamine (0.288 g, 2.1
mmol) and 2-phenoxyethyl chloride (0.335 g, 2.1 mmol). The vial was sealed
and heated at 95C for 20 h. The reaction mixture was cooled. washed
repeatedly with Et2O to give the crude product which melted at 155-160C.
Recrystallization (3x) using MeOH and MEK gave colorless crystals that
weighed 50 mg (8~), mp 178-179C.
METHOD G: R(-)-N-(3-Phenyl-3-oxopropyl)-1-phenyl-2-aminopropane
Hydrochloride. A mixture of R(-)-amphetamine hydrochloride (0.259 g, 1.5
mmol), acetophenone (0.635 g, 5.3 mmol), paraformaldehyde (87 mg), MeOH
(1.2 mL), and conc. HCI (1 drop) was placed in a 5-mL r~action vial, stirred,
and heated at 65C for 24 h. After removing the solvent using reduced
pressure and warming, the reaction mixture (which became partially solid) was
dissolved in H2O (5 mL) and was extracted twice with hexane (10 mL). The
aqueous portion was made basic with 10% NaOH and the product extracted
into hcxane (10 mL). The product was then extracted into a 10% HCI

WO 93/003t3 ~ ~ PCr/US92/05330
.. . .
2111957 -s4-
soludon and the H2O and excess HCI were removed with warming under
reduced pressure to form the crude solid, mp 135-144C. Repcated
recrystallizations using MEK and acetone gave 50 mg (11% yield) of colorless
crystals, mp 146-147C.
S METHOD H: (+)-a-lN-(3-phenylpropyl)aminolpropiophenonc Hydro-
chlodde. A mi~ture of hydrociMamaldehyde (2 g, 15 mmoL) and
norephcdrine (2.18 ~, 14.4 mmol) in EtOH (100 mL) was hydrogens~d over
a catalytic amount of Pd/C 10%, at room temperature. A hydrogen uptake
slightly in cxcess of theory was obtained. The suspension was filtered and the
? ... . ~ .
filuate was treated with 2N HCI (30 mL). The acid soiudon was evaporated
to give a residual solid, which was recrystallized twice from EtOH/Et20 to
give 2.34 g (55%) of needles: mp 211-213C.
An ice cooled mi~ture of CH2CI2 (20 mL) and pyridine (0.8 g, 10
mmol) was Ireated with dry CrO3 (0.5 g, 5 mmol), which was added in
portions within a 3~min period. The purple-brown mi~cture was sdrred at
room temperature for 2 h. A solution of the amino alcohol prepared above
(0.23 g, 1.24 mmol) in CH2CI2 (5 mL) was added to the pyridine-CrO3
mixture all at once with vigorous sdrring. After 15 min, the yellow organic
layer was decanted from the black, sticky precipitate and extracted with 5%
NaOH (100 mL). The organic portion was filtered through a bed of anhyd.
Na2SO4 and evaporated to dryness. The oily residue was treated with conc.
HCI (5 mL), warmed, and the mixture was evaporated to dryness. The solid
residue was recrystallized from 2-PrOHlEt20 (2x) to give 150 mg (40%) of
the hydrochloride salt: mp 154-155C (solidified and melted again at
17~172C).
METHOD 1: N-Benzyl-2-phenylmorpholine Hydrochloride. To a solution of
N-(2-hydroxyethyl~N-(benzoylmethyl~benzylamine hydrochloride (0.50 g, 1.6
mmol) and MeOH (5 mL) at 5C was added with stirring over 4 h sodium
borohydride (0.213 g, 5.6 mmol). The reaction was allowed to warm to room
S~SnrUlESHEr

WO 93/00313 2 1 1 1 9 ~ 7 Pcr/US92/os330
-55-
temperature over 18 h; an additional amount of sodium borohydride (70 mg,
1.8 mmol) was added, and the reaction was stîrrcd for an addidonal 24 h. A
small amount of H2O (1 ml) was added to the mixture and the solvents
rcmoved by warming under reduced pressure. Water (6 mL) and Et2O
(12 mL) were added to the reaction mixture; the ether layer was removed and
the Et20 evaporatcd under reduccd pressure to givc the crude liquid product
as the free base (0.42 g). Treatment of the fDe base with cold conc. HCI
(I mL) followed by warming under reduced pressure to remove the H20 and
excess HCI affordcd the crude product hydrocbloride. Rccrystallization from
acetone gave colorless crystals of the amine hydrochloridé 0.38 g (77%), mp
140-143C.
A pordon of these crystals (35 mg, 0.11 mmol) was heatcd at 125C
with conc. HCI (0.17 g) in a sealed reaction vial for 1.25 h. The H2O and
e~cccss HCI wcre removed by warming under reduced pressure to give 40 mg
of thecrude, tanproduct, mp 201-205C. Two recrystallizadons from acetone
gave 21 mg (66%) of the substituted morpholine hydrochloride as colorless
crystals, mp 211-212C.
METHOD J: 1-(4-Phenylbutyl) 1 (4-chlorophenyl~1,2,5,~tetrahydropyridine
Maleate. To a stirred mixture of glacial acetic acid (1.9 g, 31.7 mmol) and
acedc anhydride (0.4 g, 4 mmol) was added slowly (85%) orthophosphoric
acid (0.43 g, 4 mmol). After the exothermic reacdon had subsided,
4-phenylaminobutane (0.58 g, 4 mmol), paraformaldehyde (0.36 g) and
4-chloro-a-methylstyrene (0.62 g, 4 mmol) were added. The reacdon mixture
was stirred at 115C for 4 h then allowed to stand at room temperature for
2 days. The mixture was diluted with H2O (10 mL), extracted with hexane
and the aqueous layer made basic with Na2CO3. The crude product was
extracted into hexane, dried over anhyd. K2CO3, and the solvent removed by
evaporation. The crude free base was recrystallized from H2O-MeOH to give
the purified free base (mp 87-90C) which was dissolved in EtOH and treated

WO 93/00313 ~ Pcr/uss2/os33o
211195 7 -56-
with an Et2O solution of maleic acid to give the maleate salt. Recrystallizadon
from EtOH-Et20 gave 0.6 g (35% yield) of fine crystals, mp 162-164C.
METHOD K: N-(3-Phenylpropyl)-1-(4-hydroxyphenyl)-2-aminopropane
- Hydrobromide. A suspension of the frec base of N-(3-phenylpropyl)-
1-(4-methoxyphenyl)-2-aminopropane (200 mg, 0.63 mmol) in 48% HBr was
heated at reflux for 6 h. Thc mixturc was filtered while hot and the filtra~e
allowed to cool to room tcmpe~urc to give crystals. The crystals wcrc
collectcd by filtration and recrystallized from EtOH-Et2O to give 200 mg (88%
yield) of the hydrobromide salt, mp 15~160C. ~
~.
METHOD L: 1-(3-Chlorophenyl)~-(3-phenylpropyl)piperazine Hydro-
chloride. To a stirrcd solution of diborane:dimethyl sulfide complex (2M) in
THF (30 mL) was added drop wise a solution of dry THF (25 mL) and 1-(3-
chlorophenyl)4-(3-phenylpropionyl)piperazine (1.28 g, 3.86 mmol). The
rcaction mi~cture vas stirred at room temperature for 18 h, quenched by the ~ -
addition of MeOH-HCI (25 mL), and the solvents removed under reduced
pressure. Additional MeOH was added and rcmoved under reduced pressure
to give a tan solid. This was dried for 18 h under vacuum then recrystallized
from MEK to give 0.9 g (67%) of colorless crystals, mp 168-169C.

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EXAMPL SIGMA. PCP AND DOPAMlNE RECEPI`OR BlNDlNG
ASSAYS
Methods
Sigma receptor binding assays using guinea pig brain membranc
S homogenatcs and thc radioligand pH]DTG wcrc conducted as describcd by
Wcbcr ct al., P.MA.S. (US~lJ 83:8784-8788 (1986) which indicatcs binding
to both the sigma-l and sigma-2 sitcs. Bricfly, frozen wholc guinea-pig brains
(Biotrol, Indianapolis, IN) wcrc homogcnizcd in 10 volumcs (w/v) of icc-cold
320 mM sucrosc using a Brinkman polytJon. Thc homogcnate was ccntrifuged
at 1,000 x g for 20 minutcs at 4C. Thc supernatant was ccntrifuged at
20,000 x g for 20 minutes at 4C. The resulting pcllet was resuspended in 10
initial volumes of 50 mM Tris/HCI buffcr at pH 7.4 and centrifuged at 20,000
x g for 20 minutcs at 4C. The rcsulting pella was rcsuspcnded in 5 inidal
volumes ice-cold 50mM Tris/Hcl (pH .4), and thc final volumc was adjusted
to yield a protein concentration of 3 mg/ml. Aliquots of 2~ml werc stored
at -70C until used, with no dctectable loss of binding.
For pH]DTG binding assays, the frozen membrane suspensions were
thawed and diluted 1:3 in 50 mM Tris/HCI (pH 7.4). To 12 x 75 mm
polystyrene test tubes were added 0.8 ml of diluted membrane suspension, 0.1
ml of 13H]DTG (Dupont/NEN) to yield a final concentration of 1.4 nM, and
0.1 ml of unlabelled drugs or buffer. The protein concentration in the l-ml
final incubation volume was 800 ug/ml, corresponding to 32 mg of brain tissue
(original wet weight) and to a dssue concentration within the lincar range for
specific binding. Non-specific binding was defined as that remaining in the
presence of 10 uM haloperidol. Incubadons were terminated after 90 minutes
at room temperature by addition of 4 ml of ice-cold 50mM Tris/HCI (pH 7.4)
and rapid filtration of the membrane suspension through Whatman GF/B
glass-fiber filters under vacuum, using a 48-well cell harvester (Brandel). The
filters were washed 2 times with 4 ml of S0 mM TrislHCI (pH 7.4). Each
filter was suspcnded in 10 ml Cytoscint (ICI), and radioactivity was mcasured
` ~SIl~UlES~

WO 93/00313 - PCr/US92/05330
~ 2111957 ~
by liquid scindllation spcctrometry at a counting efficiency of approximately
50%. IC50 values were dctermined by non-linear regression analyis.
PCP rcceptor binding assays against 3H-MK-801 were conducted as
described by Kcana ct al., P~>c. Natl. Acad. Sa (USA) 86:5631-5635 (1989);
Keana a al., Lifc Sacnccs 43:965-973 (1988). For (+) 3H-MK-801 binding,
- 1 nM of radioligand was incubated with about 100 ug of thawed rat brain
memb~ane protein for 4 hr at room tempcrature. The assays wcre carried out
in 5 mM Tristacetate and were stopped by rapid filtration through Whatman
GFtB or Schleicher & Schuell no. 32 glass fiber filters (prcsoalccd in 0.05 %
polyethylcnamine). -;
Dopaminc Dl and D2 receptor binding assays werc performed as
described by Billard a al., Lfc Sa. 35:1885-1893 (1984) using l3HlSCH-
23390 for the Dl receptors and [3H]domperidone for the D2 receptors (Baudry ~ -
ct al., ~rch. Ph~rrnacol. 308:231-237 (1979). -
Rat striatal mcmbrancs were prepared from frozen dssue by Polt~on
homogenizadon in 25 volumes of ice cold Tris-EDTA buffer (50 mM Tris-
HCI, 1 mM EDTA, pH 7.4 at 4C). The homogenate was centrifuged at
48,000 ~t g for 10 min. at 4C, and the pellet was resuspended in 25 volumes
of the same buffer. This suspension was then incubated at 37C for 15 min.,
followed by recentrifugadon as before. The resuldng pellet was resuspended
in 267 volumes of assay buffer (50 mM Tris-HCI, 120 mM NaCI, 5 mM KCI,
2 mM CaCI2, 1 mM MgCI2, pH 7.4 at 37 C).
The binding assays were conducted with 100 uL of [3HlSCH-23390 or
I3H]domperidone (to give about 1 nM final), 100 uL of buffer or drug
solution, and 800 uL of membrane suspension (to give about 250 ug of striatal
membrane protein per assay). The tubes were incubated at 37C for 60 min.
The assays were stopped by rapid filtration over Schleicher & Schuell #32 or
Whatman GP/B glass fiber filters (presoaked in 0.5% polyethyleneimine for
I3H]domperidone binding), followed by two 3 mL washes of ice cold buffer
using a Brandel cell harvester. After vigorous shaking, the filter disks were
counted at 52% efficiency in 5 mL of Cytoscint (ICN).
The results of these binding assays appear in Table 4.
~SIIIU~E St~EEr

WO 93~00313 PCr/USg2~05330
21119
.
T~ble 4
# Compound Iso Sigma Sigma n Dl D2 PCP
mer ICSQ S.E.M. ICS0 (uM) ICS0
(M) (n) (M)
. _ .
¦ R- ¦ 2.87~ ¦ ¦ a)¦ ~c 43
~-N~ +~ 1.25~ w
1 3 1 ~3¦ R- ¦ 8.55~10' ¦ 1.25~ > 1~' ¦
._
R-I 6.85~ 7 2.50~ 2 ~10'
'~.:
15 [~2C~2t~3 ~ ~ 1.705xlO~ ~1.65~
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WQ. 93/00313 ` 2 1 1 1 9 5: 7 ~ ! ~
--67
16 N-~ IR ~1.22~101 ~1.65~ 2 ~ ~>1O5 1 ~
:'' '
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1~ ~~ R- 14-7~ 5-~55~ 2 ¦ 1~5
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21119~7";
-68-
~ 9.15~ ' 2.75xlO~' 2 r
12 R- 2.3Sx109 6.S3x1~1 4 ~10-'
L~ ~ 1 lLLJ
~;C ~+/ 1.22~ ' 2.50~ ' 2
~ +/-12-85~5-20~2~
~ _ _
15 1.445xlO~ 1.21xlO9 4 > 10 1.68 > 10-5
~ ) I ~
SUBSTITUTE SHEET --

W093/00313 ~ 2 1 1 1 9 5 7 I'CI/USg2/OS331~ ~
-69-
+/ ~ 1.83-10 2-6511~ ~ 2
7~ 1+~- 6.6~10~ 1.79110
~ +losllo~looo r~
~ 9 ~ +/- 1 1.493110~ 1 2.95110~ 4 1 (2)1 ~9t3425 1 ~5
5 L~`" +/ 5.17110~ 1.02~c10~3

WO 93/00313 - PCI'/US92/0533û
'2 ~ 70-
+~- 9.11~10~ 6.15~10'~ 2 >10'
¦ 22~ ~ ¦R ¦ 1.597110~ ¦ 4.64~10
2~ ~ ~ +/- 4.10~10 2.~
_ . .
~ +/ 6.91~1107 1.39~107 ~ _
! ~ ~ R- ~ 1.01 107 ~ 4.43 10~

WOg3/00313 - . rcr/us92/os33o
21119S7
-71-
5' 2.88~110'7 2.00~2 r~
5+ 3~ ~ 7
~1~'~0.00~2 ~ 5
_ l . .
~ R- 4.95~ S.00~
r~ R- 2101n 2.00~
2 T l=_

WO 93/00313 ~. P~/US92~0S330` .V
; . . ~
2111957 - -72-
; ~ 2.08~10~ :50zlO'~ 2
32 I.O9~ 2.67x109 2
1~{~ I I I 1 11
~ ) ~ 5.10 1s.60 10~ 1 2 ~
1~ 1+'' ~2.56 10~4.00 10 ~2TT~
5 ~-~3 +/ 2.59~10' 1.90~10~2
_ .

WO 93/00313 `; ' PCI~/US92/05330
73 21119~7 `
_ ;.j-,, , . -
5+ 6.85~ 1.50~'2
37 ~.75xl~9 1.45~ 9 2 > l~s `
I~C~ I I
_ _ . .:
38 4.30xl~9 2.10xl~9 2 > lo~5 .~
C~ I ~
39 1.20xlO9 2.00x10-' 2 ~ 10-5 ~ ~ `
1~' 1 I I 1` 1 1 ~
. ....
3.06xl~9 3.4x1~' 5 > 10 1.25 > 10
3.18xlO-9 3.0xlO-" 2' (2) :t.06
(3)
.. ._ .,. _
'The second set of numbers represent a second lot.
SUBSTITUTE SHEEl-

WO 93/003t3 PCI /US92/05330
.~ j ,, ~ , ...
2111~57 74
. .
41 H 4.58xlO~ 8.7xl~l S > 10 1.92 > 10
. ~5.59~10~ ~2.06~10~2'~(2) 1~
42 N S S.20xlO 2.00~10 2 > 10 ~:
~ I'+' I
~ 1(5~+) 12.D~10~ 2.l~1o~ l2 1 T7~
~ (+)16-9~1o~ 14''~'~ ~ 2
s L~ 1+ 59511r 1395"'~ I r"
SUBSTITUTE SHEET

WO 93/00313 2 1 1 1 9 ~ 7 ~ , :
-75~
46 ~ 0' 7.50x1~' 2 __ >1~'
~{)-OE~ l I
47 5.65xl04 1.02xlO~ 2 > 1~5
48 2.70xlO9 2.00x10~' 2 ->-105
_
49 1.038xlO~ 2.61x~' 4 > 10 5.77> 1~'
¦ ~N~ l I ~ ~ (2)
5 ~"A,_~ j~95~104~5~10"~2j

WO 93/00313. . . ~ I'Cr/US92/OS330 ~ ~ ~
2111gS7' :~' :
7~
.... _. _.` , "
Sl 4.23xlO~ 1.42xlo~ 4 2.99.158 > 10~' ` ` :
I ~ (3jO4 (t2jO28 1 1 ~

WO 93/00313 2 1 1 1 9 ~ 7 PCI/USg2/05330
77
Results
As can be seen in Table 4, the sigma receptor ligands of the present
invention exhibit very high binding with respect to the sigma receptors and
vcry low binding with respect to the PCP and DA receptors. Therefore, these
sigma receptor ligands can be used for the treatment of mental illness without
the extrapyramidal side effects of traditional neuroleptic agents caused by
binding to the DA receptor.
EXAMPLE 3 ~-HT,A BINDlNG ASSAYS
The sigma receptor ligands listed abovc (nos. 1-51) were further tested
for binding at the 5-HT", receptor using the method of Peroutka, S.J., J.
Ncurochcm. 47:529-540 (1986). The results appear in Table 5.

WO93/00313 `~, , F~r/US92/05330 ~
2111957 ` ` 78
- .
T~bk S
Co~ound 5-}rr,A F~io S-HSI~/o
No. i~ lO ~ D~K)
I ~ 115.~0 12.00~2) 4
S 2 90.30 28.83(3) 12
3 I776.33 579.30(3) .20
4 4052.50 372.50(2) 5.9
IS00.00 100.00~2) .88
6 3781.S0 34s8.so~2) 31
7 2475.00 9s.00y2) 40
8 43.65 1.85(2) .92
9 122.00 6.QCy2) 2
212.0~ 31.00~2) 22
11 104.30 16.70(2) 11
IS 12 131.S8 39.31(4) 56
13 288.00 62.00~2) 2
14 154.50 35.50(2) 5.4
30.70 3.43(3) 2
16 44.8 2.5(2) 2.4
17 87.80 12.20(2) 13
18 588.50 68.50(2) 54 ,
19 114.23 12.43(3) 7.6
108.05 10.95(2) 17
, ~,
21 195.50 14.50(2) 21 -
22 202.00 47.0ox2) 13
23 IOS.75 13.25(2) 25
24 955.50 33.50~2) 1.4
7S3,00 135.0~(2) 7.3
26 10000 (1) 3.5 ~ -
27 6514.00 874.oc~2) 200
.

WO 93/00313 2 1 1 1 3 ~ ~ P~r~US92/OS330
. ;
; 79
.
T~bk S -
Con~ouDd 5-Hrr~ ¦ R~io 5-HTI~/o
No. IC~ (nM) ¦ ~SEM(n) ¦
28 2442.S0 342.50(2) .05
29 15S15.005515.00~2) 3.1
54999.5044999.5~2) 2.6
31 19.30 4.20(2) .92
S 32 8.73 0.46(2) .80 -~
33 Sl.60 2.30(2) 2.6
34 6650.00 710.00~2) 2.6
10360.00360.00~2) 40
36 1626.67 378.17(3) 239
37 20.30 4.70(2) 2.6
38 107.75 27.25(2) 25
39 89.60 0.10(2) 75
2965.00 585.0C~2) 970
41 34.67 9.09(3) 7.6 -~
lS 42 S~2.50 134.50(2) 110
43 1112.33 162.85*3) S0 `
44 277.67 33.52(3) 40
S94.00 67.68(3) 100
~ 46 21.47 3.6C~3) 3
47 9.23 1.58(2) 1.6
48 6.30 0.74(2) 2.3
49 ~312.67 27.38(3) 30
S0 281.67 69.0~3) 94
SUBSrITUTE SHEE~

Wo 93/00313 . ~ Pcr/uss2/o533o
21119S7 -8~
EXAMPLE 4 FURTHER ~3HlDTG AND SHT-lA BINDING ASSAYS
Further sigma receptor binding assays against pHlDTG and 5HT-lA
binding assays wcre conduc ed according to the procedure outlined in the
previous e~amples. The results of these further studies are listed in Table 6.

WO 93/00313 - PCr/US92/05330
``) 81 2111957 -``
. .
Table 6
Sigma IC~, (nm)~ 5HT-IA ~nM)
# Compound Mean ¦ SEM(n)-- Mean ¦ SEM(n)
S2 1 1 11891.00 1 399.00(2) 1 ~
¦ N~\ 1~
, , ~ .
53 1 1 10901.50 1 1198.50(2) 1 ~
l N ~N~
54 1 I 11815.00 1 18i5.0~(2) 1 -
L N H N--P ~
ss 1 16393.67 14426;77(3) ~ ` .. ~
N ~N~
56 1 1 1190.S0 1 159.50(2) 1 ~
. . . .
¦ NH ~ ~CI
SUBSTITUTE SHEET

WO93/00313 ~ ?~ PCI~US92/0~330
211195~7 :- 82-
T~ble 6
.
Sigma ICso (nm) 5HT-IA (nM)
Compound
Mean SEM(n) Mean _ SEM~n)
57 6069.00 2S~.00(2) .
L N~N~ O~
~C 1 20S4.S0 1 14.50(2) 1 _
I ~ , I .~
59 1 12830.00 1470.00(2) 1 - ~
.. ..
l I S7S.S0 1 98.S0(2) 1 -
N H N ~ ~ ~ ~
61 1 1 14850.00 14850.00(2) 1 -
N~
SUBSrlTUTE SHEET

WO 93/00313 rC~r/US92/05330
83 21119~7 _t` ,`
. ,
Tab~ 6
_ Sigma lC~ (om) ¦ 5HT-IA (nM)
# CoDnpoundMean I SEM(nl I Mean 1~ SEM(n)
_ 11625.00 1 1625.oC~2) ~1 -
l N~
63 1 - I763.33 1 352.86~3) 1 - ~
... _. . .
I
6~
~ `' ~
'.
:~'`''`'
1 1 72
. . .
~ ~ ~ N H~
l 1 45-10 1 6.85(3) T 272.00 T 44.00~2)
L~ NH~
- ~JRSmu~ SHEEI'

WO 93/00313 P(~r/US92/05330
211195~ `^`
T~bk 6
_ Con~ound Sigma IC~ (DID) SHT-lA (nM~
Mean _I SEM(n) Mean SEM(n~
67 -59.60 1 1.12(3) 19.35 4.95(2j- ~
~X~NN~
.
68S(+) 3.25 0.85(4) -~ 1320.00 158.46(3)
L~
_ ,-",.~
~N~
701 1 116.20 1 62.8o~2) 1 3885.75 I 1466.82(4)
~ N ~
711 1 5.68 1 2.19(2) 1 225.33 1 57.50(3)
Cf ~IN~J ~

WO93~00313 PCI/US92/05330
2 ~ `7 . . ; .~ . .
- 85 -
_
Sigma IC," (nm) ¦ SHT-IA (nM)
~ CompoundMean I SEM(n) I Mw~ I SEM(n)
72 7.23 ~ 1.92(2) ~ 11.30 3.25(3)
_ :.
~ N H
73 1 1 6.98 1 2.16(2) 1 5S.70 1 0.50(2)
. . . :~
_ ~,
74 81.87 21.83(3) ~
(~ I
C~~
75 1 1~3.57 11.67(3) 1255.00 1(1)
~N~
76 1 1 2.65 1 0.63(2) 1 119.0~ )
~ ~N~ l
~ ~ I
0~ UTE S~

W O 93/003t3 P~r/US92/05330~
21119S7, :
86 -
T~bk 6 . .
SigmaIC~ (Dm ~ _ 5HT-lA (nM) ~ ~ :
# CompoundMean SE M(nl I Mean I SEM(n)
77 2.07 0.50(3) 1 7S9.00 1(~) ~
.~'
. C~ J~ ' ~ ~
78 1 13.01 10.23(2) 198-40 1(1)
C l ~N~N~
79.. L. . 1 2~5 l 1.l4(3) l l73.00 . 1 (1, ~ .
~N~,~
11 130.10 1 18.16~3) 1 -
. . . . '" . ''
~ N~
. l l
81 1 1 0.88 1 0.18(9) 1 43.90 1(1) ~ -
O
~CN--~J

WO 93/00313 Pcr/uS92/o5330
2 1 1 1 9 S 7
T~bb 6
Sigma ] C~O (nm)
# Compound Mean SEM(n) Mean SEM(n) ` -
82 0.96 0.21(9) 136.50 (1)
_ ~
-"
. ~ .,
831 17.o8 -r93(2, 177-70 1(~) ~
N11~
84 1 ~ 16.43~ ~ 1050(2) 1168.00 1(1)
~ N ~
85 ~ ~
~G~N H~
. ~
I
. . .
L~
.

WO`93iO0313 PCI~/US92/05330
2111~57 `` 88- ` ~;
~,:
T~bb 6 ~ ~
Sigma IC,o (nm) 5HT-IA (nM) ~ ;
# Compound :, '
Mcan SEM(n) Mcan SEM(n) ; ~. ,~ ,.
87 21.83 2.86(3) 67.40 (1) ~ ~ ~
Cf `IH~J~
~ ~` '
~N H ~
. .~ ..,
89 2.74 0.40(4) 106.00 7.00(2)
.. . , .
I 1 3.95 1 O.S3(4) 1 3208.00 I 14800(2)
., . . . .
~ ~N ~
1 4.07 1 0.52(4) 1732.50 1 111.50(2)
I~_~IN HJ~
~g~ .

WO 93/00313 P(~/USg2/05330
;` 2111957
- 89- ~ '
.
Tabb 6
..
Sigma IC,O (nm) 5HT-lA (nM)
I~ Compound Mean ¦ SEM(n) Mean ¦ SEM(n)
92 ~ 2.49 0.28(4) 26.30 1.10(2)
~ ~NHJ~ ¦ ~
93 11 1.40 1O.OS(4) 1596.so 12.S0(2)
[~--N~
g4 11 4.02 1 0.27(4) I S549.S0 1 ll9.S0(2)
~ NI~
~55 1 ~
.
~N/~.~
. ~ 0~0
;~T
¦ ~ ~N-- ¦ ~
~ =~ ~ ~

WO g3~00313 ` PCr/US92/05330 - ~
.
, . .. ...
Table 6 -
__ .
Sigma IC,0 (nm) 5HT-IA (nM)
# _Mean ¦ SEM(n) Mcan ¦ SEM~n) -,
97 2Q33~ 1 4.73(3) ` ~
'
";~
. ~o ` ' ~ ` ' .,.................... ~:~
98 1 16.18 11.12(4) 1-2.23--T.84(2) ~;
I
,' ... . . . ~:
1~ '''' ' '
~ .;~
100 25.65 0.75(2)
_
H~
I a~ I ~
. .
101 15.70 1.20(2) ~
. .
a ~

WO 93/00313 ~ ~ PCr/US92/05330
r ~ 2 1 1 i 9 5 7s
T~bb 6
Sigma ICso (nm) 5HT-IA (nM)
# CompoundMan SEM(n~
02 6693 .S0 1423 .S0(2) _
I , ~-"'3
~~ '' C~ .~ .,",,
~03 1 - I 7S.20 1 36.80(2) 1 -
113 N~N~9
. - . . .
104 1 176.15 1 17.05(2) 1 ~
~ C~ N ~N~9
105 1 19.S0 1 3.38(3) 14956-so 1565.~0(2)
~t 3--N~N~ ~ ~
106 1 149-75 18.6s(2) 1 - ;
. - - - . .
L~, ~ ¦ ;
'.
~SmUlESH~R '

2 1 1 1 9 5 7 PCr/US~2/~5330`
: ::
T~bk 6 ~::
Sigma IC,D (nm) SHT-IA (nM) ::
# CompoundMean SEM(nl Mean I SEM¢n) ~ ~::
_ . -
107 lO.OûO.OO 0.00(2) _
. ~N I~H
108 1 137.85 10.65(2) 1 - -j. -
, . ... ~ ,
(X! H~ `
109 1 1_ ~,',
. ..
¦ ~N H ~
~N Hf =
111 1 12.73 10.s8(3) 192.20 122.10(2)
. . . . - .
~NrJ~ ¦ ~
, .. __ _. ~ ,
SU8S~llUrE SHEEr

WO 93/Q4313 2 1 1 1 9 ~ 7 PC~r/US92/05330
~: ~ 93
..
_
# I Compound I gma IC~(nm) T SHT-IA (nM)
I Mean I SEM(D) I Mean I SEM(n)
.
_
l 112 - I2.6S L 4l~3~ ~ 1 8243.00 r8s.oc~2) ~
- I
113 1 ~ S(+) 1 2.22 - I 0.32(3) 1 2148.001 105.00(2) ~ ~
. ~ ? . ~
I
Q/~N ~ -
. .
4 - - S(+) 6.71 -I 1.07(3) 1 3400024,ooCX2)
l ,
115 1 s(~) l 3.04 1 0.42(3) 1 2000o1 10CCK~2) ``
,.``:'
i
116 S(+) 10.13 8.28(2)
I~
1~ ~- I
SUBSrllUlE S~EEl'

WO 93/00313 ? ` ` ~ PCI'/US92/05330 ~ :
` . . " ~ .
2111957
Tabk 6
Sigma ] C~ (mn) SHT-I A (nM~
t CompoundMean SEM(n) MeanSEM(n)
117 2.11 0.14(3) 781.50285.50(2)
..
C~ CIN~ ~ ~
. ~ -~
118 ~ 2.14 0.21(3) 1967.~0394.0~2)
I c~
119 1 I 21.40 ` I 4.80~2) 1 - ~
. ~I . . . ,
_
120 64.70 2.40~2)
:~
~_ ..
¦ ~ N N~ N~ ¦ ~
'

WO 93/00313 - rCr/US92/05330
-` ` 2111957
ss ~
Table 6
SiglDa IC50 (Dm) T 5HT-lA (DMj
COmPOI~nd Man I SEM(D) I MeaD I SEM(n)
125 38.83 1 9.0S(2) ` I --
-126~ 219.33 ~17.45(3) ~ -
=~ .... ... .
~fH2 ¦
27 IO.S7 1 1.28(3) _
r-- NU ~ ~
_ '`' ~ ~ .
128 2.87 0.~2(3) __ ` `
_ . ,','.,.'.'
[~
_
~291 2.29 1.37(3) __
~ ``~
su~smu ES~EEr

WO 93iO0313 " P~r/US92/OS330
,. ,.~,
2111957 ` 96
.
T~bk 6
_
Sigma IC~ (nm) SErr-lA (nM)
# CompoundMcan ¦ SEM(n~ Me~n ¦ SEM(n)
130 ~ 4.23 ~ ~.14(3) ~ _
L ~N~
~31 1 1 46.90 ~ 1S.4S(3) 1 ~ _
N ~
133 1 S(+) 1 6.44 I 1.77(3) 1 - ~ `
. . .
I~
134 1 S(+) 1 198.7~ 1 74.48(3) 1 - ~
~--L~NJ ~ ~
. L ~ I
l35 l 1 13.50 1 4.37(3) 1 -
~N~3 ~
SUBSTITUTE SHEET

WO93~00313 2 1 1 1 ~ 5 7
- 97 - .
. ,
Tabk 6 ,
Sigma IC50 (nm) 5HT-IA (nM)
t Compound Mcan r SEM(n)
.=
136 1.78 1.32(3)
L~"`'`'o ~ I
1371 11.11~ .~,
~--~N~
138 1 - 1 2.67 1 0.37(3) 1 _ ~~ .
140 1 1 69
1441 14.39 I0.95(3)
1 h~ 3
:~'`,'''.'
i ' '
`'''
SUBSr~TUTE SHEEr ` - `

WO 93/00313 ~ r/US92/05330 ~
2111957 98-
~ _
T~ble C
~ .
Sigma IC~0 (mn) . SHT-lA (nM)
Compound
Mean SEM(n! Mean SEM(n)
1.63 0.39(3) ~ - ~
.
~C 11 3
_
146 ~ 2-38 Q27(3)
O^iJ~ ~
- ` ` ~t~3 ~:
147 1 - - - 1 117.3- I 63.05(3) 1 `~ -
.
Cl~N~
148 1 1 6.43 1 0.85(3) 1 -
r~ ~ ~
~49 1 T 21.48 1 2.24(4) 1 -
L
; .
SUBSTITUTE SHEET

WO 93/003t3 ~ - 2 1 ~ 1 9 5 7 PCI/US92/05330
t~ .- -
J
.
T~ble 6
_ Sigma IC,O (nm) SHT-lA (nM)
# CompoundMcan ¦ SEM(n~ Mcan ¦ SEM(n)
50 ~ _
~N~
C`r'--N~
I . , ~ I
152 1.76 1 0.23(3) - _
_
~--N~
: .~
53 2.210.39(3) _ :-
154 1 1 39551 711(3) 1 ~
. . , .
~ i ~ ~
0~rE SHEr

WO 93/00313 : - . PCI/IJS92/05330~
2111957
Tnble 6 . ` :
~: :
Sigma C50 (nm) 5HT-lA (nM)
# Compound Mean SEM(n) Mean i SEM(n)
155 ~ 1866 113(3)
_
I ~ ' ;
:-
IC~Q~ .' ~
=l ~
' ~
~ ~ 1~/(;~
C 1 {~J~
SUBSTITUTE SHEET

WO-93/00313 ~ PCr~US92/OS330
~ 2111957`; `
- 101 - ` `, `
T~bk 6
Sigma ICso (nm) 5HT-lA ~nM)
# Compouod _
_ ~ Mean SEM(n) Man SEM(n)
161 10.87 ~ 1.70(3) _
¦ C~ 3{ ~ ~
\~1
I ,)
~. .. .. , . ~,. ................... . . .~.. .
_
' .
\o3~ ~
7 ~."'~'.
t~ ~
~ `:.~
, ~ ,
163 1 1 1.74 1 0.06(3) 1 - ~ ::
, ~:-
. . ~
'-'`~`'
' -

WO 93/00313 ~ ~ PCr/VS92/05330
21119~ 7
T~bk 6
Sigma IC~o (nm) 5HT-IA (nM)
# Compound Mean I SEM(n) Mean I SEM(n) -
1.27 1 0.o5(2)
O~--~N :~
CU3
~ 1 ~.o3 l o.ola)
L~~
167 1 1 1.96 1 0.52(3) 1 ~ ~ -
C 1~ '~~ N~ ~
169 22.80 1 2.30(2) ; -
~~
~mnE~EEr

WO 93~00313 2 1 1 1 9 5 7.` ` PCr/US92/05330
- 103-
Table 6
, siglDa IC50 (Dm) ¦ 5HT-lA (nM)
# Compound
Mcan SEM~n) Mean SEM(n)
4.18 0.56(2) - _
o
1"~
_
.
171 l 1.19 0.24(2) _ : ~
~J N~ ~
172 1 1 7.46 1 1.03(2) 1 ~
~ I ~NH~
_ _
173 17.20 4.60(2) _ :::_ . ~
~ N H~

~ 1 1 1 9 ~ 7 ~ PCI/US92/1~5330
- 104- i
T~bk ~
_ Sigma IC,o (nm) 5HT-lA (nM)
# Compound
Mean_ ` SEM(n) Mean SEM(n)
174 ~ 1-10 ~0.35(3) ~ _ .
~5-
175 1 142.901 I.64(3) 1 ~ ~ ~
~ `."'`'
F
177 1 1 7.371 1.57(2)
F~N
. . , .
. 1î8 1 1 0.8g6 10.077(2)
~N~

WO 93/00313 PCI/US92/05330
~ ! ` 2111957
- 105 - . . ,
.
Table 6
Sigma ICSD (nm) 5HT-IA (nM)
J~ Compou~d ....
Mean SEM(n) Mean SEM(n)
~79 2.82 0.02(2) l _ ~
....
L~c~
. . .
180 2.24 0.62(2) _ - ~
cl4 C3 ~ 1 ~
=
.,,.. ,~ .,
L~ ~~N~F
182 1 1 4.68 1 0.14(2) 1 -
,~N~C
SUBSI ITUTE SHEET

21119 S 7 . PCT/US92/05330 ~
- 106^
. . .
T~ble 6
Sigma lC5" (nm) 5HT-lA (nM)
#Compound _
Mean SEM(n) Mean SEM(n) ~:
83 ~ 1.97 0.05(3) ~ ;
~ { 3 r - ~ U~ ~
~
184 1 - I 1.98 I0.14C2) 1 ~
~ ~
.,
I cl~36~Cl I ~
c! ` :
185 1 _ I 1736 1 732(2) I - - -
I ~;"o N~-HCI ~
186 1 1 656 1 165(2) 1 -
~ ~o/G

WO93/00313~ PCI/US92/05330
``-"` 2111~7 ~ ~
- 107-
Table 6 ` ' . '''
. .. ,~ .
Sigma lC50 (nm) ` SHT-IA (nM) :: '
# Compou~d ~ ,
Mean SEM~n~ Mean ~ SEM(n) .
187 ~ 50.6 11.7(2)
.
~ ';~ ~'
I ~ ~o
~ ., O ~ ' ~ '
. ~ T ~ ~ ~
~ . .. ~ -. .~ .. - ~ . .~, '~
. ~ _D ~ CU2CH3 ,
\ / , ~ 1
~ ~ tOOCH2CH2-N ~ .
' '' `
'.~'
~ .. `
.
1.0~ 0.07(2) _ ':
I ~ ~o
_
191 8.14 - (1)

WO 93/00313 - ; ~ Pcr/us92/o533o
-108-
2111~57
Exampk 5 Stn~chlre-Ac~Rcla~onslupoftheSigmaRccep~orLigands
The binding data reproduced in Tables ~6 allows the idendfication of
groups of compounds having high binding and selecdvity for the sigma
receptors. For example, it has been determined that the a-methyl gtoup on
- N-(3-phenylpr~pyl)is~ptopylamine (Ki = 22 nM) is not requited for high
binding to the sigma teceptor. The corresponding des-methyl compound N-(3-
phenylpropyl)-2-phcnethylamine binds with comparable affinity (Ki = 19 nM).
This des-methyl compound posscsses two carbon atoms between the phenyl
ring and the terminal amine and, on thc other side of the molecule, possesses
three carbon atoms between the amine and the second phenyl ring (see Table
7; x = 2, y = 3). A systematic comparison of phenylalkylamine derivatives
with varrying x and y values is shown in Table 7.
As shown in Table 7, the increase of x from 2 to 3 resulted in the
retention of affinity. Interesdngly, the total carbon chain length does not
appear to be critical for high` binding to the sigma teceptor. The highest
affinity agents are those where either x or y = 5. Thus, a phenylpentylamine
is optimal while ;he length of the chain on the other side of the molecule
appears to be inconsequential.
Since a carbon length of five atoms is optimal for high binding, and if
the substituents on the other side of the molecule are relatively less important,
then the second phenyl ring may not bc important. Therefore, N-methyl-N-
propyl-5-phenylpentylamine, a des-phenyl analog, was prepared and found to
bind with high affinity (Ki = 2.2 nM).
Where x and y = 3, it has also been found that replacement of one of
the phenyl rings with a cyclohexyl ring (Ki = 2.5 nM) resulted in a nearly
six-fold inctease in affinity. Furthermore, the cyclohexyl analog N-benzyl-(5-
cyclohexyl)pentylamine, whete the cyclohexyl group is sepatated from the
amine by five carbon atoms, also binds with high affinity (Ki = 1.3 nM).
Takcn together, these data suggest that (a) phcnylpentyl-amines bind
with high affinity to the sigma teceptot, ~b) that the nature of the amine
substitucnt is telativcly unimportant, and (c) that the phenyl ring of the
~mnEsHEr ;

wo 93/003t3 Pcr/US92/o533o
~ 2111957 ~:
phenylpentylamines may bc replaced by a cyclohc~yl ring with retention (and
an increase) of affinity.
;,.' ~:
Tabk 7
Phenyl-(CH~IH-(CH2)~-Phcnyl -
S _ ~ Y Ki (~1)
_ 5 2.! i .
7 - ` 3.6 `
.
0 ¦ 2 ¦ 4 ¦ 5 5
3 ~ 3 14 :
3 S 72-6 `~
~ 4 67 -`~
1 5 1 2 1 2-
* = des-methyl N-(3-phenylpropyl)isopropyl-
phenylamine
With regard to sigma selectivity over 5-HT,A, the unsubstituted phenyl
derivative N-(3-phenylpropyl)-1-isopropylamine (cmp. no. 1) e~hibits only a
~fold selectivity for sigma receptors. Aromatic subsdtution enhances affinity
for sigma receptors whereas S-HT,A affinity remains relatively constant.
Consequently, these aromatic subsdtuted derivadves bind with a relatively low,
but constant selectivity. Ne~ct, the cffect of terminal amine modification was
cxamined where the aromatic portion was held constant as a phenyl group.

WO 93~00313 ` Pcr/uss2/o533o
~. ~
2111957
Replacement of the benzylic methylene group of cmp. #l by an oxygen atom,
carbonyl group, or ~hybridizcd carbon atom (cmps. 8, 9 and 25) gave little
cffect. Removal of the ~-mcthyl group of cmp. #l (R(-)) scems to enhancc
5-HT,~ affinity. The opdcal isomers of cmp. #I bind at sigma receptors with
comparable affinity; however, tne S(+) isomer binds at 5-HT,A recsptors with
only one-tcnth thc affinity of its andpode rcsuldng in a 48-fold selccdvity.
Similar results were obtained with the isomcrs of N-(2-
cthylphcnyl)isopropylaminc (cmp. #7). N-Monomcthyladon (c.g. cmps. 45
and 69) also scems to cnhance sigma affinity and selectivity. To further
substandate this hnding, N-methyl-N-(3-propylphcnyl~1-(4-n-propylphenyl)-
isopropylamine was prepared and found to have thc highest and most selective
affinity for the sigma receptor.
EX~PLE 6 FurthcrStn~ch~ Ac~Sh~esof5-Pcn~ cD~nva~cs
With N-subsdtuted 5-phenylpentylamines, the length of alkyl chain that
ssparates the amins from its aromatic (phenyl-B) substituent has little influence
on affinity (e.g., compare 76, 77, 89, and 111; Ki = 2.~2.7 nM). It seems
unlikely that the phenylethylamines and phenylpentyl amines bind in exactly
the same manner at the sigma recsptors due to the difference in chain length.
In order to account for the binding of these compounds, the phenylethylamines
and the phenylpsntylamines may utilize different aromatic binding sitss. Thess
results prompted a further investigation of 5-phenylpentylamine derivatives as
sigma ligands.

WO 9i/00313 ` PCI`/US92/05330 '~:
, .; 211.1gS7 ~ ~:
6~CU2)5~j--(CNz)n~3
76 n = 1
77 n _ 2 ~`
89 n = 3 .
111 n = 4
,
Gkc~: ` ' '
~ Thc compounds in Table 10 were synthesizèd by one of thc methods
described (A-H). Most of the cornpout~s were ptq~d in two threc steps
using either acyladon and reduction of the intermcdiatc amide or direct
alkylation procedures. The amides werc prepared either from tne acyl halide
and an arnine or directly using ethyl chloroformuc, an appropriate acid and
an amine. Subsequent reduction by lithium aluminum hydride afforded the
target amines. Following this procedure, the benzyl protected analog of
compound 135 was obtained and subsequent hydrogenolysis produced the
desired compound Compounds 136 and 152 were obtained by methylating the
corresponding secondary amines using Eschweiler-Clark reductive alkylation
procodure. Compounds 173 and 172 were prepared by O~emethylation of
144 and 145 respectively, using concentrated hydrobromic acid solution.
Other target compounds prepared either by direct alkylation (method C) or by
reductive alkylation (method E), using suitable aldehydes and appropriate
amines.

WO 93/00313 PCr/USg2/05330
. . ; ~
2111957 -112-
Expenment~l:
Synthesis: Proton magnetic resonance spectra were obtained on lEOL
~:X90Q or QE 300 (300 MHz) spectrometers with tetramethylsilane as internal
standard. All spçctra are consistent with the assigned structurçs. Melting
S points were determined on a Thomas Hoover apparatus and are uncorrectçd.
Elemental analysçs werç performed by Atlandc Microlab and determined
values are within 0.4% of calculated values.
Mcthod A:
N-Cyclohexylmethyl-S-cyclohexylpeDtylamineHydro~loride(lSI).
A solution of cthyl chloroformate (1.8g, 8.2 mmol) in methylene chloride (25
mL) was added in a dropwise manner to a stirrçd ice cooled solution of
cyclohe~anepentanoic acid (3g, 8.1 mmol) and Et3N (1.7g, 8.1 mmol) in dry
methylene chloride (50 ml) under N2, over 10 min. Stirring was continued for
30 min. and cyclohexylmethylamine (1.8g, 8.1 mmol) in methylene chloride
(25 ml) was added dropwise over 5 mins. Sdrring was allowed to continue
for an additional 3 h after which the reaction mi~cture was washed water (50
mL) and dried (MgS04). Solvent was removed in vacuo to afford an oil which
was crystallized from MeOH-H20 (4.1g, 91~); mp 69-72C. A solution of
the amide (3.8g, 14 mmol) in THP (50mL) was added dropwise to a
suspension of LiAlH4 (2.6g, 5 eq) in THF (100 mL). The reaction mixture
was heated under reflux in a stream of N2 for 20 h. Excess LiAlH~ was
decomposed by the ge.ntle addition of H20 and 10% NaOH soludon. Solid
matter wæ removed by filtration and solvent was removed in vacuo to obtain
an oily residue. The residue was taken up in Et2O, dried (MgS04) and solvent
was removed under reduced pressure to afford an oil (3.0 g, 80%). The
hydrochloride salt, obtained by the addition saturated solution of ethereal HCI
to an ethereal solution of 151 (free base), was recrystallized MeOH/EtOAc;
mp 223-224~C (see Table 8).
SUBSrlTUTE SHEET

WO93/00313 2 1 1 1 9 5 7 Pcr/US92/o~33o
-1 13-
Method B:
N-Methyl-N-hexyl-2-phenylethylamiDe Hydrogen Oxabte (130). A
solution of hexanoyl chloride (Ig, 7.4 mmol) in THF (40 mL) was added in
a dropwise manner to a stirred solution of N-methyl-2-phenylethylamine (Ig,
" 5 7.4 mmol) and Et3N (2.3 g, 20 mmol) in THF (100 mL) cooled to 0C. T~le
reaction mixture was allowcd to stir overnight (20 h) after which the
triethylamine salt was removed by filtration and washed with THF (2 ~ 20
mL). The combined filtrate and washings were evaporated under reducod
pressure and the rcsidue taken up in CHCl3 (30 mL). The chloroform solution
was washed with H20 (30 mL) and dried (Na2SO4). Solvent was removcd in
vacuo to obtain an oil which was shown by IR (C=O, 1644cm-') to be an
amide (1.5g, 87%). A soludon of thc amidc (0.5g, 2.1 mmol) in dry THP (60
mL) was added dropwise to a suspension of LiAlH4 (0.41g, 11 mmol) in
THF(40 mL) under a stream of N2. The mi~cture was sdrrcd overnight, cooled
to 0C and thc reaction mi~ture was qucnched by cautious addition of water ~1
and 15% NaOH solution. Solids were rcmoved by filtration. The filtrate was
evaporated to dryness under reduccd pressure and the residue ~vas taken up in
Et2O (50 mL and dried (MgSO4). Solvcnt was removed under reduced
pressure to obtain an oil (350 mg, 75%). The oil was converted to the oxalate
salt (white crystals) and recrystallized from MeOH/Et2O solution; mp 139-
140C (see Table 8).
~ethod C:
N-Methyl-N-propylhexylam~e Hydrogen Oxalate (131). A stirred
mixture of N-methylpropylamine (1.2g, 13.7 mmol), l-bromohe%ane (3.4g,
20.5 mmol) and potassium carbonate (3.8g, 27 mmol) in 1,2-dimethoxyethane
(I~ME) (8 mL) was heated under reflux for 24 h and allowed to cool to room
temperature. The solid material was removed by filtration and washed several
times with CHCl3. The combined flltrates were evaporated to dryness under
reduced pressure and the residue partitioned between Et2O (30 mL) and 10%
NaOH solution (20 mL). The ethereal fraction was washed with H,0 (10 mL)
... . . .. , .. . , . .. , ... . . . .... ~ ... .. . .... . ..... . .... . . .

Wo 93/00313 , rcr/us92/o533o
21119S ~ -114-
and dried (Na2SO4). A saturated soludon of oxalic acid in anhydrous Et2O was
added to obtain a white solid which was rccrystallized from iPrOHlEt2O (0.4g,
12%); mp 101-102C (see Tablc 8).
Mcthod D:
N-Methyl-N-cyclohexylmethyl-5-cyclohexylpentyl~mine
Hydro~loride (152). A mixture of 151 ICNS#.~I (0.5g, 1.9 mmol), formic
acid (l.lg, 23 mmol) and formaldchyde soludon (37%) (1.85g, 23 mmol) was
hcated at about 100C for 22 h and allowed to cool to room tcmperature- A
3N HCI soludon (10 mL) was added and thc solution extracted with Et20 (3
x 25 mL). The cthcreal soludon, which containcd thc acpecled product, was
washed with 10% NaOH (30 mL), then water (10 mL) and dried (MgSO4).
A saturated ethcreal HCI soludon was added, solvcnt removed in vacuo, and
the residue recrystallized from MeOH-Et~Ac (370mg, 61 %); mp 162-163C
(see Table 8).
MetJ~od E: ;
N-(3-Cyclohexylpropyl)-3-phenylpropyb~m~e Hydrochloride (92).
A solution of 3-phenyl propylamine (0.65 g, 5 mmol) and 3- -
cyclohexylpropionaldehyde (0.75 g, 5.4 mmol) in MeOH (40 mL) was
hydrogenated in a Parr bottle containing 10% Pd/C (0.3 g) until sufficicnt H2
20 , was taken up (40 min). The catalyst was removed by filtration; the filtratewas concentrated to about 10 mL under reduced pressure and added to lN
HCI solution (20 mL). The precipitate was collected by filtration and washed
thoroughly with anhydrous Et20 (3 x 10 mL). Recrystallization from 2-
butanone afforded the desired compound as white shiny plates (0.75 g, 53%);
mp 203-205C (see Table 8).
Mcthod F:
N-12-(3-hydroxypheDyl)ethyq-5-pheDylpeDtylamineHydrobromide
(172). A mi~tture of 145 (free base) (0.19 g, 0.65 mmol) and hydrobromic

WO 93/00313 PCr/US92/05330
s 1~ 1 13 ~ 7
acid solution (48%) (0.22 mL, 1.3 mmol) was heated at reflux for 2 h and
solvent was removed in vacuo. The solid residue was recrystallized from
MeOH/anhydrous Et20 to afford the desired compound (100 mg, 42%); mp
151-lS3C (see Table 8).
S A~c~kod G:
N-Pheoyl-S-pbeDylpentylamiDe Hydrogen Ox~late (135). A mixture
of N^benzyl-N-phenyl-5-phenylpentylamine (0.89 g, 2.5 mmol) in EtOH (20
mL) and 10% Pd/C (0.1 g) was hydrogcnated at 50 psi for about 3 h. The
catalyst was removed by filtration and the filtratc was evaporated to dryncss
under reduced pressure. The residue was partitioned between 10% HCI
solution (20 mL) and Et20 (20 mL); tt e agueous portion was basified with
10% NaOH and e%tracted with Et2O (20 mL). The Et20 portion was dried ~ ~-
(MgSO~) and solvent was removed in vacuo to afford an oil (0.3 g, 49%). The
oxatate salt was prepared by the addition of a saturated solution of o~calic acid~ ~
and subsequently recrystallized from EtOAc; mp 133-134C (see Table 8). `
Med~od H: . ~
5-Cycltohexylpentylami~e Hydrogen Oxabte (126). A solution of ~`
cyclohexanepentanoic acid (2 g, 10.9 mmol) in SC~CI2 (8 mL) was heated on
a steam bath for 3 h. The SOCI2 was removed under vacuum. Chloroform (2
20 , x 10 mL) was added and reevaporated to give the crude acid chlonde as a
yellow liquid. A saturated solution of ammonia in dry THF (ammonia gas
bubbled through 10 mL of THP for 5 min), was slowly added to a solution of
the acid chloride in dry THF (50 mL) while cooling in an ice bath. The
reaction mixture was allowed to stir at room temperature for 3 h and was then
concentrated to half of its volume and poured onto water (100 mL). The solid
was removed by filtration, washed with water and dried (MgSO4).
Recrystaltization from aqueous MeOH gave 5-cyclohexylvaleramide (I.lg,
55%); mp 121-122C (repor~ed mp 122-123C) (Katsellson and Dubinin,
Compt. Rcnd. ~Icad. Sci. U.R.S.S. IN.5.]4:405 (!936); Charn. Abstr. 31:3449
... .. . . .

WO 93/00313 PCr/USg2/05330
, ,~ ~ . ....
-1 1~
21119~7
(1937)). A suspension of the amide (183 mg, 1 mmol) in anhydrous Et2O (9
mL) was slowly added to a sdrred suspension of LiAlH4 (114 mg, 3 mmol) in
Et2O (15 mL). After addition was complete, the mi~ture was heated at reflux
for 2 h and then allowed to stir overnight at room temperature. Thc reaction
mi~ture was cooled to 0C and excess LiAlH4 was decomposed by successive
addidon of water (2 mL), 2N NaOH (2 mL) and water (5 mL). After sdrring
vigorously for 20 min, the mi~ture was filtered and the inorganic residue was
washed with warm Et20 (3 ~ 8 mL). The combined Et20 soludon was drie~
over anhydrous K2CO3 and evaporatcd to dryness. The residue was distilled
under reduced pressure to yield a clear oil (99 mg, 59%); bp 30-36C (0.35
mm), Lit. bp 108-113C (15 nm) (Skinner, C.G., a a~., J. Am. C7~em. Soc.
~g:2844 (1957)). A solution of the free bæ in anhydrous Et2O was added to
a solution of o%alic acid (52 mg) in anhydrous Et2O (8 mL) with condnuous
shaking. The precipitated solid was rccrystallized from MeOH/anhydrous
Et2O; mp 164C (seeTablc 8).
Rad~oligand~ ng. The o binding assay was conducted using guinea
pig (Taconic) brain membranes and 13H]di~tolylguanidine (DTG) as
radioligand. Briefly, membranes (P2 microsomal fraction) were diluted 1:3
with 50 mM Tris HCI (pH 7.4) and 0.4 mL was combined with 50 ~L
~3H]DTG (1-2 nM final concentration~ and 50 ~L of competing drug or buffer.
After 90 min at room temperature, incubation was terminated by rapid
filtration under ~acuum through Whatman GP/B glass fiber filters using a
Brandel 48-well cell harvester. Pilters were washed three times with S mL of
cold Tris HCI buffer and each filter was suspended in 5 mL of Cytoscint (ICN
Biomedical). Radioactivity was measured by liquid scintillation spectrometry
at a coundng efficiency of 50%. Non-specific binding was measured in the
presence of 10 ~M haloperidol.
R~mlJ~ S~lEET

wo 93/00313 PcT/uss2/os33o
111957
; . . :
Micn~u~ical Da~
C~cula~/FDund
C ~ ` H N
152 70.56 7.61 3.92
70.43 7.59 3.93
136 71.66 8.11 3.63 -~
71.37` 8.08 3.59
~ ~.
44 71.94 8.45 4.20 ~-~
71.88~ 8;49, 4;19 -~
8 67.54 7.29 3.75 ` ~
67.47 7.33 3.69 --`
145 71.94 8.45 4.20 -
7r.87 ` ` ~8.49 4.21
72 62.02~ 7.12 3.81 ;~
62.017.22 3.81 `
-- .
46 71.188.48 4.15
71.238.46 4.17
68.907.06 4.23
68.527.22 4.23
2 65.998.80 4.53
65.828.75 4.51
~_ 65.998.80 4.53
65.928.79 4.57
31 58.2710.19 5.66
58.2010.17 5.66
93 73.0610.22 4.75
72.9510.23 4.74
~2 73.0610.22 4.73
72.9610.22 4.77
SUBSTITUTE SHEET

WO g3/00313 ` '`~ j P~/US92/05330 ;
.. ` . `~ -`.,
211195~ -118-
12658.10 9.76 5.23 `
58.18 9.77 5.22
2761.6~ 9.97 5.12
61.51 9.96 5.12
. .
12862.71 10.16 4.92
62.69 10.17 4.87
.~
~2563.94 8.19 5.~0
- 64 03 8 24 4 98
.-. ` : ~
~4 73.~6~ 10.22 4.73
73.12 10.27 4.78
2370.55 12.01 4.57
70.36 12.01 4.57
247~.21 12.11 4.37
71.27 12.04 4.33
SUBSJITUTE SHEET

W093/00313 ` 2 1 1 1 9 5 7 PCI/US92/053~0
-1 19-
~T ~
oo ~ ~ ~5' ~ ~ ~ ~ ~ ~ :~: ~ ~ X :~" :~ :~ ';~
1~1 ~1 ~ I J
I ~ ~13 ~
J ~1 _ __ _ -- ~
~c : .e c~ ~ ~ _~ ~ c~ ~ ~ _ _ ~ ~
.~1 ~E~ 3
~s~

WO 93/00313 ~ /US92/05330
21119S~ -120_
b $~1
~ I~e ~ ~ ~ ~ ~ ~ :~
.~ ~. æ ~ ~ ~
T ~ ~ :
1: ~ m m 1: ~: ~ i~
L~3~

WO 93~00313 ~ 2 1 1 1 9 ~ 7 Pcr/us9
- 121 -
Resultsand D~scuss~on : .
Binding data are shown in Table 9. N-Methylation of N-substituted
phenylethylamines typically doubles and aromatic substitution at the 3- and
4-position has essentially no effect on sigma receptor affinity. N-Methyladon
of 151 and 111 (i.e., 152 and 136, respecdvely) doubles affinity (Table 9).
Incorporadon of phenolic or metho~y groups at the 3- and 4-posidons (a~,
172, and ~ has little effect on affinity, whereas the 2-hydro%y derivative 8
binds with about 7-fold lower affinity than its unsubsdtuted parent 89 (Ki =
2.4 nM). E%cision of the N-alkyl chain separating the amine from phenyl-B.
to afford the anilinc derivadve 135 (Ki = 12 nM), rcduces affnity by only
~fold; this decrease in affinity may reflect a decrease in the basicity of the
amine.
The above rcsults (i.e., lack of influence of chain length and aromatic
substitudonon sigmaaffinity) suggcstthatthearomadc amine substitucntplays
only a small role in binding, and that it may be possible to replace the
phenyl-B ring with a non-aromadc group. Indeed, compound 122, which may
be vicwed either as either an N-methyl analog of 89 where the phenyl-B group
has bcen rcplaccd by methyl, or as an analog of 136 where the phenyl group
has been eliminatcd, binds with high affinity (Ki = 2.4 nM). Interestingly,
the phenyl-A ring can also be replæd by a mcthyl group (130; Ki = 3.8 nM)
with little reducdon in affinity. Rcplæment of both phenyl groups by methyl
(~; Ki = 45 nM) results in a significant reduction in affinity. Apparently,
either phenyl-A or phenyl-B can be replaced by a methyl group; however,
rcplacement of both results in decreased affinity.
Because both phenyl groups are uMeccssary for b.nding, we e~tamined
several additional compounds bcaring a single phenyl. Compound 93, the
phenyl-B reduced analog of 151, binds with twice the affinity (lCi = 1.2 nM)
of 151. Compound 92 (Ki = 2.4 nM), an analog of 93 where the position of
the amine has been shifted, also binds with high affinity.
lllUlE SHEEr

WO g3/00313 ~ Pcr/us92/os33
- 122-
2111957
~ ~CH2)3-1-- ~CH2)3 ~
-92 -
C~l~, ;
. . ''
.
Examination of thrcc simple S-(cyclohexyl)pentylamines, the primary
aminc 126 (Ki = 200 nM), the N-monomethylamine 127 (lCi 10 nM), and the
N,N~imethylamine 128 (Ki = 2.6 nM), revea!s that tertiary amines are most
favorable for binding. The affinity of the latter compound ~, was comparcd
Witil the aromadc analog 125 (Ki = 35 nM), revealing that roducdon rcsults
in about a 10-fold increasc in affinity. However, reducdon of the phenyl-A
ring of 151 (!~; Ki = 3.4 nM) results in essentially no change in affinity.
This may bc relatcd to the fact that 128 and 125 are tertiary amines whercas
94 is a secondary amine; nevertheless, it is apparent from thesc results that
both phenyl-A and phenyl-B can replaced with a cyclohexyl group. Thc final
two compounds cxamined, lSl and 152, possess two cyclohexyl shortened or
lengtheneid without adverse effect on sigma receptor aMnity (e.g., see
compounds 151, ~2. 111 and ~0. That is, affinity is independent of the
Icngth of the alkyl chain that separates the phenyl-B ring from thc amine. To
account for thcsc observations, the sigma receptors may possess at last two
distinct aromadc binding sites: one that utilizcs the phenyl-B ring of
phenylethylamincs, and one that utilizes the phenyl-A ring of the
phenylpentylamines. The phenyl-B ring of lSI, 89, 111 and 76 is unnecessa~y
for binding; it can be replaced by a small alkyl group (e.g. ~) or with a

W O n/00313 : 2111957 F1~r/US n/05330
- 123 -
cyclohexyl group (e.g. ~) with retention of affinity. Interestingly, the
phenyl-A ring can also be replaced with a methyl or cyclohexyl gr~up (e.g.,
130 and 2~. respecdvely) with little change in affinity. Had only one of the
phenyl groups been replaceable by methyl (or cyclohexyl) without loss of
affinity, this would have provided direct evidence for the t~,vo distinct sites on
sigma receptors. Nevertheless, in as much as compounds such as 151 and 152
bind ~,vith high affinity, it would appear that, independent of mode of binding,an aromadc moiety is not a requirement for high affinity.
~ .
mU~ S~EEr

WO g3/00313 PCr/US92/OS330
2111~7 - 124-
Table 9 Sigma receptor bhdiog data.*
X-~CH2)5-N(R)-(CH2).-Y
_ . ~
X R n _ Ki nM (SEM)
1 77 Phenyl H 1 Phenyl 2.0
- ¦~ Phcnyl H 2 Phcnyl 2.4
111 Phcnyl H 3 Phcnyl 2.7
_
76 Phcnyl H 4 Phenyl 2.5
¦ 137 Phcnyl Me 1 Phenyl 1.0(+0.4)
¦ 136 Phcnyl Me 3 Phenyl 1.6(:t 1.2)
¦ 144 Phenyl H 2 2~Me Phenyl 4.0(iO.9)
¦ 173 Phenyl H 2 2~H Phcnyl 15.6(i4.1)
145 Phenyl H 2 3~Mc Phcnyl 1.5(+0.4)
172 Phenyl H 2 3~H Phenyl 6.8(iO.9)
¦ 146 Phcnyl H 2 4~Me Phenyl 2.2(+0.3)
¦ 135 Phenyl ~ H O Phenyl 12.2(i4.0)
¦ 112 Phenyl Me 2 Methyl 2.4(+0.4)
¦ 130 Methyl Me 2 Phcnyl ~.8(iO.l)
131 Methyl Me 2 Methyl 45(+ 14)
l . . I
¦ 93 Phenyl H 1 Cyclohexyl 1.2(iO.0)
1 126 Cyclohexyl H O H 200(i7)
127 Cyclohexyl H O Me~yl lO(i 1) I
128 Cyclohexyl Me O Methyl 2.6( :t 0.7) ¦ -
125 Phenyl Me O Methyl 35(i8) ¦
94 Cyclohexyl H 1 Phenyl 3.4(iO.3)
151 Cyclohexyl H _ ~ Cyclohexyl 1.2(iO. l)
_ ~
152 Cyclohexyl Me _ Cyclohexyl 1.6(+0 2)
~ .
SUBSrlTUTE SHEET

WO 93/00313 PCr/US92/05330
`` 21119~7
- 1 25
Example 7 Discnmu~ on between the Si~ma-l and Si~ma-2 Binding
Si~es
Ma~e~ds
13H](+)pentazocine (35 Ci/mmol) was generously provided by Dr.
S Steven Huntof DuPont/NEN. I3H]DTG waspurchased from DuPont/NEN.
(+)Pentazocine was obtained from the NIDA Rcsearch Technology Branch,
Division of Research. Guinea pig whole membrane preparations (P2
microsomal fracdon` were obtained and used asdescribed by Weber, E. ~tal.,
Proc. I~atl. Acad. Sa. 83:878~8788 (1986). ~ ~
. .
Sigma-l bind;ngassay (I~(+)pentazocioe)
The sigma-l selective binding assay was performed using
13H](+)pentwcine as the radioligand (34 nM final concentration unless
othenvise specified) and appro%imately 100 ~g of guinea pig membrancs in a
final volume of 500 ~l of 50 mM TRIS-HCI, pH 8Ø Non-s~pecific binding
was determined in the presence of 10 f.M haloperidol. For the standard
equilibrium assay, the mixtures were incubated for 4-5 hours at 37C,
quenched with 4 ml of ice cold incubation buffer and rapidly filtered over
Whatman GF/B fiber filters, followed by three 4 ml rinses with additional ice
cold incubadon buffer. The radioactivity on the filters was determined by
scintillation spectrometry at an efficiency of about S0 % using Cytoscint (ICN)
scintillation fluid.
Sigma-2 binding assay
The sigma-2 selective binding assay was performed using about 2 nM
13H]DTG as the radioligand in the presence of 200 nM (+)pentwcine to
blork the sigma-l sites, with 400 ~g of guinea pig membranes in a total
volume of 0.5 ml of 50 mM TRIS-HCI, pH 7.4. Non-specific binding was
determined in the presence of 10 ~M haloperidol. For the standard
equilibrium assay, the mixtures were incubated for 30 min. at room
temperature, then filtered and the radioactivity determined as described above.

WO 93/00313 ~ ~ i Pcr/us92/os330
- 126-
Data ADalys2lsl 1 1 9 5 7
Equilibrium binding data were analyzed by least squares nonlinear
regression techniques as described by Fischer, ~.B. and Schonbrunn, A., .1.
~ol. C~an. 263:2808-2816 (1988). Two site binding curves were fit to an
equation describing the sum of two independent sites with Hill slopes of 1.
Affinity constants (K~) values were calculated from IC50 values using the
Cheng-Prussoff equation (Cheng, Y.-C. and Prusoff, W.H., Biochcm. Phann.
22:3099 3108 (1973)). The results are reported in Table 10 for DTG, several
lots of an N,N'-disubstituted guanidine, haloperidol and BMY-1480Q, as well
as for cerlain of the compounds of the invention. Por companson, Table 11
shows the sigma-l and sigma-2 binding data for a number of other known
compounds.
` SUBS~UTES~EEr

WO 93/003l3 `. ' ` 2 1 1 1 3 ~ 7PCI/US92/05330
~ -127-
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WO 93/00313 2 1 1 1 Pcr/usg2/os330
- 135 -
E:xompk 8 Struch~ Act~ Anatys~s with Rcgardto Sigma~
As shown in Table 12, compound 1 binds with an IC,0 value of 10.8
nM at sigma-l. Subsdtution on thc phenyl A ring has essentdally no effect on
binding.
~ J' ~3 '~
.
T~bk 12 ~ -
Cmp.#; K ~ ~ .
I : ~ R~-) . 10.1
43 H S(+)
3-Br ~: (+) 9.6
21 4-Br (+) 12.0
22 ~1 R(-) 17.7
.... ..
23 3-CF3 (_) 8.8
_
83 4~Et (i) 3.4
lS Rcplaccment of the phcnyl-A with l-naphthyl has no effect on binding.
(Compare compound no. 1 to compound no. 16 (Table 13)). However,
rcphcement of the l-naphthyl group with a 2-naphthyl group ~educes sigma-l
affinity about three fold. (Compare compound no. 16 to compound no. 17
(Table 13)). In addition, replacement of phenyl-B with l-naphthyl or 2-
naphthyl has little effect on binding. (Compare compound no. 1 to compound
nos. 11 and 12 (Table 13)).
SUBSTITUTE SHEET -` ~
`'`;"```

wo g3~00313 Pcr/Us92/os330
2 1 1 1 !~ ~ 7 136 - ~ ;
Table 13
Sigma-l
Cmp. _ IC~o (DM~
¦10.8
~ ?J~N~
5 ~ ~ 3~-0 ~ ~ ~
~ C~
' : :
Incrusing thc length of the N-phenyl-B alkyl chain of compound No.
1 from 3 ~ 4 methylene groups doubles affinity to the sigma-1 receptor. A
10 ' further incruse to 5 mcthylene groups substantially increases affinity.
(Compare compound no. 1 to compound nos. 10 and 45 (Table 14)). Removal
of the cr-methyl group has little effect on sigma-l binding. (Compare
compound no. 1 to compound no. 87 ~able 14)).
f ~j R
, ( C H ) j~
H
SUE~STITU~E SHEET

WO 93~00313 2 1 1 1 9 ~ 7 pcr/us92/os33o
- 137- `
Table 14
.
Cmp. # n Isomer IC50 (nM)
.
1 R = CH3 3 R(-) 10.8
_
10 R = CH3 4 (i)_ _ 4.?
44 R = CH3 S(+)
45 R = CH3 S(+) I .88
87 R = H 3 113
Holding the inethylene groups linking the phcnyl-B ring constant at
four and removing the a-methyl group does t affect substantially the affinity
to sigma-l. (Compare cmp. s. 71 and 10 (N-phcnyl-A; n=2), which have
binding affinities of 2.6 and 4.7 nM, respectivdy). Sh~ncning thë number of
mcthylene groups li dcing the phenyl-A substituent to one decreases affinity.
(Compare cmp. nos. 71 and 75. which have binding affinities of 2.6 and 9.6,
respcctively.) In cont ast, increasing the number of methylene groups linhng
the phenyl-A ring to five increases affnity. (Compare cmp. nos. 71 and 76,
which have binding affinities of 2.6 and 0.48 nM, respectively.)
Since five methylenes between the phenyl-A ring and the amine is
associated with high binding to sigma-l, a homologous series of related
analogs were examined (Table 15).
, ~Jl--~c~n~
: ....

WO 93/00313 ~;; Pcr/us92/os33o
- 138-
"111~7
Tabk 15
cmp. # n R IC50 (nM) ~
__ l l , .
76 4 H 048 -
111 3 H 0.28 ~ ;
89 2 H 0.17
77 1 H 0 32
.
137 I CH3 0.19
As is evident from Table 15, thc length of the N-phenyl^B chain has
. ;., . - . . :
littlc cffcct on binding to the sigma-l site. In addition, elimination of the N-.. . . . ~ .
phenyl-B ring has litde effect on sigma-l rcceptor binding. (Cmp. #112, N~
methyl-N-propyl-5-phenylpentyl mine, lC~"=0.29nM). However, anincrease
in ~e phcnyl-A chun leng~ results in a deae~se in affinity to sigma-i
(comparc cmp. nos. 90, N-benzy1-7~henylheptylamine, and cmp. 91, N-
phencthyl-7~henylheptylamine which havc binding affinities at sigma-l of 2.3
and 1.5 nM, rcspectivcly).
Reduction of the phenyl-A ring of cmp. . 77 (N-benzyl-5-
phcnylp ntylamine, IC50=0.32) has little cffect on sigma-l binding affinity
(cmp. #94, N-bcnzyl-5-cyclohcxylpentylamine, IC50=0.81).
Removal of the aromadc phenyl-B ring of the A-ring cyclohexyl
compounds is also well tolerated. However, the tertiary amines appear to
have enhanced affini~,r compared to the primary and secondary amines ~able
16).
SUBSTITUTE SHEET

WO 93/00313 2 1 1 ~ 9 j 7PCI~/US92/05330
. :
- 139-
, i." .
Tabk 16
Cmp. Sigma-l
# St~ucture IC~ M)
~ . ~
1~ IC'^`I~JI' I
1~ ~ l
. .. :
n . ~ J`~ . -
L ~ ~NH2 1~1 ~
~ .
ll e most selecdvc sigma-l binding compound is N,N~imethyl-5- ~
cyclohexylpentyhmine (cmp. # 128, sigma-2/sigma-1 selectivity of 6SO). -
10Othcr sigma-l selective ligands include N-methyl-5-cyclohexylpentylamine
(cmp. # 127, sigma-2/sigma-1 selecdvity of 51), 5-cyclohexylpentyl-amine --
(cmp. # 126, sigma-2/sigma-1 selecdvity of 13), N-me~yl-N-propyl-S-
phenylpentylamine (cmp. # 112, sigma-2/sigma-1 selectivity of 137), N- ;
benzyl-7-phenylheptylamine (cmp. # 90, sigma-2/sigma-1 selecdvity of 126), i
15N-(S-phenyl)pentylpipcridinc(cmp. # 124, sigma-2/sigma-1 selectivityof 100~, -
and N,N~imethyl-5-phenylpentylamine (cmp. # 125, sigma-2/sigma-1 ~`
selectivity of 96).

Wo 93/00313 Pcr/us92/os33o
2 1 1 1 9 S 7 ; !
- 140-
Ex~mpk 9 StrUCh~K-AC~ Y Analysis Wi~ Rcgar~l to Sigm~-2
Many alterations in structure do not improve the binding of the
compounds of the present invention to the sigma-2 site. Compound #1 binds
at the sigma-2 site with modest affinity (60 nM). Aromatic subsdtudon in the ~ -
- phenyl-A ring has little effect on binding at sigma-2 (Table 17).
X ~ "~)
... . . . . . ......... . .. .
_
Tabk 17
~ ~ lC50 (n,M?
_ .. ....
43 H S(;)
'~
3-Br (+) 26 ~ ~
:
21 4-Br (:~) 39
~ -
22 4-1 R(-) 76
23 3-CF3 (:~) 21 -
.,~
83 j 4-OEt (i) 34
However7 replacement of phenyl-A with a naphdlyl ring decreases -
affinity to sigma-2 several fold. (Compare cmp. #1, ICso= 60 with cmp. ,Y
16, N-(3-phenylpropyl)-1-(1-naphthyl)-2-isopropylamine, and #17, N-(3-
phenylprowl)-l-(2-naphd~yl)-2-isoprowlamine, which have binding affinities -
of 150 and 220 nM, respectively.) In addition, replacement of phenyl-B with
a naphthyl ring reduces affinity about 4 fold. (Compare cmp. #1, IC,0= 60
with cmp. # 11, N-(3-(1-naphthyl)propyl)-1-phenyl-2-isopropylamine, and #1,
N-(3-(2-naphthyl)propyl)-1-phenyl-2-isopropylamine, which have binding
affinitics of 280 and 260 nM, respectively.) Removal of the tx-methyl group
of cmp. # 1 has essentially no effect (IC5" of cmp. no. 87, N-(3-phenylprowl)-
8UBSTITUTE SHEET

WO 93/00313 2 1 1 1 9 5 7 `: I
- 141 -
2-phenethylamine, = 90 nM). Increasing the phenyl-B chain length from 3
to4 also has littleeffect (lC50of cmp. 71, N-(4-phenylbutyl)-2-phenethylamine
= 120 nM). Decreasing the phenyl-A alkyl chain length by one methylene
slightly decreases affinity (IC50 of cmp. # 75, N-(4-phenylbutyl)bcnzylamine,
= 160 nM).
However, it is possibk to improve binding affinity to sigma-2 by
keeping the phenyl-B chain at 4 methylenes and increasing thie phenyl-A chain
~o 5 methylenes to ~ive a 3-fold increase in affinity ~able 18). An alkyl
chain of n=3 appears to be opdmal. In addidon, N-methyladon triplcs
affinity.
C C H ~
',`. ''~
.,','.
Table 18
I cmp # I n ¦ R ¦ IC5~ (nM)
... ._ _
l 76 i I H j 48
lS l 111 3 i 1 9.8
t~ l 2 ¦ H ¦ 15 ¦
37 1 l CH3 l 12
Removal of the phenyl-B ring results in a reduction in sigma-2 affinity.
(Comparecmp. l l l, N-~3-phenylpropyl)-5-phenylpentylamine, withN-methyl-
N-propyl-5-phenylpentylamine, lCso=40 nM).
The most selective sigma-2 ligand of the present invention is N-phenyl-
N'-(3-(1-phthalimido)propyl)piperazine (cmp. #96)whichhasasigma-1/sigma-
2 ratio of 87. Other sigma-2 selecdve ligands include N-(~phthalimido)butyl-
N'-(o-methoxyphenyl)piperazine (cmp. #120; sigma-1/sigma-2 raitio of 7) and

WO 93/0031 3 : ~ Pcr/USg2/OS330 ~
, -
~1119~7 142-
N-(4-phthalimido)bu~ N'-phenylpiperazine (cmp. #97; sigma-11sigma-2ratio
of 10).
Having now fully described ~is invendon, it will be understood by
~ose of skill in ~e art that ~e same can bc practiced within a wide range of
equi~alelltcondidons, formuladons, structural variadons and otncr puuncters
without affecting the scopc of dlc invendon or any embodiment thereof.
., .
' ~MES~Er