2-PIPERAZINO ALKYLAMINO BENZOAZOLE DERIVATIVES: DOPAMINE RECEPTOR SUBTYPE SPECIFIC LIGANDS

DERIVES DE 2-PIPERAZINO -ALKYL- AMINOBENZOAZOLE: LIGANDS SPECIFIQUES DU SOUS-TYPE DU RECEPTEUR DE LA DOPAMINE

English Abstract

Disclosed are compounds of formula (I) or pharmaceutically acceptable salts
thereof, wherein: A is (un)substituted alkylene; R1 and R2 are the same or
different and represent hydrogen, halogen, alkyl, alkoxy, alkylthio, hydroxy,
(un)substituted amino, cyano, nitro, sulfonamide, trifluoromethyl or
trifluoromethoxy; R3, R4, R5, R6 and R8 are independently hydrogen or alkyl;
and X is sulfur, oxygen or NR7 where R8 is defined herein; m is an integer
chosen from 0, 1 or 2; and Ar is an aryl or heteroaryl group as further
defined herein, which compounds are useful for the treatment and/or prevention
of neuropsychological disorders including, but not limited to, schizophrenia,
mania, dementia, depression, anxiety, compulsive behavior, substance abuse,
Parkinson-like motor disorders and motion disorders related to the use of
neuroleptic agents.

French Abstract

Cette invention a trait à des composés correspondant à la formule (I) ou à leurs sels acceptables du point de vue pharmaceutique. Dans cette formule, A représente un alkylène substitué ou non, R¿1? et R¿2? sont identiques ou différents et représentent un hydrogène, un halogène, un alkyle, un alcoxy, un alkylthio, un hydroxy, un amino, substitué ou non, un cyano, un nitro, un sulfonamide, un trifluorométhyle ou un trifluorométhoxy, R¿3?, R¿4?, R¿5?, R¿6? et R¿8? représentent, de manière indépendante, un hydrogène ou un alkyle, X représente un soufre, un oxygène ou NR¿7?, la définition de R¿8? étant donnée dans le descriptif, m est un nombre entier dont la valeur est choisie entre 0, 1 ou 2, Ar représente un groupe aryle ou hétéroaryle comme défini dans le descriptif. Ces composés se révèlent des plus utiles pour le traitement et/ou la prévention de troubles neuropsychologiques, notamment mais sans se limiter à cette énumération, la schizophrénie, la manie, la démence, la dépression, l'anxiété, le comportement compulsif, l'abus de substances intoxicantes, les désordres moteurs du type maladie de Parkinson et les troubles du mouvement liés à l'utilisation d'agents neuroleptiques.

Claims

What is claimed is:
1. A compound of the formula:
<IMG>
or pharmaceutically acceptable salts thereof wherein:
A is C1-C6 alkylene optionally substituted with one or two C1-C6
alkyl groups;
R1 and R2 are the same or different and represent hydrogen,
halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy,
amino, mono- or di (C1-C6) alkylamino, cyano, nitro, C1-C6
alkylsulfonyl, sulfonamide, perfluoro C1-C6 alkyl or
perfluoro C1-C6 alkoxy;
R3, R4, R5, and R6 are the same or different and represent
hydrogen or C1-C6 alkyl; and
X is sulfur, oxygen or NR7 where R7 is hydrogen or C1-C6 alkyl;
R8 is hydrogen or C1-C6 alkyl;
m is 0, 1 or 2; and
Ar represents mono or bicyclic aryl or heteroaryl, each of
which is optionally substituted independently with up to
five groups selected from C1-C6 alkyl, C1-C6 alkoxy,
halogen, C1-C6 alkylthio, hydroxy, amino, mono- or di(C1-
C6)alkylamino, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 alkylsulfonyl, sulfonamide, or alkyl
sulfonamide.
-51-

2. A compound according to claim 1, wherein A is
unsubstituted C1-C4 alkylene.
3. A compound according to claim 1 wherein A is C2, C3,
or C4 alkylene.
4. A compound according to claim 3 wherein Ar is
selected from
<IMG>
where each of R9 and R10 is independently selected from
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl.
5. A compound according to claim 4, wherein R9 and R10
are independently selected from hydrogen, C1-C3 alkyl, C1-C3
alkoxy, chloro or fluoro, or trifluoromethyl.
6. A compound according to claim 3 wherein Ar is
selected from
<IMG>
-52-

where each of R9 and R10 is independently selected from
hydrogen, 4-C1-C3 alkyl, 2-C1-C3 alkoxy, 4-halogen, or 3-
trifluoromethyl, provided that one of R9 and R10 is hydrogen.
7. A compound according to claim 6, wherein R9 and R10
are independently selected from hydrogen, methyl, methyoxy,
ethoxy, isopropoxy, chloro, or fluoro.
8. A compound according to claim 3, wherein R1 and R2
independently represent hydrogen, halogen, C1-C6 alkoxy, C1-C6
alkyl, C1-C6 alkylsulfonyl, sulfonamide, or alkyl sulfonamide.
9. A compound according to claim 8, wherein at least one
of R1 and R2 is hydrogen and the other is methoxy, methyl,
chloro, fluoro, methoxy, ethoxy, or methylsulfonyl.
10. A compound according to claim 9, wherein R1 is
hydrogen and R2 is in the 4 or 6 position on the nitrogen
containing ring system.
11. A compound according to claim 1, which has the
formula
<IMG>
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wherein:
A is C1-C6 alkylene optionally substituted with one or two C1-C6
alkyl groups;
R1 and R2 are the same or different and represent hydrogen,
halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 alkylthio, hydroxy,
amino, mono- or di (C1-C6) alkyl amino, cyano, nitro, C1-C6
alkylsulfonyl, sulfonamide, trifluoromethyl or
trifluoromethoxy;
R3, R4, R5, and R6 are the same or different and represent
hydrogen or methyl; and
R8 is hydrogen or C1-C6 alkyl;
m is 0, 1 or 2; and
Ar represents mono or bicyclic aryl or heteroaryl, each of
which is optionally substituted independently with up to
five groups selected from C1-C6 alkyl, C1-C6 alkoxy,
halogen, C1-C6 alkylthio, hydroxy, amino, mono- or di (C1-
C6)alkylamino, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 alkylsulfonyl, sulfonamide, or alkyl
sulfonamide.
12. A compound according to claim 11, wherein Ar is not
unsubstituted phenyl when R1-R6 are hydrogen, A is ethylene, R8
is hydrogen, and m is 0.
13. A compound according to claim 3, wherein Ar is
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<IMG>
where each of R9 and R10 is independently selected from
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl.
14. A compound according to claim 13, wherein X is NH.
15. A compound according to claim 1, which has the
formula:
<IMG>
wherein:
A is C1-C6 alkylene optionally substituted with one or two C1-C6
alkyl groups;
R1 and R2 are the same or different and represent hydrogen,
halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 alkylthio, hydroxy,
amino, mono- or di (C1-C6) alkyl amino, cyano, nitro, C1-C6
alkylsulfonyl, sulfonamide, trifluoromethyl or
trifluoromethoxy;
R3, R4, R5, and R6 are the same or different and represent
hydrogen or methyl; and
R8 is hydrogen or C1-C6 alkyl;
m is 0, 1 or 2; and
-55-

Ar represents mono or bicyclic aryl or heteroaryl, each of
which is optionally substituted independently with up to
five groups selected from C1-C6 alkyl, C1-C6 alkoxy,
halogen, Cl-C6 alkylthio, hydroxy, amino, mono- or di (C1-
C6)alkylamino, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 alkylsulfonyl, sulfonamide, or alkyl
sulfonamide.
16. A compound according to claim 1, which has the
formula
<IMG>
wherein:
A is C1-C6 alkylene optionally substituted with one or two C1-C6
alkyl groups;
R1 and R2 are the same or different and represent hydrogen,
halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 alkylthio, hydroxy,
amino, mono- or di (C1-C6) alkyl amino, cyano, nitro, C1-C6
alkylsulfonyl, sulfonamide, trifluoromethyl or
trifluoromethoxy;
R3, R4, R5, and R6 are the same or different and represent
hydrogen or methyl;
R7 is hydrogen or C1-C6 alkyl; and
R8 is hydrogen or C1-C6 alkyl;
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m is 0, 1 or 2; and
Ar represents mono or bicyclic aryl or heteroaryl, each of
which is optionally substituted independently with up to
five groups selected from C1-C6 alkyl, C1-C6 alkoxy,
halogen, C1-C6 alkylthio, hydroxy, amino, mono- or di (C1-
C6)alkylamino, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 alkylsulfonyl, sulfonamide, or alkyl
sulfonamide.
17. A compound according to claim 1 which is
1-(Pyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine.
1-(Pyrimidin-2-yl)-4-(4-[benzothiazol-2-
yl]aminobutyl)piperazine;
1-(5-Fluoropyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine;
1-(5-Fluoropyrimidin-2-yl)-4-(4-[benzothiazol-2-
yl]aminobutyl) piperazine;
1-(5-Methylpyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine;
1-Phenyl-4-(2-[benzothiazol-2-yl]aminoethyl)piperazine; or
1-(Pyridin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine.
18. A compound according to claim 1 which is
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1-(4-Chlorophenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine;
1-(4-Fluorophenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(3-[benzothiazol-2-yl]aminopropyl)
piperazine;
1-(2-Methoxyphenyl)-4-(2-[4-methoxybenzothiazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(2-[4-methylbenzothiazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(2-[4-chlorobenzothiazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(2-[6-ethoxybenzothiazol-2-
yl]aminoethyl)piperazine; or
1-(2-Methoxyphenyl)-4-(2-[6-methylsulfonylbenzothiazol-2-
yl]aminoethyl)piperazine.
19. A compound according to claim 1 which is
1-(Pyrimidin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine;
1-Benzyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine;
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1-(4-Chlorobenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl) piperazine;
1-(2-Ethoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl) piperazine;
1-(5-Fluoropyrimidin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine;
1-(5-Methylpyrimidin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine; or
1-(Pyridin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine.
20. A compound according to claim 1 which is
1-(3-Trifluoromethylphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine;
1-Phenyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine;
1-(4-Fluorophenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl) piperazine;
1-(2-Isopropoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl) piperazine;
1-(2-Methoxybenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl) piperazine;
1-(2-Isopropoxybenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl) piperazine;
1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzoxazol-2-
yl]aminoethyl)piperazine;
-59-

1-(Pyridin-2-yl)-4-(2-[benzoxazol-2-
yl]aminoethyl)piperazine; or
1-(Pyrimidin-2-yl)-4-(2-[benzoxazol-2-
yl]aminoethyl)piperazine.
21. A compound according to claim 1 which is
1-(2-Methoxyphenyl)-4-(2-[benzimidazol-2-
yl]aminoethyl)piperazine;
1-Phenyl-4-(2-[benzimidazol-2-yl]aminoethyl)piperazine;
1-(Pyridin-2-yl)-4-(2-[benzimidazol-2-
yl]aminoethyl)piperazine;
1-(Pyridin-2-yl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine;
1-(Pyridin-2-yl)-4-(2-[1-isopropylbenzimidazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine;
1-(2-Isopropoxylphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine;
1-(3-Trifluoromethylphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine;
1-(2-Methoxyphenyl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine;
1-Phenyl-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine; or
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1-Phenyl-4-(2-[1-isopropylbenzimidazol-2-
yl]aminoethyl)piperazine.
22. A compound of the formula
<IMG>
wherein:
A is C1-C6 alkylene optionally substituted with one or two C1-C6
alkyl groups;
R3, R4, R5, and R6 are the same or different and represent
hydrogen or C1-C6 alkyl; and
m is 0, 1 or 2; and
Ar represents mono or bicyclic aryl or heteroaryl, each of
which is optionally substituted independently with up to
five groups selected from C1-C6 alkyl, C1-C6 alkoxy,
halogen, C1-C6 alkylthio, hydroxy, amino, mono- or di(C1-
C6)alkylamino, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 alkylsulfonyl, sulfonamide, or
alkyl sulfonamide.
23. A method of the treatment and/or prevention of
neuropsychological disorders, which comprises administering to
-61-

a host in need of such treatment an effective amount of a
compound as claimed in Claim 1.
24. A method according to claim 23, wherein the
neuropsychological disorders are selected from, schizophrenia,
mania, dementia, depression, anxiety, compulsive behavior,
memory impairment, cognitive disorders, substance abuse,
Parkinson-like motor disorders and motion disorders related to
the use of neuroleptic agents.
25. The use of a compound according to claim 1 for the
preparation of a medicament for use in treatment of
neuropsychological disorders.
26. A salt according to claim 1 which is
1-(5-Fluoropyrimidin-2-yl)-4-(2-[6-benzothiazol-2-
ylamino]butyl) piperazine difumarate;
1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
ylamino]ethyl) piperazine difumarate;
1-(Pyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine difumarate;
1-(Pyrimidin-2-yl)-4-(4-[benzothiazol-2-
yl]aminobutyl)piperazine difumarate;
1-(5-Fluoropyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine difumarate;
-62-

1-(5-Meth~rtpyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine difumarate;
1-Phenyl-4-(2-[benzothiazol-2-yl]aminoethyl)piperazine
difumarate;
1-(Pyridin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine difumarate;
1-(4-Chlorophenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine dihydrochloride; or
1-(4-Fluorophenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine dihydrochloride.
27. A salt according to claim 1 which is
1-(2-Methoxyphenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine difumarate;
1-(2-Methoxyphenyl)-4-(3-[benzothiazol-2-yl]aminopropyl)
piperazine hydrobromide;
1-(2-Methoxyphenyl)-4-(2-[4-methoxybenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(2-Methoxyphenyl)-4-(2-[4-methylbenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(2-Methoxyphenyl)-4-(2-[4-chlorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(2-Methoxyphenyl)-4-(2-[6-ethoxybenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(2-Methoxyphenyl)-4-(2-[6-methylsulfonylbenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide
-63-

1-(Pyrimidin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine difumarate;
1- (2-Methoxyphenyl) -4- (2- [6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine difumarate;
1-Henzyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine difumarate; or
1-(4-Chlorobenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide.
28. A salt according to claim 1 which is
1-(2-Ethoxyphenyl)-4-(2-(6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(5-Fluoropyrimidin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(5-Methylpyrimidin-2-yl)-4-(2-(6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(Pyridin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(3-Trifluoromethylphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl)aminoethyl)piperazine hydrobromide;
1-Phenyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(4-Fluorophenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(2-Isopropoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide;
-64-

1-(2-Methoxybenzyl)-4-(2-(6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide; or
1-(2-Isopropoxybenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide.
29. A salt according to claim 1 which is
1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzoxazol-2-
yl]aminoethyl)piperazine hydrochloride;
1-(Pyrimidin-2-yl)-4-(2-(benzoxazol-2-
yl]aminoethyl)piperazine hydrochloride;
1-(Pyridin-2-yl)-4-(2-[benzoxazol-2-
yl]aminoethyl)piperazine hydrochloride;
1-(2-Methoxyphenyl)-4-(2-(benzimidazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-Phenyl-4-(2-[benzimidazol-2-yl]aminoethyl)piperazine
hydrobromide;
1-(Pyridin-2-yl)-4-(2-[benzimidazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(Pyridin-2-yl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(Pyridin-2-yl)-4-(2-[1-isopropylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(2-Methoxyphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide; or
1-(2-Isopropoxylphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide.
-65-

30. A salt according to claim 1 which is
1-(3-Trifluoromethylphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-(2-Methoxyphenyl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-Phenyl-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide;
1-Phenyl-4-(2-[1-isopropylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide.
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Description

CA 02345944 2001-03-29
WO 00/18767 PC'T/US99/22791
2-PIPERAZINOALKYLAMINOBENZOAZOLE DERIVATIVES:
DOPA_H!TNE RECEPTOR SUBTYPE SPECIFIC L,~GANDS
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to 2-piperazinoalkylaminobenzo-
azole derivatives and to pharmaceutical compositions containing
such compounds. It also relates to the use of such compounds
in the treatment or prevention of psychotic disorders such as
schizophrenia and other central nervous system diseases.
Descri.~~tion of the Related Art
The therapeutic effect of conventional antipsychotics,
known as neuroleptics, is generally believed to be exerted
through blockade of dopamine receptors. However, neuroleptics
are frequently responsible for undesirable extrapyramidal side
effects CEPS) and tardive dyskinesias, which are attributed to
blockade of D2 receptors in the striatal region of the brain.
The dopamine D4 receptor subtype has recently been identified
(Nature, 3~0: 610 (Van Tol et al., 1991); Nature, ~: 146
(Sokoloff et al., 1990)). Its unique localization in limbic
brain areas and its differential recognition of various
antipsychotics indicates that the D4 receptor plays a major
role in the etiology of schizophrenia. Selective D,
antagonists are considered effective antipsychotics free from
the neurological side effects displayed by conventional
neuroleptics.
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
U.S. Patent No. 5,632,898 discloses N-benzothiazol-2-yl-2-
(4-phenylpiperazinyl)acetamide.
U.S. Patent No. 5,229,398 discloses aminomethylpiperidine
derivatives.
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
SUMMARY OF THE I r~'T(~N
This invention provides novel compounds of Formula I which
interact with dopamine subtypes. Accordingly, a broad
embodiment of the invention is directed to a compound of
S Formula I:
R3 R4
/~(\R
N A-N N-(CH2)m-Ar
~>--N
C, ~ . >--~
R X Ra Rs Rs
z
I
wherein
A is C1-C6 alkylene optionally substituted with one or two C1-C6
alkyl groups;
R1 and Rz are the same or different and represent hydrogen,
halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy,
amino, mono- or di (C,-C~) alkyl amino, cyano, vitro, C1-C6
alkylsulfonyl, sulfonamide or C1-C6 alkyl sulfonamide,
perfluoro (C1-C6) alkyl or perfluoro (C1-C6) alkoxy;
R3 , R4 , RS , and R6 are the same or di f f erent and represent
hydrogen or C1-C6 alkyl;
X is sulfur, oxygen or NR, where R, is hydrogen or C1-C6 alkyl;
Rg is hydrogen or C1-C6 alkyl;
m is 0 or an integer chosen from 1 and 2; and
Ar represents mono or bicyclic aryl or heteroaryl, each of
which is optionally substituted independently with up to
five groups selected from C1-C6 alkyl, C1-C~ alkoxy,
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
halogen, C1-Cs alkylthio, hydroxy, amino, mono- or di (Cl-
C5)alkylamino, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C1-C~ alkylsulfonyl, sulfonamide, or
alkyl sulfonamide.
Dopamine D4 receptors are concentrated in the limbic
system (Science, 265: 1034 (Taubes, 1994)) which controls
cognition and emotion. Therefore, compounds that interact with
these receptors are useful in the treatment of cognitive
disorders. Such disorders include cognitive deficits which are
a significant component of the negative symptoms (social
withdrawal and unresponsiveness) of schizophrenia. Other
disorders include those involving memory impairment or
attention deficit disorders.
Compounds of the present invention demonstrate high
affinity and selectivity in binding to the D, receptor subtype.
These compounds are therefore useful in treatment of a variety
of neuropsychological disorders, such as, for example,
schizophrenia, psychotic depression and mania. Other dooamine-
mediated diseases such as Parkinsonism and tardive dyskinesias
can also be treated directly or indirectly by modulation of D,
receptors.
Compounds of this invention are also useful in the
treatment of depression, memory-impairment or Alzheimer's
disease by modulation of D, receptors since they exist
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791 _
selectively in areas known to control emotion and cognitive
functions.
Thus, in another aspect, the invention provides methods
for treatment and/or prevention of neuropsychological or
affective disorders including, for example, schizophrenia,
mania, dementia, depression, anxiety, compulsive behavior,
substance abuse, memory impairment, cognitive deficits,
Parkinson-like motor disorders, e.g., Parkinsonism and
dystonia, and motion disorders related to the use of
neuroleptic agents. In addition, the compounds of the
invention are useful in treatment of depression, memory-
impairment or Alzheimer's disease. Further, the compounds of
the present invention are useful for the treatment of other
disorders that respond to dopaminergic blockade, e.g.,
substance abuse and obsessive compulsive disorder. These
compounds are also useful in treating the extrapyramidal side
effects associated with the use of conventional neuroleptic
agents.
In yet another aspect, the invention provides
pharmaceutical compositions comprising compounds of Formula I.
In another aspect, the invention provides intermediates
useful in the preparation of compounds of Formula I.
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the invention relates to compounds of
Formula I. Preferred compounds of Formula I include those
where R3, R4, R5, and R6 independently represent hydrogen or
methyl; and R8 is hydrogen. In more preferred compounds of I,
m is 0 or 1; and A is unsubstituted C1-C" more preferably
unsubstituted C2, C" or C4, alkylene. In preferred compounds
of Formula I, Ar is not unsubstituted phenyl when X is S, R1
and R2 are both hydrogen, all of RZ-R5 are hydrogen, and m is 0.
Preferred Ar groups in Formula I are those having up to
three non-hydrogen substituents selected from the group
mentioned above. More preferred Ar groups in Formula I are
those having no more than two substituents. Particularly
preferred compounds of Formula I include those where Ar is
selected from
Rs Rs Rs
1 ~1 N ~1
= Rio ~ ~ Rio ~ ~ Rio
' '~ N ~ N
where each of R9 and Rlo is independently selected from
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl.
In other particularly preferred compounds of I, R9 and Rla
are independently selected from hydrogen, C1-C, alkyl, C1-C,
alkoxy, chloro or fluoro, or trifluoromethyl. In yet other
highly preferred compounds of Formula I, Ar is
-6-

CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
R9
j Rio
where each of R9 and Rlo is independently selected from
hydrogen, 4-C1-C, alkyl, 2-C1-C3 alkoxy, 4-halogen, or 3-
trifluoromethyl, provided that one of R9 and Rlo is hydrogen.
Even more preferred axe compounds where R9 and Rlo are
independently selected from hydrogen, methyl, methoxy, ethoxy,
isopropoxy, chloro, or fluoro.
In another group of preferred compounds of Formula I, R1
and Rz independently represent hydrogen, halogen, C1-C6 alkoxy,
C1-C6 alkyl, C1-C5 alkylsulfonyl, alkyl sulfonamide, or
sulfonamide. A highly pref erred group of such compounds
include those where at least one of R1 and RZ is hydrogen and
the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy,
or methylsulfonyl. Particularly preferred compounds of this
group include those where R1 is hydrogen and Rz is in the 4 or
6 position on the nitrogen containing ring system.
In still another group of preferred compounds of Formula
I, Ar is a naphthyl group of the formula
R9
\.
i
~ ~ / Rio
where each of R9 and Rlo is independently selected from
hydrogen, C:-C5 alkyl , C1-C6 alkoxy, halogen, or
trifluoromethyl. A preferred group of compounds having the
above naphthyl and where X is NH.
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A preferred group of compounds of the invention is
represented by Formula II:
Ra Ra
----~R
N A-N N-(CH2)m'Ar
C,, ?-N. >--C
R S Rs Rs Rs
2
II
wherein
A is Cz-Ce alkylene optionally substituted with one or two C=-C6
alkyl groups;
R1 and R2 are as defined above for Formula I;
R3, R4, R5, and R6 independently represent hydrogen or C.-C,
alkyl, preferably methyl;
RB is hydrogen or C1-CZ alkyl;
m is an integer chosen from 0, 1 or 2; and
Ar is as defined above for Formula I.
In more preferred compounds of II, rn is 0 or 1; and A is
unsubstituted C:-C" more preferably unsubstituted C2, C" or C~,
alkylene.
Particularly preferred compounds of Formula II include
those where Ar is selected from
Rs Rs R
y y Nw
Rio ( ~ Rio I ~ Rio
J ~ J
N '~ N
_g_

CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791 _
where each of R9 and Rlo is independently selected from
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl. In highly preferred such compounds, not both
R9 and Rlo are hydrogen when Ar is phenyl, R1-R6 are hydrogen, m
is 0, and A is ethylene. In other highly preferred compounds
of Formula II, Ar is selected from pyridyl and pyrimidinyl
groups of the formula:
R9 Rs
\\
~\~ Rio ~ ~ Rio
J -L J
.~ N .~ N
where each of R9 and Rio is independently selected from
hydrogen, C1-C5 alkyl, C:-C6 alkoxy, halogen, or
trifluoromethyl.
In other particularly preferred compounds of II, R9 and Rlo
are independently selected from hydrogen, C1-C3 alkyl, C1-C,
alkoxy, chloro or fluoro, or trifluoromethyl, provided not both
R9 and Rl~ are hydrogen when Ar is phenyl, R1-R6 are hydrogen, A
is ethylene, and m is 0. In yet other highly preferred
compounds of Formula II, Ar is
Rs
Rio
where each of R~ and R:, is independently selected from
hydrogen, 4-C.-C, alkyl, 2-C1-C, alkoxy, 4-halogen, or 3-
trifluoromethyl, provided that on=y one of R9 and R_, is
hydrogen. Even more preferred are compounds where R9 and Rlo
_g_

CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
are independently selected from hydrogen, methyl, methoxy,
ethoxy, isopropoxy, chloro, or fluoro~with the proviso that
when Rl-R6 are hydrogen, A is ethylene, m is 0, and Ar is
phenyl , not both R9 and Rlo are hydrogen .
In another group of preferred compounds of Formula II, R1
and Rz independently represent hydrogen, halogen, C:-C6 alkoxy,
C1-C6 alkyl, C1-C5 alkylsulfonyl, alkyl sulfonamide or
sulfonamide. A highly preferred group of such compounds
include those where at least one of R, and RZ is hydrogen and
the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy,
or methylsulfonyl. Particularly preferred compounds of this
group include those where R1 is hydrogen and Rz is in the 4 or
6 position on the nitrogen containing ring system.
In still another group of preferred compounds of Formula
II, Ar is a naphthyl group of the formula
R9
i
Rio
where each of R9 and R1~ is independently selected from
hydrogen, C_-C5 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl. A preferred group of compounds are those
having the above naphthyl where X is NH.
Another preferred group of compounds of the invention is
represented by Formula III:
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
R3 R4 _
R
v ~ N A-N N-(CH2)m-Ar
C~, >--N ~--~
R ~ Re Rs Rs
z
III
wherein:
A is C~-C~ alkylene optionally substituted with one or two CI-C6
alkyl groups;
R1 and R2 are as defined above for Formula I;
R3, R4, R5, and R5 independently represent hydrogen or C1-C3
alkyl, preferably methyl;
R8 is hydrogen or C,-C2 alkyl;
m is an integer chosen from 0, 1 or 2; and
Ar is as defined above for Formula I.
In more preferred compounds of III, m is 0 or 1; and A is
unsubstituted C,-C~, more preferably unsubstituted C~, C" or C"
alkylene.
Particularly preferred compounds of Formula III include
those where Ar is selected from
Rs Rs Rs
~'1 ~1 N ~ w
Rio I ~ Rio ~ ~ Rio
~ J
N .~ N
where each of R, and Rla is independently selected from
hydrogen, C1-C5 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl.
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In other particularly preferred compounds of III, R9 and
R,o are independently selected from hydrogen, C:-C3 alkyl, C,-C,
alkoxy, chloro or fluoro, or trifluoromethyl.
In highly preferred compounds of Formula III, Ar is
S selected from pyridyl and pyrimidinyl groups of the formula:
R9 Rs
\1 N~1
J Rio ~ ~ Rio
N y N
where each of R9 and R,o is independently selected from
hydrogen, C,-C6 alkyl, C,-C6 alkoxy, halogen, or
trifluoromethyl.
In Iyet other highly preferred compounds of Formula III,
Ar is
R9
Rio
where each of R9 and R,o is independently selected from
hydrogen, 4-C,-C, alkyl, 2-C,-C3 alkoxy, 4-halogen, or 3-
trifluoromethyl, provided that one of R~ and R.~ is hydrogen.
Even more preferred are compounds where R3 and R,o are
independently selected from hydrogen, methyl, methyoxy, ethoxy,
isopropoxy, chloro, or fluoro.
In another group of preferred compounds of Formula III, R,
and Rz independently represent hydrogen, halogen, C,-C; alkoxy,
C,-C6 alkyl, C,-C6 alkylsulfonyl, sulfonamide, or alkyl
sulfonamide. A highly preferred group of such compounds
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include those where at least one of R, and R2 is hydrogen and
the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy,
or methylsulfonyl. Particularly preferred compounds of this
group include those where R, is hydrogen and RZ is in the 4 or
6 position on the nitrogen containing ring system.
In still another group of preferred compounds of Formula
III, Ar is a naphthyl group of the formula
R9
~ ~ / Rio
where each of R~ and R1~ is independently selected from
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl. A preferred group of compounds having the
above naphthyl and where X is NH.
Yet another preferred group of compounds of the invention
is represented by Formula IV:
R~R4
\R
N A-N N-(CH2)m-A~
~--N
~/ /
R N Rs Rs Rs
2 v
R~
IV
wherein:
A is CZ-C~ alkylene optionally substituted with one or two C1
alkyl groups;
R1 and R2 are as defined above for Formula I;
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CA 02345944 2001-03-29
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R3. R4. R5, and R6 independently represent hydrogen or C1-C,
alkyl, preferably methyl;
R, is hydrogen or C1-C, alkyl;
R3 is hydrogen or C1-CZ alkyl;
m is an integer chosen from 0, 1 or 2; and
Ar is as defined above for Formula I.
In more preferred compounds of III, m is 0 or 1; and A is
unsubstituted C1-C" more preferably unsubstituted CZ, C,, or C"
alkylene.
Particularly preferred compounds of Formula III include
those where Ar is selected from
Rs Rs Rs
\1 \'1 N
Rio ~ ~ Rio I ~ Rio
J
N '~ N
where each of R: and Rla is independently selected from
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, or
trifluoromethyl.
In other particularly preferred compounds of III, R9 and
R:, are independently selected from hydrogen, C~-C, alkyl, -C1-C3
alkoxy, chloro or fluoro, or trifluoromethyl. In yet other
highly preferred compounds of Formula III, Ar is
Rs
I / Rio
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
where each of R9 and R,o is independently selected from
hydrogen, 4-C1-C, alkyl, 2-C1-C, alkoxy, 4-halogen, or 3-
trifluoromethyl, provided that one of R9 and Rlo is not
hydrogen. Even more preferred are compounds where R9 and Rla
S are independently selected from hydrogen, methyl, methyoxy,
ethoxy, isopropoxy, chloro, or fluoro.
In another group of preferred compounds of Formula III, R1
and Rz independently represent hydrogen, halogen, C1-C5 alkoxy,
CI-C5 alkyl, C1-C6 alkylsulfonyl, sulfonamide, or alkyl
sulfonamide. A highly preferred group of such compounds
include those where at least one of R1 and RZ is hydrogen and
the other is methoxy, methyl, chloro, fluoro, methoxy, ethoxy,
or methylsulfonyl. Particularly preferred compounds of this
group include those where R, is hydrogen and Rz is a non-
hydrogen group as specified immediately above and is in the 4
or 6 position on the nitrogen containing ring system.
In still another group of preferred compounds of Formula
III, Ar is a naphthyl group of the formula
R9
.\. \
Rio
where each of R9 and R1~ is independently selected from
hydrogen, C1-Cfr alkyl, CI-C6 alkoxy, halogen, or
trifluoromethyl. A preferred group of compounds having the
above naphthyl and where X is NH.
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The invention also provides intermediates useful in
preparing compounds of Formula I. These intermediates have
Formulae VIII.
O
R3 R4
VIII
A- ~ -
O ~ ((%f"'~2)m'A~
Rs Rs
In Formula VIII, R3, R4, RS, R6, A, m and Ar are as defined
above for Formula I.
In preferred compounds of VIII, m is 0 or 1; and A is
unsubstituted C,-C4, more preferably unsubstituted Cz, C,, or C4,
alkylene.
Particularly preferred compounds of Formula VIII include
those where Ar is selected from
Rs Rs Rs
N ~1
~ R'° , ~ J Rio ~ ~ Rio
N '~ N
where each of R9 and R,~ is independently selected from
hydrogen, C=-C6 alkyl, C:-C6 alkoxy, halogen, or
trifluoromethyl.
In other particularly preferred compounds of VIII, R9 and
R:~ are independently selected from hydrogen, C:-C, alkyl, C1-C,
alkoxy, chloro or fluoro, or trifluoromethyl. In yet other
highly preferred compounds of Formula VIII, Ar is
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/Z2791
R9
Rio
where each of R9 and Rlo is independently selected from
hydrogen, 4-C,-C, alkyl, 2-C1-C, alkoxy, 4-halogen, or 3-
trifluoromethyl. Even more preferred are compounds where Rg
and Rlo are independently selected from hydrogen, methyl,
methyoxy, ethoxy, isopropoxy, chloro, or fluoro.
In still another group of preferred compounds of Formula
VIII, Ar is a naphthyl group of the formula
R9
\.
Rya
where each of R9 and R,o is independently selected from
hydrogen, C1-C6 alkyl, C1-C5 alkoxy, halogen, or
trifluoromethyl.
In certain situations, the compounds of Formula I may
contain one or more asymmetric carbon atoms, so that the
compounds can exist in different stereoisomeric forms. These
compounds can be, for example, racemates or optically active
forms. In these situations, the single enantiomers, i.e.,
optically active forms, can be obtained by asymmetric synthesis
or by resolution of the racemates. Resolution of the racemates
can be accomplished, for example, by conventional me~hods such
as crystallization in the presence of a resolving agent, or
chromatography, using, for example a chiral HPLC column.
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Representative compounds of the present invention, which
are encompassed by Formula I, include, but are not limited to
the compounds in Table 1 and their pharmaceutically acceptable
acid addition salts. In addition, if the compound of the
invention is obtained as an acid addition salt, the free base
can be obtained by basifying a solution of the acid salt.
Conversely, if the product is a free base, an addition salt,
particularly a pharmaceutically acceptable addition salt, may
be produced by dissolving the free base in a suitable organic
solvent and treating the solution with an acid, in accordance
With conventional procedures for preparing acid addition salts
from base compounds.
Non-toxic pharmaceutical salts include salts of acids such
as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,
formic, toluenesulfonic, methanesulfonic, nitric, benzoic,
citric, tartaric, malefic, hydroiodic, alkanoic such as acetic,
HOOC-(CH2)n-COOH where n is 0-4, and the like. Those skilled
in the art will recognize a wide variety of non-toxic
pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated
prodrugs of the compounds of Formula I. Those skilled in the
art will recognize various synthetic methodologies which may be
employed to prepare non-toxic pharmaceutically acceptable
addition salts and acylated prodrugs of the compounds
encompassed by Formula I.
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Where a compound exists in various tautomeric forms, the
invention is not limited to any one of the specific tautomers.
The invention includes all tautomeric forms of a compound.
By "C1-C6 alkyl" or "lower alkyl" in the present invention
is meant straight or branched chain alkyl groups having 1-6
carbon atoms, such as, for example, methyl, ethyl, propyl,
isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,
isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3
methylpentyl. Preferred C1-C6 alkyl groups are methyl, ethyl,
propyl, butyl, cyclopropyl and cyclopropylmethyl.
By "C1-C6 alkoxy" or "lower alkoxy" in the present
invention is meant straight or branched chain alkoxy groups
having 1-6 carbon atoms, such as, for example, methoxy, ethoxy,
propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,
pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-
hexoxy, and 3-methylpentoxy. Preferred alkoxy groups herein
are C1-C4 alkoxy groups .
By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and iodine.
Where a substituent is a di(C_-C6)alkylamino group, the
two alkyl groups are the same or different. Representative
di(C1-C5)alkylamino groups include dimethylamino,
methylpropylamino, diisopropylamino, and ethylpentylamino.
By aryl is meant an aromatic carbocyclic group having one
ring (e. g., phenyl), or two rings (e. g., biphenyl). Such
groups are unsubstituted or substituted with up to five groups
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selected from C,-C6 alkyl, C1-C6 alkoxy, halogen, Cl-C6
alkylthio, hydroxy, amino, mono- or di(C1-C6)alkylamino, cyano,
vitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkylsulfonyl,
alkyl sulfonamide and sulfonamide.
By heteroaryl (aromatic heterocycle) in the present
invention is meant one or more aromatic ring systems of 5-, 6-,
or 7-membered, preferably S- or 6-membered, rings containing at
least one and up to four, preferably one or two, hetero atoms
selected from nitrogen, oxygen, or sulfur. The heteroaryl Ar
groups are bound to the parent alkylpiperazine moiety through a
carbon atom in the heteroaryl group, preferably a carbon atom
immediately adjacent a hetero atom such as nitrogen. Such
heteroaryl groups include, for example, thienyl, furanyl,
thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl,
(iso)quinolinyl, naphthyridinyl, benzimidazolyl, and
benzoxazolyl.
By "C1-C5 alkyl sulfonyl" is meant groups of the formula:
O~~O
S
C~-C6 alkyl .
By the terms "C1-C6 alkyl sulfonamide" and "alkyl
sulfonamide" is meant groups of the formula:
O'~O
S~-
Ra-N
Rb
where Ra and R~ independently represent C;-C~ alkyl.
-20-

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Preferred C1-C6 alkyl sulfonamides are methylsulfonamide,
dimethylsulfonamide, and diethylsulfonamide.
By the term "sulfonamide" is meant groups of the formula:
O~~O
S
HZN
The convention for numbering the substituents about the
nitrogen containing ring system herein is as follows:
3N
5~~~ ~2
s /
X~
R2 7
Representative compounds of the invention are shown in
Table 1.
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99l22791
Table 1
i H3C0
/ \ W / \
N N CF3 F
N ~N
N~N~'N~ SJ'LN'~NJ
H3C H H
Compound 1 Compound 2
N i
/ \ ~ ~ / \ ~ I i
~N ~N N ~N
O~N~N~ S~N~N
H H
Compound 3 Compound 4
F
O N
F / \ N ~N I ~ ~N
S~N~N J ~ ~N
H (N J
Compound 5 ~ N
~ '?--NH
S
Compound 6
N~ F i
/ \ ~~ C2H50 / \ N N
N ~N N
S~N,~~NJ S N~NJ OCH3
H H
Compound 9 Compound 20
N' (
/ \
~N ~N N
OJ~N~N
H
Compound 37
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The invention also pertains to the use of compounds of
general Formula I in the treatment of neuropaychological
disorders. The interaction of compounds of the invention with
dopamine receptors is shown in the examples. This interaction
results in the pharmacological activity of these compounds.
The compounds of general formula I may be administered
orally, topically, parenterally, by inhalation or spray or
rectally in dosage unit formulations containing conventional
non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular,
intrasternal injection or infusion techniques. In addition,
there is provided a pharmaceutical formulation comprising a
compound of general formula I and a pharmaceutically acceptable
carrier. One or more compounds of general formula I may be
present in association with one or more non-toxic
pharmaceutically acceptable carriers and/or diluents and/or
adjuvants and if desired other active ingredients. The
pharmaceutical compositions containing compounds of general
formula I may be in a form suitable for oral use, for example,
as tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsion, hard or soft
capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared
according to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain
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one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant
and palatable preparations. Tablets contain the active
ingredient in admixture with non-toxic pharmaceutically
acceptable excipients which are suitable for the manufacture of
tablets. These excipients may be for example, inert diluents,
such as calcium carbonate, sodium carbonate, lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating
agents, for example, corn starch, or alginic acid; binding
agents, for example starch, gelatin or acacia, and lubricating
agents, for example magnesium stearate, stearic acid or talc.
The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action
over a longer period. For example, a time delay material such
as glyceryl monosterate or glyceryl disteara~e may be employed.
Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the
active ingredient is mixed with water or an oil medium, for
example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the ac~ive materials in
admixture with excipients suitable for she manufacture of
aqueous suspensions. Such excipients are suspending agents,
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for example sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing
or wetting agents may be a naturally-occurring phosphatide, for
example, lecithin, or condensation products of an alkylene
oxide with fatty acids, for example polyoxyethylene stearate,
or condensation products of ethylene oxide with long chain
aliphatic alcohols, for example heptadecaethyleneoxycetanol, or
condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene
sorbitol monooleate, or condensation products of ethylene oxide
with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The
aqueous suspensions may also contain one or more preservatives,
for example ethyl, or n-propyl p-hydroxybenzoate, one or more
coloring agents, one or more flavoring agents, and one or more
sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the
active ingredients in a vegetable oil, for example arachis oil,
olive oil, sesame oil or coconut oil, or in a mineral oil such
as liquid paraffin. The oily suspensions may contain a
thickening agent, for example beeswax, hard paraffin or cetyl
alcohol. Sweetening agents such as those set forth above, and
flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the
addition of an anti-oxidant such as ascorbic acid.
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Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide the
active ingredient in admixture with a dispersing or wetting
agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those already mentioned above. Additional
excipients, for example sweetening, flavoring and coloring
agents, may also be present.
Pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally-occurring gums,
for example gum acacia or gum tragacanth, naturally-occurring
phosphatides, for example soy bean, lecithin, and esters or
partial esters derived from fatty acids and hexitol,
anhydrides, for example sorbitan monoleate, and condensation
products of the said partial esters with ethylene oxide, for
example polyoxyethylene sorbitan monoleate. The emulsions may
also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents. The
pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleaginous suspension. This suspension
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may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents
which have been mentioned above. The sterile injectable
preparation may also be sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among
the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally employed as
a solvent or suspending medium. For this purpose any bland
fixed oil may be employed including synthetic mono-or
diglycerides. In addition, fatty acids such as oleic acid find
use in the preparation of injectables.
The compounds of general formula I may also be
administered in the form of suppositories for rectal
administration of the drug. These compositions can be prepared
by mixing the drug with a suitable non-irritating excipient
which is solid at ordinary temperatures but liquid at the
rectal temperature and will therefore melt in the rectum to
release the drug. Such materials are cocoa butter and
polyethylene glycols.
Compounds of general formula I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as
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local anesthetics, preservatives and buffering agents can be
dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about
140 mg per kilogram of body weight per day are useful in the
treatment of the above-indicated conditions (about 0.5 mg to
about 7 g per patient per day). The amount of active
ingredient that may be combined with the carrier materials to
produce a single dosage form will vary depending upon the host
treated and the particular mode of administration. Dosage unit
forms will generally contain between from about 1 mg to about
500 mg of an active ingredient.
It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time
of administration, route of administration, and rate of
excretion, drug combination and the severity of the particular
disease undergoing therapy.
A representative synthesis of the compounds of the
invention is presented in Scheme I. Those having skill in the
art will recognize that the starting materials may be varied
and additional steps employed to produce compounds encompassed
by the present invention.
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Scheme I
O Rs
\ L
N-A~ + H
/ N-(CH2)m-Ar
vI o ~ vII
Rs f'~s
Base
O
R3 R4
VIII N~
A-N N-(CH2)m-A~
I Rs Rs
NHZNHZ
R3 R4
H2N
~A-N N-(CHz)m-Ar
IX
Rs Rs
R~ ~ \ N
Base
R/ / X
2
x
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R3 R4
R~
N A-N N-(CHz)m-Ar
~~--NH
Rs Rs
z
I,
where Rg is H Rs~s
R3 R4
R~
N~ A-N N-(CHz)m-Ar
N
R ~ X Ra Rs Rs
z
I
wherein Rl, R2, R3, R4, R5, R6, Ra, X, m and Ar are as defined
above for Formula I. L1, L2 and L, represent leaving groups as
discussed below.
As shown in Scheme I, an N-alkylphthalimide VI substituted
with an appropriate leaving group L may be reacted with an
appropriately substituted piperazine VII in the presence of a
base to afford N-(piperazinylalkyl)phthalimide VIiI. The
leaving group L on VI may be a halogen, a trialkylamino group,
a sulphonate ester, or the like. Any suitable base can be
employed; representative bases include inorganic bases such as
sodium hydroxide, potassium carbonate or the like, and organic
bases such as a triethylamine, pyridine or the like.
Phthalimide VIII may be treated with hydrazine or the like
to afford amine IX. Amine IX may then be reacted with an
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appropriately substituted compound of Formula X having a
leaving group Lz at the 2-position to afford compounds of
Formula I. The leaving group LZ on alkylating agent X may be a
halide, sulphonate ester or the like. Conversion of I where R8
is hydrogen to compounds of I where Re is alkyl may be achieved
by treating I with an appropriately alkyl halide, RBL,.
Where they are not commercially available, the compounds
of general structure VI, VII and X may be prepared by
procedures analogous to those described in literature. The
compounds of general structure VI, VII, and X are either known
or capable of being prepared by the methods known in the art .
Those having skill in the art will recognize that the starting
material may be varied and additional steps employed to produce
compounds encompassed by the present invention. The base
employed may be an inorganic base such as potassium carbonate,
sodium hydroxide or the like; or an organic base such as
triethylamine, pyridine or the like.
Alternatively, a compound of Formula X where Lz is NHS may
be sequentially reacted with chloroacetyl chloride and a
compound of general structure VII in the presence of base
followed by reduction to provide a compound of Formula I
wherein A is ethylene.
~xamDle 1
Z-(5-Fluoroovrimidin-2-vl)-4-(4 aminobutyl)niperazine
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A solution of 4-bromo-N-butylphthalimide (8.37 g) and 1
(5-fluoropyrimidin-2-yl)piperazine (5.4 g) in dimethylformamide
(100 mL) containing potassium carbonate (8.2 g) is stirred at
80 °C for 12 hours. After cooling, the mixture is poured into
water and extracted with ether. The ether layer is dried over
sodium sulfate, filtered and concentrated to give the
intermediate as a yellow solid. The resulting phthalamide is
then taken up in hydrazine monohydrate (100 ml) and refluxed
under nitrogen overnight. After cooling, the mixture is poured
into a 30% solution of potassium carbonate (500 ml), and
extracted with methylene chloride, dried and concentrated to
give an orange semisolid (4.66 g). This material is dissolve
in a mixture of 10~ methanol/isopropanol (50 ml), treated with
fumaric acid (4.27 g, 2 eq) and the solvent volume reduced to
20 ml. The resulting yellow crystals are collected by
filtration (6.5 g).
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~-(5-Fluoronvrimidin-2-vl)-4-(2-(6,-benzothiazol-2-
~a~cinolbutvl) Rigerazine difumarate
F
N~
>-=N
~N
~N-'
N
~NH
S
A solution of 2-chlorobenzothiazole (920 mg) and 1-(5-
Fluoropyrimidin-2-yl)-4-(4-aminobutyl)piperazine (254 mg) in
acetonitrile (10 mL) containing potassium carbonate (300 mg) is
refluxed under nitrogen for 10 hours. After cooling, the
mixture is concentrated, and the resulting residue partitioned
between ethyl acetate and water. The organic layer is
separated and extracted with 10% citric acid. The acidic
aqueous layer is basified with 10 N NaOH solution and extracted
with chloroform. The chloroform layer is then dried over
sodium sulfate, filtered ar_d concentrated to give a white solid
(0.31 g) to provide the title compound. [alternatively named
benzothiazol-2-yl{4-[4-(5-fluoropyrimidin-2-
yl)piperazinyl]butyl~amine). This material is dissolved in 10%
methanol/isopropanol and treated with fumaric acid (190 mg).
The volume of solvent is partially reduced and the resulting
crystals are isolated by filtration (347 mg, m.p. 168-170 °C).
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Example 3
2- a o -4- lu b of iazo -2- 1 m' a 1
p"~perazine difumarate
H3C0 /
/ \
~N
S NON
H
A solution of 6-fluoro-2-aminobenzothiazole (5 g) and
triethylamine (5 ml) in chloroform (100 ml) is vigorously
stirred during the dropwise addition of a solution of
chloroacetyl chloride (5 ml) in chloroform (10 ml). The
reaction mixture is stirred overnight, filtered and
concentrated. The residue is triturated with isopropanol to
give an off white solid (3.82 g).
A portion of this solid (150 mg, 0.61 mmol) was dissolved
in acetonitrile (10 ml) and to the resulting solution is added
1-(2-methoxyphenyl)piperazine (118 mg) and potassium carbonate
(150 mg). The mixture is refluxed overnight. After cooling,
the solvent is removed and the resulting residue partitioned
between ethyl acetate and water. The organic layer is dried
and evaporated to provide a yellow oil which is purified by
preparative thin layer chromatography eluting with 9%
methanol/chloroform.
The product isolated after chromatography is dissolved in
tetrahydrofuran (5 ml) and the resulting solution combined with
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a 1 M solution of alane in tetrahydrofuran. After 2 hours, the
reaction mixture is treated with 20 ml of 15% sodium hydroxide
solution, stirred, and extracted with chloroform. The organic
layer is dried and concentrated. The resulting residue is
purified by preparative TLC eluting with 10 %
methanol/chloroform. The resulting oil is dissolved in
isopropanol (5 mL) and the solution is treated dropwise with a
saturated solution of fumaric acid in methanol until the pH was
3. After 2 hours, crystals are collected of the desired 1-(2-
Methoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
ylamino]ethyl)piperazine difumarate (180 mg, m.p. 169-170 °C)
as an off white solid. Compound 2, base, 1H NMR (CDC1,) 7.45
(m, 1H), 7.25 (m, 1H), 6.8-7.05 (m, 5H), 6.18 (bs, 1H). 3.85
(s, 3H), 3.55 (m, 2H), 3.0-3.1 (b, 4H), 2.7 (b, 6H).
Example 4
The following compounds are prepared essentially according
to the procedures set forth above in Examples 1-3.
(a) 1-(Pyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine difumarate (Compound 7, m.p. 161-163
°C) .
(b) 1-(Pyrimidin-2-yl)-4-(4-[benzothiazol-2-
yl]aminobutyl)piperazine difumarate (Compound 8).
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(c) 1-(5-Fluoropyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine difumarate (Compound 9, m.p. 174-175
°C) .
(d) 1-(5-Methylpyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine difumarate (m.p. 167-170 °C)
[alternatively named benzothiazol-2-yl{2-[4-(5-methylpyrimidin-
2-yl)piperazinyl]ethyl}amine] (Compound 10).
(e) 1-Phenyl-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine difumarate (m.p. 131-132 °C)
[alternatively named benzothiazol-2-yl[2-(4-
phenylpiperazinyl)ethyl]amine (Compound 11).
(f) 1- (Pyridin-2-yl) -4- (2- [benzothiazol-2-
yl]aminoethyl)piperazine difumarate (m. p. 159-160 °C).
[benzothiazol-2-yl[2-(4-(2-pyridyl)piperazinyl)ethyl]amine)
(Compound 12).
(g) 1- (4-Chlorophenyl) -4- (2- [benzothiazol-2-
yl]aminoethyl)piperazine dihydrochloride (m. p. 230-232 °C).
[benzothiazol-2-yl{2- [4- (4-
chlorophenyl)piperazinyl]ethyl}amine] (Compound 13).
(h) 1- (4-Fluorophenyl) -4- (2- [benzothiazol-2-
yl]aminoethyl)piperazine dihydrochloride (m. p. 229-231 °C).
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[benzothiazol-2-yl{2- [4- (4-
fluorophenyl)piperazinyl]ethyl}amine] (Compound 14).
(i) 1-(2-Methoxyphenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine difumarate (m. p. 101-103 °C).
[benzothiazol-2-yl{2-[4-(2-
methoxyphenyl)piperazinyl]ethyl}amine] (Compound 15).
(j) 1-(2-Methoxyphenyl)-4-(3-[benzothiazol-2-
yl]aminopropyl) piperazine hydrobromide (m. p. 195-197 °C).
[benzothiazol-2-yl{3-[4-(2-methoxyphenyl)piperazinyl]propyl}
amine] (Compound 16).
(k) 1-(2-Methoxyphenyl)-4-(2-[4-methoxybenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 17, m.p. 171-
173 °C) .
(1) 1-(2-Methoxyphenyl)-4-(2-[4-methylbenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 18, m.p. 226-
227 °C).
(m) 1-(2-Methoxyphenyl)-4-(2-[4-chlorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 19, m.p. 194-
195 °C). ((4-chlorobenzothiazol-2-yl){2-[4-(2-
methoxyphenyl)piperazinyl]ethyl} amine]
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(n) 1-(2-Methoxyphenyl)-4-(2-[6-ethoxybenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 20, m.p. 227-
228 °C).
(o) I-(2-Methoxyphenyl)-4-(2-[6-
methylsulfonylbenzothiazol-2-yl]aminoethyl)piperazine
hydrobromide (Compound 21, m.p. 190-196 °C) [2- ( {2- [4- (2-
methoxyphenyl)piperazinyl)ethyl}amino)-6-
(methylsulfonyl)benzothiazole]
(p) 1-(Pyrimidin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine difumarate (Compound 22, m.p. 179-180
°C) [(6-fluorobenzothiazol-2-yl)[2-(4-pyrimidin-2-
ylpiperazinyl)ethyl]amine]
(q) 1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine difumarate (Compound 23, m.p. 169-170
°C) .
(r) 1-Benzyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine difumarate (Compound 24, m.p. 228-229
°C) .
(s) 1-(4-Chlorobenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 25, m.p. 238-
240 °C) .
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(t) 1-(2-Ethoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 26, m.p. 235-
237 °C) .
(u) 1-(5-Fluoropyrimidin-2-yl)-4-(2-[6-
fluorobenzothiazol-2-yl]aminoethyl)piperazine hydrobromide
(Compound 27, m.p. 279-281 °C).
(v) 1-(5-Methylpyrimidin-2-yl)-4-(2-(6-
fluorobenzothiazol-2-yl]aminoethyl)piperazine hydrobromide
(Compound 28, m.p. 240-250 °C).
(w) 1- (Pyridin-2-yl) -4- (2- [6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 29, m.p. 259-
260 °C) .
(x) 1-(3-Trifluoromethylphenyl)-4-(2-[6-
fluorobenzothiazol-2-yl]aminoethyl)piperazine hydrobromide
(Compound 30, m.p. 259-261 °C).
(y) 1-Phenyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 31, m.p. 268-
270 °C) .
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(z) 1- (4-Fluorophenyl) -4- (2- [6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 32, m.p. 270-
271 °C) .
(aa) 1-(2-Isopropoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 33, m.p. 216-
217 °C) (alternatively named (6-fluorobenzothiazol-2-yl)[2-(4-
{[2-(methylethoxy)phenyl]methyl}piperazinyl)ethyl]amine]
(bb) 1-(2-Methoxybenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 34).
(cc) 1- (2-Isopropoxybenzyl) -4- (2- [6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine hydrobromide [(6-fluorobenzothiazol-2-
yl) [2- (4-{ [2-
(methylethoxy)phenyl]methyl}piperazinyl)ethyl]aminel (Compound
35) .
(dd) 1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzoxazol-2-
yl]aminoethyl)piperazine hydrochloride; (alternatively named
(6-fluorobenzoxazol-2-yl){2-[4-(2-
methoxyphenyl)piperazinyl]ethyl}amine] (Compound 36).
(ee) 1-(Pyrimidin-2-yl)-4-(2-[benzoxazol-2-
yl]aminoethyl)piperazine hydrochloride (Compound 37, m.p. 197-
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202 °C) [alternatively named benzoxazol-2-yl[2-(4-pyrimidin-2-
ylpiperazinyl)ethyl]amine].
(ff) 1-(Pyridin-2-yl)-4-(2-[benzoxazol-2-
yl]aminoethyl)piperazine hydrochloride (m.p. 255-265 °C)
[alternatively named benzoxazol-2-yl[2-(4-(2-
pyridyl)piperazinyl)ethyl]amine (Compound 3).
(gg) 1-(2-Methoxyphenyl)-4-(2-[benzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 38, m.p. 215-
216 °C) [benzimidazol-2-yl(2- [4- (2-
methoxyphenyl)piperazinyl]ethyl} amine]
(hh) 1-Phenyl-4- (2- [benzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 39, m.p. 241-
247 °C) .
(ii) 1-(Pyridin-2-yl)-4-(2-[benzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 42, m.p. 290-
291 °C) .
(jj) 1-(Pyridin-2-yl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide; [(1-ethylbenzimidazol-2-
yl) [2- (4- (2-pyridyl) piperazinyl) ethyl] amine] (Compound 41) .
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(kk) 1-(Pyridin-2-yl)-4-(2-[1-isopropylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 42).
(11) 1-(2-Methoxyphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 43, m.p. 273-
274 °C).
(mm) 1-(2-Isopropoxylphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 44, m.p. 285
°C, dec) .
(nn) i- (3-Trifluoromethylphenyl) -4- (2- [1-
methylbenzimidazol-2-yl]aminoethyl)piperazine hydrobromide
(Compound 1, m.p. 283 °C, dec) [alternatively named (1-
methylbenzimidazol-2-yl)(2-{4-[3-
(trifluoromethyl)phenyl]piperazinyl}ethyl)amine].
(oo) 1-(2-Methoxyphenyl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 45, m.p. 109-
110 °C) .
(pp) 1-Phenyl-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 46, m.p. 270
°C, dec) .
-42-
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(qq) 1-Phenyl-4-(2-[1-isopropylbenzimidazol-2-
yl]aminoethyl)piperazine hydrobromide (Compound 47).
(rr) benzothiazol-2-yl[2-(4-(2-naphthyl)piperazinyl)ethyl]
amine (Compound 4).
Example 5
The following salts are prepared essentially according to
the procedures set forth above in Examples 1-6 and, where
necessary, with reference to literature methods for preparing
pharmaceutically acceptable salts.
1-(5-Fluorogyrimidin-2-yl)-4-(2-[6-benzothiazol-2-
ylamino]butyl) piperazine (Compound 48).
1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
ylamino] ethyl) piperazine (Compound 49) .
(a) 1-(Pyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine (Compound 50).
(b) 1-(Pyrimidin-2-yl)-4-(4-[benzothiazol-2-
yl]aminobutyl)piperazine (Compaund 51).
(c) 1-(5-Fluoropyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine (Compound 52).
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(d) 1-(5-Methylpyrimidin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl) piperazine (Compound 53).
(e) 1-Phenyl-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine (Compound 54).
(f) 1-(Pyridin-2-yl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine (Compound 55).
(g} 1-(4-Chlorophenyl)-4-(2-[benzothiazol-2-
y.l]aminoethyl)piperazine (Compound 56).
(h) 1-(4-Fluorophenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine (Compound 57).
(i) 1-(2-Methoxyphenyl)-4-(2-[benzothiazol-2-
yl]aminoethyl)piperazine (Compound 58).
(j) 1-(2-Methoxyphenyl)-4-(3-[benzothiazol-2-
yl]aminopropyl) piperazine (Compound 59).
(k) 1-(2-Methoxyphenyl)-4-(2-[4-methoxybenzothiazol-2-
yl]aminoethyl)piperazine (Compound 60).
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(1) 1-(2-Methoxyphenyl)-4-(2-[4-methylbenzothiazol-2
yl]aminoethyl)piperazine (Compound 61).
(m) 1-(2-Methoxyphenyl)-4-(2-[4-chlorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 62).
(n) 1-(2-Methoxyphenyl)-4-(2-[6-ethoxybenzothiazol-2-
yl]aminoethyl)piperazine (Compound 63).
(o) 1-(2-Methoxyphenyl)-4-(2-[6-
methylsulfonylbenzothiazol-2-yl]aminoethyl)piperazine (Compound
64 ) .
(p) 1-(Pyrimidin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 65).
(q) 1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 66).
(r) 1-Benzyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 67).
(s) 1-(4-Chlorobenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 68).
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(t) 1-(2-Ethoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 69).
(u) 1-(5-Fluoropyrimidin-2-yl)-4-(2-[6-
fluorobenzothiazol-2-yl]aminoethyl)piperazine (Compound 70).
(v) 1-(5-Methylpyrimidin-2-yl)-4-(2-[6-
fluorobenzothiazol-2-yl]aminoethyl)piperazine (Compound 71).
(w) 1-(Pyridin-2-yl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 72).
(x) 1- (3-Trifluoromethylphenyl) -4- (2- [6-
fluorobenzothiazol-2-yl]aminoethyl)piperazine (Compound 73).
(y) 1-Phenyl-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 74).
(z) 1-(4-Fluorophenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 75).
(aa) 1-(2-Isopropoxyphenyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 76).
(bb) 1-(2-Methoxybenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 77).
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(cc) 1-(2-Isopropoxybenzyl)-4-(2-[6-fluorobenzothiazol-2-
yl]aminoethyl)piperazine (Compound 78).
(dd) 1-(2-Methoxyphenyl)-4-(2-[6-fluorobenzoxazol-2-
yl]aminoethyl)piperazine (Compound 79).
(ee) 1-(Pyrimidin-2-yl)-4-(2-(benzoxazol-2-
yl]aminoethyl)piperazine (Compound 80).
(ff) 1-(Pyridin-2-yl)-4-(2-[benzoxazol-2-
yl]aminoethyl)piperazine (Compound 81).
(gg) 1-(2-Methoxyphenyl)-4-(2-(benzimidazol-2-
yl]aminoethyl)piperazine (Compound 82).
(hh) 1-Phenyl-4- (2- [benzimidazol-2-
yl]aminoethyl)piperazine (Compound 83).
(ii) 1-(Pyridin-2-yl)-4-(2-[benzimidazol-2-
yl]aminoethyl)piperazine (Compound 84).
(jj) 1-(Pyridin-2-yl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine (Compound 85).
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(kk) 1-(Pyridin-2-yl)-4-(2-[1-isopropylbenzimidazol-2
yl]aminoethyl)piperazine (Compound 86).
(11) 1-(2-Methoxyphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine (Compound 87).
(mm) 1-(2-Isopropoxylphenyl)-4-(2-[1-methylbenzimidazol-2-
yl]aminoethyl)piperazine (Compound 88).
(nn) 1- (3-Trifluoromethylphenyl) -4- (2- [1-
methylbenzimidazol-2-yl]aminoethyl)piperazine (Compound 89).
(oo) 1-(2-Methoxyphenyl)-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine (Compound 90).
(pp) 1-Phenyl-4-(2-[1-ethylbenzimidazol-2-
yl]aminoethyl)piperazine (Compound 91).
(qq) 1-Phenyl-4-(2-[1-isopropylbenzimidazol-2-
yl]aminoethyl)piperazine (Compound 92).
Example 6
Assays For D~, D3 and D4 Receptor HindinQ Activitv
Pellets of COS cells containing recombinantly produced D2
or D4 receptors from human are used for the assays. The sample
is homogenized in 100 volumes (w/vol) of 0.05 M Tris HC1 buffer
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at 4° C and pH 7.4. The sample is then centrifuged at 30,000 x
g and resuspended and rehomogenized. The sample is then
centrifuged again at 30,000 x g and the final tissue sample is
frozen until use. The tissue is resuspended 1:20 (wt/vol) in
0.05 M Tris HC1 buffer containing 100 mM NaCl.
Incubations are carried out at 48°C and contain 0.4 ml of
tissue sample, 0.5 nM 3H-YM 09151-2 (Nemonapride, cis-5-Chloro-
2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-
pyrrolidinyl)benzamide) and the compound of interest in a total
incubation of 1.0 ml. Nonspecific binding is defined as that
binding found in the presence of 1 mM spiperone; without
further additions, nonspecific binding is less than 20~ of
total binding. The binding characteristics of examples of the
invention for D2 and D4 receptor subtypes are shown in Table 2
for rat striatal homogenates.
Table 2
Compound Number D4 Ki (nM) D2 Ki (nM)
I 3 >10,000
2 1 175
3 11 >10,000
6 6 1637
The binding constants of compounds of Formula I for she
receptor, expressed in nM, generally range from about 0.1
nanomolar (nM) to about 75 nanomolar (nM). Preferably, such
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CA 02345944 2001-03-29
WO 00/18767 PCT/US99/22791
compounds have binding constraints of from about 0.1 to 20 nM.
These compounds typically have binding constants for the DZ
receptor of at least about 100 nM. Thus, the compounds of the
invention are generally at least about 10 time more selective
for the D, receptor than the DZ receptor. Preferably, these
compounds are at least 20, and more preferably at least 25-50,
times more selective for the D, receptor than the Dz receptor.
Most preferably, the compounds of Formula I are at least 500
times more selective for the D, receptor than the DZ receptor.
The invention and the manner and process of making and
using it, are now described in such full, clear, concise and
exact terms as to enable any person skilled in the art to which
it pertains, to make and use the same. It is to be understood
that the foregoing describes preferred embodiments of the
present invention and that modifications may be made therein
without departing from the spirit or scope of the present
invention as set forth in the claims. To particularly point
out and distinctly claim the subject matter regarded as
invention, the following claims conclude this specification.
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Representative Drawing