Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-26
2003-04-15
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06548502
ABSTRACT:
The present invention relates to a method of treating or preventing a novelty-seeking disorder selected from pathological gambling, attention deficit disorder with hyperactivity disorder, substance addiction, such as drug addiction and alcohol addiction, and sex addiction, using a dopamine D4 ligand. It also relates to a method of treating or preventing such disorders in mammals by administering a pyrido[1,2a]pyrazine derivative, benzimidazole derivative, bicyclic compound, spirocyclic benzo furan derivative, indole derivative or a related compound that is a dopamine D4 receptor ligand.
It has been determined that dopamine D4 receptors are related to various behavioral and personality disorders including novelty seeking disorders (See, e.g., Tarazi et al.,
Mol. Psychiatry,
4, 529-538(1999). The trait of novelty seeking was found to be related to dopaminergic activity in alcoholic men (Wiesbeck et al.,
Psychoneuroendocrinology,
20, 7(1999)). A large Finnish study provides support for an association between the D4 receptor gene (DRD4) and the behavioral trait of novelty seeking (Ekelund et al.,
Am. J. Psychiatry,
156, 1453-5 (1999)). Recent evidence has accumulated which supports a clinical linkage between attention deficit disorder with hyperactivity disorder, which has been associated with the novelty seeking trait, and dopamine receptor expression (see, e.g., Tarazi et al., supra; Anderson et al.,
Neuroscience
&
Biobehavioral Rev.,
24, 137-41 (2000)) and dopamine transporter gene expression (see, e.g., Dougherty et al.,
The Lancet,
354, 2132-2133 (1999)). Further evidence has been found for an association between the D4 gene and a susceptibility to pathological gambling (Comings,
CNS Spectr.,
3, 20-37 (1998)) and a susceptibility to opioid addiction and substance abuse (Kotler et al.,
Mol. Psychiatry,
2, 251-254 (1997)).
The following references refer, collectively, to pyrido[1,2a]pyrazine derivatives, benzimidazole derivatives, bicyclic compounds, spirocyclic benzofuran derivatives, indole derivatives or related compounds that exhibit activity as dopamine D4 receptor ligands: U.S. Pat. No. 5,852,031, issued on Dec. 22, 1998; U.S. Pat. No. 5,883,094, issued on Mar. 16, 1999; U.S. Pat. No. 5,889,010, issued on Mar. 30, 1999; PCT International Application PCT/IB97/00978, published as WO98/08835 on Mar. 5, 1998; U.S. patent application Ser. No. 5,877,317 issued on Mar. 2, 1999; U.S. patent application Ser. No. 5,021,420, issued on Jun. 4, 1991; U.S. patent application Ser. No. 5,633,376, issued on May 27, 1997; U.S. patent application, Ser. No. 5,432,177, issued on Nov. 9, 1994; U.S. patent application Ser. No. 5,622,950, issued on Apr. 22, 1997, PCT International Application No. PCT/EP93/01438, published as WO94/00458 on Jan. 6, 1994; PCT International Application No. PCT/IB98/01198, published as WO99/09025 on Feb. 25, 1999; U.S. patent application Ser. No. 5,998,414, issued on Dec. 7, 1999; U.S. patent application Ser. No. 5,968,478, issued on Oct. 19, 1999; U.s. patent application Ser. No. 6,040,448, issued on Mar. 21, 2000; U.S. patent application Ser. No. 6,051,605, issued on Apr. 18, 2000; U.S. patent application Ser. No. 5,945,421, issued on Aug. 31, 1999; and U.S. patent application Ser. No. 5,798,350, issued on Aug. 25, 1998. All of the foregoing PCT International Applications designate the United States. The foregoing patents and patent applications are incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
This invention relates to a method of treating or preventing a novelty-seeking disorder selected from pathological gambling, attention deficit disorder with hyperactivity disorder (ADHD), substance addiction (e.g., drug addiction and alcohol addiction) and sex addiction in a subject, including a human, comprising administering to the subject an effective amount of:
(a) a compound of formula I:
wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, or benzoxazolyl;
Ar
1
is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzisoxazolyl, or benzisothiazolyl; A is O, S, SO, SO
2
, C═O, CHOH, or —(CR
3
R
4
)—; n is 0, 1 or 2; each of Ar and Ar
1
may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO
2
R, —NHSO
2
R, —(C1-C6)alkoxy, —NR
1
R
2
, —NRCOR
1
, —CONR
1
R
2
, Ph, —COR, COOR, —(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkyl substituted with one to six halogens, —(C
3
-C
6
)cycloalkyl, and trifluoromethoxy;
each and every R, R
1
, and R
2
is independently selected from the group consisting of hydrogen, —(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, —(C
2
-C
6
)alkenyl, —(C
3
-C
6
)cycloalkyl, and —(C
1
-C
6
)alkoxy;
each and every R
3
and R
4
is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, or i-propyl; diastereomeric and optical isomers thereof; and pharmaceutically acceptable salts thereof;
(b) a compound of formula II:
II:
wherein X
1
, X
2
and X
3
are independently selected from carbon and nitrogen;
R
0
, R
1
and R
2
are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms and (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
R
3
is hydrogen, (C
1
-C
6
)alkyl or benzyl, wherein the phenyl moiety of said benzyl group may optionally be substituted with from one or more substituents, preferably with from zero to three substituents, independently selected from halo (e.g., chloro, fluoro, bromo or iodo), cyano, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkylsulfonyl, (C
1
-C
6
)alkylamino, amino, di—(C
1
-C
6
)alkylamino and (C
1
-C
6
)carboxamido;
R
4
, R
5
and R
6
are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), cyano, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkylsulfonyl, (C
1
-C
6
)acylamino, (phenyl)[(C
1
-C
6
)acyl]amino, amino, (C
1
-C
6
)alkylamino and di-(C
1
-C
6
)alkylamino;
with the proviso that when X
3
is nitrogen, R
2
is absent;
(c) a compound of formula III:
wherein each of the dotted lines represents an optional double bond;
X is carbon or nitrogen;
R
1
is benzyl, aryl selected from phenyl, indanyl and naphthyl, or heteroaryl selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl, wherein each of the foregoing aryl, heteroaryl and (C
1
-C
4
)alkyl groups, and the phenyl moiety of the benzyl group, may optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from halo (e.g., chloro, fluoro, bromo or iodo), (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms, cyano, —C(═O)R
8
, aryl and heteroaryl, wherein said aryl is selected from phenyl, indanyl and naphthyl and said heteroaryl is selected from pyridyl, thienyl, fiuyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;
R
2
and R
3
are independently selected from hydrogen, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, cyano, —CONH
2
and —NHC(═O)R
9
, or R
2
and R
3
together form an oxo group;
R
4
is hydrogen, sulfur, oxygen, (C
1
-C
6
)alkyl, amino, —NHR
10
, —SR
10
, OR
10
or hydroxy;
R
5
, R
6
and R
7
are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), cyano, (C
1
-C
6
)alkyl optionall
Fliri Antor F.
Sanner Mark A.
Seymour Patricia A.
Zorn Stevin H.
Ginsburg P. H.
Joran A. D.
Pfizer Inc
Richardson P. C.
Spivack Phyllis G.
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