Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-02
2001-06-12
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S082000, C546S199000, C548S151000, C548S218000, C548S242000, C548S257000, C548S302100, C548S359500
Reexamination Certificate
active
06245796
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel tricyclic pyrrole or pyrazole derivative or a pharmaceutically acceptable salt thereof. This invention also relates to a pharmaceutical composition which comprises said tricyclic pyrrole or pyrazole derivative or a salt thereof and a pharmaceutically acceptable carrier, especially a pharmaceutical composition which is useful as a drug for the prevention and treatment of central nervous system diseases such as sexual disorders, eating disorders, anxiety, depression and sleeping disorders.
BACKGROUND ART
With the advance of aging society, improvement and betterment of living conditions for the aged have been reconsidered, so that attention has been focused on the prevention and treatment of diseases which have so far been disregarded as diseases (e.g., sexual disorders and the like).
Though the role of the 5-HT
2C
receptor which is mainly distributed in the central nerve has not been sufficiently revealed, it is considered that this receptor is related to the central nervous system diseases such as sexual disorders, eating disorders, anxiety, depression and sleeping disorders (
Curr. Opin. Invest. Drugs,
2 (4), 317 (1993)). In consequence, it is believed that the 5-HT
2C
receptor ligand is effective for the prevention or treatment of the aforementioned diseases, particularly diseases which have so far been disregarded as diseases and have no effective therapeutic method (e.g., sexual disorders and the like).
Regarding tricyclic pyrrole or pyrazole derivatives which are 5-HT
2C
receptor ligands, a tricyclic pyrrole derivative fused with a benzene ring (EP 657426-A), a tricyclic pyrazole derivative fused with a benzene ring (EP 700905-A) and the like have been reported.
In addition, a tricyclic pyrrole or pyrazole derivative which is fused with a pyrazine ring, a pyridine ring, a thiophene ring, a furan ring or a pyrrole ring is reported as a retinoid antagonist in International Publication WO 96/13478, and a compound having a tricyclic pyrrole or pyrazole nucleus which is fused with an aromatic heterocyclic ring and also has a substituent on a carbon atom of the pyrrole or pyrazole ring in said nucleus is reported as a dopamine receptor ligand in International Publication WO 95/07893.
DISCLOSURE OF THE INVENTION
As a result of extensive studies on a unknown tricyclic pyrrole or pyrazole derivative in which an amino group is linked at the 1-position via an alkylene chain and which is fused with an unsaturated heterocyclic ring, the inventors of the present invention have found that a novel tricyclic pyrrole or pyrazole derivative was possessed of high selectivity and affinity for the 5-HT
2C
receptor and accomplished the present invention.
Accordingly, the present invention relates to a novel tricyclic pyrrole or pyrazole derivative represented by the following general formula (I) which shows high selectivity and affinity for the 5-HT
2C
receptor, or a pharmaceutically acceptable salt thereof
(each symbol in the above formula means as follows;
Y ring: an unsaturated five-membered ring which may have 1 to 3 of one or more types of hetero atom(s) each selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom or an unsaturated six-membered ring having 1 or 2 nitrogen atom(s),
X: a bond or a carbon atom,
a double bond or a single bond,
V: a nitrogen atom or a group represented by a formula CH,
A: a straight or branched lower alkylene group which may be substituted with a halogen atom or a cycloalkyl group,
R
1
and R
2
: may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group, or
R
1
and R
2
or A may form a nitrogen-containing saturated heterocyclic ring together with the adjacent nitrogen atom,
R
3
and R
4
: may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino group or a halogen atom, and
R
5
to R
9
: may be the same or different from one another and each represents a hydrogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group,
with the proviso that, when
is a double bond, then R
6
and R
9
do not exist and that, when X is a bond, then
is a single bond and R
7
and R
8
do not exist).
The compound (I) of the present invention is characterized by its chemical structure in which an amine is linked to the 1-position of the tricyclic pyrrole or pyrazole nucleus fused with an unsaturated heterocyclic ring, always via an alkylene chain.
Among the compounds (I) of the present invention, the compounds wherein
are preferable, the compounds in which A is ethylene or propylene group are more preferable, the compounds in which the Y ring is furan or thiophene are still more preferable, and 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine, 2-(7-bromo-1H-thieno[2,3-g]indazol-1-yl)ethylamine, 2-(7-iodo-1H-thieno[2,3-g]indazol-1-yl)ethylamine, 2-(7-methoxy-1H-thieno[2,3-g]indazol-1-yl)ethylamine, (S)-2-(1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, 2-(7-methyl-1H-thieno[2,3-g]indazol-1-yl)ethylamine, (S)-2-(7-methoxy-1H-thieno[2,3-g]indazol-1-yl)-1-methylethylamine, (S)-1-methyl-2-(7-methyl-1H-thieno[2,3-g]indazol-1-yl)ethylamine, 2-(7-ethyl-1H-thieno[2,3-g]indazol-1-yl)ethylamine, (S)-2-(7-ethyl-1H-thieno[2,3-g]indazol-1-yl)-1-methylethylamine or a pharmaceutically acceptable salts thereof are particularly preferable.
The present invention is to provide a pharmaceutical composition which comprises a tricyclic pyrrole or pyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, preferably a pharmaceutical composition which shows high selectivity and affinity for the 5-HT
2C
receptor, more preferably a pharmaceutical composition which is a drug for the treatment of central nervous system diseases including sexual disorders such as impotence, eating disorders such as obesity, bulimia and anorexia, anxiety, depression or sleeping disorders, most preferably a pharmaceutical composition which is a drug for the treatment of sexual disorders such as impotence.
The following describes the compound (I) of the present invention in detail.
The term “5-HT
2C
receptor ligand” means a compound which has the affinity for the 5-HT
2C
receptor and shows agonism or antagonism.
In the definition of the general formula as used herein, unless otherwise noted, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms.
Illustrative examples of the “lower alkylene group” include methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene and the like, of which ethylene group and propylene group are preferred.
Illustrative examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and the like, of which alkyl groups having 1 to 4 carbon atoms are preferred and methyl group is particularly preferred.
The term “cycloalkyl group” means a monocyclic hydrocarbon ring group having 3 to 8 ring atoms, and its illustrative examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, of which cyclohexyl group is preferred.
The term “lower alkoxy group” means an oxy group substituted with the aforementioned lower alkyl group.
The term “mono- or di-lower alkylamino group” means an amino group substituted with 1 or 2 of the aforementioned lower alkyl groups.
The term “lower alkanoylamino group” means a carbonylamino group substituted with hydrogen atom or the aforementioned lower alkyl group.
Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine atoms, of which chlorine, bromine or iodine atom is preferred.
Illustrative examples of the “five-membered unsaturated ring
Kazuta Ken-ichi
Kimizuka Tetsuya
Kubota Hideki
Maeno Kyoichi
Sakamoto Shuichi
Ramsuer Robert W.
Sughrue Mion Zinn Macpeak & Seas, PLLC
Yamanouchi Pharmaceutical Co. Ltd.
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