Cyanophenyl derivative

Details Cyanophenyl derivative Cyanophenyl derivative

2001-03-21

2004-01-06

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S395000, C544S360000, C544S390000, C514S255030, C514S255010

Reexamination Certificate

active

06673799

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel cyanophenyl derivatives useful as medicaments, particularly as an anti-androgen, and salts and pharmaceutical compositions thereof.
BACKGROUND ART
Androgen as a steroid hormone is secreted from testis and adrenal cortex and induces male sex hormone actions. Androgen, when incorporated into target cells, acts upon an androgen receptor and the receptor to which androgen binds forms a dimer. Subsequently, this dimer binds to an androgen-response-element on DNA to accelerate synthesis of mRNA and to thereby induce proteins which control the androgen actions, thus expressing various actions within living organism (
Prostate Suppl.,
6, 1996, 45-51, Trends in Endocrinology and Metabolism, 1998, 9 (8), 317-324).
Prostatic cancer, benign prostatic hyperplasia, virilism, hirsutism, baldness, acne, seborrhea and the like can be exemplified as diseases which are progressed by androgen. Accordingly, anti-androgens are used for the treatment of these diseases in which androgen is concerned.
Anti-androgens, which have substrate resembling steroidal structure or nono-steroidal structure are currently used in the clinical field. Though chlormadinone acetate and the like are known as the steroidal anti-androgen, it is known that, since separation of actions of these compounds from other steroids having similar structures is not sufficient, they cause changes in the blood hormone level and induces serious side effects such as reduction of libido and the like (
Jpn. J. Clin. Oncol.,
1993, 23 (3), 178-185). On the other hand, flutamide (JP-A-49-81332; the term “JP-A” as used herein means an “unexamined published Japanese patent application”), bicalutamide (GB 8221421, WO 95/19770) and the like acylanilide derivatives are known as non-steroidal anti-androgens, but their anti-androgenic actions are not sufficient. Thus, combined therapy with an LH-RH agonist is usual for the treatment of prostatic cancer (Nipponrinsho, 1998, 56 (8), 2124-2128).
Regarding the compounds having piperazinocyanophenyl skeletons, substances having oxitocin and vasopressin receptor antagonism are disclosed in WO 95/25443, and substances having 5HT receptor antagonism in WO 96/02525, substances as intercellular mutual action inhibitors in DE 4234295, substances as production intermediates of cell adhesion inhibitors in WO 97/2245 and substances having antitumor actions in WO 98/00402 and WO 98/21648, but they do not disclose or suggest on anti-androgen actions.
DISCLOSURE OF THE INVENTION
The object of the invention is to provide a novel cyanophenyl derivative and salts thereof having strong anti-androgen actions and to further provide medicaments containing the same.
With the aim of solving the aforementioned problems incidental to the existing anti-androgens, the inventors of the invention have conducted intensive studies and found unexpectedly that a novel cyanophenyl derivative to which a substituted carbamoyl or substituted sulfamoyl group is bound has strong anti-androgen actions and good oral activities, thus resulting in the accomplishment of the invention.
Accordingly, the invention relates to a cyanophenyl derivative represented by the following general formula (I) or a salt thereof
wherein each symbol has the following meaning,
R: cyano or nitro group,
R
1
: a hydrogen atom, a halogen atom or a cyano, halogeno-lower alkyl, vitro, carboxyl, lower alkyl, R
6
—A—, R
7
—S(O)
p
—, lower alkyl-C(═O)— or lower alkyl-O—C(═O)— group,
R
2
, R
3
and R
4
: these may be the same or different from one another and each means a hydrogen atom, a lower alkyl group, a carbamoyl group which may be substituted by 1 or 2 lower alkyl groups, a lower alkyl-C(═O)—, lower alkyl-O—C(═O)— group, wherein R
2
and R
3
bind to optional carbon atoms on the ring,
R
5
: a lower alkyl; aryl-lower alkyl-O—; carboxyl; lower alkyl-O—C(═O)—; amido which may be substituted by 1 or 2 lower alkyl groups; or aryl, heterocyclic or cycloalkyl group which may have a substituent group; N(R
13
)R
14
-lower alkyl-O—; with the proviso that when m=1, R
4
and R
5
may together form a five- or six-membered heterocycle which may have other hetero atom,
R
6
: a halogeno-lower alkyl; aryl; or lower alkyl which may be substituted by N(R)R
10
, OH or lower alkyl-O—,
R
7
: a lower alkyl, aryl or N(R
11
)R
12
—,
R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
: hydrogen, lower alkyl or aryl, with the proviso that R
6
and R
8
, R
9
and R
10
or R
13
and R
14
may together form a nitrogen-containing cycloalkyl which may have other hetero atom and may have la substituent group,
k or n: 1, 2 or 3,
m: 0 or 1,
p: 0, 1 or 2,
A: an oxygen atom or NR
8
,
X═—C(═O)—, —C(═S)— or —S(O)
2
— group,
Y: a bond, lower alkylene, —C(═O)— or —S(O)
2
— group,
with the proviso that, when R
5
is a lower alkyl group, Y is a group other than lower alkylene, and Z
1
or Z
2
: these may be the same or different from each other and each means CH or nitrogen atom,
with the proviso that 1) when R
1
is hydrogen atom, at least one of R
2
and R
3
is a lower alkyl, 2) when R is a nitro group, X is —C(═O)— or —S(O)
2
—, and n is 1, k is 2 and m is 0, at least one of R
2
and R
3
is a group other than a hydrogen atom, and 3) when R is a cyano group, Z
1
is a nitrogen atom, and X is —C(═O)— and n is 1, k is 2, m is 0, and R
5
is a methyl group, R
1
is a group other than a fluorine atom.
Preferred is a cyanophenyl derivative or a salt thereof according to the first aspect of the invention, wherein R is a cyano group;
also preferred is a cyanophenyl derivative or a salt thereof according to the first aspect of the invention, wherein R
1
is a halogen atom, cyano, halogeno-lower alkyl, nitro or lower alkyl-O—; R
2
and R
3
: at least one of them is a lower alkyl group; R
4
: a hydrogen atom or a lower alkyl group; R
5
: an aryl, heterocyclic or cycloalkyl group which may have substituent(s) group; k is 2, n is 1; m is 1, X is —C(═O)— group; Y is a bond; and Z
1
or Z
2
both means CH;
more preferred is a cyanophenyl derivative according to the first or second aspect of the invention, wherein the substituent group of the aryl, heterocyclic or cycloalkyl group of R
5
which may have substituent(s) is a radical selected from the group consisting of a halogen atom, halogeno-lower alkyl, lower alkyl, lower alkyl-O—, lower alkyl-S—, lower alkyl-S(═O)—, lower alkyl-S(O)
2
—, sulfamoyl which may be substituted by 1 or 2 lower alkyl groups, halogeno-lower alkyl-O—, cyano, nitro, oxo(═O), lower alkyl-C(═O)—, aryl-C(═O)—, amino which may be substituted by 1 or 2 of lower alkyl or lower alkyl-C(═O)— or lower alkyl-O-C(═O)—, aryl-O—, amino-O—, carbamoyl which may be substituted by a lower alkyl, carboxyl, lower alkyl-O— C(═O)—, heterocyclic and OH group; and
most preferred is a compound, or a salt thereof, selected from (2R,5S)4-(4-cyano-3-trifluoromethylphenyl)-N-(6-methoxy-3-pyridyl)-2,5-dimethylpiperazine-1-carboxamide; (2R,5S)-N-(2-amino-pyrimidin-4-yl)-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carboxamide; (2R,5S)-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethyl-N-(6-trifluoromethyl-3-pyridyl)piperazine-1-carboxamide; (2R,5S)-4-(4-cyano-3-trifluoromethylphenyl)-N-(2-fluoro-4-pyridyl)-2,5-dimethylpiperazine-1-carboxamide; and (2R,5S)-N-(2-bromo-4-pyridyl)-4-(4-cyano-3-trifluoromethylphenyl)-2,5 -dimethylpiperazine-1-carboxamide.
Another object of the invention is a pharmaceutical composition which comprises the cyanophenyl derivative of general formula (I) or a salt thereof as the active ingredient;
preferably an anti-androgen agent which comprises the cyanophenyl derivative of general formula (I) or a salt thereof as the active ingredient; and
more preferably a therapeutic agent for diseases which are progressed by androgen, which comprises the cyanophenyl derivative of general formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient, wherein the diseases which are progressed by androgen include prostatic cance

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