1-N-phenylamino-1H-imidazole derivatives as aromatase...

Details 1-N-phenylamino-1H-imidazole derivatives as aromatase... 1-N-phenylamino-1H-imidazole derivatives as aromatase...

2002-12-16

2004-05-18

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S331100

Reexamination Certificate

active

06737433

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to 1-N-phenylamino-1H-imidazole derivatives as aromatase inhibitors and to pharmaceutical compositions containing them.
Aromatase is the physiological enzyme responsible for the specific conversion of androgens such as androstenedione or testosterone, into estrogens such as estrone and estradiol, respectively (Simpson E R et al., Endocrine Reviews, 1994, 15: 342-355). Inhibition of aromatase iso, therefore, a strategy of choice to interfere with normal or pathological estrogen-induced or estrogen-dependent biological processes such as female sexual differentiation, ovulation, implantation, pregnancy, breast and endometrial cell proliferation as well as regulation of spermatogenesis or prostate cell proliferation in male or of non-reproductive functions such as bone formation or immune T cell and cytokine balance (Simpson E R et al., Recent Progress in Hormone Research, 1997, 52: 185-213 and the whole issues of Endocrine Related Cancer (1999, volume 6, n° 2) and Breast Cancer Research Treatment (1998, volume 49, supplement n° 1)).
A large number of azole derivatives are known as antifungal agents. Some imidazole or triazole derivatives have already been described as inhibitors of the enzyme aromatase. Generally, the imidazolyl or the triazolyl group is associated with aromatic rings as found in letrozole (EP-A-236 940; Lamb H M and Adkins J C, Drugs, 1998, 56: 1125-1140):
or anastrozole (EP-A-296 749; Wiseman L R and Adkins J C, Drugs Aging, 1998, 13: 321-332):
Imidazoles or triazoles linked via a methylene group to a benzotriazole are described in EP-A-293 978:
Diterbutyl phenols having a N-amino-imidazole moiety in the para position are described in U.S. Pat. No. 4,908,363 and are presented as having inflammation-inhibiting and oedema-inhibiting properties:
More recently, M. OKADA et al. (Chem. Pharm. Bull., 44 (10), 1996, 1871-1879) described a series of [4-(bromophenylmethyl)-4-(cyanophenyl)amino]-azoles and their azine analogs:
SUMMARY OF THE INVENTION
It has now been found that imidazole derivatives which invariably contain a 1-[N-phenylamino]group demonstrate an unexpectedly high potency to inhibit aromatase.
Accordingly, one object of this invention is to provide 1-[N-phenylamino]imidazole derivatives which are potent aromatase inhibitors.
Another object of this invention is to provide a pharmaceutical composition containing, as active ingredient, a 1-[N-phenylamino]imidazole derivative as depicted below or a pharmaceutically acceptable acid addition salt thereof.
A further object of this invention is to provide the use of a 1-[N-phenylamino]imidazole derivative in the manufacture of a medicament intended for treating or preventing various diseases and for managing reproductive functions in women, in men as well as in female and male wild or domestic animals.
The 1-[N-phenylamino]imidazole derivatives of this invention are represented by the following general formula (I):
and acid addition salts, solvates and stereoisomeric forms thereof, wherein:
R
1
and R
2
are each independently hydrogen, a (C
1
-C
6
)alkyl or a (C
3
-C
8
)cycloalkyl;
n=0, 1, 2;
R
3
, R
4
, R
5
and R
6
are each independently hydrogen, or a (C
1
-C
6
)alkyl, halogen, cyano, (C
1
-C
6
)alkoxy, trifluoromethyl, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkylsulfonyl, sulfonamido, acyl, (C
1
-C
6
)alkoxycarbonyl, or carboxamido group;
R
3
and R
6
together with the phenyl ring bearing them can also form a benzofurane or a N-methylbenzotriazole.
DETAILED DESCRIPTION OF THE INVENTION
In the description and claims, the term “(C
1
-C
6
)alkyl” is understood as meaning a linear or branched hydrocarbon chain having 1 to 6 carbon atoms. A (C
1
-C
6
)alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl radical.
The term “halogen” is understood as meaning a chlorine, bromine, iodine or fluorine atom.
The term “(C
3
-C
8
)cycloalkyl” is understood as meaning a saturated monocyclic hydrocarbon having 3 to 8 carbon atoms. A (C
3
-C
8
)cycloalkyl radical is for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical.
The term “(C
1
-C
6
)alkoxy” is understood as meaning a group OR in which R is a (C
1
-C
6
)alkyl as defined above. A (C
1
-C
6
)alkoxy radical is for example a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentyloxy or isopentyloxy radical.
The term “acyl” is understood as meaning a group
in which R′ is hydrogen or a (C
1
-C
6
)alkyl as defined above.
Compounds of formula (I) form acid addition salts, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic carboxylic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid and the like.
Preferred compounds of formula (I) are those wherein:
n is 0 or 1;
R
1
and R
2
are each independently hydrogen or (C
1
-C
6
)alkyl;
R
3
is cyano or trifluoromethyl;
R
4
is hydrogen, (C
1
-
6
)alkyl, halogen, cyano, (C
1
-C
6
)alkoxy, trifluoromethyl, (C
1
-C
6
)alkylthio, (C
1
-C
6
)alkylsulfonyl or (C
1
-C
6
)alkoxycarbonyl;
R
5
is hydrogen, halogen, (C
1
-C
6
)alkoxy or trifluoromethyl;
R
6
is hydrogen;
or R
3
and R
6
together with the phenyl ring form a N-methylbenzotriazole.
Also preferred are the compounds of formula (I) wherein:
n is 0 or 1;
R
1
, R
2
and R
6
are each hydrogen;
R
4
is halogen, cyano or trifluoromethyl.
Especially preferred compounds of formula (I) are those wherein R
3
is cyano; those wherein R
5
is hydrogen or trifluoromethyl; and those wherein n is 1.
Valuable compounds are selected from the group consisting of:
4-[N-(1H-imidazol-1-yl)-N-(4-trifluoromethylphenylmethyl)amino]benzonitrile
4-[N-(1H-imidazol-1-yl)-N-(4-chlorophenylmethyl)amino]benzonitrile,
4-[N-(1H-imidazol-1-yl)-N-(4-cyanophenylmethyl)amino]benzonitrile,
4,4′-[N-(1H-imidazol-1-yl)amino]bis-benzonitrile,
4-[N-(1H-imidazol-1-yl)-N-(4-fluorophenylmethyl)amino]benzonitrile,
4-[N-(1H-imidazol-1-yl)-N-(3,4-difluorophenylmethyl)amino]benzonitrile, and the acid addition salts, solvates or stereoisomeric forms thereof.
By virtue of their capability to inhibit aromatase, and thus to exhaust all sources of endogenous estrogens, the compounds of the present invention can be used alone or in combination with other active ingredients for the treatment or the prevention of any estrogen-dependent disorder or for the management of estrogen-regulated reproductive functions, in humans as well as in wild or domestic animals.
The breasts being sensitive targets of estrogen-stimulated proliferation and/or differentiation, inhibitors of aromatase are especially useful in the treatment or prevention of benign breast diseases in women, gynecomastia in men and in benign or malignant breast tumors with or without metastasis both in men and women (Brodie A M and Njar V C, Steroids, 2000, 65: 171-179; Pritchard K I, Cancer, 2000, 85, suppl 12: 3065-3072), or in male or female domestic animals.
Due to the involvement of estrogens in the mechanisms of ovulation, implantation and pregnancy, inhibitors of aromatase according to the invention can be used, respectively, for contraceptive, contragestive or abortive purposes in women (Njar V C and Brodie A M, Drugs, 1999, 58: 233-255) as well as in females of wild or domestic animal species.
The uterus is another reproductive organ responsive to estrogenic stimulation and inhibition of aromatase is therefore useful to treat or prevent endometriosis, benign uterine diseases or benign or malignant uterine tumors with or without metastasis in women (Njar V C and Brodie A M, Drugs, 1999, 58: 233-255) or in female domestic animals.
The ovary being the physiological source of estrogen, inhibitors

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