Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-24
2003-07-22
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S491000, C548S492000
Reexamination Certificate
active
06596753
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of an effective amount of at least one compound of the indolecarboxylic family for treating disorders associated with overactivity of 5&agr;-reductase, and more particularly androgen-dependent disorders.
2. Background of the Related Art
Androgens are hormones defined as belonging to the steroid family which have a specific structure.
Androgens act at many sites in the human body and are similarly involved in a large number of disorders, among which mention may be made of prostate carcinomas, benign hyperplasia of the prostate, acne, hursutism, seborrhoea, androgenic alopecia, cheloids and adhesions, ovarian polycystic syndrome, premenstrual syndrome, lung cancer in man, precocious puberty and Fox-Fordyce disease.
Androgens are lipid substances which easily cross cell membranes. The mechanism of action of androgens takes place by interaction with a receptor which is specific to them: the androgen receptor.
Testosterone emerges as the major androgen. The metabolic routes for the androgens, in particular for testosterone, are nowadays well known.
One of the metabolic routes for testosterone is its conversion via 5&agr;-reductase into dihydrotestosterone (DHT). Testosterone and DHT bind to the androgen receptor, but DHT has a much higher affinity for this receptor than testosterone. Furthermore, the DHT/receptor binding is much more stable than the testosterone/receptor binding.
Two isoforms of 5&agr;-reductase have been isolated and cloned to date. Type 1 5&agr;-reductase is mainly expressed in the skin and the various compartments of hair follicles, particularly in the keratinocytes of the epidermis and/or of the follicles, in the cells of the dermal papilla, the outer sheath of the hair follicles, the sebaceous glands and in the sweat glands.
Type 2 5&agr;-reductase is itself expressed in the epididymis, the seminal vesicles, the prostate, foetal genital skin or alternatively the inner sheath of the hair follicles or in the fibroblasts of adult genital skin.
Since type 1 5&agr;-reductase is mainly expressed in the skin and the various compartments of the hair follicles, the development of type 1 5&agr;-reductase inhibitors represents an approach of choice for treating androgen-dependent disorders, whether they are manifested in the skin or in the hair follicles.
It has long been sought to develop 5&agr;-reductase inhibitors as a treatment for androgen-associated disorders. Many compounds have been proposed in this conceptual vein. To date, two classes of inhibitor have been synthesized: steroidal inhibitors and non-steroidal inhibitors (see in this respect the article by Chen et al. “The 5&agr;-reductase system and its inhibitors” (Dermatology, 1996, 193, 177-184)).
Among the steroidal inhibitors, mention may be made of 6-azasteroid derivatives and especially 4-azasteroid derivatives, including [17p-(N-tert-butylcarbamoyl)-4-aza-5&agr;-androstan-1-en-3-one](finasteride), which is an inhibitor specific for the isotype 2, and 7&bgr;-methyl-4-azacholestan-3-one (MK-386), which is an inhibitor specific for the isotype 1. The drawback of steroidal inhibitors is that they have non-negligible side effects which make them problematic to use.
Among the non-steroidal inhibitors, mention may be made of certain benzoylaminophenoxybutanoic acid derivatives, benzoquinolines such as trans-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (LY 191704), 4-[3-([bis(4-isobutylphenyl)methylamino]benzoyl)-1H-indol-1-yl]butyric acid (FK143), polyunsaturated fatty acids, cations such as copper and zinc, and epicatechin derivatives. Similarly, indole derivatives have been described, such as, for example, in patent applications EP-458,207, EP-511,477, EP-600,084, EP-628,040, WO 91/13060, WO 93/02050, WO 93/02051, WO 93/05019, WO 93/16996, WO 94/27990, WO 95/05375, WO 95/23143, JP-07,304,736 and JP-07,188,164.
Relatively little has been described regarding the class of indolecarboxylic derivatives. Holt et al. (J. Med. Chem., 1995, 38, 13-15) have described molecules which have strong inhibitory activity with respect to type 2 5&agr;-reductase.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
Thus, a first subject of the invention relates to the use, in a composition, of an effective amount of at least one compound corresponding to the general formula (I)
in which X and Y, which may be identical or different,
represent a hydrogen atom or a radical —O—CHR
3
R
4
, in which R
3
is a hydrogen atom or an optionally substituted phenyl radical or alternatively a 5- or 6-membered heterocycle and R
4
is an optionally substituted phenyl radical or alternatively a 5- or 6-membered heterocycle, or R
3
and R
4
taken together form, with the carbon atom, a 5- or 6-membered ring or heterocycle;
or, taken together, form, with the 2 carbon atoms bearing them, a ring or a heterocycle containing 5 or 6 carbon atoms;
Z represents a hydrogen atom or a radical —O—R
5
in which R
5
is a C
1
-C
6
alkyl radical or a C
6
-C
12
aralkyl radical;
R
1
represents a hydrogen atom or a C
1
-C
6
alkyl radical or a C
6
-C
12
aralkyl radical which is optionally substituted;
R
2
represents a hydrogen atom or a C
1
-C
6
alkyl radical or a radical —CHR
3
R
4
, in which R
3
and R
4
have the above definitions;
it being understood that when R
2
is a hydrogen atom or a methyl radical and X is a hydrogen atom, then Y must be other than an —O—CH
2
Phenyl radical and Z must be other than a hydrogen atom, and that when R
2
is a hydrogen atom or a methyl radical and X is a hydrogen atom, then Y must be other than a hydrogen atom and Z must be other than an —O—CH
2
Phenyl radical and that R, X, Y and Z cannot simultaneously be a hydrogen atom, the compound or the composition being intended to treat disorders associated with androgens and/or with overactivity of 5&agr;-reductase.
The compounds of the invention corresponding to the formula (I) can be used, for example, to treat prostate carcinomas, benign hyperplasia of the prostate, acne, hirsutism, seborrhoea, androgenic alopecia, cheloids and adhesions, ovarian polycystic syndrome, premenstrual syndrome, lung cancer in man, precocious puberty and Fox-Fordyce disease.
Preferably, the compounds corresponding to formula (I) according to the invention can be used to induce and/or stimulate hair growth and/or to slow down hair loss and/or in the treatment of hyperseborrhoea and/or of acne.
Particularly, the invention relates to the use, in a composition, of an effective amount of at least one compound corresponding to the general formula (I) as defined above, this compound or the composition being intended to treat disorders associated with overactivity of 5&agr;-reductase.
Thus, a subject of the invention is the use, in a composition, of an effective amount of at least one compound corresponding to the general formula (I) as defined above, this compound and/or the composition being intended to treat acne, hirsutism, seborrhoea, androgenic alopecia, cheloids and adhesions, prostate carcinomas, benign hyperplasia of the prostate, ovarian polycystic syndrome, premenstrual syndrome, lung cancer in man, precocious puberty and Fox-Fordyce disease.
Preferably, a subject of the invention is the use, in a composition, of an effective amount of at least one compound corresponding to the general formula (I) as defined above, this compound the composition being intended to induce and/or stimulate hair growth and/or to slow down hair loss and/or to treat hyperseborrhoea and/or acne.
Needless to say, the compounds corresponding to the formula (I) according to the invention can be used alone or as a mixture.
Among the compounds preferably used according to the invention, mention may be made of
4-benzyloxy-6-methoxy-1H-indole-2-carboxylic acid,
4-[3,5-bis(trifluoromethyl)benzyloxy]-6-methoxy-1H-indole-2-carboxylic acid,
5-benzyloxy-6-methoxy-1H-indole-2-carboxylic acid,
5-[3,5-bis(trifluoromethyl)benzyloxy]-6-methoxy-1H-indole-2-c
Bernard Bruno
Dalko Maria
Galey Jean-Baptiste
Gerst Catherine
Pichaud Patrick
Burns Doane Swecker & Mathis L.L.P.
Societe L'Oreal S.A.
Solola Taofiq
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