This application is a 371 of PCT/FR98/01853 filed Aug. 26, 1998.
The present invention relates to the use an effective amount of at least one compound of the indolecarboxylic family for treating disorders associated with overactivity of 5a-reductase, and more particularly androgen-dependent disorders.
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 polycyclic 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 5xcex1-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 5xcex1-reductase have been isolated and cloned to date. Type 1 5xcex1-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 5xcex1-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 5xcex1-reductase is mainly expressed in the skin and the various compartments of the hair follicles, the development of type 1 5xcex1-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 5xcex1-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. xe2x80x9cThe 5xcex1-reductase system and its inhibitorsxe2x80x9d (Dermatology, 1996, 193, 177-184)).
Among the steroidal inhibitors, mention may be made of 6-azasteroid derivatives and especially 4-azasteroid derivatives, including [17xcex2-(N-tert-butylcarbamoyl)-4-aza-5xcex1-androstan-1-en-3-one](finasteride), which is an inhibitor specific for the isotype 2, and 7xcex2-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 (LY191704), 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 5xcex1-reductase.
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 xe2x80x94Oxe2x80x94CHR3R4,
in which R3 is a hydrogen atom or an optionally substituted phenyl radical or alternatively a 5- or 6-membered heterocycle and R4 is an optionally substituted phenyl radical or alternatively a 5- or 6-membered heterocycle, or R3 and R4 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 xe2x80x94Oxe2x80x94R5 in which
R5 is a C1-C6 alkyl radical or a C6-C12 aralkyl radical;
R1 represents a hydrogen atom or a C1-C6 alkyl radical or a C6-C12 aralkyl radical which is optionally substituted;
R2 represents a hydrogen atom or a C1-C6 alkyl radical or a radical xe2x80x94CHR3R4, in which R3 and R4 have the above definitions;
it being understood that when R2 is a hydrogen atom or a methyl radical and X is a hydrogen atom, then Y must be other than an xe2x80x94Oxe2x80x94CH2Phenyl radical and Z must be other than a hydrogen atom, and that when R2 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 xe2x80x94Oxe2x80x94CH2Phenyl 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 5xcex1-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 5xcex1-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 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 and/or 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-carboxylic acid, 5-(3,4,5-trimethoxybenzyloxy)-6-methoxy-1H-indole-2-carboxylic acid, 5,6-bis(benzyloxy)-3-methyl-1H-indole-2-carboxylic acid, 5,6-bis(benzyloxy)-1H-indole-2-carboxylic acid, 5-(4-methoxybenzyloxy)-6-methoxy-1H-indole-2-carboxylic acid, 5-(4-cyanobenzyloxy)-6-methoxy-1H-indole-2-carboxylic acid, 1-[3,5-bis(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)benzyloxy]-6-methoxy-1H-indole-2-carboxylic acid, 3H-benz[e]indole-2-carboxylic acid, 3-methyl-3H-benz[e]indole-2-carboxylic acid, 3-benzyl-3H-benz[e]indole-2-carboxylic acid, 3-[3,5-bis(trifluoromethyl)benzyl]-3H-benz[e]indole-2-carboxylic acid.
Among these compounds, the ones most particularly preferred are: 5-benzyloxy-6-methoxy-1H-indole-2-carboxylic acid, 5-[3,5-bis(trifluoromethyl)benzyloxy]-6-methoxy-1H-indole-2-carboxylic acid, 3H-benz[e]indole-2-carboxylic acid, 3-methyl-3H-benz[e]indole-2-carboxylic acid, 5,6-bis(benzyloxy)-1H-indole-2-carboxylic acid.
The amount of compounds of formula (I) which can be used according to the invention depends, needless to say, on the desired effect and can thus vary within a wide range.
In order to give an order of magnitude, the compound of formula (I) can be used according to the invention in an amount representing from 0.001% to 10% of the total weight of the composition and preferably in an amount representing from 0.01% to 5% of the total weight of the composition.
According to the invention, the compounds of formula (I) can be used in compositions for cosmetic or pharmaceutical use. Preferably, according to the invention, the compounds of formula (I) are used in compositions for cosmetic use.
In the treatment of hair loss, as in that of seborrhoea or acne, the cosmetic composition according to the invention is to be applied to the areas to be treated and is optionally left in contact for several. hours and is optionally to be rinsed off. It is possible, for example, to apply the composition containing an effective amount of at least one compound as defined above, in the evening, keep this composition in contact throughout the night with the areas to be treated, and optionally rinse it off in the morning. These applications can be repeated daily for one or more months depending on the individual.
Thus, a second subject of the present invention is a cosmetic treatment process for the hair and/or the scalp and/or the skin, characterized in that it consists in applying to the hair and/or the scalp and/or the skin a cosmetic composition comprising an effective amount of at least one compound corresponding to formula (I), in leaving this composition in contact with the hair and/or the scalp and/or the skin, and in optionally rinsing it out.
The treatment process has the characteristics of a cosmetic process since it improves the beauty of the hair and/or the skin by giving them greater vigour and a better appearance.
Thus, the indolecarboxylic compounds have noteworthy activities which justify their use for treating disorders associated with androgens and/or with overactivity of 5xcex1-reductase.
In this regard, after extensive studies, the Applicant has discovered novel indolecarboxylic derivatives which are specific inhibitors of type 1 or type 2 5xcex1-reductase, or which can be considered as mixed inhibitors, i.e. compounds with pronounced inhibitory activity with regard to the two forms.
Thus, a third subject of the invention is an indolecarboxylic derivative corresponding to the general formula (Ixe2x80x2): 
in which Xxe2x80x2 and Yxe2x80x2, which may be identical or different,
represent a hydrogen atom or a radical xe2x80x94Oxe2x80x94CHRxe2x80x23Rxe2x80x24,
in which Rxe2x80x23 is a hydrogen atom or an optionally substituted phenyl radical or alternatively a 5- or 6-membered heterocycle and Rxe2x80x24 is an optionally substituted phenyl radical or alternatively a 5- or 6-membered heterocycle, or Rxe2x80x23 and Rxe2x80x24 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 xe2x80x94Oxe2x80x94Rxe2x80x25 in which Rxe2x80x25 is a C1-C6alkyl radical or a C6-C12 aralkyl radical;
Rxe2x80x21 represents a hydrogen atom or a C1-C6 alkyl radical or a C1-C12 aralkyl radical, which is optionally substituted;
Rxe2x80x22 represents a hydrogen atom or a C1-C6 alkyl radical or a radical xe2x80x94CHRxe2x80x23Rxe2x80x24, in which Rxe2x80x23 and Rxe2x80x24 have the above definitions;
or the esters thereof or the optical isomers thereof, alone or as a mixture in all proportions, the acylated forms thereof or alternatively the pharmaceutically acceptable salts thereof,
it being understood:
that when Xxe2x80x2 is a hydrogen atom and Yxe2x80x2 is a radical xe2x80x94OCHRxe2x80x23Rxe2x80x24 in which CHRxe2x80x23Rxe2x80x24 represents an aralkyl radical, then Zxe2x80x2 cannot be a radical xe2x80x94ORxe2x80x25, and that when Xxe2x80x2 is an xe2x80x94Oxe2x80x94CH2Phenyl radical, then Yxe2x80x2 and Zxe2x80x2 must not be a hydrogen atom.
According to the invention, the term xe2x80x9cheterocyclexe2x80x9d preferably refers to a ring optionally containing one or more nitrogen and/or oxygen atoms, and particularly pyridine, imidazole, tetrahydrofuran or furan. A heterocycle which is particularly preferred according to the invention is pyridine.
According to the invention, the term xe2x80x9cC1-C6 alkyl radicalxe2x80x9d preferably refers to linear or branched, saturated or unsaturated alkyl radicals containing from 1 to 6 carbon atoms.
Preferably, according to the invention, the alkyl radical is C1-C4 and is chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl radicals and more particularly methyl and ethyl radicals.
According to the invention, the term xe2x80x9cC6-C12 aralkyl radicalxe2x80x9d preferably refers to alkylaryl radicals containing from 6 to 12 carbon atoms, in which lo definition the term xe2x80x9carylxe2x80x9d is understood as a 5- or 6-membered aromatic ring or a 5- or 6-membered aromatic heterocycle. Preferably, according to the invention, the aralkyl radical is C7-C10. An aralkyl radical which is particularly preferred according to the invention is the benzyl radical.
According to the invention, the term xe2x80x9csubstituted phenyl radicalxe2x80x9d preferably refers to a phenyl radical substituted with a cyano (xe2x80x94CN) group, a trifluoromethyl (xe2x80x94CF3) group, a methoxy (xe2x80x94Oxe2x80x94CH3) radical or a halogen atom. The halogen atom can be chosen from chlorine, bromine, fluorine and iodine. A substituted phenyl radical which is particularly preferred according to the invention is the phenyl radical substituted with a trifluoromethyl (xe2x80x94CF3) group.
According to one specific embodiment of the invention, Rxe2x80x21 is preferably a methyl radical.
According to another embodiment of the invention, Rxe2x80x21 is a benzyl radical.
According to one specific embodiment of the invention, Rxe2x80x22 is preferably a methyl radical.
According to another embodiment of the invention, Rxe2x80x22 is a 3,5-bis(trifluoromethyl)benzyl radical.
When Rxe2x80x23 is a substituted phenyl radical, Rxe2x80x23 is preferably a 3,5-bis(trifluoromethyl)phenyl radical.
When Rxe2x80x23 is a heterocycle, Rxe2x80x23 is preferably a pyridine.
When Rxe2x80x24 is a substituted phenyl radical, Rxe2x80x24 is preferably a 3,5-bis(trifluoromethyl)phenyl radical.
When Rxe2x80x24 is a heterocycle, Rxe2x80x24 is preferably a pyridine.
According to one specific embodiment of the invention, Rxe2x80x21 is preferably a methyl radical.
According to another embodiment of the invention, Rxe2x80x25 is an ethyl radical.
As compounds of formula (Ixe2x80x2), 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-[3,5-bis(trifluoromethyl)benzyloxy]-6-methoxy-1H-indole-2-carboxylic acid, 5-(3,4,5-trimethoxybenzyloxy)-6-methoxy-1H-indole-2-carboxylic acid, 5-(4-methoxybenzyloxy)-6-methoxy-1H-indole-2-carboxylic acid, 5-(4-cyanobenzyloxy)-6-methoxy-1H-indole-2-carboxylic acid, 1-[3,5-bis(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)benzyloxy]-6-methoxy-1H-indole-2-carboxylic acid, 3H-benz[e]indole-2-carboxylic acid, 3-methyl-3H-benz[e]indole-2-carboxylic acid, 3-benzyl-3H-benz[e]indole-2-carboxylic acid, 3-[3,5-bis(trifluoromethyl)benzyl]-3H-benz[e]indole-2-carboxylic acid.
Among these compounds, the ones most particularly preferred are: 5-[3,5-bis(trifluoromethyl)benzyloxy]-6-methoxy-1H-indole-2-carboxylic acid, is 3H-benz[e]indole-2-carboxylic acid, 3-methyl-3H-benz[e]indole -2-carboxylic acid .
A fourth subject of the invention relates to cosmetic or pharmaceutical compositions, in particular dermatological compositions, which comprise at least one of the compounds corresponding to formula (Ixe2x80x2) defined above.
Needless to say, the compositions according to the invention can comprise the compounds of formula (Ixe2x80x2) alone or as mixtures in all proportions.
The amount of compounds of formula (Ixe2x80x2) contained in the compositions of the invention depends, needless to say, on the desired effect and can thus vary within a wide range.
In order to give an order of magnitude, the composition of the invention can contain at least one compound of formula (Ixe2x80x2) in an amount representing from 0.001% to 10% of the total weight of the composition, and preferably in an amount representing from 0.01% to 5% of the total weight of the composition.
The composition of the invention can be a composition for cosmetic or pharmaceutical use. Preferably, according to the invention, the composition of the invention can be a composition for cosmetic use.
The composition can be ingested, injected or applied onto the skin (on any area of body skin), the hair, the nails or mucous membranes (buccal, jugal, gingival, genital or conjunctival membranes). Depending on the mode of administration, the composition according to the invention can be in any pharmaceutical form normally used.
For topical application to the skin, the composition can be, in particular, in the form of an aqueous or oily solution or of a dispersion of the lotion or serum type, of emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase (O/W) or, conversely, (W/O), or of suspensions or emulsions of soft consistency of the aqueous or anhydrous cream or gel type, or alternatively of microcapsules or microparticles, or of vesicular dispersions of ionic and/or nonionic type. These compositions are prepared according to the usual methods.
They can also be used for the hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions or mousses, or alternatively in the form of aerosol compositions also comprising a propellant under pressure.
The composition according to the invention can also be a hair care composition, and in particular a shampoo, a hairsetting lotion, a treating lotion, a styling cream or gel, a dye composition (in particular an oxidation dye composition) optionally in the form of colouring shampoos, restructuring lotions for the hair, a permanent-waving composition (in particular a composition for the first stage of a permanent-waving operation), a lotion or gel for preventing hair loss, an antiparasitic shampoo, etc.
For injection, the composition can be in the form of an aqueous or oily lotion or in the form of a serum. For the eyes, it can be in the form of drops, and for ingestion, it can be in the form of capsules, granules, syrups or tablets.
The amounts of the various constituents in the compositions according to the invention are those conventionally used in the fields considered.
The compositions according to the invention can also consist of solid preparations constituting cleansing soaps or bars.
The compositions can also be packaged in the form of an aerosol composition also comprising a propellant under pressure.
When the composition is an emulsion, the proportion of the fatty phase can range from 5% to 80% by weight, and preferably from 5% to 50% by weight, relative to the total weight of the composition. The oils, the waxes, the emulsifiers and the co-emulsifiers used in the composition in emulsion form are chosen from those conventionally used in the cosmetics field. The emulsifier and the co-emulsifier are present in the composition in a proportion ranging from 0.3% to 30% by weight, and preferably from 0.5 to 20% by weight, relative to the total weight of the composition. The emulsion can also contain lipid vesicles.
When the composition is an oily solution or gel, the fatty phase can represent more than 90% of the total weight of the composition.
In a known manner, the cosmetic composition can also contain adjuvants that are common in the cosmetics field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preserving agents, antioxidants, solvents, fragrances, fillers, screening agents, odour absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the cosmetics field and, for example, from 0.01% to 10% of the total weight of the composition. Depending on their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase and/or into the lipid spherules.
As oils or waxes which can be used in the invention, mention may be made of mineral oils (liquid petroleum jelly), plant oils (liquid fraction of karite butter, sunflower oil), animal oils (perhydrosqualene), synthetic oils (purcellin oil), silicone oils or waxes (cyclomethicone), fluoro oils (perfluoropolyethers), beeswax, carnauba wax or paraffin wax. Fatty alcohols and fatty acids (stearic acid) can be added to these oils.
As emulsifiers which can be used in the invention, mention may be made, for example, of glyceryl stearate, polysorbate-60 and the mixture of PEG-6/PEG-32/glycol stearate sold under the name Tefose(copyright) 63 by the company Gattefosse.
As solvents which can be used in the invention, mention may be made of lower alcohols, in particular ethanol and isopropanol, and propylene glycol.
As hydrophilic gelling agents which can be used in the invention, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropyl cellulose, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids such as aluminium stearates, and hydrophobic silica, ethyl cellulose and polyethylene.
The composition can contain other hydrophilic active agents, such as proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts and hydroxy acids.
Lipophilic active agents which may be used are retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides, essential oils and salicyclic acid and its derivatives.
According to the invention, the composition can combine at least one compound of formula (I) with other active agents. Among these active agents, mention may be made, for example, of:
agents for improving the activity with regard to the regrowth of the hair and/or with regard to slowing down hair loss, and which have already been described for this activity, such as, for example, nicotinic acid esters including, in particular, tocopheryl nicotinate, benzyl nicotinate and C1-C6 alkyl nicotinates such as methyl or hexyl nicotinates, pyrimidine derivatives, for instance 2,4-diamino-6-piperidinopyrimidine 3-oxide or xe2x80x9cMinoxidilxe2x80x9d described in U.S. Pat. Nos. 4,139,619 and 4,596,812, and agents for promoting regrowth of the hair, for instance those described by the Applicant in the European patent application published under the number 0,648,488;
agents for reducing skin differentiation and/or proliferation and/or pigmentation, such as retinoic acid and its isomers, retinal and its esters, vitamin D and its derivatives, oestrogens such as oestradiol, kojic acid or hydroquinone;
antibacterial agents such as clindamycin phosphate, erythromycin or antibiotics of the tetracycline class;
antiparasitic agents, in particular metronidazole, crotamiton or pyrethroids;
antifungal agents, in particular the compounds belonging to the imidazole class, such as econazole, ketoconazole or miconazole or their salts, polyene compounds, such as amphotericin B, compounds of the allylamine family, such as terbinafine, or alternatively octopirox;
antiviral agents such as acyclovir;
steroidal anti-inflammatory agents, such as hydrocortisone, betamethasone valerate or clobetasol propionate, or non-steroidal anti-inflammatory agents such as, for example, ibuprofen and its salts, diclofenac and its salts, acetylsalicylic acid, acetaminophen or glycyrrhizic acid;
anaesthetics such as lidocaine hydrochloride and its derivatives;
anti-pruriginous agents such as thenaldine, trimeprazine or cyproheptadine;
keratolytic agents such as xcex1- and xcex2-hydroxycarboxylic or xcex2-ketocarboxylic acids, their salts, amides or esters and more particularly hydroxy acids such as glycolic acid, lactic acid, salicylic acid, citric acid and fruit acids in general, and 5-(n-octanoyl)salicylic acid;
anti-free-radical agents, such as xcex1-tocopherol or its esters, superoxide dismutases, certain metal-chelating agents or ascorbic acid and its esters;
antiseborrhoeic agents such as progesterone;
antidandruff agents such as octopirox or zinc pyrithione;
anti-acne agents such as retinoic acid or benzoyl peroxide;
extracts of plant or bacterial origin.
Other compounds can also be added to the above list, namely, for example, diazoxide, spiroxazone, phospholipids such as lecithin, linoleic acid, linolenic acid, salicylic acid and its derivatives described in French patent FR 2,581,542, for instance salicylic acid derivatives bearing an alkanoyl group containing from 2 to 12 carbon atoms in position 5 of the benzene ring, hydroxycarboxylic or ketocarboxylic acids and their esters, lactones and their corresponding salts, anthralin, carotenoids, eicosatetraenoic acid and eicosatrienoic acid or their esters and amides, vitamin D and its derivatives, and extracts of plant or bacterial origin.
Thus, according to one specific mode, the composition according to the invention also comprises at least one agent chosen from antibacterial agents, antiparasitic agents, antifungal agents, antiviral agents, anti-inflammatory agents, anti-pruriginous agents, anaesthetics, keratolytic agents, anti-free-radical agents, anti-seborrhoeic agents, antidandruff agents, anti-acne agents and/or agents for reducing skin differentiation and/or proliferation and/or pigmentation, and extracts of plant or bacterial origin.
It can also be envisaged for the composition comprising at least one compound as defined above to be in liposomal form, as described in particular in patent application WO 94/22468 filed on Oct. 13, 1994 by the company Anti Cancer Inc. Thus, the compound encapsulated in the liposomes can be delivered selectively to the hair follicles.
When the composition according to the invention is a pharmaceutical composition, it can be administered parentally, enterally or topically. Preferably, the pharmaceutical composition is administered topically.
A fifth subject of the invention relates to the use, as a medicinal product, of the compounds of general formula (I).
The compounds of the invention can be synthesized by entirely conventional processes generally used in organic synthesis.
Detailed examples of these syntheses are furthermore given in the examples.
However, as an example and in very general terms, in order to obtain a compound of the invention substituted in positions 4 and 6,2-hydroxy-4-alkoxybenzaldehyde of formula 
is reacted, in a first step, with a bromide of formula
Brxe2x80x94R
in which R represents a hydrogen atom or a radical Oxe2x80x94CHRxe2x80x23Rxe2x80x24 as defined above, and Rxe2x80x25 is as defined above, in the presence of anhydrous tetrahydrofuran (THF), of sodium hydride at 60% in oil and of tetrabutylammonium iodide.
After incubation for 6 hours at room temperature, the compound obtained is purified by chromatography on silica gel.
The term xe2x80x9croom temperaturexe2x80x9d refers to a temperature of between 180C and 350C, preferably of between 20xc2x0 C. and 30xc2x0 C.
In a second step, the compound obtained in the first step is reacted in the presence of sodium methoxide and ethyl azidoacetate in the presence of methanol for 20 hours at room temperature.
The compound thus obtained is purified by chromatography on silica gel or by recrystallization.
In a third step, the compound obtained in the second step is reacted in the presence of toluene, at ref lux for one and a half hours. The compound thus obtained is purified by precipitation.
In a fourth step, the compound obtained in the third step is reacted in the presence of methanol, acetone and sodium hydroxide for 4 hours. The compound thus obtained is purified by precipitation.
Similarly, as an example and in very general terms, in order to obtain a compound of the invention substituted in positions 5 and 6, the 3-aralkoxy-4-alkoxybenzaldehyde of formula 
in which Xxe2x80x2 and Yxe2x80x2 are defined as above, is nitrated, in a first step, with nitric acid at room temperature, for a period of between 2 h and 12 h.
The compound obtained is isolated by filtration.
In a second step, the compound obtained in the 1st step is reacted in the presence of potassium carbonate (K2CO3) with triethyl phosphonate in a mixture of ethanol and dimethoxyethane at 80xc2x0 C. for a period of between 10 and 20 hours. The compound obtained is purified by chromatography on a column of silica.
In a third step, the compound obtained in the 2nd step is reacted with triethyl phosphate at reflux for a period of between 2 and 6 hours. The compound obtained is purified by chromatography on a column of silica.
In a fourth step, the compound obtained in the 3rd step is saponified with sodium hydroxide in an acetone/methanol mixture for a period of between 1 and 6 hours at a temperature of between 20xc2x0 C. and 40xc2x0 C. The compound obtained is purified by crystallization.
In order to obtain a compound for which Xxe2x80x2 and Yxe2x80x2 form a ring or a heterocycle, a bicyclic aromatic aldehyde is reacted, in a first step, in the presence of sodium methoxide, ethyl azidoacetate and methanol.
After incubation for several hours at room temperature, the compound obtained is purified by chromatography on a column of silica.
In a second step, the compound obtained in the first step is reacted in the presence of refluxing toluene for several hours. The compound thus obtained is purified by recrystallization.
In a third step, the compound obtained in the second step is reacted in the presence of methanol, acetone and sodium hydroxide for 4 hours. The compound thus obtained is purified by recrystallization.
For the preparation of compounds in which Rxe2x80x22 is not a hydrogen atom, the compound obtained in the second step is placed in contact with an alkyl halide for 30 minutes at room temperature. The compound thus obtained is then reacted in the presence of acetone and sodium hydroxide for 1 hour at room temperature. The compound thus obtained is purified by recrystallization.
The indole carboxylic derivatives have inhibitory activities on 5xcex1-reductase which it was possible to demonstrate by means of a screening test based on the in vitro expression of the isoforms 1 or 2 of 5xcex1-reductase.
The details of these tests and the results obtained are given in the examples.