Stilbene compounds comprising an adamantyl group, compositions and methods thereof

Abstract

The invention relates to novel stilbene compounds having the general formula (I): as well as to pharmaceutical compositions for use in human or veterinary medicine, including dermatological, rheumatic, respiratory, cardiovascular and ophthalmic conditions and cosmetic compositions and methods of use thereof.

What is claimed is:  
     
         1 . A stilbene compound, corresponding to formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  represents 
 (i) the —CH 3  radical,  
 (ii) the radical —CH 2 —O-R 6 ,  
 (iii) the radical —O—R 6 , or  
 (iv) the radical —CO—R 7 ,  
 wherein the radicals R 6  and R 7  having the meanings given below,  
 
 Ar represents a radical comprising one of the radicals of formulae (a) to (f):  
                     
 wherein R 8  and R 9  having the meanings given below,  
 R 2  and R 3 , which may be identical or different, represent a hydrogen atom or a lower alkyl radical,  
 R 4  represents the radical —(X) m —(CH 2 ) n —Y—(CH 2 ) p —R 10    
 the values m, n and p and the radicals X, Y and R 10  having the meanings given below,  
 R 5  represents a hydrogen or halogen atom, a lower alkyl radical or a radical —O—R 6 ,  
 R 6  represents a hydrogen atom, a lower alkyl radical or a radical —CO—R 11 ,  
 R 7  represents a hydrogen atom, a lower alkyl radical, a radical —OR 12  or a radical  
                     
 wherein R′ and R″, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or peptide or sugar residue, or alternatively, taken together, form a heterocycle, wherein  
 m is an integer equal to 0 or 1  
 n is an integer ranging from 1 to 6, inclusive,  
 p is an integer ranging from 1 to 6, inclusive,  
 X represents O or S(O) q ,  
 Y represents O, S(O) q  or N—R 9 ,  
 q is an integer ranging from 0 to 2, inclusive,  
 R 8  represents a hydrogen or halogen atom, a lower alkyl radical or a radical —O—R 6 ,  
 R 9  represents a hydrogen atom, a lower alkyl radical or a radical —CO—R 11 ,  
 R 10  represents a mono- or polyhydroxyalkyl radical wherein the hydroxyls are optionally protected in the form of methoxy, ethoxy, acetoxy or acetonide, a radical —CO—R 7  or an optionally substituted aryl or aralkyl radical,  
 R 11  represents a lower alkyl radical,  
 R 12  represents a hydrogen atom, an alkyl radical, an alkenyl radical, a mono- or polyhydroxyalkyl radical in which the hydroxyls are optionally protected in the form of methoxy, ethoxy, acetoxy or acetonide, an optionally substituted aryl or aralkyl radical, a sugar residue or an amino acid or peptide residue, or salts thereof or optical or geometrical isomers thereof.  
 
     
     
         2 . The compound as defined by  claim 1 , which is in the form of a salt of an alkali metal or alkaline earth metal, of zinc, of an organic amine or of an inorganic or organic acid.  
     
     
         3 . The compounds as defined by  claim 1 , wherein the lower alkyl radical comprises a methyl, ethyl, propyl, isopropyl, tert-butyl or hexyl radical.  
     
     
         4 . The compound as defined by  claim 1 , wherein the polyhydroxyalkyl radical comprises 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, or 2,3,4,5-tetrahydroxypentyl radical or the pentaerythritol residue.  
     
     
         5 . The compound as defined by  claim 1 , wherein the aryl radical comprises a phenyl radical optionally substituted with at least one halogen atom, a hydroxyl radical, an alkyl radical, a nitro function, a methoxy group or an optionally substituted amine function.  
     
     
         6 . The compound as defined by  claim 1 , wherein the aralkyl radical comprises benzyl or phenethyl radicals, optionally substituted with at least one halogen atom, a hydroxyl, a nitro function or a methoxy group.  
     
     
         7 . The compound as defined by  claim 1 , wherein the alkenyl radical comprises radicals containing from 2 to 5 carbon atoms and having one or more ethylenic unsaturations, and in particular the allyl radical.  
     
     
         8 . The compound as defined by  claim 7 , wherein the alkenyl radical comprises an allyl radical.  
     
     
         9 . The compound as defined by  claim 1 , wherein the sugar residue comprises a glucose, galactose, mannose or glucuronic acid residue.  
     
     
         10 . The compound as defined by  claim 1 , wherein the amino acid residue comprises a residue derived from lysine, glycine or aspartic acid.  
     
     
         11 . The compound as defined by  claim 1 , wherein the peptide residue comprises dipeptide or tripeptide residues.  
     
     
         12 . The compound as defined by  claim 1 , wherein the heterocyclic radical comprises piperidino, morpholino, pyrrolidino and piperazino radicals optionally substituted in position 4 with a C 1 -C 6  alkyl or polyhydroxyalkyl radical.  
     
     
         13 . The compound as defined by  claim 1 , wherein the halogen atom comprises fluorine, bromine or chlorine.  
     
     
         14 . The compound as defined by  claim 1 , comprising: 
 Ethyl 4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethenyl]benzoate;    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)ethenyl]benzoic acid;    Ethyl 4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]benzoate;    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoic acid;    4-[(Z)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoic acid;    Methyl 5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(E)-yl}pyridine-2-carboxylate;    5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}pyridine-2-carboxylic acid;    5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}pyridine-2-carboxylic acid;    Ethyl 6-{2-[3-adamant-1-yl-4-(2-methoxy-ethoxymethoxy)phenyl]propen-(E)-yl}nicotinate;    6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}nicotinic acid;    6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}nicotinic acid;    Methyl 4-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(Z)-yl}-2-methoxybenzoate;    4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}-2-methoxybenzoic acid;    4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}-2-methoxybenzoic acid;    Ethyl 4-{2-[3-adamant-1-yl-4-(3-ethoxy-methoxypropyl)phenyl]propen-(E/Z)-yl}benzoate;    4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxy-propyl)phenyl]propen-(E)-yl}benzoic acid;    4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]propen-(Z)-yl}benzoic acid;    Ethyl 4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/Z)-yl}-benzoate;    4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(E)-yl}-benzoic acid;    4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(Z)-yl}benzoic acid;    Ethyl 4-{2-[3-adamant-1-yl-4-(3-diethylcarbamoyl-methoxypropyl)phenyl]propenyl}benzoate;    4-{2-[3-Adamant-1-yl-4-(3-diethylcarbamoylmethoxy-propyl)phenyl]propenyl}benzoic acid;    Ethyl 4-{2-[3-adamant-1-yl-4-(3-carboxymethoxypropyl)phenyl]propenyl}benzoate;    4-{2-[3-Adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}benzoic acid;    Ethyl 4-{2-[3-adamant-1-yl-4-(3-carbamoylmethoxy-propyl)phenyl]propenyl}benzoate;    4-{2-[3-Adamant-1-yl-4-(3-carbamoylmethoxypropyl)-phenyl]propenyl}benzoic acid;    N-Ethyl-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]benzamide;    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzamide;    N-4-(Hydroxyphenyl)-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)-1-propenyl]benzamide;    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzenemethanol;    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzaldehyde;    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]phenol;    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoic acid morpholide; or    4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethyl-sulphanylphenyl)-1-propenyl]benzoic acid; or mixtures thereof.    
     
     
         15 . The compound as defined by  claim 1 , having at least one of the following characteristics: 
 R 1  is the radical —CO—R 7 ,    Ar represents the radicals of formulae (a) or (b),    X and Y, which may be identical or different, independently represent an oxygen or sulfur atom,    R 3  represents a lower alkyl radical.    
     
     
         16 . A pharmaceutical composition comprising at least one stilbene compound as defined by  claim 1  and pharmaceutically acceptable carrier therefor.  
     
     
         17 . The pharmaceutical composition as defined by  claim 16 , wherein said stilbene compound ranges from 0.01% to 5% by weight relative to the weight of the entire composition.  
     
     
         18 . A cosmetic composition comprising at least one stilbene compound as defined by  claim 1  and a cosmetically acceptable carrier therefor.  
     
     
         19 . The cosmetic composition as defined by  claim 18 , wherein said stilbene compound ranges from 0.001% to 3% by weight relative to the weight of the entire composition.  
     
     
         20 . The cosmetic composition as defined by  claim 18 , which is applied to the body or the hair.  
     
     
         21 . A method for the prevention or treatment of a dermatological condition at least one compound as defined by  claim 1 , to a patient in need of such prevention or treatment.  
     
     
         22 . The method as defined by  claim 21 , wherein said dermatological condition comprises a condition involving at least one of common acne, comedones, polymorphonuclear leukocytes, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acnes, medication-induced acne, occupational acne, ichthyosis, ichthyosiform states, Darrier's disease, palmoplantar keratoderma, leucoplasia, a leucoplasiform state, cutaneous or mucous (buccal) lichen, keratinization disorder having an inflammatory and/or immunoallergic component, cutaneous, mucous or ungual psoriasis, psoriatic rheumatism, cutaneous atopy, eczema, respiratory atopy, gingival hypertrophy; inflammatory complaints which do not exhibit a disorder of keratinization; dermal or epidermal proliferations, common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatoses, basocellular and spinocellular epitheliomas; bullosis and collagen diseases; ophthalmological disorders, corneopathies; light-induced and chronological aging of the skin, actinic keratoses and pigmentations; stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, skin atrophy; cicatrization disorders, stretch marks; sebaceous functioning, hyperseborrhoea of acne or simple seborrhoea; cancerous or precancerous states, promyelocytic leukemias; inflammatory complaints, arthritis; viruses; alopecia; dermatological complaints having an immunological component; complaints of the cardiovascular system, arteriosclerosis, hypertension, insulin-independent diabetes; or skin disorders due to exposure to UV radiation.