GB2228734A - Aromatic compounds - Google Patents

Aromatic compounds Download PDF

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GB2228734A
GB2228734A GB9007490A GB9007490A GB2228734A GB 2228734 A GB2228734 A GB 2228734A GB 9007490 A GB9007490 A GB 9007490A GB 9007490 A GB9007490 A GB 9007490A GB 2228734 A GB2228734 A GB 2228734A
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compound
methyl
acid
formula
adamantyl
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GB2228734B (en
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Jean Maignan
Gerard Lang
Gerard Malle
Serge Restle
Braham Shroot
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LOreal SA
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LOreal SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/26—Polyhydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C07C65/26—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/34—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/34—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic
    • C07C65/36—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups

Abstract

<IMAGE> R7 is hydrogen or a methyl group; or a salt thereof, including the optical and geometrical isomers of said compounds, are useful in human and veterinary medicine and in cosmetics.

Description

"AROMATIC COMPOUNDS, PROCESS FOR THEIR PREPARATION, AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND IN COSE:TICS " The present invention relates to new aromatic compounds, the process for their preparation, and their use in human and veterinary medicine and in cosmetics. This application is a divisional application of application No. 8707990.
The compounds according to the invention show activity in the topical and systemic treatment of dermatological complaints related to a keratinization (differentiation-proliferation) disorder and of dermatological (or other) complaints with an inflammatory and/or immunoallergic component and in the treatment of degenerative diseases of conjunctive tissue, as well as an antitumour activity. In addition, these compounds may be employed in the treatment of atopy, whether cutaneous or respiratory, and of rheumatoid psoriasis.
These compounds also possess good activity against the bacteria involved in acne.
Lastly, they find an application in the field of ophthalmology, especially in the treatment of corneopathy.
The aromatic compounds according to the invention may be denoted by the following general formula:
in which: n is O or 1 1) When n=1 R' denotes a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms, R" denotes a hydrogen atom, an OH radical, an acyloxy radical containing from 1 to 4 carbon atoms, an alkoxy radical containing from 1 to 4 carbon atoms or an amino (NH2) radical, or R' and R" taken together form an oxo (tO), methano (=CH2) or hydroxyimino (=N-OH) radical, R1 denotes the radical -CH20H or the radical -COR10, R10 denoting a hydrogen atom, the radical -OR or
R1l denoting a hydrogen atom, a straight-chain or branched alkyl radical, containing from 1 to 20 carbon atoms, or a monohydroxyalkyl, polyhydroxyalkyl, aryl or aralkyl radical, this or these being optionally substituted, or'a sugar residue or the radical
p being 1, 2 or 3 and r' and r" denoting a hydrogen atom, a lower alkyl radical or a sionohydroxyalkyl radical optionally interrupted by a heteroatom, a polyhydroxyalkyl radical, an aryl or benzyl radi cal, where this or these may be optionally substi tued, an amino acid residue or an amino sugar resi due or, taken together, form a heterocyclic ring, Rz, R3, R4, Rs and R6 denote a hydrogen atom, -OH, a straight-chain or branched alkyl radical, containing from 1 to 12 carbon atoms, a cycloalkyl, cycloalkenyl or phenyl radical, optionally substituted, or a radical corresponding to one of the following formulae:: (i) -X-C6H5 (ii) -X-R12 or (iii) -NHCOR13 in which: X denotes -0-, -S-, -SO-, -SOz- or -OCO-, R12 denotes a lower alkyl or fluoroalkyl radical, and R13 denotes denotes an alkyl or phenyl radical, at least one of the radicals R2 to R6 being other than a hydrogen atom, R7, R8 and Rg denote a hydrogen atom or the methyl radical, R7 and Rg taken together may form, with the benzene nucleus, a naphthalene ring, excluding compounds of formula (I) in which R7 is a hydrogen atom or a methyl radical when R4 denotes a methyl radical or an OH radical, when R2, R3, R5 and R6 denote a hydrogen atom or when R6 denotes a hydroxyl radical, 2) When n=O R' denotes a hydrogen atom, R" denotes an OH radical or R' and R", taken together, form an oxo (=0) radical, R1 denotes the radical -CH2OH, -CH=O or -COOR11, R11 being a hydrogen atom or a lower alkyl radical, R2 and R3 denote a hydrogen atom or an alkyl radical containing from 3 to 6 carbon atoms, R5 denotes (i) either a cycloalkyl or alkyl radical containing from 3 to 6 carbon atoms and, in this case, R4 denotes a tower alkyl radical, a hydroxyl radical or an alkoxy radical, (ii) or a hydrogen atom and, in this case, R4 denotes a lower alkyl radical, R6 denotes a hydrogen atom, and R7 denotes a hydrogen atom or the methyl radical, and the salts of these aromatic compounds as well as their optical and geometrical isomers.
A lower alkyl radical should be understood to mean a radical containing from 1 to 6 carbon atoms.
Among the lower alkyl radicals and those containing up to 20 carbon atoms, there may be mentioned methyl, ethyl, isopropyl, butyl, tert-butyl, isooctyl, dodecyl, hexadecyl and octadecyl radicals.
A monohydroxyalkyl radical should be understood to mean a radical containing from 2 to 6 carbon atoms, particularly a 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxyethoxyethyl radical.
A polyhydroxyalkyl radical should be understood to mean a radical containing from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups such as the 2,3-dihydroxypropyl and 1,3-dihydroxypropyl radicals or the pentaerythritol residue.
An aryl radical should be understood to mean a phenyl radical optionally substituted by a halogen atom, -OH, -NO2, a lower alkyl radical, a trifluoromethyl radical or a carboxylic acid group.
As preferred aralkyl radical there may be mentioned the benzyl radical and the phenethyl radical.
A sugar residue should be understood to mean a residue derived, for example, from glucose, mannose, erythrose or galactose.
An amino acid residue should be understood to mean a residue derived, for example, from methionine or from aor B-alanine.
Among the amino sugar residues there may be mentioned those derived from glucosamine, galactosamine or mannosamine.
A cycloalkyl radical should be understood to mean the radicals containing from 5 to 12 carbon atoms, particularly the cyclopentyl, cyclohexyl and adamantyl radicals.
A cycloalkenyl radical should preferably be understood to mean 1-cyclohexenyl and 1-cyclopentenyL radicals.
Among the preferred fluoroalkyl radicals there may be mentioned trifluoromethyt and pentafluoroethyl radicals.
When the radicals r' and r" together form a hetero cyclic ring, the latter is preferably a piperidsno, piperazino, morpholino, pyrrolidino or 4-(2-hydroxyethyl)piperazino radical.
When the compounds according to the invention are in the form of salts, these may be either alkali or alkalineearth metal or zinc salts or salts of an organic amine when they contain at least one free acid group or saLts of an inorganic or organic acid, especially hydrochloride, hydrobromide or citrate when they contain at least one amino group.
Depending on the formula (I) below, the compounds of the present application may be benzene derivatives or naphthalene derivatives corresponding to the following for mulae (II) and (III):
in which: R1 to R7, R' and R" have the same meanings as those given for the formula (I), when n-O,
in which: R1 to R6, R' and R" have the same meanings as those given for the formula (I) when n=1.
It should be noted that these compounds of formula (III) exhibit good stability towards light and oxygen.
Among the compounds of formula (II) those particularly preferred correspond to the following formula (IV)
in which: R' denotes a hydrogen atom, R" denotes an OH radical or R' and R" taken together form an oxo (=0) radical, R'1 denotes the radical -CHzOH, -CH=0 or -COOR' R'11 being a hydrogen atom or a tower alkyl radical, R'2 and R'3 denote a hydrogen atom or an alkyl radical containing from 3 to 6 carbon atoms, and R'5 denotes (i) either a cycloalkyl or alkyl radical containing from 3 to 6 carbon atoms and, in this case, R'4 denotes a lower alkyl radical, a hydroxyl radical or an alkoxy radical, (ii) or a hydrogen atom and, in this case, R'4 denotes a lower alkyl radical.
Among the compounds of the formula (III), those particularly preferred correspond to the following formulae (V) and (VI):
in which: R'10 denotes -OR'11 or -NHR'11, R'11 denoting a hydrogen atom or a lower alkyl radical, R'2 denotes a hydrogen atom or a lower alkyl radical, and R"4 denotes a lower alkyl radical, preferably an isopropyl or tert-butyl radical, or a cycloalkyl radical, preferably the cyclohexyl radical.
in which: R'10 denotes -OR'11 or -NHR'111 R'11 denoting a hydrogen atom or a lower alkyl radical, R"2 and R'6 denote a hydrogen atom or a lower alkyl radical, R'3 denotes a hydrogen atom, a lower alkyl radical, a phenyl radical or an adamantyl radical, and R'12 denotes a lower alkyl radical or a phenyl radical.
Among the compounds of formula (I) according to the invention, the following may be mentioned in particular: methyl 6-(2,4-diisopropylbenzoyl)naphthalene-2-carboxylate, 6-(2,4-diisopropylbenzoyl)naphthalene-2-carboxylic acid, methyl 6-(4-methoxy-2,3,6-trimethylbenzoyl)naphthalene- 2-carboxylate, 6-(4-methoxy-2,3,6-trimethylbenzoyl)naphthalene-2-carboxylic acid, methyl 6-(4-tert-butylbenzoyl)naphthalene-2-carboxylate, 6-(4-tert-butylbenzoyl)naphthalene-2-carboxylic acid, N-ethyl-6-(4-tert-butylbenzoyl)naphthalene-2-carboxamide, methyl 6-(3-adamantyl-4-methoxybenzoyl)naphthalene-2- carboxylate, 6-(3-adamantyl-4-methoxybenzoyl)naphthalene-2-carboxylic acid, methyl 6-(4-methoxybenzoyl)naphthalene-2-carboxylate, methyl 6-(4-cyclohexylbenzoyl)naphthalene-2-carboxylate, 6-(4-cyclohexylbenzoyl)naphthalene-2-carboxylic acid, methyl 6-(4-methoxy-3-phenylbenzoyl )naphthalene-Z-carboxy- late, 6-(4-methoxy-3-phenylbenzoyl)naphthalene-2-carboxylic acid, methyl 6-(4-phenoxybenzoyl)naphthalene-2-carboxylate, 6-c(2t4-diisopropylphenyl)hydroxymethylJnaDhthalene-2 carboxylic acid, 6-t(2,4-diisopropylphenyl)hydroxymethylJnaphthalene-2- carbinol, 6-(2,4-diisopropylbenzyl)naphthalene-2-carboxylic acid, methyl 4-(2,4-diSsopropylbenzoyl)benzoate, 4-(2,4-diisopropylbenzoyl)benzoic acid, 4-[(2,4-diisopropylphenyl)hydroxymethyl]benzoic acid, 1-(2,4-diisopropylphenyl)-1-(4-hydroxymethylphenyl)- methanol, 4-(2,4-diisopropylbenzoyl)benzaldehyde, ethyl 4-(2,4-diisopropylbenzoyl)-a-methyleinnamate, 4-(2,4-diisopropylbenzoyl)-&alpha;-methylcinnamic acid, methyl 4-[(3-adamantyl-4-methoxyphenyl)hydroxymethyl] benzoate, 4-EC3-adamantyl-4-methoxyphenyl)hydroxymethyl)benzoic acid, 4-(3-adamantyl-4-methoxybenzoyl)benzoic acid, 4-(3-adamantyl-4-hydroxybenzoyl)benzoic acid, methyl 4-(3-adamantyl-4-hydroxybenzoyl)benzoate, methyl 4-(3,5-ditert-butyl-4-hydroxybenzoyl)benzoate and 4-(3,5-ditert-butyl-4-hydroxybenzoyl)benzoic acid.
Another subject of the present invention is the process for the preparation of the compounds of formula (I) as defined above.
The compounds of formula (II) in which R' and R" together form an oxo radical and n-O are obtained according to the following reaction scheme:
R11 : alkyl vith 1 to 20 C.
The starting 4-alkoxyzarbonylbenzoic acid (1) is obtained by oxidation of the alkyl 4-for.ylbenzoate, preferably methyl 4-formylbenzoate, which is a commercial product.
The corresponding acid chloride is prepared by reaction with thionyl chloride according to the conventional method for preparing acid chlorides.
The condensation reaction of the chloride of 4alkoxycarbonylbenzoic acid (2) with the benzene derivative (3) is performed under Friedel-Crafts reaction conditions, that is to say in the presence of anhydrous aluminium chloride in an organic solvent such as 1,2-dichloroethane at a temperature of between 0 and 250C with stirring.
Saponification of the ester (4) provides access to the corresponding acid (S), which can then be converted to amide of formula (6) by reaction with an amine of formula
in the presence of N,N'-carbonyldiimidazole (CDI).
In the case of some meanings of R11 in formula (I), especially when R11 denotes a monohydroxy- or polyhydroxyalkyl radical, it is preferable to prepare the acid (5) from the methyl ester (4) (R1l=-CH3) and then to esterify the acid thus obtained to the ester of the alcohol chosen, according to the known methods.
When n:1 in the compounds of formula (I), the latter are obtained according to the following reaction scheme:
The keto-acid (5) is reduced in the presence of lithium aluminium hydride to the corresponding diol (7), which is then oxidized in the presence of pyridinium chlorochromate (PCC) to give the keto-aldehyde (8). By means of a Wittig-Horner reaction with a substituted or unsubstituted alkyl phosphonoacetate, the keto-aldehyde leads, in the presence of sodium hydride in an organic solvent such as THF,to the unsatuiated ester of formula (9).
The ester of formula (9) may then be converted as before to the corresponding acid and then to amide by reaction with an amine of formula
The compounds of formula II in which R'=H and R" =OH are obtained from ketone derivatives by reduction with sodium borohydride in THF or methanol.
The compounds of formula (II) in which R'=R"=H are obtained by zinc reduction of the ketone derivatives, in acetic acid in the presence of hydrochloric acid.
These carbonyl reduction reaction lust, of course, be compatible with the nature of the various substituents (R2 to R7) and with the radical R1. it may be desirable to ensure that these are protected, if necessary, although the reduction of the carbonyl presents no difficulty when R1=-COzH.
The acyloxy derivatives of the compounds of formula (II) (R'=H and R"=C1-C4 acyloxy) are obtained by reacting an activated form of acid such as an anhydride or an acid chloride with a compound of formula (11) in which R'=H and R"=OH.
The alkoxy derivatives of the compounds of formula (II) (R'=H and R"=C1-C4 alkoxy) are similarly obtained from the compounds of formula (II) (R'tH and R"=OH) according to known methods.
For the preparation of acyloxy and alkoxy derivatives it is preferable that the radical R1 should be an ester, acid or amide group.
The compounds of formula (III) in which R' and R" together form an oxo radical are obtained according to the following reaction scheme:
X = Br or Cl and R11 t C1-C20 alkyl The starting 6-alkoxycarbonylnaphthalene-2- carboxylic acid (10) is obtained by a monosaponification reaction of the alkyl 2,6-naphthalenedicarboxylate, preferably from methyl 2,6-naphthalenedicarboxylate, which is a commercial product. The corresponding acid chloride (11) is prepared by reaction with thionyl chloride according to the conventional method for preparing acid chlorides.
The condensation reaction of the chloride of 6 alkoxycarbonylnaphthalene-2-carboxylic acid (11) may be carried out either with the benzene derivative (12) under Friedel-Crafts reaction conditions or with the agnesium halobenzene derivative (13).
The Friedel-Crafts reaction conditions are the same as those given above for the preparation of the compounds of formula (4). The preparation of the magnesium halobenzene derivative (13) is carried out in refluxing anhydrous THF and the condensation of the acid chloride is carried out at a temperature of about 0 C in the same solvent.
Using the same methods as those described above for the compounds of formula (II), access may be obtained to the other compounds of formula CIII), namely the compounds of formulae (15) and (16), as well as to compounds of formula (III) in which R' and R" taken together are different from an oxo radical.
Another subject of the present invention is, by way of medication, the compounds of formula (I) such as defined above.
These compounds are active in the ornithine decarboxylase inhibition test after induction by "tape stripping", in the hairless rat (M. Bouclier et al., Dermatologica 169 No. 4 (1984)). This test is accepted as a measurement of an antiproliferative activity.
These compounds are particularly suitable for the treatment of dermatological complaints related to a keratinization (differentiation-proliferation) disorder and of dermatological or other complaints with an inflammatory and/or immunoallergic component, particularly: common, comedonian or polymorphous acnes, senile, solar acnes and medicamentous or occupational acnes, extensive and/or severe forms of psoriasis and other keratinization disorders, and particularly ichthyosis and ichthyosiform states, Darier 's disease, palmo-planter keratosis, leukoplakias and leukoplakiform states, lichen planus and all benign or malignant, severe or extensive dermatological proliferations.
They are also active in the treatment of tumours, of rheumatoid psoriasis, of cutaneous or respiratory atopies and of some ophthalmological problems related to corneopathy.
Another subject of the present invention is therefore medicinal compositions containing at least one compound of formula (I) such as defined above or one of its salts or one of its optical or geometrical isomers.
Another subject of the present invention is therefore also a new medicinal composition intended, in particular, for the treatment of the abovementioned complaints, characterized in that it comprises, in a pharmaceutically acceptable substrate, at least one compound of formula (I) and/or one of its salts and/or one of its optical or geometrical isomers.
The compounds according to the invention are generally administered in a daily dosage of approximately 2 VgSkg to 2 mg/kg of body weight.
Any conventional substrate may be employed as a substrate for the compositions, the active compound being present in the vehicle either in the dissolved or in the dispersed state.
The administration may be performed by an enteral, parenteral, topical or ocular route. By the enteral route, the medications may be presented in the form of tablets, gelatine capsules, coated pills, syrups, suspensions, solutions, powders, granules or emulsions. By the parenteral route, the compositions may be presented in the form of solutions or suspensions for perfusion or for injection.
By topical route, the pharmaceutical compositions based on the compounds according to the invention are presented in the form of ointments, tinctures, creams, salves, powders, adhesive patches, saturated pads, solutions, lotions, gels, sprays or suspensions.
These compositions for topical administration may be presented either in anhydrous form or in an aqueous form depending on the clinical indication.
In the case of the ocular route, they are chiefly eye lotions.
The compositions for topical or ocular adminis- tration contain preferably from 0.0005 to approximately 5X by weight of at least one compound of formula (I) as defined above based on the total weight of the composizion.
The compounds of formula (I) according to the invention, also find application in the field of cosmetics, particularly in body hygiene and hair care and, in particular, for the treatment of skin with a tendency to acne, for regrowth of hair, for combating hair loss, for combating the oily appearance of the skin or hair, for the prevention or the treatment of the harmful effects of sunlight or in the treatment of physiologically dry skins.
The present invention consequently also provides a cosmetic composition containing, in a cosmetically acceptable substrate, at least one compound of formula (I) or one of its salts and/or one of its isomers, this composition being in particular in the form of a lotion, gel, cream, soap or shampoo.
The concentration of compound of formula (I) in the cosmetic compositions is between 0.0005 and 2X by weight and preferably between 0.01 and 1X by weight.
The medicinal and cosmetic compositions according to the invention may contain inert or even pharmacodynamically or cosmetically active additives and, in particular: hydrating agents such as thiamorpholinone and its derivatives or urea, antiseborrhoeic or antiacne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, thioxolone or benzoyl peroxide, antibiotics such as erythromycin and its esters, neomycin, tetracyclines and 4,5-polymethylene-3-isothiazolones, agents promoting the regrowth of hair, such as minoxidil C2,4-diamino-6-piperpyridinopyrimidine 3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-1,2,4benzothiadiazine 1,1-dioxide) and phenytoin (5,5-diphenylimidazolidine-2,4-dione), steroid and nonsteroid antiinflammatory agents, carotenoids and, in particular, Bcarotene, antipsoriatic agents such as anthralin and its derivatives and eicosa-5,8,11,14-tetraynoic and -5,8,11triynoic acids as well as their esters and amides.
The compositions according to the invention may also contain flavour-improving agents, preserving agents, stabilizers, moisture-controlling agents, pH-controlling agents, agents modifying osmotic pressure, emulsifying agents, UV-A and UV-B screens, and antioxidants such as -tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
A number of examples of preparation of the active compounds of formula (I) according to the invention, as well as examples of compositions containing these, will now be given, by vay of illustration and without limitation of any nature being implied.
EXAMPLES OF PREPARATION EXAMPLE 1 Preparation of ethyl 6-(2,4-diisopropylbenzoyl)naPhtha- Lene-2-carboxylate (Compound of formula V in which R'10 =-OCH3, R'2= R '4=isoC3H7).
1.87 g (14 mmol) of anhydrous aluminium chloride are added portionwise to a suspension of 1.62 g (10 mmol) of m-diisopropylbenzene and of 2.49 g (10 mmol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid chloride in 80 cm3 of anhydrous 1,2-dichloroethane. The mixture is stirred for 4 h at ambient temperature and is then poured into 100 cm3 of acidified iced water. The organic phase is separated off. The aqueous phase is extracted twice with 70 cm3 of dichloroethane. The dichloroethane phases are combined, washed with sodium bicarbonate and with water, are dried over sodium sulphate and are then concentrated down. The solid obtained is purified by chromatography on silica gel in a 60/40 toluene/dichloromethane mixture, followed by reslurrying in isopropyl ether.After filtration and drying, 1.2 9 of methyl 6 (2,4-diisopropylbenzoyl)naphthalene-2-carboxylate are obtained in the form of a white powder whose melting point is 71-730C.
The 60 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C25H25O3 C% H% O% Calculated: 80.40 6.75 12.85 Found: 80.16 7.00 13.13 EXAMPLE 2 Preparation of 6-(2,4-diisopropylbenzoyl)naphthalene-2- carboxylic acid (Compound of formula V in which: R'10=-OH, R'2=R"4=isoC3H7).
A suspension of 0.9 g (2.4 mmol) of methyl 6-(2,4diisopropylbenzoyl)naphthalene-2-carboxylate obtained in Example 1 is stirred for 2 h in a mixture of 15 cm3 of alcohol and 15 cm3 of 6N aqueous potassium hydroxide, heated under reflux. After addition of 50 cm3 of water, the alcohol is removed by evaporation under vacuum. The aqueous phase produced in this manner is diluted to 200 cm3, cooled to between 0 and 50C and acidified with 15 cm3 of 12N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried at 80 0C over potassium hyd rox i de.
After recrystallization from isopropyl ether, 0.5 g of white crystals of 6-(2,4-diisopropylbenzoyl)naphthatene-2-carboxylic acid are obtained, whose melting point is 187-189 0C.
The 250 MHz 1 H NMR spectrum is consistent with the expected structure.
Elemental analysis: C24H2403 eX NX OX Calculated: 79.97 6.71 13.32 Found: 79.94 6.72 13.25 EXAMPLE 3 Preparation of methyl 6-(4-methoxy-2,3,6-trimethylbenzoyl)- naphthalene-2-carboxylate compound of formula VI in which R'10=-OCH3, R"2=R'3=R'6= -CH3, R'12=-CH3) 1.87 g (14 mmol) of anhydrous aluminium chloride are added portionwise to a suspension of 1.5 g (10 mmol) of 2,3,5-trimethylanisole and 2.5 g (10 mmol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid chloride in 80 cm3 of anhydrous 1,2-dichloroethane. The mixture is stirred for 3 hours at ambient temperature and is then poured into 100 cm3 of acidified iced water. The organic phase is separated off.The aqueous phase is extracted once again with 100 cm3 of dichtoroethane. The dichloroethane phases are combined, washed with sodium bicarbonate and with water, and are dried over sodium sulphate and then concentrated down. The solid obtained is purified by chromatography on silica gel in a 60/40 toluene/dichloromethane mixture. After evaporation and drying, 1.2 g of methyl 6 (4-methoxy-2,3,6-trimethylbenzoyl)naphthalene-2-carboxylate are obtained in the form of a yellow powder whose melting point is 144-1450C.
The 60 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C23H2204 CX HX OX Calculated: 76.22 6.12 17.66 Found: 76.30 6.09 17.50 EXAMPLE 4 Preparation of 6-(4-methoxy-2,3,6-trimethylbenzoyl)naptha- lene-2-carboxylic acid (Compound of formula VI in which: R10=-OH, R"2=R'3=R'6= -CH3, R'12=-CH3) A suspension of 0.98 g (2.7 mmol) of methyl 6-(4- methoxy-2,3,6-trimethylbenzoyl)naphthalene-2-carboxylate obtained in Example 3 is stirred for 2 h in a mixture of 20 cm3 of alcohol and 20 cm3 of 6N aqueous potassium hydroxide, heated under reflux. After addition of 60 cm3 of water, the alcohol is removed by evaporation under vacuum. The aqeuous phase obtained is diluted to 300 cm3, cooled to between 0 and 50C and then acidified with 20 cm3 of 12N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried at 800C over potas siul hydroxide.
After recrystallization, firstly from a mixture of cyclohexane and ethylacetate and then from a mixture of hexane and acetone, 0.71 g of white crystals of 6-(4- methoxy-2,3,6-trimethylbenzoyl)naphthalene-2-carboxylic acid is obtained, whose melting point is 260 C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C22H2004 CX HX Calculated 75.84 5.79 18.37 Found: 75.64 5.87 18.50 EXAMPLE 5 Preparation of methyl 6-(4-tert-butylbenzoyl)naphthalene-2- carboxylate (Compound of formula V in which: R'10=-OCH3, R'2=H, R"4= tert-C4Hg) 3.2 g (24 mmol) of anhydrous aluminium chloride are added portionvise to a suspension of 1.61 g (12 mmol) of tert-butylbenzene and 3 g (12 mmol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid chloride in 80 cm3 of anhydrous 1,2-dichloroethane. The mixture is stirred for 5 h at ambient temperature and is then poured into 100 cm3 of acidified iced water.The organic phase is separated off and the aqueous phase is extracted once again vith 100 cm3 of dichloroethane. The dichloroethane phases are combined1 are washed vith sodium bicarbonate, are dried over sodium sulphate and are then concentrated down. The crude solid obtained is recrystallized twice from methanol and then once from isopropanol. After drying, 1.62 g of white crystals of methyl 6-(4-tert-butylbenzoyl)naphthalene-2-carboxy- late are obtained; their melting point is 133.5-134.5 C.
The 60 MHz 1H NMR spectrum is consistent vith the expected structure.
Elemental analysis: C23H2203 CX HX OZ Calculated: 79.74 6.40 13.86 Found: 79.88 6.50 13.53 EXAMPLE 6 Preparation of 6-(4-tert-butylbenzoyl)naphthalene-2- carboxylic acid (Compound of formula V in which: R'10=-OH, R'2=H, R"4=tert C4Hg) A suspension of 1.25 g (3.6 mmol) of methyl 6 (4-tert-butylbenzoyl)naphthalene-2-carboxylate obtained in Example 5 is stirred for 2 h in a mixture of 25 cm3 of alcohol and 25 cm3 of 6N aqueous potassium hydroxide, heated under reflux. After addition of 100 cm3 of water, the alcohol is removed by evaporation under vacuum. The aqueous phase obtained is diluted to 250 cm3, is cooled to between 0 and 50C and is then acidified with 20 cm3 of 12N hydrochloric acid.The precipitate obtained is filtered off, washed with water and dried at 800C over potassium hydroxide.
After recrystalli:ation from isopropyl ether, 0.84 g of white crystals of 6-(4-tert-butylbenzoyl)naphthalene- 2-carboxylic acid is obtained; their melting point is 233 2340C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C22H20O3 C% H% O% Calculated: 79.49 6.06 14.44 Found: 79.54 6.07 14.36 EXAMPLE 7 Preparation of N-ethyl-6-(4-tert-butylbenzoyl)naphthalene- 2-carboxamide (Compound of formula V in which: R'10z-NHC2H5, R'2=H, R"4=tert-C4Hg) A suspension of 250 mg (0.75 mmol) of 6-(4-tertbutylbenzoyl)naphthalene-2-carboxylic acid obtained in Example 6 and 150 mg (0.92 mmol) of N,N'-carbonyldiimidazole in 8 cm3 of anhydrous dichloromethane is stirred for 1 h at ambient temperature. 0.06 cm3 (0.88 mmol) of anhydrous ethylamine is then added to the solution obtained.After being stirred for 1 h, the reaction mixture is diluted with 20 cm3 of dichloromethane, and is washed successively with 10 cm3 of water, 10 cm3 of normal sodium hydroxide, 10 cm3 of water, 10 cm3 of normal hydrochloric acid and lastly 10 cm3 of water. The dichloromethane phase is dried over sodium sulphate and is then evaporated to dryness. The crude amide is dried under vacuum at 600 C and is then recrystallized from isopropyl ether. 190 ag of white crystals of N-ethyl-6-(4-tert-butylbenzoyl)-naphthalene-2-carboxa- mide are obtained; their melting point is 1390C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C24H25N 2 CX HX NZ OX Calculated: 80.19 7.01 3.90 8.90 Found: 79.98 7.00 4.03 9.11 EXAMPLE 8 Preparation of methyl 6-(3-adamantyl-4-methoxybenzoyl)- naphthalene-2-carboxylate (Compound of formula VI in which: R'10=-OCH3, R"2=R'6=H, R'3=1.adamantyl, R'12=-CH3).
A solution of 6.6 g (0.02 mol) of 2-adamantyl-4bromoanisole in 75 cm3 of anhydrous tetrahydrofuran is added to 500 mg (0.02 mol) of magnesium covered with tetrahydrofuran and is heated under reflux until all the magnesium has disappeared. The reaction mixture is then cooled to 0 C and is added to a solution of 2.5 g (0.01 mol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid chloride in anhydrous THF. The mixture is kept at ambient temperature for 1 h and is then poured onto an aqueous solution of ammonium chloride. The expected product is extracted with ether, which is then dried over magnesium sulphate and concentrated down under reduced pressure.
The methyl 6-(3-adamantyl-4-methoxybenzoyl)naphthalene-2carboxylate is purified by chromatography on silica gel (eluent: hexane/ethyl acetate), and is then crystallized from methanol.
1.2 g of a white powder are obtained; its melting point is 130-1320C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
EXAMPLE 9 Preparation of 6-(3-adamantyl-4-methoxybenzoyl)naphthalene- 2-carboxylic acid (Compound of formula VI in which: R'10=OH, R"2=R'6=H, R'3= 1-adamantyl, R'12=-CH3) A suspension of 1 g of methyl 6-(3-adamantyl-4 methoxybenzoyl)naphthalene-2-carboxylate obtained in Example 8 is stirred for 1 h in a mixture of 50 cm3 of ethanol and 50 cm3 of 6N aqueous potassium hydroxide at a temperature of between 50 and 600C. After the addition of 100 cm3 of water, the ethanol is removed by evaporation under vacuum. The aqueous phase is acidified to pH - 1 by addition of hydrochloric acid and is then extracted with 2 x 100 cm3 of ethyl acetate. The organic phase is dried and concentrated down under reduced pressure. 6-(3-Adamantyl-4methoxybenzoyl)naphthalene-2-carboxylic acid crystallizes from methanol. After evaporation, a slightly pink powder is obtained; its melting point is 270-272 0c.
Elemental analysis: C29H2804 CX HX OX Calculated: 79.06 6.40 14.52 Found: 78.58 6.43 14.64 EXAMPLE 10 Preparation of methyl 6-(4-methoxybenzoyl)napthalene-2- carboxyl ate (Compound of formula VI in which: R'10=-OCH3, R112=R'3=R'6=H, R'12=-CH3) 8.05 g (0.06 mol) of anhydrous aluminium chloride are added in smalL portions to a solution of 4.5 g (0.04 mol) of anisole and 10 g (0.04 mol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid chloride in approximately 80 cm3 of anhydrous dichloroethane. The mixture is left to stand overnight at ambient temperature and is then poured into 100 cm3 of iced water The organic phase is separated off. The aqueous phase is extracted with 300 cm3 of dichloromethane.The organic phases are combined, are washed with sodium bicarbonate, are dried over magnesium sulphate and are then concentrated under reduced pressure.
The expected product is purified by recrystallization from acetonitrile, followed by a recrystallization from methyl ethyl ketone. 2.5 g of a white powder are obtained; its melting point is 170-171 C.
Elemental analysis: C20H16O4 C% H% O% Calculated: 74.98 5.03 19.97 Found 75.05 4.95 19.94 EXAMPLE 11 Preparation of methyl 6-(4-cyclohexylbenzoyl)naphthalene-2- carboxylate (Compound of formula V in which: R'10=-OCH3, R'2=H, R"4= cyclohexyl).
3.33 g (25 mmol) of anhydrous aluminium chloride are added portionwise to a suspension of 2.08 9 (13 emol) of phenyl cyclohexane and 3.23 g (13 mmol) of 6-methoxy carbonyinaphthalene-2-carboxylic acid chloride in 80 cm3 of anhydrous 1,2-dichloroethane. The mixture is stirred for 6 h at ambient temperature and is then poured into 150 cm3 of acidified iced water. The organic phase is separated off. The aqueous phase is extracted twice with 60 cm3 of dichloroethane. The dichloroethane phases are combined, are washed with sodium bicarbonate, are dried over sodium sulphate and are then concentrated under reduced pressure. The crude product is recrystallized twice from methanol and then from isopropanol.After drying, 2.4 g of white crystals of methyl 6-(4-cyclohexylbenzoyl)naph- thalene-2-carboxylate are obtained; their melting point is 1300c.
The 60 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C25H24O3 C% H% O% Calculated: 80.62 6.50 12.89 Found: 80.12 6.58 13.28 EXAMPLE 12 Preparation of 6-(4-cyclohexylbenzoyl)naphthalene-2carboxylic acid (Compound of formula V in which: R'10=-OH, R'2=H, R"4=cyclohexyl).
A suspension of 1.2 g (3.2 mmol) of methyl 6-(4cyclohexylbenzoyl)naphthalene-2-carboxylate obtained in Example 11 is stirred for 3 h in a mixture of 25 cm3 of alcohol and 25 cm3 of 6N aqueous potassium hydroxide, heated under reflux After addition of 150 cm3 of water, the alcohol is removed by evaporation under vacuum. The aqueous phase obtained is diluted to 400 cm3, is cooled to between 0 and 50C and is then acidified with 20 cm3 of 12N hydrochloric acid. The precipitate obtained is filtered off, washed with water, and is dried under vacuum at 80 C. After recrystallization from isopropyl alcohol,0.95 g of pinkwhite crystals of 6-(4-cyclohexylbenzoyl)naphthalene-2- carboxylic acid are obtained, with a melting point of 241 2420C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C24H2203 CX HX OX Calculated: 80.42 6.19 13.39 Found: 80.36 6.19 13.23 EXAMPLE 13 Preparation of methyl 6-(4-methoxy-3-phenylbenzoyl)naphtha- lene-2-carboxylate (Compound of formula VI in -which: R'10=-OCH3, R"2=R'6=H, R'3=-C6H5, R'12=-CH3).
3.33 g (25 mmol) of anhydrous aluminium chloride are added portionwise to a suspension of 2.4 g (13 mmol) of 2-methoxybiphenyl and 3.23 g (13 mmol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid in 80 cm3 of anhydrous 1,2dichloroethane. The mixture is stirred for 4h at ambient temperatureand is then poured into 150 cm3 of acidified iced water. The organic phase is separated off. The aqueous phase is extracted twice with 60 cm3 of dichloroethane. The dichloroethane phases are combined, are washed with sodium bicarbonate, are dried over sodium sulphate and are then concentrated down under reduced pressure. The solid obtained is taken up with 200 cm3 of methanol, filtered, and recrystallized twice from methanol and then from acetonitrile.After drying, 2 g of white crystals of methyl 6-(4- methoxy-3-phenylbenzoyl)naphthalene-2-carboxylate are obtained; their melting point is 160-162 C.
The 60 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C26H2004 CZ HX OX Calculated: 78.77 5.09 16.14 Found: 78.79 5.08 15.98 EXAMPLE 14 Preparation of 6-(4-methoxy-3-phenylbenzoyl)naphthalene-2- carboxylic acid (Compound of formula VI in which: R'10=-OH, R"2=R'6=H, R'3=-C6H5, R'12=-cH3) A suspension of 1.3 g (3.28 mmol) of methyl 6-(4- methoxy-3-phenylbenzoyl)naphthalene-2-carboxylate obtained in Example 13 is stirred for 3 h in a mixture of 30 cm3 of alcohol and 30 cm3 of 6 N aqueous potassium hydroxide heated under reflux. After addition of 200 cm3 of water, the alcohol is removed by evaporation under vacuum. The aqueous phase obtained is diluted with 500 cm3 of water, is cooled to between 0 and 50C and is then acidified with 25 cm3 of 12N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried under vacuum at 800C. The crude product is purified rapidly by chromatography on silica gel 60, which is eluted first with dichloromethane and then with a mixture of dichloromethane and isopropanol. After evaporation under vacuum and recrystallibation from a mixture of acetonitrile and acetic acid, 0.6 g of white crystals of 6-(4-methoxy-3-phenylbenzoyl)- naphthalene-2-carboxylic acid are obtained, with a melting point of 221-2Z30c.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C25H1804 CX HZ OX Calculated: 78.52 4.74 16.74 Found: 78.63 4.83 16.55 EXAMPLE 15 Preparation of methyl 6-(4-phenoxybenzoyl)naphthalene-2carboxyl ate (Compound of formula VI in which: R'10=-OCH3, R"2=R'3:R16=H, R'12=-C6HS) 3.33 g (25 mmol) of anhydrous aluminium chloride are added portionwise to a suspension of 2.21 g (13 mmol) of diphenyl ether and 3.23 g (13 mmol) of 6-methoxycarbonylnaphthalene-2-carboxylic acid chloride in 80 cm3 of anhydrous 1,2-dichloroethane. The mixture is stirred for 5 h at ambient temperature and is then poured into 150 cm3 of acidified iced water. The organic phase is separated off and the aqueous phase is extracted twice with 80 cm3 of dichloroethane.The dichloroethane phases are combined, are washed with sodium bicarbonate, are dried over sodium sulphate and are then concentrated down under reduced pressure.
The solid obtained is purified by washing with boiling methanol and is then recrystallized from isopropanol. After drying, 3.2 g of white crystals of methyl 6-(4-phenoxybenzoyl)naphthalene-2-carboxylate are obtained; their melting point is 1736C.
The 60 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C25H1804 CX HX OX Calculated: 78.52 4.74 16.74 Found: 78.55 4.83 16.64 EXAMPLE 16 Preparation of 6[(2,4-diisopropylphenyl)hydroxymethyl]- naphthalene-2-carboxylic acid (Compound of formula III in which R'=H, R"=OH, R2=R4= isoC3H7, 3=R5=R6=H, R1=-CO2H) 170 mg (4.5 mmol) of sodium borohydride are added to a solution, cooled to OOC, of 0.54 g (1.5 mmol) of 6 (2,4-diisopropylbenzoyl)naphthalene-2-carboxylic acid obtained in Example 2 in 15 cm3 of anhydrous tetrahydrofuran, and is stirred for 1 hour while being allowed to return to ambient temperature and then for about 30 min while being heated until it refluxes. The reduction is then complete.
The reaction mixture is then cooled to 0 C and is then acidified by slow addition of 0.1N hydrochloric acid and is extracted with ethyl ether.
The ether phase is washed with water, is dried over sodium sulphate and is evaporated to dryness. The crude product obtained is recrystallized from hexane containing a little acetone. After drying at 70 C, 0.4 g of white crystals of 6-EC2,4-diisopropylphenyl)hydroxymethyl)naphthalene- 2-carboxylic acid is obtained; their melting point is 2250C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C24H2603 CZ HX OX Calculated: 79.53 7.23 13.24 Found: 79.16 7.23 13.44 EXAMPLE 17 Preparation of 6-[(2,4-diisopropylphenyl)hydroxymethyl] naphthalene-2-carbinol (Compound of formula III in which R'=H, R"=OH, R2=R4:jSOC3H7, R3=R5=R6=H, R1=cH2OH).
A solution of 0.72 g (2 mmol) of 6-(2,4-diisopropylbenzoyl)naphthalene-2-carboxylic acid obtained in Example 2 in 10 cm3 of anhydrous tetrahydrofuran is added to a suspension of 230 mg (6 mmol) of lithium aluminium hydride in 5 cm3 of anhydrous tetrahydrofuran, cooled to -10 C.
After 1 hour's stirring while being allowed to return to ambient temperature, the reaction mixture is cooled to 0 0C, is acidified by slow addition of 0.1N hydrochloric acid and is extracted with ethyl ether.
The ether phase is washed with water, is dried over sodium sulphate and is evaporated to dryness. The crude product is purified by rapid chromatography on silica 60 in the eluent mixture of 30/40/30 toluene/dichloromethane/ethyl acetate, followed by a recrystallization from a mixture of hexane and acetone.
After drying under vacuum at 700C, 0.52 g of white needles of 6-[(2,4-diisopropylphenyl)hydroxymethyl)naphtha- lene-2-carbinol is obtained; their melting point is 1360C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C24H2802 CZ HZ OZ Calculated: 82.72 8.10 9.18 Found: 82.54 8.07 9.48 EXAMPLE 18 Preparation of 6-(2,4-diisopropylbenzyl)naphthalene-2carboxylic acid (Compound of formula III in which R'=R"+R3=R5=R6=H, R2=R4= isoC3H7, and R1=-C 2H) 0.72 g (2 mmol) of 6-(2,4-diisopropylbenzoyl) naphthalene-2-carboxylic acid obtained in Example 2 is added to a suspension of 1,3 g (20 mmol) of zinc powder in 20 cm3 of glacial acetic acid and is heated for 1 hour under reflux. 2 cm3 of 12N hydrochloric acid are then added dropwise and refluxing is continued for 30 min.
After cooling to ambient temperature and the addition of 20 cm3 of 12N hydrochloric acid, the reaction mixture is diluted with 100 cm3 of water and is extracted with dichloromethane. The organic phase is washed with water, is dried over sodium sulphate and is concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel 60 in the eluent mixture of 30/40/30 toluene/dichloromethane/ethyl acetate, followed by a recrystallization from hexane containing a trace of acetone.
After drying under vacuum at 600C, 0.4 g of white crystals of 6-(2,4-diisopropylbenzyl)naphthalene-2- carboxylic acid is obtained; their melting point is 1831850C.
The 250 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C24H2602 CZ HZ Calculated: 83.20 7.56 9.24 Found: 83.08 7.49 9.41 EXAMPLE 19 Preparation of methyl 4-(2,4-^iisopropylbenzoyl)benzoate (Compound of formula IV in which: R'2=R'4=isoC3H7, R' and R"=oxo, R'3=R's=H, and R'1s-CO2CH3) 2.40 g of powdered anhydrous aluminium chloride are added in small portions, so as to maintain the temperature below 350C, to a stirred solution, at ambient temperature, of 1.20 cm3 of 1,3-diisopropylbenzene (0.011 mol) and 2 g (0.01 mol) of 4-methoxycarbonylbenzoyl chloride in 50 cm3 of anhydrous 1,2-dichloroethane.
Stirring is continued for 1 hour till the starting material has completely disappeared. The reaction mixture is poured onto 100 cm3 of iced water and is extracted with dichloromethane. The organic phase is washed with an aqueous solution of sodium hydrogen carbonate and then with water, is dried over magnesium sulphate and is concentrated down under reduced pressure.
An oil is recovered which crystallizes from hexane, and 2.7 g of methyl 4-(Z,4-diisopropylbenzoyl)benzoate are obtained, melting at 64-650C.
The 80 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C21H2403 CX Ht OZ Calculated: 77.75 7.46 14.79 Found: 77.55 7.46 14.87 EXAMPLE 20 Preparation of 4-(2,4-diSsopropylbenzoyl)benzoic acid (Compound of formula IV in which: R'2=R'4=isoC3H7, R' and R"=oxo, R'3=R'5=H and R'1=-CO2H) 75 cm3 of a 6N aqueous solution of potassium hydroxide are added to a solution of 2.7 g of methyl 4-(2,4diisopropylbenzoyl)benzoate obtained in Example @ 9 in 200 cm3 of absolute alcohol. The reaction mixture is heated to 400C for about 1 hour until the starting material has completely disappeared and then the alcohol is evaporated off under reduced pressure.The aqueous phase is diluted with 300 cm3 of water, is cooled to 0 C and is acidified with concentrated hydrochloric acid.
The product obtained is filtered off and recrystal lized from a mixture of toluene and hexane. 1.3 g of a white powder melting at 181-1820C are recovered.
The 80 MHz 1H NMR spectrum is consistent with the expected structure.
Elemental analysis: C20H22 3 CZ HZ OZ Calculated: 77.39 7.15 15.46 Found: 77.19 7.15 15.56 EXAMPLE 21 Preparation of 1-C2,4-diisopropylphenyl)-1-(4-hydroxy- methylphenyl )methanol (Compound of formula IV in which: R'2=R'4=isoC3H7, R'=H, R"=OH, R'3=R's=H and R'1 =-CH2OH) A solution of 10 g of methyl 4-(2,4-diisopropylbenzoyl)benzoate obtained in Example 19 in 50 cm3 of tetrahydrofuran is added dropwise to a suspension of 3.5 g of lithium aluminium hydride in 200 cm3 of anhydrous tetrahydrofuran, maintained at OOC. When the addition is complete the reaction mixture is stirred continuously at ambient temperature until the starting material and the reduction intermediates have completely disappeared.
After the addition of 50 cm3 of ethyl acetate to destroy excess hydride, the solution is poured onto 200 cm3 of water, is acidified with 3N hydrochloric acid and is extracted with ethyl acetate. The organic phases are washed, are dried over magnesium sulphate and are concentrated down under reduced pressure.
6 g of l-(2,4-diisopropylphcnyl)-1-(4-hydroxy- methylphenylmethanol) are recovered; this crystallizes from hexane in the form of a white powder melting at 85-86 0C and whose 80 MHz 1H NMR spectrum is consistent with the expected structure.
EXAMPLE 22 Preparation of 4-[2,4-diisopropylphenyl)hydroxymethyl]- benzoic acid (Compound of formula IV in which: R'2=R'4=isoC3H7, R':H, R"OH, R'3=R's=H and R'1=-CO2H).
2 g of sodium borohydride are added at ambient temperature to a stirred solution of 1 g of 4-(2,4-diisopropylbenzoyl)benzoic acid obtained in Example 20 in 100 cm3 of methanol.
Stirring is continued for two hours until the starting material has completely disappeared.
The reaction mixture is hydrolysed with 100 cm3 of water and is then acidified with a 3N hydrochloric acid solution.
After evaporation of the methanol under reduced pressure, the aqueous phase is extracted vith ethyl acetate. The organic phase is washed vith water, is dried over magnesium sulphate and is concentrated down under reduced pressure.
The residue is taken up with r little diisopropyl ether, and 400 mg of 4-t(2,4-diisopropylphcnyl)hydroxy- methylZbenzoic acid, melting at 114-115 C, are obtained.
The 80 MHz 1H NMR spectrum is consistent with the expected structure.
EXAMPLE 23 Preparation of 4-(2,4-diisopropylbenzoyl)benzaldehyde (Compound of formula IV in which: R'2=R'4=isoC3H7, R' and R"= oxo, R'3=R'5=H and R'1=-CHO) 10.8 g of pyridinium chtorochromate are added to a solution of 6 g of (2,4-diisopropylphenyl)-I-(4- hydroxymethylphenyl)methanol obtained in Example 21 in 200 cm3 of anhydrous dichloromethane.
Stirring is continued for about 3 hours until the starting material has completely disappeared and then, after the addition of some twenty grams of silica and of 300 cm3 of dichloromethane, the solution is filtered, washed with a solution of ammonium chloride and with water, is dried over magnesium sulphate and is concentrated down under reduced pressure.
After purification by chromatography on silica gel (eluent: 9/1 hexane/ethyl acetate), 3 g of 4-(2,4- diisopropylbenzoyl)benzaldehyde are recovered in the form of oil.
The 80 MHz 1H NMR spectrum is consistent with the expected structure.
EXAMPLE 24 Preparation of ethyl 4-(Z,4-diisopropylbenzoyl)-a- methylcinnamate (Compound of formula I in which n=1, R2sR4:iSoC3H7, R' and R"=oxo, R3=R5=R6=R7=R8=H, R9=CH3 and R1=-CO2C2CH5) 1 g of sodium hydride is added in small portions to a solution of 3.5 cm3 of triethyl 2-phosphonopropionate in 200 cm3 of anhydrous tetrahydrofuran. A release of gas is observed.
Stirring is continued for about 2 hours, and then, in the absence of light, a few drops of crown ether are added, followed by a solution of 3 g of 4-(2,4-diisopropylbenzoyl)benzaldehyde obtained in Example 23, dissolved in 50 cm3 of anhydrous tetrahydrofuran. When the addition is complete stirring is continued for 2 hours and then the reaction medium is poured onto a saturated solution of ammonium chloride and is extracted with ethyl acetate.
The organic phases are washed, dried and concentrated down under reduced pressure.
After purification by chromatography on silica gel (eluent: 9.5/0.5 hexane/ethyl acetate), 2 g of ethyl 4 (2,4-diisopropylbenzoyl)--methylcinnamate are recovered in the form of an oil whose 80 MHz 1H NMR spectrum corresponds to the expected structure.
EXAMPLE 25 Preparation of 4-(2,4-diisopropylbenzoyl)-a-methylcinnamic acid (Compound of formula I in which: ntl, R2=R4=isoC3H7, R' and R"=oxo, R3=Rs=R6=R7=Rg=Ht R9=CH3 and R1=-CO2H).
A solution of 1.5 g of ethyl 4-(2,4-diisopropylben zoyl)--methylcinnamate obtained in Example 24 is stirred for 2 hours in a mixture of 100 cm3 of ethanol and 50 cm3 of 6N aqueous potassium hydroxide at a temperature of between 40 and 500C.
After evaporation of the ethanol under reduced pressure, the residue is taken up with 500 cm3 of water and is acidified with 3N hydrochloric acid.
The expected acid is extracted with ethyl acetate.
The organic phases are washed, are dried and are concentrated down under reduced pressure.
After crystallization from hexane, 0.9 g of a white powder melting at 119-1200C is obtained and the 80 MHz 1H NMR spectrum corresponds to the structure of 4-(2,4-diiso- propylbenzoyl)-a-methylcinnamic acid.
Elemental analysis: C23H2603 C H O Calculated: 78.82 7.48 13.70 Found: 78.91 7.49 13.90 EXAMPLE 26 Preparation of methyl 4-[(3-adamantyl-4-methoxyphenyl)- hydroxymethyl]benzoate (Compound of formula IV in which R'1=-COzCH3, R'=H, R"=OH, R' 5=adamantyl, R'4=OCH3, R 2=R 3=H) A solution of 38 g (0.118 mol) of Z-adamantyl-4- bromoanisole in 350 cm3 of tetrahydrofuran is added to 2.87 g (0.118 mol) of magnesium. The tetrahydrofuran is kept refluxing until the magnesium has completely disappeared. After the reaction mixture has been cooled to 00C, a solution of 13.7 g of methyl 4-formylbenzoate in 50 cm3 of tetrahydrofuran is added dropwise.The mixture is kept at ambient temperature for 1 hour and is then poured onto a saturated solution of ammonium chloride. The expected product is extracted vith ether.
The organic phases are washed, are dried over magnesium sulphate and are concentrated down under reduced pressure.
After chromatography on silica gel under pressure Celuent: 95/5 toluene/ethyl acetate), there are recovered 19 g of a crystalline white product melting at 109-110 C and whose 80 MHz 1H NMR spectrum corresponds to the structure of methyl 4-Ef3-adamantyl-4-methoxyphenyl)hydroxy- methylZbenzoate.
EXAMPLE 27 Preparation of 4-[(3-adamantyl-4-methoxyphenyl)hydroxy- methylZbenzoic acid (Compound of formula IV in which R'1=-CO2H, R'=R'2=R'3=H, R"=OH, R'5=adamantyl) A suspension of 19 g of methyl 4E(3-adamantyl-4- methoxyphenyl)hydroxymethylJbenzoate obtained in Example 26 is heated for 1 h 30 min at 600C in a mixture of 300 cm3 of ethanol and 200 cm3 of 6N aqueous potassium hydroxide.
After evaporation of the ethanol under reduced pressure, the residue is taken up with 300 cm3 of water and is acidified to pH 2 with 3N hydrochloric acid.
The expected acid is extracted with ether. The organic phases are washed, are dried and are concentrated down under reduced pressure.
17 g of a slightly cream-coloured product are obtained; this melts at 219-2200C and its 80 MHz 1H NMR spectrum corresponds to the structure of 4-C(3-adamantyl-4- methoxyphenyl )hydroxymethyl)benzoic acid.
Elemental analysis: C25H2804 C H O Theoretical value: 76.50 7.19 16.31 Found value: 76.17 7.08 15.93 EXAMPLE 28 Preparation of 4-(3-adamantyl-4-methoxybenzoyl)benzoic acid (Compound of formula IV in which: R'1=-CO2H, R'2=R'3=H, R' and R"=oxo, R'5=adamantyl, R'4=-OCH3).
A solution of 8 g of K2Cr207, 7 cm3 of concentrated sulphuric acid and 50 cm3 of water is added dropwise at ambient temperature to a solution of 10 g of 4-t(3-adamantyl- 4-methoxyphenyl)hydroxymethyl)benzoic acid obtained in Example 27 in 700 cm3 of acetone.
Stirring is continued for 1 hour until the starting material has disappeared.
After evaporation of the acetone under reduced pressure, the residue is taken up with 500 cm3 of water and is extracted with ethyl ether.
The organic phases are washed, are dried over magnesium sulphate and are concentrated down under reduced pressure. 9.5 g of 4-(3-adamantyl-4-methoxybenzoyl)benzoic acid are recovered; its 80 MHz H spectrum corresponds to the expected structure.
2.5 9 of acid whose melting point is 235-2360c are obtained by recrystallization of a 3 g specimen of crude acid from a mixture of toluene and hexane.
Elemental analysis: C25H2604 C H O Calculated: 76.90 6.71 16.39 Found: 76.97 6.76 16.52 EXAMPLE 29 Preparation of methyl 4-C3-adamantyl-4-hydroxybenzoyl)- benzoate (Compound of formula IV in which: R'1=-CO2CH3, R't=R'3=H, R' and R"=oxo, R's=adamantyl, R'4=OH.
1 cm3 of a concentrated solution of hydrochloric acid is added to a suspension of 1.5 g of 4-(3-adamantyl4-methoxybenzoyl)benzoic acid obtained in Example 28 in 150 cm3 of methanol. The mixture is stirred for 4 hours at the boiling point of the solvent. It is then poured at ambient temperature into 200 cm3 of water, is extracted three times with 100 cm3 portions of ethyl acetate. The ethyl acetate phases are combined, are washed with water, are dried over magnesium sulphate and are concentrated down under reduced pressure. The crude product is then fractionated by being passed through a column of silica gel.
Methyl 4-(3-adamantyl-4-hydroxybenzoyl)benzoate is eluted with a mixture of hexane and ethyl acetate (8/2).
After evaporation of the solvent the expected product is isolated in the form of white crystals with a melting point of 270 C.
Elemental analysis: C25H2604 C H O Calculated: 76.90 6.71 16.39 Found: 76.50 6.97 16.11 EXAMPLE 30 Preparation of methyl 4-(3,5-ditert-butyl-4-hydroxybenzoyl)- benzoate (Compound of formula IV in which: R'1=-CO2CH3, R'2=H, R' and R"=oxo, R'3=R's=tert-C4Hg, R'4=OH.
11.6 cm3 of stannic chloride diluted with 50 cm3 of toluene are added dropwise at OOC to a stirred solution containing 20 g of 2,6-ditert-butylphenol and 19 g of 4methoxycarbonylbenzoyl chloride in 300 cm3 of toluene. The solution gradually becomes red in colour. Stirring is continued for another 2 hours at OOC after the addition is complete and then the reaction mixture is left overnight at ambient temperature. The mixture is then poured into 300 cm3 of iced water and is extracted three times with 150 cm3 portions of ethyl acetate. The ethyl acetate phases are combined, are vashed uith an aqueous solution of sodium bicarbonate, are dried over magnesium sulphate and are concen- trated down.
The crude product obtained is diluted in the minimum quantity of toluene and is deposited onto a column of silica gel. The expected product is eluted with a mixture of hexane and ethyl acetate (1/1). After evaporation of the solvent and after drying, 3 g of methyl 4-(3,5-ditert-butyl-4-hydro xybenzoyl)benzoate are obtained in the form of a fluffy white powder whose melting point is 172 C.
Elemental analysis: C23H2804 C H O Calculated: 74.97 7.66 17.37 Found: 75.00 7.70 17.52 EXAMPLE 31 Preparation of 4-(3,5-ditert-butyl-4-hydroxybenzoyl)benzoic acid (Compound of formula IV in which R'1=-CO2H, R'2=H, R' and R"=oxo, R'3=Rts=tert-C4Hg, R'4=OH) A solution of 1 g of methyl 4-(3,5-ditert-butyl-4hydroxybenzoyl)benzoate obtained according to Example 30 in a mixture of 40 cm3 of 6N aqueous potassium hydroxide solution and of 100 cm3 of ethanol is heated for 1 hour at a temperature of 500C. Ethanol is then removed by evaporation under vacuum, the product obtained is stirred into 200 cm3 of water and the solution is acidified by adding 6N hydrochloric acid and is then extracted with 300 cm3 of ethyl acetate.The ethyl acetate phase is washed three times with water and is dried over magnesium sulphate. The ethyl acetate is removed by evaporation under vacuum. After recrystallization of the crude product from toluene in the presence of a trace of methanol, 0.7 g of 4-(3,5-ditert-butyl4-hydroxybenzoyl)benzoic acid is obtained in the form of white crystals with a melting point of 2550C.
The NMR spectrum is consistent with the expected structure.
Elemental analysis: C22C2604 C H O Calculated: 74.55 7.39 18.06 Found: 74.12 7.42 18.61 EXAMPLES OF COMPOSITION A. ORAL ROUTE Example 1 - 0.2 9 tablet 6-(4-Methoxy-2,3,6-trimethylbenzoyl)naphthalene- 2-carboxylic acid ...................... 0.010 g Starch ................................. 0.115 g Dicalcium phosphate .................... 0.020 g Silica ................................. 0.020 g Lactose ................................ 0.030 g Talc 0.010 g Magnesium stearate ..................... 0.005 g Example II - Drinkable suspension is S-ml vials 6-(3-Adamantyl-4-methoxybenzoyl)naphthatene-2- carboxylic acid ........................ 0.010 g Glycerin ............................... 0.500 g 70% Sorbitol ........................... 0.500 g Sodium saccharinate .................... 0.010 g Methyl-para-hydroxybenzoate ............ 0.040 g Flavouring ............................. q.s.
Purified water ..... q.s................ 5.000 g B. TOPICAL ROUTE Example III - Ointment Methyl 6-(4-methoxy-3-phenylbenzoyl)naphthalene- 2-carboxylate ............................ 0.100 g Isopropyl myristate ..................... 81.700 g Liquid paraffin .......................... 9.100 g Silica sold by the Degussa company under the name of "Aerosil 200" .................... 9.100 g Example IV - Anionic oil-in-water cream Methyl 6-(4-methoxy-2,3,6-trimethylbenzoyl) naphthalene-2-carboxylate ................ 0.100 g Sodium dodecyl sulphate .................. 0.800 g Glycerol ................................. 2.000 g Stearyl alcohol .......................... 20.000 g Triglycerides of capric/caprylic acids sold by the Dynamit Nobel company under the name of "Miglyol 812" ............................ 20.000 g Preservatives ............................ q.s.
Demineralized water ..... q.s............. 100.000 g In examples III and IV above the active compound may be replaced with an equivalent quantity of 6-(2,4diisopropylbenzoyl)naphthalene-2-carboxylic acid.
Example V - GeL N-ethyl-6-(4-tert-butylbenzoyl)naphthalene-2- carboxamide .............................. 0.500 g Hydroxypropyl cellulose sold by the Hercules company under the name of "Klucel HF" .... 2.000 g Water/ethanol (50/50) ... q.s. 100.000 g Example VI - Antiseborrhoeic cream Polyoxyethylene stearate (40 moles of ethylene oxide) sold under the name of "Myrj 52" by the "Atlas" company ........................... 4.000 g Mixture of lauric esters of sorbitol and of sorbitan, polyoxyethylenated with 20 moles of ethylene oxide, sold under the name of "TWEEN 20" by the "Atlas" company ................... 1.800 g Mixture of glycerol mono- and distearate sold under the name of "Geleol" by the "Gattefosse" company ................................. 4.200 g Propylene glycol ........................ 10.000 g Butylated hydroxyanisole ................ 0.010 g Butylated hydroxytoluene ................ 0.020 g Cetostearyl alcohol ..................... 6.200 g Preservatives ........................... q.s.
Perhydrosquatene ........................ 18.000 g Mixture of caprylic-capric triglycerides sold under the name of "Miglyol 812" by the "Dynamit Nobel" company .................. 4.000 g S-carboxymethylcysteine .................. 3.000 g 99X triethanolamine ...................... 2.500 g 6-(2,4-Diisopropylbenzoyl)naphthalene-2-carboxylic acid ................................... 0.100 g Water q.s..............................100.000 g Example VII - Antiseborrhoeic cream Polyoxyethylene stearate (40 mols of ethylene oxide) sold under the name of "Myri 52" by the "Atlas" company ......... 4.000 g Mixture of lauric esters of sorbitol and of sorbitan, polyoxyethylenated with 20 moles of ethylene oxide, sold under the name of "Tween 20" by the "Atlas" company................................... 1.800 g Mixture of glycerol mono- and distearate sold under the name of "Geleol" by the "Gattefosse" company ..................... 4.200 g Propylene glycol ......................... 10.000 g Butylated hydroxyanisole ................. 0.010 g Butylated hydroxytoluene ................. 0.020 g Cetostearyl alcohol ...................... 6.200 g Preservatives ............................ q.s.
Perhydrosqualene ......................... 18.000 g Mixture of caprylic-capric triglycerides sold under the name of "Miglyol 812" by the "Dynamit Nobel" company .............. 4.000 g 2-Benzylth ioethylammonium 5-amino-5-carboxy 3-thiapentanoate ......................... 3.000 g 6-(4-tert-Butylbenzoyl)naphthalene-2- carboxylic acid .......................... 0.500 g Water q.s. ..............................100.000 g Example VIII - Hair lotion Propylene glycol .........................20.000 g Ethanol ..................................34.870 g Polyethylene glycol with a molecular mass of 400 ..40 .000 9 Water .................................... 4.000 g Butylated hydroxyanisole ................. 0.010 g Butylated hydroxytoluene ................. 0.020 g 6-(3-Adamantyl-4-methoxybenzoyl )naphthalene- 2-carboxylic acid ........................ 0.100 g Minoxidil ................................ 1.000 g Example IX - Antiacne gel 6-(2,4-Diisopropylbenzoyl)naphthalene-2- carboxylic acid .......................... 0.200 g Isopropyl alcohol ........................ 40.000 g Acrylic acid polymer sold under the name "Carbopol 940" by the "Goodrich Chemical Co" .............................. 1.000 g 99X triethanolamine 0.600 ................. 0,600 g Butylated hydroxyanisole .................. 0.010 g Butylated hyrdoxytoluene ................. 0.020 g Thioxolone ............................... 0.500 g Propylene glycol ......................... 8.000 g Purified water q.s....................... 100.000 g

Claims (21)

  1. CLAIMS 1. A compound which is a product of formula:
    in which: R' is hydrogen; and R" is an OH group; or R' and R'X, taken together, form an oxo (=0) group; R1 is a -CH2OH, -CH=O or - COOR11 group, wherein R11 is hydrogen or a lower alkyl group; R2 and R3, which may be identical or different, are each hydrogen or an alkyl group containing from 3 to 6 carbon atoms; R5 is either (i) a-cycloalkyl or alkyl group containing from 3 to 6 carbon atoms and, in this case, R4 is a lower alkyl group, a hydroxyl group or an alkoxy group, or (ii) hydrogen and, in this case, R4 is a lower alkyl group; R6 is hydrogen; and R7 is hydrogen or a methyl group; or a salt thereof, including the optical and geometrical isomers of said compound.
  2. 2. A compound according to claim 1 wherein each lower alkyl group is a methyl, ethyl, isopropyl, butyl or tert-butyl group.
  3. 3. A compound according to claim 1 or 2 wherein the cycloalkyl group is a cyclopentyl or cyclohexyl group.
  4. 4. A compound according to any one of claims 1 to 3 wherein R7 is hydrogen.
  5. 5. A compound according to any one of claims 1 to 4 wherein the product is: methyl 4-(2,4-diisopropylbenzoyl)benzoate, 4-(2,4-diisopropylbenzoyl)benzoic acid, 4-[(2,4-diisopropylphenyl)hydroxymethyll]benzoic acid, 1-(2,4-diisopropylphenyl)-1-(4-hydroxymethylphenyl)-methanol, 4-(2,4-diisopropylbenzoyl)benzaldehyde, methyl 4-[(3-adamantyl-4-methoxyphenyl)hydroxymethyl] benzoate, 4-[(3-adamantyl-4-methoxyphenyl)hydroxymethyl]benzoic acid, 4-(3-adamantyl-4-methoxybenzoyl)benzoic acid, 4-(3-adamantyl-4-hydroxybenzoyl)benzoic acid, methyl 4- (3-adamantyl-4-hydroxybenzoyl) benzoate, methyl 4-(3,5-ditert-butyl-4-hydroxybenzoyl) benzoate, or 4-(3,5-ditert-butyl-4-hydroxybenzoyl)benzoic acid.
  6. 6. A process for the preparation of a compound as defined in any one of claims 1 to 5 which comprises reacting or condensing, in an organic solvent medium, an acid chloride of formula:
    in which: R7 is hydrogen or a methyl group; and R11 is an alkyl group containing from 1 to 20 carbon atoms, with a benzene derivative of formula:
    in which: X is Br or C1; and R2 to R6 are as defined in claim 1; followed by, if required, saponifying the keto-ester obtained to obtain the corresponding keto-acid, and subsequently converting the keto-acid to a hydroxyacid or diol and oxidizing, if desired, the diol to the corresponding keto-aldehyde.
  7. 7. A process according to claim 6 wherein the condensation is performed under Friedel-Crafts reaction conditions in the presence of anhydrous aluminium chloride in 1,2-dichloroethane at a temperature of from O- to 25C with stirring.
  8. 8. A process according to claim 6 wherein the condensation reaction of the acid chloride with-the organomagnesium derivative of formula (13) is carried out in tetrahydrofuran at a temperature of about OC.
  9. 9. A process according to any one of claims 6 to 8 wherein the conversion of the keto-acid to the corresponding hydroxacid is performed in the presence of sodium borohydride in tetrahydrofuran or methanol.
  10. 10. A process according to any one of claims 6 to 9 wherein the keto-aldehyde is obtained by oxidation of the diol using pyridinium chlorochromate, the diol resulting from a reduction of the keto-acid in the presence of lithium aluminium hydride.
  11. 11. A process according to claim 6 substantially as hereinbefore described with reference to any one of Examples 1 to 31.
  12. 12. A compound as defined in any one of claims 1 to 5 or a compound obtained by a process as defined in any one of claims 6 to 11 for use in a method of treatment of the human or animal body by theraphy.
  13. 13. A pharmaceutical composition suitable for enteral, parenteral, topical or ocular administration comprising, in a suitable carrier, at least one compound as defined in any one of claims 1 to 5 or obtained by a process as defined in any one of claims 6 to 11.
  14. 14. A composition according to claim 13 suitable for topical or ocular administration which comprises from 0.0005 to 5% by weight of the compound relative to the total weight of the composition.
  15. 15. A composition according to claim 13 substantially as hereinbefore defined with reference to any one of Example I to IX.
  16. 16. Use of a compound as defined in any one of claims 1 to 5 or a compound obtained by a process as defined in any one of claims 6 to 11, for the preparation of a pharmaceutical composition for the treatment of a dermatological, respiratory or ophthalmological complaint.
  17. 17. A cosmetic composition for body hygiene or hair care which comprises, in an appropriate cosmetic carrier, at least one compound as defined in any one of claims 1 to 5 or obtained in a process as defined in any one of claims 6 to 11.
  18. 18. A composition according to claim 17 which comprises from 0.0005 to 2% by weight of the compound relative to the total weight of the composition.
  19. 19. A composition according to claim 18 which comprises from 0.01 to 1% by weight of the compound.
  20. 20. A composition according to any one of claims 13, 14 or 17 to 19 which comprises at least one inert or pharmacodynamically or cosmetically active additive.
  21. 21. A composition according to claim 17 substantially as hereinbefore described in any one of Examples I to IX.
GB9007490A 1986-04-04 1990-04-03 Aromatic compounds,process for their preparation,and their use in human and veterinary medicine and in cosmetics Expired - Lifetime GB2228734B (en)

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GB8707990A GB2189784B (en) 1986-04-04 1987-04-03 Cinnamic and naphthoic acid derivatives

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FR2755965A1 (en) * 1996-11-19 1998-05-22 Cird Galderma BIAROMATIC COMPOUNDS, PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING THEM AND USES
US5780676A (en) * 1992-04-22 1998-07-14 Ligand Pharmaceuticals Incorporated Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors
US5962731A (en) * 1992-04-22 1999-10-05 Ligand Pharmaceuticals Incorporated Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors

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US7655699B1 (en) 1992-04-22 2010-02-02 Eisai Inc. Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors

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NL6412637A (en) * 1964-10-30 1966-05-02
EP0211548A1 (en) * 1985-07-22 1987-02-25 Riker Laboratories, Incorporated Antiallergic agents

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NL6412637A (en) * 1964-10-30 1966-05-02
EP0211548A1 (en) * 1985-07-22 1987-02-25 Riker Laboratories, Incorporated Antiallergic agents

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5780676A (en) * 1992-04-22 1998-07-14 Ligand Pharmaceuticals Incorporated Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors
US5962731A (en) * 1992-04-22 1999-10-05 Ligand Pharmaceuticals Incorporated Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors
US6043279A (en) * 1992-04-22 2000-03-28 Ligand Pharmaceuticals, Incorporated Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors
FR2755965A1 (en) * 1996-11-19 1998-05-22 Cird Galderma BIAROMATIC COMPOUNDS, PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING THEM AND USES
WO1998022423A1 (en) * 1996-11-19 1998-05-28 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Bi-aromatic compounds, pharmaceutical and cosmetic compositions containing same and uses
AU719468B2 (en) * 1996-11-19 2000-05-11 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) Biaromatic compounds, pharmaceutical and cosmetic compositions containing them and uses thereof
US6258775B1 (en) 1996-11-19 2001-07-10 Centre International De Recherches Dermatologiques Galderma Bi-aromatic compounds, pharmaceutical and cosmetic compositions containing same and uses

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