Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/67—Vitamins
  • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q5/00—Preparations for care of the hair
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q7/00—Preparations for affecting hair growth
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/55—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
  • C07C57/50—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid containing condensed ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
  • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
  • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
  • C07C69/90—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl and carboxyl groups

Definitions

• the invention relates, as new and useful industrial products, to biaromatic compounds. It also relates to the use of these new compounds in pharmaceutical compositions intended for use in human or veterinary medicine, or even in cosmetic compositions.
• the compounds according to the invention have a marked activity in the fields of cell differentiation and proliferation, and find applications more particularly in the topical and systemic treatment of dermatological conditions linked to a keratinization disorder, dermatological conditions (or others) with an inflammatory and / or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant.
• These compounds can also be used in the treatment of degenerative diseases of the connective tissue, to fight against aging of the skin, whether photoinduced or chronological, and to treat scarring disorders. They also find an application in the ophthalmological field, in particular in the treatment of corneopathies.
• the compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
• R-1 represents (i) the radical -CH 3
• Y represents a radical chosen from the radicals of formulas (a) to (c) below:
• Ar represents a radical chosen from the radicals of formulas (d) to (g) below:
• X represents a radical chosen from the radicals of formulas (h) to (p) below which can be read from left to right or vice versa,
• R2 and R3, identical or different, represent an atom or a radical chosen from:
• R4 and Rg identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, or a radical -OR5,
• R5 identical or different, represents a hydrogen atom, a lower alkyl radical or a -COR-J Q radical,
• R ⁇ represents an atom or a radical chosen from:
• R7, R'7 and Rg identical or different, represent a hydrogen atom or a lower alkyl radical
• n 0, 1 or 2
• R-J O represents a lower alkyl radical
• Rj -j represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono or polyhydroxyalkyl radical, an aryl or aralkyl radical, optionally substituted, or a sugar residue or an amino acid or peptide residue.
• R 'and R ", identical or different, represent a hydrogen atom, a lower alkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or a residue of amino acid or of peptide or of sugar or taken together form a heterocycle,
• the compounds according to the invention are in the form of salts, by addition of an acid, they are pharmaceutically or cosmetically acceptable salts obtained by addition of a mineral or organic acid, in particular hydrochloric, sulfuric acid , acetic, citric, fumaric, hemisuccinic, maleic and mandelic.
• a mineral or organic acid in particular hydrochloric, sulfuric acid , acetic, citric, fumaric, hemisuccinic, maleic and mandelic.
• a base they are preferably salts of an alkali or alkaline earth metal or also of zinc or of an organic amine.
• the alkyl radicals having from 1 to 20 carbon atoms mention may advantageously be made of methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, nonyl, 2-ethyl-hexyl and dodecyl radicals .
• these radicals Preferably, these radicals have from 1 to 12 carbon atoms.
• the alkyl radical generally comprises from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Mention may be made, as lower alkyl radical, of the methyl, ethyl, propyl, isopropyl, tert-butyl and hexyl radicals.
• alkenyl radical is meant a radical having from 2 to 20 linear or branched carbon atoms comprising one or more double bonds.
• alkenyl radicals a radical containing from 2 to 5 carbon atoms and having one or more ethylenic unsaturations is preferred, such as more particularly the allyl radical.
• monohydroxyalkyl or polyhydroxyalkyl radical is meant a radical containing from 1 to 6 carbon atoms and from 1 to 5 hydroxyl groups.
• a radical preferably containing 1 or 3 carbon atoms is preferred, in particular the hydroxymethyl, 2-hydroxyethyl, 2 or 3-hydroxypropyl radicals.
• a radical having 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups is preferred, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5 radicals -tetrahydroxypentyle or the rest of pentaerythritol.
• a phenyl, thiophene or pyridine radical is preferred, 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.
• the optionally substituted phenyl radical is preferred.
• the benzyl or phenethyl radical is optionally substituted with at least one halogen atom, a hydroxyl radical, a nitro function or a methoxy group.
• sugar residue is meant a residue derived in particular from glucose, galactose or mannose, or alternatively from glucuronic acid.
• amino acid residue is understood to mean in particular a residue deriving from one of the amino acids such as lysine, glycine or aspartic acid, and the term “peptide residue” means more particularly a residue of resulting dipeptide or tripeptide of the combination of amino acids.
• heterocycle is preferably meant a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in position 4 by a C-1-C5 alkyl or polyhydroxyalkyl radical as defined above.
• radicals R4 and Rg represent a halogen atom
• the latter is preferably a fluorine, bromine or chlorine atom.
• -Acid 4- [N-methyl-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloylamino] benzoic.
• -Acid 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2-butenoyloxy] benzoic.
• the compounds of formula (I) which are more particularly preferred are those for which at least one and preferably all of the conditions below are met:
• R-1 represents the radical -CO-R5
• Ar represents the radical of formula (d) or (f),
• X represents the radical of formula (h), (j), (n) or (o)
• R and R3 have the meaning:
• At least one of the two substituents R 2 and R3 represents a branched radical having from 1 to 20 carbon atoms, or
• R and R3 taken together form with the adjacent aromatic ring a 5 or 6-membered ring optionally substituted by methyl groups and / or optionally interrupted by an oxygen or sulfur atom,
• the compounds have the formula (I) in which R 2 and R 3 taken together form with the adjacent aromatic ring a 5 or 6-membered ring optionally substituted by methyl groups and / or optionally interrupted by a d atom oxygen or sulfur,
• the subject of the present invention is also the processes for preparing the compounds of formula (I), in particular according to the reaction schemes given in FIG. 1.
• the bromine derivatives (1) can be transformed: - in aldehyde derivatives (4) by formation of lithian derivatives then reaction with DMF.
• Derivatives (3) and (5) can be obtained respectively from derivatives (2) and (4) by a Horner-Emmons type reaction with triethylphosphonoacetate in the presence of a base such as sodium hydride and then saponification of the ester function with soda or potash in an alcoholic solvent.
• the derivatives (7) can be obtained from the acetylenic derivatives (6) by lithiation then reaction with CO.
• the cyclopropanecarboxylic derivatives (8) can be obtained by a series of reactions from the derivatives (7): esterification of the acid function then reaction with diazomethane in the presence of palladium acetate (J. Vallgarda J. Med. Chem. 1996 , 39, 1485-1493 and U. Appelberg Bioorg. & Med. Chem. Letters 1996, Vol 6, N ° 4) and saponification in the presence of soda or potash. They can also be obtained by a series of reactions comprising the reduction of the acid function to alcohol then protection of this function with for example tetrahydropyran, reaction then with chloroform in the presence of soda, deprotection of the alcohol function and oxidation for example with Jones' reagent (Y. Tanabe Synthesis 1996, 388-92).
• the compounds of formula (I) can thus be obtained from the derivatives (3), (5), (7), (8) by reaction with compounds (9) in which W can represent an amino or hydroxy radical either by through the acid chloride or in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine in a solvent, such as THF or dichloromethane.
• R- represents the radical -COOH
• the compounds are preferably prepared by protecting Rj with a protective group of allylic, benzyl or tert-butyl type.
• the transition to free form can be carried out: -
• a catalyst such as certain transition metal complexes in the presence of a secondary amine.
• R-j represents an alcohol function
• the compounds can be obtained from the corresponding aldehyde derivatives by the action of an alkaline hydride, such as sodium borohydride, in an alcoholic solvent (for example methanol).
• an alkaline hydride such as sodium borohydride
• an alcoholic solvent for example methanol
• R-j represents an amide function
• the compounds can be obtained from the corresponding carboxylic derivatives by reaction with aliphatic, aromatic, heterocyclic amines either via an acid chloride or in the presence of dicyclohexylcarbodiimide or carbonyidiimidazole.
• the compounds according to the invention exhibit activity in the differentiation test of mouse embryonic teratocarcinoma (F9) cells (Cancer Research 43, p. 5268, 1983) and / or in the inhibition test of omithine decarboxylase after TPA induction in mice (Cancer Research 3_8, p. 793-801, 1978). These tests show the activities of these compounds respectively in the fields of cell differentiation and proliferation.
• F9 mouse embryonic teratocarcinoma
• an agonist activity such as an antagonist activity at retinoic acid receptors. Indeed, an antagonist is inactive when it is alone in this test, but partially or totally inhibits the effect produced by an agonist retinoid on the morphology and on the secretion of the plasminogen activator.
• RAR antagonist molecules Some of these Compounds therefore also exhibit activity in a test which consists in identifying RAR antagonist molecules, as described in French patent application No. 95-07302 filed on June 19, 1995 by the Applicant.
• This test comprises the following steps: (i) a topical application of a RAR agonist molecule is applied topically to a portion of the skin of a mammal, (ii) it is administered systemically or topically to the same mammal or to this same part of the mammalian skin, before, during or after step (i), a molecule capable of exhibiting an antagonistic activity of RARs and (iii) the response is evaluated on the part of the skin thus treated of the mammal.
• the response to a topical application to the ear of a mammal of a RAR agonist molecule which corresponds to an increase in the thickness of this ear can be inhibited by the administration by the systemic or topical route of a RAR antagonist molecule.
• some of these compounds can bring synergy to the biological activity of products which bind to nuclear receptors.
• a subject of the present invention is also, as a medicament, the compounds of formula (I) as defined above.
• a keratinization disorder with an inflammatory and / or immuno-allergic component and in particular all forms of psoriasis, whether it be cutaneous, mucous or nail, and even psoriatic arthritis, or still cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy; the compounds can also be used in certain inflammatory conditions which do not have a keratinization disorder,
• the compounds according to the invention can be advantageously used in combination with other compounds with retinoid activity, with vitamins D or their derivatives, with corticosteroids, with anti-free radicals , ⁇ -hydroxy or ⁇ -keto acids or their derivatives, or alternatively with ion channel blockers.
• vitamins D or their derivatives one understands for example the derivatives of vitamin D or D3 and in particular the 1, 25-dihydroxyvitamin D3.
• free anti-radicals is meant, for example, the tocopherol, the Super Oxide Dismutate, Ubiquinol or certain metal chelators.
• ⁇ -hydroxy or ⁇ -keto acids or their derivatives is meant for example lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or their salts, amides or esters.
• ion channel blockers is meant for example Minoxidil (2,4-diamino-6-pivichdino-pyrimidine-3-oxide) and its derivatives.
• the present invention also relates to medicinal compositions containing at least one compound of formula (I) as defined above, one of its optical or geometric isomers or one of its salts.
• the present invention therefore therefore relates to a new medicinal composition intended in particular for the treatment of the aforementioned conditions, and which is characterized in that it comprises, in a pharmaceutically acceptable carrier and compatible with the mode of administration chosen for the latter, at least one compound of formula (I), one of its optical or geometric isomers or one of its salts.
• the administration of the compounds according to the invention can be carried out by enteral, parenteral, topical or ocular route.
• the drugs can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles allowing controlled release.
• the compositions may be in the form of solutions or suspensions for infusion or for injection.
• the compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg / kg to 100 mg / kg in body weight, and this at the rate of 1 to 3 intakes.
• the pharmaceutical compositions based on compounds according to the invention are more particularly intended for the treatment of the skin and mucous membranes and can then be in the form of ointments, creams, milks, ointments, powders, soaked swabs, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or of polymeric patches and of hydrogels allowing controlled release.
• These topical compositions can moreover be presented either in anhydrous form or in an aqueous form, depending on the clinical indication.
• compositions for topical or ocular use contain at least one compound of formula (I) as defined above, or one of its optical or geometric isomers or one of its salts, at a concentration preferably between 0.001% and 5% by weight relative to the total weight of the composition
• the compounds of formula (I) according to the invention also find application in the cosmetic field, in particular in body and hair hygiene and in particular for the treatment of skin prone to acne, for hair regrowth, anti- fall, to fight against the oily appearance of the skin or hair, in protection against the harmful aspects of the sun or in the treatment of physiologically dry skin, to prevent and / or to fight against photo-induced or chronological aging
• the compounds according to the invention can moreover be advantageously used in combination with other compounds with retinoid activity, with vitamins D or their derivatives, with corticosteroids, with anti-free radicals, ⁇ -hydroxy or ⁇ -keto acids or their derivatives, or alternatively with ion channel blockers, all of these different products being as defined above
• the present invention therefore also relates to a cosmetic composition which is characterized in that it comprises, in a cosmetically acceptable support and suitable for topical application, at least one compound of formula (I) as defined above or the one of its optical or geometric isomers or one of its salts, this cosmetic composition possibly being in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid or polymer vesicles, soap or shampoo
• the concentration of compound of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight relative to the whole of the composition
• the medicinal and cosmetic compositions according to the invention may also contain inert additives or even pharmacodynamically or cosmetically active additives or combinations of these additives, and in particular wetting agents, depigmenting agents such as hydroquinone, azelaic acid, l caffeic acid or kojic acid, emollients, hydrating agents such as glycerol, PEG 400, thiamorpholmone, and its derivatives or alternatively urea, antiseborrheic or antiacneic agents, such as S-carboxymethylcysteine, S-benzyl-cysteamine, their salts or derivatives, or benzoyl peroxide, antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines, antifungal agents such as ketokonazole or polymethylene -4.5 isothiazolidones- 3, agents promoting hair regrowth, such as Minoxidil (2,4
• compositions according to the invention may also contain flavor-improving agents, preserving agents such as esters of parahydroxybenzoic acid, stabilizing agents, humidity-regulating agents, pH-regulating agents, agents osmotic pressure modifiers, emulsifiers, UV-A and UV-B filters, antioxidants, such as ⁇ -tocopherol, butylhydroxyanisole or butylhydroxytoluene.
• reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate, evaporated. 14.1 g (98%) of the expected ethyl ester are collected in the form of a yellow oil.
• Example 2 Analogously to Example 1 (d) by reacting 1.5 g (10 mmol) of methyl 4-aminobenzoate with 2.8 g (10 mmol) of 3- (5,6,7,8) chloride -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloyl, 3.2 g (82%) of the expected methyl ester are obtained.
• Example 1 Analogously to Example 1 (d) by reacting 2.3 g (10 mmol) of benzyl 4-hydroxybenzoate with 2.8 g (10 mmol) of 3- (5,6,7,8) chloride -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloyl, 1.7 g (37%) of the expected benzyl ester of melting point 97-9 ° C. are obtained.
• reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate, evaporated.
• the solid obtained is triturated in hexane, filtered and dried. 1.6 g (83%) of the expected methyl ester of melting point 167-8 ° C. are collected.
• Example 2 Analogously to Example 1 (b) from 1.6 g (4 mmol) of the methyl ester prepared above, 600 mg (39%) of 4- [N-methyl-3- ( 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloylamino] benzoic with a melting point of 252-3 ° C.
• Example 1 Analogously to Example 1 (a) by reacting 10.9 g (50 mmol) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acetylnaphthalene with 1 1 , 9 ml (60 mmol) triethylphosphonoacetate, 10.2 g (68%) of the expected ethyl ester are obtained in the form of a colorless oil.
• Example 1 Analogously to Example 1 (b) from 10.3 g (34 mmol) of the above ethyl ester, 6.1 g (65%) of the expected acid with melting point 173 are obtained. 4 ° C.
• Example 1 Analogously to Example 1 (c) from 2.3 g (10 mmol) of 4-allyloxycarbonylbenzoic acid, 2.5 g (100%) of the expected acid chloride are obtained which will be used as it is for the rest of the synthesis.
• Example 1 Analogously to Example 1 (d) by reacting 2.5 g (10 mmol) of 4-allyloxycarbonylbenzoyl chloride with 2 g (10 mmol) of 5,6,7,8- tetrahydro-5.5, 8,8-tetramethyl-2-naphthol, 3.2 g (78%) of the expected allyl ester with a melting point of 1 14-5 ° C. are obtained.
• Example 6 Analogously to Example 6 (b) from 3.2 g (7.6 mmol) of the preceding allyl ester, 1.8 g (62%) of 4- (5.6) acid are obtained. , 7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthyloxycarbonylvinyl) benzoic with a melting point of 226-7 ° C.
• the ethereal phase is decanted, washed with water, dried over magnesium sulfate, evaporated.
• the residue obtained is purified by chromatography on a silica column, eluted with hexane. After evaporation of the solvents, 18.8 g (66%) of the expected product are collected in the form of a colorless oil.
• the reaction medium is poured into a saturated solution of ammonium chloride, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulphate, evaporated. The residue obtained is triturated in hexane, filtered, dried. 3.5 g (73%) of the expected propargylic acid are collected with a melting point of 175-7 ° C.
• the residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (95-5). After evaporation of the solvents, 400 mg (77%) of the expected acid with a melting point of 185 ° -6 ° C. are collected.
• Example 1 Analogously to Example 1 (a) by reacting 10.9 g (50 mmol) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acetylnaphthalene with 1 1 , 9 ml (60 mmol) triethylphosphonoacetate, 10.2 g (68%) of the expected ethyl ester are obtained in the form of a colorless oil.
• Example 12 Analogously to Example 12 (a) by reaction of 4 g (17.4 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylcarboxaldehyde with 4 , 15 ml (20.9 mmol) of triethylphosphonoacetate, 4.91 g (94%) of 3- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- are obtained. naphthyl) ethyl acrylate.
• Example 12 Analogously to Example 12 (b) from 4.7 g (15.9 mmol) of the above ethyl ester, 3.66 g (84%) of 3- (3.5 , 5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) acrylic.
• Example 1 Analogously to Example 1 1 (b) by reacting 1.15 g (6.44 mmol) of allyl 4-hydroxybenzoate with 1.7 g (5.85 mmol) of 3- (3 , 5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) acryloyl, 1.8 g (71%) of the expected allyl ester with melting point 86-7 ° are obtained vs.
• Example 1 Analogously to Example 1 1 (b) by reacting 710 mg (4 mmol) of allyl 4-hydroxybenzoate with 1 g (3.62 mmol) of 3- (5,6,7,8 chloride) - tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloyl obtained in Example 1 (c), 500 mg (33%) of E) -2- [3- (5.5, 8,8-tetramethyl-5,6,7,8-tetrahydronaphthhalen-2-yl) acryloyloxy] allyl benzoate melting point 92-3 ° C.
• Acid 3-13-1 (5.5.8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalene-2-carbonyl) -amino] phenyl ⁇ acrylic.
• Acid 3-12-1 (3, 5.5.8.8-pentamethyl-5, 6, 7.8-tetrahydro-naphthalene-2-carbonyl) amino] phenyl ⁇ acrylic.
• Example 1 in Example 1 (c) in 20 ml of THF and stirred at room temperature for six hours.
• the reaction medium is poured into water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, evaporated.
• the residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80-20). After evaporation of the solvents, 1 g (45%) of (E) -N-Methoxy-N-methyl-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen) is collected.
• the reaction medium is poured into water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, evaporated.
• the residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80-20). After evaporation of the solvents, 400 mg (43%) of N-methoxy-N-methyl-2- (5, 5.8, 8-tetramethyl-5, 6,7,8- tetrahydro-naphthalen-2-yl) are collected. ) cyclopropanecarboxamide in the form of an oil.
• Example 1 Analogously to Example 1 (c) from 190 mg (0.7 mmol) of 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen- acid) 2-yl) cyclopropanecarboxylic, 124 mg (61%) of the expected acid chloride are obtained.
• Example 18 Analogously to Example 18 (b) by reacting 96 mg (0.54 mmol) of allyl 4-aminobenzoate with 155 mg (0.54 mmol) of the acid chloride prepared in Example 25 ( d), 165 mg (71%) of 4 - ⁇ [2- (5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) cyclopropanecarbonyl] amino ⁇ benzoate are obtained. allyl.
• ORAL ROUTE (a) The following composition is prepared in the form of a 0.8 g tablet Compound of Example 1 0.005 g
• the capsules used are made up of gelatin, titanium oxide and a preservative.
• This cream will be applied to psoriatic skin 1 to 2 times a day for 30 days.
• a gel is prepared by carrying out the following formulation:
• Hydroxypropylcellulose sold by the company Hercules under the name of "KLUCEL HF" 2,000 g
• This gel will be applied to skin affected by dermatosis or acne-prone skin 1 to 3 times a day for 6 to 12 weeks depending on the severity of the case treated.
• An antiseborrheic lotion is prepared by mixing the following ingredients: Compound of Example 5 0.030 g
• This lotion will be applied twice a day to a seborrheic scalp and there is a significant improvement within 2 to 6 weeks.
• a cosmetic composition is prepared against the harmful effects of the sun by mixing the following ingredients:
• This composition will be applied daily, it helps to fight against photoinduced aging.
• Vitamin D3 0.020 g
• This cream will be applied to psoriatic skin 1 to 2 times a day for 30 Days.
• a topical gel is prepared by mixing the following ingredients:
• Carboxyvinyl polymer sold under the name “Carbopol 941” by the company “Goodrich” 0.500 g
• Triethanolamine in aqueous solution at 20% by weight 3,800 g
• a hair loss and hair regrowth lotion is prepared by mixing the following ingredients
• Polyethylene glycol (molecular weight 400) 40.00 g
• Retinoic acid 0.010 g Mixture of glycerol stearates and polyethylene glycol (75 moles) sold under the name “Gelot 64" by the company "GATTEFOSSE” 15,000 g
• Disodium salt of ethylene diamine tetracetic acid 0.050 g
• An oil-in-water cream is prepared by carrying out the following formulation:
• Sorbitan monolaurate polyoxyethylene containing 20 moles of ethylene oxide sold under the name "Tween 20" by the company
• This cream will be applied twice a day to skin affected by dermatosis for 30 days.
• Sorbitan monolaurate polyoxyethylene containing 20 moles of ethylene oxide sold under the name Tween 20 "by the company
• This cream will be applied 1 time per day, it helps to fight against aging whether it is photoinduced or chronological.

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• 1997
  • 1997-02-10 FR FR9701501A patent/FR2759368B1/fr not_active Expired - Fee Related
• 1998
  • 1998-02-09 US US09/171,098 patent/US6326510B1/en not_active Expired - Fee Related
  • 1998-02-09 EP EP98908154A patent/EP0901462A1/de not_active Withdrawn
  • 1998-02-09 AU AU66265/98A patent/AU718198B2/en not_active Ceased
  • 1998-02-09 WO PCT/FR1998/000248 patent/WO1998034909A1/fr not_active Application Discontinuation
  • 1998-02-09 CA CA002253221A patent/CA2253221A1/fr not_active Abandoned
  • 1998-02-09 JP JP10533895A patent/JPH11507960A/ja not_active Ceased

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