FR2590566A1 - Keto-naphthalene derivatives, process for their preparation and their application in the pharmaceutical and cosmetic fields - Google Patents
Keto-naphthalene derivatives, process for their preparation and their application in the pharmaceutical and cosmetic fields Download PDFInfo
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- FR2590566A1 FR2590566A1 FR8515106A FR8515106A FR2590566A1 FR 2590566 A1 FR2590566 A1 FR 2590566A1 FR 8515106 A FR8515106 A FR 8515106A FR 8515106 A FR8515106 A FR 8515106A FR 2590566 A1 FR2590566 A1 FR 2590566A1
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- naphthyl
- naphthalene
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- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
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- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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Abstract
Description
La présente invention a pour objet des dérivés céto-naphtaléniques ci-après désignés sous la dinomination de "céto-naphtodifférines", leur procédé de préparation et leur utilisation dans les domaines thérapeutique et cosmétique. The present invention relates to keto-naphthalene derivatives hereinafter designated under the name of "keto-naphthodifferins", their preparation process and their use in the therapeutic and cosmetic fields.
Les céto-naphtodifférines trowent une application dans le traitement topique et systémique des affections dermatologiques liées à un désordre de la kératinisation (dlfférenclation, prolifération) et d'affections dermatologiques, ou autres, à composante inflammatoire et/ou immuno-allergique et dans le traitement des maladies de dégénérescence du tissu conjonctif, ainsi qu'une activité anti-tumorale. Keto-naphthodifferins find application in the topical and systemic treatment of dermatological conditions linked to a disorder of keratinization (dlfférenclation, proliferation) and of dermatological conditions, or others, with an inflammatory and / or immuno-allergic component and in the treatment degenerative diseases of the connective tissue, as well as anti-tumor activity.
En outre, ces dérivés peuvent être utilisés dans le traitement de l'atopie, qu'elle soit cutanée ou respiratoire, et du psoriasis rhumatotde. In addition, these derivatives can be used in the treatment of atopy, whether cutaneous or respiratory, and rheumatoid psoriasis.
Ils trouvent également une application dans le domaine ophtalmologique, notamment pour le traitement des cornéopathies. They also find an application in the ophthalmological field, in particular for the treatment of corneopathies.
Les céto-naphtodifférines selon l'invention peuvent être représentés par la formule générale suivante
dans laquelle
R1, R2, R3 et R4 > identiques ou differents, représentent un atome
d'hydrogène ou un radical alkyle inférieur ayant de 1 à 6 atomes de carbone,
ou R1 et R3 pris ensemble forment un pont méthylène ou diméthylène,
R5 représente un radical alkyle inférieur, le radical -CH20H ou le radical -COR
R6 représentant un atome d'hydrogène, le radical -OR7
représentant un atome d'hydrogène, un radical alkyle ayant de 1 à 20 atomes de
carbone, un radical monohydroxyalkyle ou polyhydroxyalkyle, un radical aryle n*s ara1Evle ventuellement substitué(s), ou un reste d'un sucre, ou encore le radical
p étant 1,2 ou 3,
r' et r" identiques ou différents, représentant un atome d'hydrogène, un radical alkyle inférieur, un radical monohydroxyalkyle ou polyhydroxyalkyle éventuellement interrompu(s) par un hétéroatome, un radical aryle éventuellement substitué ou un reste d'amino-acide, d'amino ester ou de sucre aminé, ou encore pris ensemble forment un hétérocycle, substitué ou non,
et les sels des dits composés de formule (I).The keto-naphthodifferins according to the invention can be represented by the following general formula
in which
R1, R2, R3 and R4> identical or different, represent an atom
hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms,
or R1 and R3 taken together form a methylene or dimethylene bridge,
R5 represents a lower alkyl radical, the radical -CH20H or the radical -COR
R6 representing a hydrogen atom, the radical -OR7
representing a hydrogen atom, an alkyl radical having from 1 to 20 atoms of
carbon, a monohydroxyalkyl or polyhydroxyalkyl radical, an aryl radical n * s ara1Evle optionally substituted, or a residue of a sugar, or the radical
p being 1,2 or 3,
r 'and r "identical or different, representing a hydrogen atom, a lower alkyl radical, a monohydroxyalkyl or polyhydroxyalkyl radical optionally interrupted by a heteroatom, an optionally substituted aryl radical or an amino acid residue, d amino ester or amino sugar, or taken together form a heterocycle, substituted or not,
and the salts of said compounds of formula (I).
Par radical alkyle ayant de 1 à 20 atomes de carbone on doit entendre notamment les radicaux méthyle, éthyle, propyle, éthyl-2-hexyle, octyle, dodécyle, hexadécyle et octadécyle. By alkyl radical having from 1 to 20 carbon atoms should be understood in particular the methyl, ethyl, propyl, ethyl-2-hexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
Par radical alkyle inférieur on doit entendre un radical ayant de 1 à 4 atomes de carbone, notamment les radicaux méthyle, éthyle, isopropyle, butyle et tertiobutyle. By lower alkyl radical is meant a radical having from 1 to 4 carbon atoms, in particular the methyl, ethyl, isopropyl, butyl and tert-butyl radicals.
Par radical monohydroxyalkyle, on doit entendre un radical ayant de 2 à 4 atomes de carbone, notamment un radical hydroxy-2 éthyle, hydroxy-2 propyle ou hydroxy-2 éthoxyéthyle. The term “monohydroxyalkyl radical” should be understood to mean a radical having from 2 to 4 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxyethoxyethyl radical.
Par radical polyhydroxyalkyle, on doit entendre un radical contenant de 3 à 6 atomes de carbone et de 2 à 5 groupes hydroxyles tels que les radicaux dihydroxy-2,3 propyle, dihydroxy-1,3 propyl-2 ou le reste du pentaérythritol. The term “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-dihydroxy-propyl, 1,3-dihydroxy-1,3-propyl radicals or the rest of pentaerythritol.
Par reste d'un sucre, on doit entendre un reste dérivant du glucose, du mannitol ou de l'érythritol. The remainder of a sugar should be understood to mean a residue derived from glucose, mannitol or erythritol.
Parmi les restes de sucres aminés on peut citer ceux dérivant de glucosamine, de galactosamine ou de mannosamine. Among the amino sugar residues, mention may be made of those derived from glucosamine, galactosamine or mannosamine.
Parmi les radicaux alkoxy ayant de 1 à 6 atomes de carbone, on peut citer le radical méthoy, isopropoxy et tert-butoxy. Among the alkoxy radicals having from 1 to 6 carbon atoms, there may be mentioned the methoy, isopropoxy and tert-butoxy radical.
Lorsque les radicaux r' ct r" pris ensemble forment un hétérocycle celui-ci est de préférence un radical pipéridino, pipérazino, morpholino pyrrolidino ou (hydroxy-2 éthyl)-4 pipérazino. When the radicals r 'ct r "taken together form a heterocycle, this is preferably a piperidino, piperazino, morpholino pyrrolidino or (2-hydroxyethyl) -4 piperazino radical.
Lorsque les composés selon l'invention se présentent sous forme de sels, il peut s'agir soit de sels de zinc, d'un métal alcalin ou alcalino-terreux, ou d'une amine organique, lorsqu'ils comportent au moins une fonction acide libre (R5-COOH) soit de sels. d'un acide minéral ou organique, notamment de chlorhydrate, de bromhydrate ou de citrate lorsqu'ils comportent au moins une fonction amine. When the compounds according to the invention are in the form of salts, they may be either zinc salts, an alkali or alkaline earth metal, or an organic amine, when they contain at least one function free acid (R5-COOH) or salts. of a mineral or organic acid, in particular of hydrochloride, hydrobromide or citrate when they contain at least one amine function.
Parmi les céto-naphtodifférines de formule (I) particulièrement préférés selon l'invention, on peut mentionner ceux correspondant aux formules suivantes
dans laquelle
R1, R2, R3 et R4, identiques ou différents représentent un atome d'hydrogène ou le radical -CH3,
R5 représente le radical -CH2OH ou le radical -COR6,
R6 représentant un atome d'hydrogène, le radical -OR7
Among the keto-naphthodifferins of formula (I) which are particularly preferred according to the invention, mention may be made of those corresponding to the following formulas
in which
R1, R2, R3 and R4, identical or different, represent a hydrogen atom or the radical -CH3,
R5 represents the radical -CH2OH or the radical -COR6,
R6 representing a hydrogen atom, the radical -OR7
R7 représentant un atome d'hydrogène ou un radical alkyle ayant de 1 à 6 atomes de carbone,
et r' ou r" représentant un atome d'hydrogène, un radical alkyle inférieur, hydroxy-4 phényle, hydroxy-2 éthoxy éthyle ou carboxy-l méthylthio-3 propyle.
R7 representing a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms,
and r ′ or r ″ representing a hydrogen atom, a lower alkyl, 4-hydroxy phenyl, 2-hydroxy ethoxy ethyl or carboxy-1 methylthio-3 propyl radical.
dans laquelle R6 représente -OR7 ou
in which R6 represents -OR7 or
R7 représentant un atome d'hydrogène ou un radical alkyle ayant de 1 à 6 atomes de carbone,
et r' ou r" représentant un atome d'hydrogène ou un radical alkyle inférieur.R7 representing a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms,
and r 'or r "representing a hydrogen atom or a lower alkyl radical.
Parmi les composés de formule (I) on peut notamment citer les suivants
1) l'acide (tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-20 carbonyl-6 naphtalène carboxylique-2 et son ester méthylique,
2) le N-éthyl [(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-2] carbonyl-6 naphtalène carboxamide-2,
3) le rc (tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-20 carbonyl-6 naphtalène carboxaldéhyde-2,
4) le tétramétbyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)-il carbonyl-6 hydroxyméthyl-2 naphtalène,
5) le N-hydroxy-2 éthoxyéthyl [(tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl carbonyl-6 naphtalène, carboxamide-2,
6) le N-p-hydroxyphényl (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène carboxamide-2,
7) le N-(éthoxycarbonyl-l méthylthio-3 propyl) [(tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)-2 carbonyl-6 naphtalène carboxamide-2, 8) le N-(carboxy-l méthylthio-3 propyl) t (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)-2] carbonyl-6 naphtalène carboxamide-2,
9) l'acide méthano-5,8 tétrahydro-5,6,7,8 naphtyl)-2 carbonyl-6 naphtalène carboxylique-2 et son ester méthylique,
10) l'acide 0(tétrahydro-5,6,7,8 naphtyl)- carbonyl-6 naphtalène carboxylique-2 et son ester méthylique,
11) le N-éthyl[(tétrahydro-5,6,7,8 naphtyl)- carbonyl-6 naphtalène carboxamide-2,
les composés particulièrement préféres selon l'invention étant les composés de formule II ci-dessus, et plus particulièrement les composés 1 à 6 et 8.Among the compounds of formula (I), the following may especially be mentioned
1) (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -20 carbonyl-6 naphthalene-carboxylic-2 and its methyl ester,
2) N-ethyl [(tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -2] carbonyl-6 naphthalene carboxamide-2,
3) rc (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -20 carbonyl-6 naphthalene carboxaldehyde-2,
4) tetrametbyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl) -il carbonyl-6 hydroxymethyl-2 naphthalene,
5) N-hydroxy-2 ethoxyethyl [(tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl carbonyl-6 naphthalene, carboxamide-2,
6) Np-hydroxyphenyl (tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2) carbonyl-6 naphthalene carboxamide-2,
7) N- (ethoxycarbonyl-1-methylthio-propyl) [(tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl) -2 carbonyl-6 naphthalene carboxamide-2, 8) N - (carboxy-1-methylthio-propyl) t (tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl) -2] carbonyl-6 naphthalene carboxamide-2,
9) methano-5,8 tetrahydro-5,6,7,8 naphthyl) -2 carbonyl-6 naphthalene carboxylic-2 and its methyl ester,
10) acid 0 (tetrahydro-5,6,7,8 naphthyl) - carbonyl-6 naphthalene carboxylic-2 and its methyl ester,
11) N-ethyl [(tetrahydro-5,6,7,8 naphthyl) - carbonyl-6 naphthalene carboxamide-2,
the particularly preferred compounds according to the invention being the compounds of formula II above, and more particularly compounds 1 to 6 and 8.
La présente demande a également pour objet le procédé de préparation des céto-naphtodifférines de formule (I) par condensation dans les conditions de la réaction de FRIEDEL-CRAFTS d' un halogénure d'acide naphtalénique (2) sur le tétrahydro-1,2,3,4 naphtalène (1) éventuellement substitué en position-1,4, selon le schéma réactionnel suivant
The present application also relates to the process for the preparation of keto-naphthodifferins of formula (I) by condensation under the conditions of the FRIEDEL-CRAFTS reaction of a naphthalenic acid halide (2) on 1,2-tetrahydro , 3,4 naphthalene (1) optionally substituted in position-1,4, according to the following reaction scheme
X = lal (de préférence Cl)
Cette réaction est effectuée à température ambiante dans un solvant chloré tel que le dichlorométhane ou le dichloro-1,2 éthane.X = lal (preferably Cl)
This reaction is carried out at room temperature in a chlorinated solvent such as dichloromethane or 1,2-dichloroethane.
Parmi les dérivés substitués du tétrahydro-1,2,3,4 naphtalène de formule (1) (R1 = R2 5 R3 = R4 7{ H particulièrement appropriés pour la réaction de condensation, on peut citer le tétraméthyl-1,1,4,4 tétrahydro-1,2,3,4 naphtalène (décrit dans J.A.C.S., 62, 36-44, 1940) et le méthano-1,4 tétrahydro-1,2,3,4 naphtalène ou benzonorbornène (décrit dans
J.O.C. 32, 893-901, 1967).Among the substituted derivatives of 1,2,3,4 tetrahydro naphthalene of formula (1) (R1 = R2 5 R3 = R4 7 {H particularly suitable for the condensation reaction, there may be mentioned 1,1,4 tetramethyl , 4-1,2,3,4 tetrahydro naphthalene (described in JACS, 62, 36-44, 1940) and 1,4-methano-1,2,3,4 naphthalene or benzonorbornene (described in
JOC 32, 893-901, 1967).
De préférence, la réaction de condensation est effectuée à l'aide d'un halogénure d'acide alkoxycarbonyl-6 naphtalène carboxylique-2 (composé de formule (2) dans laquelle R5 = COOR7, R7 = alkyle C1-C6\
Les halogénures des acides alkoxy carbonyl-6 naphtalène carboxyliques-2 sont obtenus par réaction de monosaponification d'un naphtalène dicarboxylate d'alkyle-2,6 et formation du chlorure d'acide correspondant par action du chlorure de thionyle.Preferably, the condensation reaction is carried out using a 6-alkoxycarbonyl acid halide-2 naphthalene carboxylic acid (compound of formula (2) in which R5 = COOR7, R7 = C1-C6 alkyl \
The halides of the alkoxy-carbonyl-6 naphthalene carboxylic-2 acids are obtained by monosaponification reaction of a 2,6-alkyl naphthalene dicarboxylate and formation of the corresponding acid chloride by action of thionyl chloride.
A partir des esters ainsi obtenus, il est possible d'accéder par réaction de saponification aux acides correspondants, ces derniers pouvant être transformés en amides, par action d'une amine en présence de
N,N'-carbonyl diimidazole (C.D.I.) ou encore par réaction de cette amine sur les halogénures d'acides.From the esters thus obtained, it is possible to access the corresponding acids by saponification reaction, the latter being able to be transformed into amides, by the action of an amine in the presence of
N, N'-carbonyl diimidazole (CDI) or also by reaction of this amine with the acid halides.
De même à partir des esters on peut accéder par réduction aux alcools correspondants puis par oxydation de ces derniers aux aldéhydes. Similarly, from the esters, access can be obtained by reduction to the corresponding alcohols and then by oxidation of the latter to the aldehydes.
La présente invention a également pour objet à titre de médicament les céto-naphtodifférines de formule (I) telle que définie ci-dessus. The present invention also relates to, as medicament, the keto-naphthodifferins of formula (I) as defined above.
Ces composés présentent une excellente activité dans le test d'inhibition de l'ornithine décarboxylase, après induction par "tape stripping" chez le rat nu (voir Dermatologica 169 n" 4, 1984 M. Bouclier et al). Ce test est admis comme mesure de l'action des rétinoIdes sur les phénomènes de prolifération cellulaire. These compounds exhibit excellent activity in the ornithine decarboxylase inhibition test, after induction by "tape stripping" in the naked rat (see Dermatologica 169 n "4, 1984 M. Bouclier et al). measurement of the action of retinoids on cell proliferation phenomena.
Les céto-naphtodifférines selon l'invention présentent également une activité dans le test de différenciation des cellules de tératocarcinome embryonnaire de souris (cellule Fg: Cancer.Res. 43 p.52-68, 1983). Enfin ces composés présentent une activité bactéricide et en particulier sur les germes spécifiques de l'acné. The keto-naphthodifferins according to the invention also exhibit activity in the differentiation test of mouse embryonic teratocarcinoma cells (Fg cell: Cancer.Res. 43 p.52-68, 1983). Finally, these compounds exhibit bactericidal activity and in particular on the specific germs of acne.
Les céto-naphtodifférines selon l'invention présentent, par rapport aux composés du meme type, une meilleure stabilité à la lumière et à l'oxygène, ceci étant essentiellement du au fait qu'ils ne possèdent pas de double liaison facilement isomérisable ou oxydable. The keto-naphthodifferins according to the invention have, compared to compounds of the same type, better stability to light and to oxygen, this being essentially due to the fact that they do not have an easily isomerizable or oxidizable double bond.
Ces composés conviennent particulièrement bien pour traiter les affections dermatologiques liées à un désordre de la kératinisation (différenciation-prolifération) ainsi que les affections dermatologiques, ou autres, à composante inflammatoire et/ou immunoallergique notamment
- les acnés vulgaires, comédoniennes ou polymorphes, les acnés séniles, solaires, et les acnés médicamenteuses ou professionnelles.These compounds are particularly suitable for treating dermatological conditions linked to a disorder of keratinization (differentiation-proliferation) as well as dermatological conditions, or others, with an inflammatory and / or immunoallergic component in particular.
- vulgar, comedonian or polymorphic acnes, senile, solar acnes, and medical or professional acnes.
- les formes étendues et/ou sévères de psoriasis, et les autres troubles de la kératinisation, et notamment les ichtyoses et états ichtyosiformes
- la maladie de Darier
- les kératodermies palmo-plantaires
- les leucoplasies et états leucoplasiformes, le lichen plan
- toutes proliférations dermatologiques bénignes ou malignes, sévères ou étendues.- widespread and / or severe forms of psoriasis, and other keratinization disorders, including ichthyosis and ichthyosiform states
- Darier's disease
- palmoplantar keratoderma
- leukoplakias and leukoplasiform states, lichen planus
- any benign or malignant, severe or extensive dermatological proliferation.
Ils sont également actifs dans le traitement des tumeurs, du psoriasis rhumatofde, des atopies cutanées ou respiratoires ainsi que pour certains problèmes ophtalmologiques relatifs aux cornéopathies. They are also active in the treatment of tumors, rheumatoid psoriasis, cutaneous or respiratory atopy and for certain ophthalmological problems relating to corneopathies.
La présente invention a donc aussi pour objet une nouvelle composition médicamenteuse, destinée notamment au traitement des affections susmentionnées, caractérisée par le fait qu'elle comporte, dans un support pharmaceutiquement acceptable, au moins un composé de formule (I) et/ou un de ses sels. The present invention therefore also relates to a new medicinal composition, intended in particular for the treatment of the aforementioned conditions, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound of formula (I) and / or one of its salts.
Comme support des compositions, on peut utiliser tout support conventionnel, le composé actif se trowant soit à l'état dissous, soit à l'état dispersé dans le véhicule. As support for the compositions, any conventional support can be used, the active compound being dissolved either in the dissolved state or in the dispersed state in the vehicle.
L'administration peut être effectuée par voie entérale, parentérale, topique ou oculaire. Par voie entérale, les médicaments peuvent se présenter sous forme de comprimés, de gélules, de dragées, de sirops, de suspensions, de solutions, de poudres, de granulés, d'émulsions. Par voie parentérale, les compositions pewent se présenter sous forme de solutions ou suspensions -pour perfusions ou pour injections. Administration can be by enteral, parenteral, topical or ocular route. Enterally, the drugs can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions. Parenterally, the pewent compositions are in the form of solutions or suspensions - for infusions or for injections.
Les composés selon l'invention sont généralement administrés à une dose journalière d'environ 0,01 pg/kg à l mg/kg de poids corporel. The compounds according to the invention are generally administered at a daily dose of approximately 0.01 pg / kg to 1 mg / kg of body weight.
Par voie topique, les compositions pharmaceutiques à base des composés selon l'invention se présentent sous forme d'onguents, de teintures, de crèmes, de pommades, de poudres, de timbres, de tampons imbibés, de solutions, d'émulsions, de lotions, de gels, de sprays ou encore de suspensions. Topically, the pharmaceutical compositions based on the compounds according to the invention are in the form of ointments, tinctures, creams, ointments, powders, patches, soaked pads, solutions, emulsions, lotions, gels, sprays or suspensions.
Ces compositions par voie topique peuvent se présenter soit sous forme anhydre, soit sous forme aqueuse selon l'indication clinique. These topical compositions can be presented either in anhydrous form or in aqueous form according to the clinical indication.
Lorsque les composés selon l'invention sont utilisés par voie topique, on observe une bonne activité de ces composés sur une très grande gamme de dilution ; on peut utiliser, notamment, des concentrations en produit actif allant de 0,0001 Z à 5 Z en poids. I1 est bien entendu possible d'utiliser des concentrations supérieures lorsque ceci est rendu nécessaire pour une application thérapeutique particulière ; toutefois, les concentrations préférées en produit actif sont comprises entre 0,001 Z et 1 Z en poids. When the compounds according to the invention are used topically, good activity of these compounds is observed over a very wide dilution range; one can use, in particular, concentrations of active product ranging from 0.0001 Z to 5 Z by weight. It is of course possible to use higher concentrations when this is made necessary for a particular therapeutic application; however, the preferred concentrations of active product are between 0.001% and 1% by weight.
Par voie oculaire, ces compositions se présentent de préférence sous forme de collyres. By ocular route, these compositions are preferably in the form of eye drops.
les céto-naphtodifférines de formule (I), selon l'invention, trouvent également une application dans le domaine cosmétique, en particulier dans l'hygiène corporelle et capillaire et notamment pour l'acné pour la repousse des cheveux, l'anti-chute, pour lutter contre l'aspect gras de la peau ou des cheveux, dans la prévention ou le traitement des effets néfastes du soleil ou dans le traitement des peaux physiologiquement sèches. the keto-naphthodifferins of formula (I), according to the invention, also find an application in the cosmetic field, in particular in body and hair hygiene and in particular for acne for hair regrowth, anti-fall , to combat the oily appearance of the skin or hair, in the prevention or treatment of the harmful effects of the sun or in the treatment of physiologically dry skin.
La présente invention vise donc également une composition cosmétique contentant, dans un support cosmétiquement acceptable, au moins un composé de formule (I) ou un de ses sels, cette composition se présentant notamment sous forme de lotion, gel, savon ou shampooing. The present invention therefore also relates to a cosmetic composition containing, in a cosmetically acceptable carrier, at least one compound of formula (I) or one of its salts, this composition being in particular in the form of a lotion, gel, soap or shampoo.
La concentration en composé de formule (I), dans les compositions cosmétiques, est comprise entre 0,0001 et 2 % en poids et de préférence entre 0,001 et 0,1 % en poids. The concentration of compound of formula (I), in the cosmetic compositions, is between 0.0001 and 2% by weight and preferably between 0.001 and 0.1% by weight.
Les compositions médicamenteuses et cosmétiques selon l'invention peuvent contenir des additifs inertes ou même pharmacodynamiquement ou cosmétiquement actifs et notamment : des agents hydratants comme la thiamorpholinone et ses dérivés ou l'urée ; des agents antiséborrhéiques, tels que la S-carboxyméthylcystéine, la S-benzyl-cystéamine et leurs dérivés, la tioxolone ; des agents anti-acnéiques comme le peroxyde de benzoyle ; des antibiotiques comme llérythromycine et ses esters, la néomycine, les tétracy dindes ou les polyméthylène-4,5 isotiazolinones-3 ; des agents favorisant la repousse des cheveux, comme le "Minoxidil" (diamino-2,4-pipéridino-6-pyri- midine oxyde-3) et ses dérivés, le Diazoxide (chlorométhyl-3 benzothiadiazine-1,2,4 dioxyde-l,l) et le Phénytoln(diphényl-5,5 imidazolidinedione-2,4) ou encore l'iodure dsoxapropanium ; des agents anti-inflammatoires stéroidiens et non stéroidiens ; des caroténoIdes et, notamment, le ss-carotène ; des agents anti-psoriasiques tels que l'anthraline et ses dérivés et les acides eicosatétraynoSque-5,8,11,14 et triynoIque-5,8,11 et leurs esters et amides. The medicinal and cosmetic compositions according to the invention can contain inert additives or even pharmacodynamically or cosmetically active and in particular: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrhoeic agents, such as S-carboxymethylcysteine, S-benzyl-cysteamine and their derivatives, tioxolone; anti-acne agents such as benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, tetracy turkeys or polymethylene-4,5 isotiazolinones-3; agents promoting hair regrowth, such as "Minoxidil" (diamino-2,4-piperidino-6-pyridinine oxide-3) and its derivatives, Diazoxide (chloromethyl-3 benzothiadiazine-1,2,4 dioxide- l, l) and Phenytoln (5,5-diphenyl imidazolidinedione-2,4) or dsoxapropanium iodide; steroidal and nonsteroidal anti-inflammatory agents; carotenoids and, in particular, ss-carotene; anti-psoriatic agents such as anthralin and its derivatives and the acids eicosatetraynoSque-5,8,11,14 and triynoIque-5,8,11 and their esters and amides.
Les compositions selon l'invention peuvent également contenir des agents d'amélioration de la saveur, des agents conservateurs, des agents stabilisants, des agents régulateurs d'humidité, des agents régulateurs de pH, des agents modificateurs de pression osmotique, des agents émulsionnants, des filtres UV-A et UV-B, des anti-oxydants tels de 1' a -tocophérol, le butylhydroxy-anisole ou le butylhydroxy-toluène. The compositions according to the invention can also contain flavor-enhancing agents, preserving agents, stabilizing agents, humidity-regulating agents, pH-regulating agents, agents for modifying osmotic pressure, emulsifying agents, UV-A and UV-B filters, antioxidants such as α-tocopherol, butylhydroxy-anisole or butylhydroxy-toluene.
On va maintenant donner, à titre d'illustration et sans aucun caractère limitatif, plusieurs exemples de préparation des composés actifs de formule (I) selon l'invention ainsi que des exemples de compositions les contenant. We will now give, by way of illustration and without any limiting character, several examples of preparation of the active compounds of formula (I) according to the invention as well as examples of compositions containing them.
EXEMPLE I
Préparation du [(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl) carbonyl-6 naphtalène carboxylate de méthyle2.EXAMPLE I
Preparation of [(tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) carbonyl-6 methyl naphthalene carboxylate 2.
(Composé de formule II avec R1=R2=R3=R4= -CH3 et R5 -COOCH3)
A une suspension de 1,5 g (11,2 mmoles) de chlorure d'aluminium anhydre dans 10 cm3 de dichlorométhane anhydre, on ajoute goutte à goutte une solution de 1,88 g (10 mmoles) de tetrahydro-1,2,3,4 tétraméthyl-1,1,4,4 naphtalène et de 2,49 g (10 mmoles) de chlorure de l'acide méthoxy carbonyl-6 naphtalène carboxylique-2 dans 60 cm3 de dichlorométhane anhydre. Le mélange est agité pendant 4 heures à température ambiante, puis versé dans 100 cm3 d'eau glacée acidulée. La phase organique est décantée. La phase aqueuse est extraite encore une fois à l'aide de 100 cmX de dichlorométhane.Les phases de chlorure de méthylène sont rassemblées, lavées au bicarbonate de sodium, séchées sur sulfate de sodium puis concentrées. On obtient 3,9 g d'un liquide jaune qui cristallise à température ordinaire. Ce solide est lavé au méthanol puis recristallisé dans 70 cm > dtisopropanol. (Compound of formula II with R1 = R2 = R3 = R4 = -CH3 and R5 -COOCH3)
To a suspension of 1.5 g (11.2 mmol) of anhydrous aluminum chloride in 10 cm 3 of anhydrous dichloromethane, a solution of 1.88 g (10 mmol) of 1,2-tetrahydro is added dropwise, 3.4 tetramethyl-1,1,4,4 naphthalene and 2.49 g (10 mmol) of chloride of 6-methoxycarbonyl acid-2-naphthalene carboxylic-2 in 60 cm3 of anhydrous dichloromethane. The mixture is stirred for 4 hours at room temperature, then poured into 100 cm3 of acidulated iced water. The organic phase is decanted. The aqueous phase is extracted once again using 100 cm × of dichloromethane. The methylene chloride phases are combined, washed with sodium bicarbonate, dried over sodium sulfate and then concentrated. 3.9 g of a yellow liquid are obtained, which crystallizes at ordinary temperature. This solid is washed with methanol and then recrystallized from 70 cm> dtisopropanol.
On obtient 2,1 g de C(tétrahydro-5 > 6s7 8 tétraméthyl-5,5,8,8 naphtyl)-g carbonyl-6 naphtalène carboxylate de méthyle-2. 2.1 g of C (tetrahydro-5> 6s7 8 tetramethyl-5,5,8,8 naphthyl) -g carbonyl-6 methyl-2-naphthalene carboxylate are obtained.
L'isopropanol est évaporé, le solide obtenu est lavé par le minimum de méthanol puis ensuite recristallisé dans ce solvant. On isole ainsi une seconde fraction de 0,7 g de produit attendu identique à celui obtenu précédemment sous forme de cristaux blancs dont le point de fusion est de 134 C. The isopropanol is evaporated, the solid obtained is washed with a minimum of methanol and then recrystallized from this solvent. A second fraction of 0.7 g of expected product is thus isolated, identical to that obtained previously in the form of white crystals, the melting point of which is 134 C.
Le spectre R.M.N.1H 60 HHz est conforme à la structure attendue. The R.M.N.1H 60 HHz spectrum conforms to the expected structure.
Analyse élémentaire: C27 H28 3
Cal. % C: 80,97 H: 7,05 0:11,98
Tr. Z 80,85 7,00 12,02
EXEMPLE II
Préparation de l'acide C(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-22 carbonyl-6 naphtalène carboxylique-2 (Composé de formule II avec R1R2=R3=R4=-CH3 1 2 et R5=-COOH)
Une suspension de 2,5 de [(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-2] carbonyl-6 naphtalène carboxylate de méthyle-2 obtenu à l'exemple
I est agitée pendant trois heures dans un mélange de 30 cm3 de méthanol et 30 cm9 de potasse aqueuse 6N à une température comprise entre 50 et 600C puis abandonnée une nuit à température ordinaire. Après avoir ajouté 40 cm3 d'eau, le méthanol est éliminé par évaporation sous vide.La phase aqueuse -ainsi obtenue est refroidie entre 0 et 50C, puis acidifiée à pH#1 par addition d'acide chlorhydrique 6N. Le précipité obtenu est alors essoré, lavé à l'eau, séché à 800C sur potasse.Elementary analysis: C27 H28 3
Cal. % C: 80.97 H: 7.05 0: 11.98
Tr. Z 80.85 7.00 12.02
EXAMPLE II
Preparation of acid C (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -22 carbonyl-6 naphthalene carboxylic-2 (Compound of formula II with R1R2 = R3 = R4 = -CH3 1 2 and R5 = -COOH)
A suspension of 2.5 of [(tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -2] carbonyl-6 methyl-2 naphthalene carboxylate obtained in the example
I is stirred for three hours in a mixture of 30 cm3 of methanol and 30 cm9 of 6N aqueous potassium hydroxide at a temperature between 50 and 600C and then left overnight at ordinary temperature. After adding 40 cm3 of water, the methanol is removed by evaporation under vacuum. The aqueous phase-thus obtained is cooled to 0 to 50C, then acidified to pH # 1 by addition of 6N hydrochloric acid. The precipitate obtained is then drained, washed with water, dried at 800C on potassium hydroxide.
Après deux recristallisations, l'une dans 40 cm3 dtisopropanol, l'autre dans 100cm3 de méthanol, 1,7 g d'acide C(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-7 carbonyl-6 naphtalène carboxylique-2 est isolé sous forme de cristaux blancs dont le point de fusion est de 2240 C. After two recrystallizations, one in 40 cm 3 of isopropanol, the other in 100 cm 3 of methanol, 1.7 g of acid C (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) - 7 carbonyl-6 naphthalene carboxylic-2 is isolated in the form of white crystals with a melting point of 2240 C.
Le spectre de R.M.N. H 250 MHz est conforme à la structure attendue. The spectrum of R.M.N. H 250 MHz conforms to the expected structure.
Analyse élémentaire: C26 H26 03
Calc. % C: 80,80 H: 6,78 O: 12,42
Tr. % 80,57 6,93 12,50
EXEMPLE III
Préparation du N-éthyl (tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-2} carbonyl-6 naphtalène carboxamide-2
(Composé de formule II avec R1=R2=R3=R4= -CH3 et R = -CONHC2H5)
A une suspension de îg (2,5 mmoles) d'acide (tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-2i1 carbonyl-6 naphtalène carboxylique-6, obtenu à l'exemple II, dans 10 cm3 de dichlorométhane anhydre, on ajoute 0,49 g (3 mmoles) de N,N'carbonyl diimidazole sous agitation à température ambiante.Elementary analysis: C26 H26 03
Calc. % C: 80.80 H: 6.78 O: 12.42
Tr.% 80.57 6.93 12.50
EXAMPLE III
Preparation of N-ethyl (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -2} carbonyl-6 naphthalene carboxamide-2
(Compound of formula II with R1 = R2 = R3 = R4 = -CH3 and R = -CONHC2H5)
To a suspension of Ig (2.5 mmol) of acid (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -2i1 carbonyl-6 naphthalene carboxylic-6, obtained in the example II, in 10 cm3 of anhydrous dichloromethane, 0.49 g (3 mmol) of N, N'carbonyl diimidazole is added with stirring at room temperature.
Le gaz carbonique se dégage. Après une heure d'agitation 0,17 cm3 (2,6 mmoles) d'éthylamine anhydre sont ajoutés. Une heure après, l'acide de départ est totalement transformé en amide correspondant. Carbon dioxide is released. After one hour of stirring 0.17 cm3 (2.6 mmol) of anhydrous ethylamine are added. One hour later, the starting acid is completely transformed into the corresponding amide.
Le milieu réactionnel est alors dilué par 20 cm3 de dichlorométhane, lavé avec 20 cm3 de soude normale, puis à liteau jusqu'à pH neutre des eaux de lavage, séché sur sulfate de sodium et concentré à sec. The reaction medium is then diluted with 20 cm3 of dichloromethane, washed with 20 cm3 of normal sodium hydroxide, then with a batten until the pH of the washing waters is neutral, dried over sodium sulfate and concentrated to dryness.
On obtient 1 g de solide beige que l'on recristallise dans un mélange éther isopropylique-acétonitrile. On isole ainsi, après avoir essoré et séché les cristaux, 0,65 g de N-éthyl C(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-2] carbonyl-6 naphtalène carboxamide-2, sous forme de cristaux blancs dont le point de fusion est de 1550 C. 1 g of beige solid is obtained which is recrystallized from an isopropyl ether-acetonitrile mixture. Is thus isolated, after draining and drying the crystals, 0.65 g of N-ethyl C (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -2] carbonyl-6 naphthalene carboxamide -2, in the form of white crystals with a melting point of 1550 C.
Les spectres R.M.N1H et infra-rouge correspondent à la structure attendue. The R.M.N1H and infrared spectra correspond to the expected structure.
Analyse élémentaire: C28 H31 NO2
Calc.% : C: 81,32 H:7,56 N:3,39 0:7,74
Tr. Z : 81,33 7,53 3,30 7,72
EXEMPLE IV
Préparation du (méthano-5,8 tétrahydro-5,6,7,8 naphtyl) - carbonyl-6 naphtalène carboxylate de méthyle-2
(Composé de formule III avec R6 OCH3)
Une suspension de 1,08 g (7,5 mmoles) de méthano-1,4 tétrahydro-1,2,3,4 naphtalène et de 2 g (8 mmoles) de chlorure de l'acide méthoxycarbonyl-6 naphtalène carboxylique-2 dans 30 cm3 de dichloro-1,2 éthane anhydre, on ajoute par portions en 45 mn, 1,3 g (9,75 mmoles) de chlorure d'aluminium anhydre. Le mélange est agité pendant 5 heures à température ambiante puis versé dans 80 cm3 d'eau glacée acidulée. La phase organique est décantée.La phase aqueuse est extraite encore une fois à l'aide de 60 cm9 de dichloro-1,2 éthane. Les phases de dichloro-1,2 éthane sont rassemblées, lavées au bicarbonate de sodium, séchées sur sulfate de sodium puis concentrées. Le solide obtenu est séché sous vide à 600C puis recristallisé d'abord dans l'acétate d'éthyle puis dans l'isopropanol. On obtient ainsi 1 g [(méthano-5,8 tétrahydro-5,6,7,8 naphtyl)-2 carbonyl-6 naphtalène carboxylate de méthyle-2 sous forme de cristaux blancs dont le point de fusion est de 119"C. Elementary analysis: C28 H31 NO2
Calc.%: C: 81.32 H: 7.56 N: 3.39 0: 7.74
Tr. Z: 81.33 7.53 3.30 7.72
EXAMPLE IV
Preparation of (methano-5,8 tetrahydro-5,6,7,8 naphthyl) - carbonyl-6 methyl-2-naphthalene carboxylate
(Compound of formula III with R6 OCH3)
A suspension of 1.08 g (7.5 mmol) of 1,4-methano-1,2,3,4-tetrahydro naphthalene and 2 g (8 mmol) of chloride of 6-methoxycarbonyl acid-2 naphthalene carboxylic-2 in 30 cm3 of anhydrous 1,2-dichloroethane, 1.3 g (9.75 mmol) of anhydrous aluminum chloride are added in portions over 45 min. The mixture is stirred for 5 hours at room temperature then poured into 80 cm3 of acidulated iced water. The organic phase is decanted. The aqueous phase is extracted once again using 60 cm9 of 1,2-dichloroethane. The 1,2-dichloroethane phases are combined, washed with sodium bicarbonate, dried over sodium sulfate and then concentrated. The solid obtained is dried under vacuum at 600C and then recrystallized first from ethyl acetate then from isopropanol. 1 g [(methano-5.8 tetrahydro-5,6,7,8 naphthyl) -2 carbonyl-6 methyl naphthalene carboxylate-2 is thus obtained in the form of white crystals with a melting point of 119 "C.
Le spectre RMN 1H 60MHz est conforme à la structure attendue. The 1H 60MHz NMR spectrum conforms to the expected structure.
Analyse élémentaire: C24 H20 03
Calc. Z C: 80,87 H: 5,66 O: 13,47
Tr. % 80,82 5,69 13,25
EXEMPLE V
Préparation de l'acide gméthano-5,8 tétrahydro-5,6,7,8 naphtyl)- carbonyl-6 naphtalène carboxylique-2
(Composé de formule III avec R6 = OH)
Une suspension de 0,88 g (2,46 mmoles) de (méthano-5,8 tétrahydro-5,6,7,8 naphtyl)-2 carbonyl-6 naphtalène carboxylate de méthyle-2 obtenu à l'exemple IV est agitée pendant deux heures dans un mélange de 15 cm3 d'alcool et 15 cm3 de potasse aqueuse 6 N chauffé au reflux. Après avoir ajouté 60 cm9 d'eau, l'alcool est éliminé par évaporation sous vide. La phase aqueuse ainsi obtenue est refroidie entre 0 et 50C puis acidifiée par addition de 15 cm3 d'acide chlorhydrique 12 N. Le précipité obtenu est essoré, lavé à l'eau, séché à 800C sur potasse.Elementary analysis: C24 H20 03
Calc. ZC: 80.87 H: 5.66 W: 13.47
Tr.% 80.82 5.69 13.25
EXAMPLE V
Preparation of 5,8-gethano-5,6,7,8 naphthyl tetrahydro) - 6-carbonyl-2-naphthalene carboxylic-2
(Compound of formula III with R6 = OH)
A suspension of 0.88 g (2.46 mmol) of (methano-5,8 tetrahydro-5,6,7,8 naphthyl) -2 carbonyl-6 methyl-naphthalene carboxylate-2 obtained in Example IV is stirred for two hours in a mixture of 15 cm3 of alcohol and 15 cm3 of 6N aqueous potassium hydroxide heated to reflux. After adding 60 cm9 of water, the alcohol is removed by evaporation under vacuum. The aqueous phase thus obtained is cooled to 0 to 50C and then acidified by adding 15 cm3 of 12N hydrochloric acid. The precipitate obtained is drained, washed with water, dried at 800C on potassium hydroxide.
Après recristallisation dans 110 cm9 de méthanol, on obtient 0,62 g de cristaux blancs d'acide l (méthano-5,8 tétrahydro-5,6,7,8 naphtyl)- carbonyl-6 naphtalène carboxylique-2 dont le point de fusion est de 243"C. After recrystallization from 110 cm9 of methanol, 0.62 g of white crystals of acid 1 (5,8-methano-5,6,7,8 naphthyl) - 6-carbonyl-2-naphthalene-carboxylic-2 are obtained, the point of which is fusion is 243 "C.
Les spectres de R.M.N. 1H 250 MHz et 13C sont conformes à la structure attendue. The spectra of R.M.N. 1H 250 MHz and 13C conform to the expected structure.
Analyse élémentaire: C23 H18 03
Calc. % C: 80,68 H: 5,30 0: 14,02
Tr. 7O 80,83 5,43 13,71
EXEMPLE VI
Préparation du [(tétrahydro-5,6,7,8 napRhtyl)-22 carbonyl-6 naphtalène carboxylate de méthyle-2 (Composé de formule Il avec R 1=R2=R3=R4= H et R5=-COOCH3)
A une suspension de 1,59 g (12 mmoles) de tétrahrdro-1,2,3,4 naphtalène et de 3 g (12,05 mmoles) de chlorure de acide méthoeycnrbonyl-6 naphtalène carboxylique-2 dans 60 cm3 de dichloro-1,2 éthane anhydre, on ajoute par portions, 2,4 g (18 mmoles) de chlorure d'aluminium anhydre Le mélange est agité pendant 6 heures à température ambiante puis versé dans 100 cm3 d'eau glacée acidulée. La phase organique est décantée. La phase aqueuse est extraite encore une fois à l'aide de 100 cm3 de dicsaloro-1,2 éthane.Les phases de dichloroéthane sont rassemblées, layées au bicarbonate de sodium, séchées sur sulfate de sodium puis concentrées à sec. t1 ester brut obtenu est purifié rapidement par chromatographie sur gel de silice avec un mélange hexane/éther 8/2, puis recristallisé dans 1 'isopropanol. On obtient ainsi 2 g de cristaux blancs de [(tétrahydro-5,6,7,8 naphtyl)-2] carbonyl-6 naphtalène carboxylate de méthyle-2 dont le point de fusion est de 1710C.Elementary analysis: C23 H18 03
Calc. % C: 80.68 H: 5.30 0: 14.02
Tr. 7O 80.83 5.43 13.71
EXAMPLE VI
Preparation of [(tetrahydro-5,6,7,8 napRhtyl) -22 carbonyl-6 methyl naphthalene carboxylate-2 (Compound of formula II with R 1 = R2 = R3 = R4 = H and R5 = -COOCH3)
To a suspension of 1.59 g (12 mmol) of 1,2,3,4-tetrahrdro-naphthalene and 3 g (12.05 mmol) of 6-methoeycnrbonyl acid chloride-2 naphthalene carboxylic acid in 60 cm3 of dichlor 1.2 anhydrous ethane, 2.4 g (18 mmol) of anhydrous aluminum chloride are added in portions. The mixture is stirred for 6 hours at room temperature and then poured into 100 cm3 of acidulated ice water. The organic phase is decanted. The aqueous phase is extracted once again using 100 cm3 of 1,2-dicsaloroethane. The dichloroethane phases are combined, layered with sodium bicarbonate, dried over sodium sulfate and then concentrated to dryness. t1 crude ester obtained is rapidly purified by chromatography on silica gel with an 8/2 hexane / ether mixture, then recrystallized from isopropanol. 2 g of white crystals of [(tetrahydro-5,6,7,8 naphthyl) -2] carbonyl-6-2-naphthalene carboxylate-2 are thus obtained, the melting point of which is 1710 C.
Le spectre de R.M.N. H 60 MHz est conforme à la structure attendue. The spectrum of R.M.N. H 60 MHz conforms to the expected structure.
Analyse élementaire : C23 H20 O3
Cal. % C: 80,21 H: 5,85 0:13,94
Tr. % 80,16 5,91 13,85
EXEMPLE VII
Préparation de l'acide [(tétrahydro-5,6,7,8 naphtyl)- carbonyl-6 naphtalène carboxylique-2
(Composé formule II avec R1=R2=R3=R4= H et R5 =-COOH)
Une suspension de 1,50g (4,35 mmoles) de (tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène carboxylate de méthyle 2 obtenu à ltexem- ple VI, est agitée pendant trois heures dans un mélange de 25 cm3 d'alcool et de 25 cm3 de potasse aqueuse 6 N chauffé au reflux. Après avoir ajouté 50 cm3 d'eau, l'alcool est éliminé par évaporation sous vide.La phase aqueuse ainsi obtenue est diluée à 500 cm3 pour solubiliser entièrement le carboxylate puis acidifiée par addition de 25 cm3 d'acide chlorhydrique 12 N. Le précipité obtenu est essoré, lavé à l'eau, séché à 80 C sur potasse.Elemental analysis: C23 H20 O3
Cal. % C: 80.21 H: 5.85 0: 13.94
Tr.% 80.16 5.91 13.85
EXAMPLE VII
Preparation of [(tetrahydro-5,6,7,8 naphthyl) - 6-carbonyl-naphthalene carboxylic-2 acid
(Compound formula II with R1 = R2 = R3 = R4 = H and R5 = -COOH)
A suspension of 1.50 g (4.35 mmol) of (tetrahydro-5,6,7,8 naphthyl-2) carbonyl-6 methyl naphthalene carboxylate 2 obtained in Example VI, is stirred for three hours in a mixture 25 cm3 of alcohol and 25 cm3 of 6 N aqueous potassium hydroxide heated to reflux. After adding 50 cm3 of water, the alcohol is removed by evaporation under vacuum. The aqueous phase thus obtained is diluted to 500 cm3 to completely dissolve the carboxylate and then acidified by addition of 25 cm3 of 12N hydrochloric acid. obtained is drained, washed with water, dried at 80 ° C. on potassium hydroxide.
Après recristallisation d'abord dans l'isopropanol puis dans un mélange méthanol/acétone 8/2 on obtient 1,1 g de cristaux blancs d'acide [(tétrahydro-5,6,7,8 naphtyl carbonyl-6 naphtalène carboxylique-2 dont le point de fusion est de 267 C. After recrystallization first from isopropanol and then from a methanol / acetone mixture 8/2, 1.1 g of white crystals of acid are obtained ((tetrahydro-5,6,7,8 naphthyl carbonyl-6 naphthalene carboxylic-2). with a melting point of 267 C.
Les spectres de R.M.N. H 250 MHz et 13C sont conformes à la structure attendue. The spectra of R.M.N. H 250 MHz and 13C conform to the expected structure.
Analyse élémentaire
C22 H18 O3
Cal. % C: 79,98 H: 5,49 O: 14,53
Tr. % 80,18 5,52 14,24
EXEMPLE VIII
Préparation du N-éthyl [(tétrahydro-5,6,7,8 naphtyl)-2]carbonyl-6 naphtalène carboxamide-2
(Composé de formule Il avec R1=R2=R3=R4 = H et R5 =-CONR C2H5)
Une suspension de 165g (0,5 mmole) d'acide [(tétradydro-5,6,7,8 naphtyl)-2 carbonyl-6 naphtalène carboxylique-2, obtenu à 11 exemple VII, et de 97,5 mg (0,6 mmole) de N,N'-carbonyldiimidazole dans 5 cm3 de dichlorométhane sec est agitée 2 heures à température ambiante. On ajoute alors 0,04 cm3 (0,6 mmole) d'éthylamine anhydre à la solution obtenue.Après 30 minutes d'agitation, le milieu réactionnel est dilué par 10 cm9 d'eau, lavé successivement par 10 cm3 de soude normale, 2 fois 10 cm9 d'eau, 10 cm3 d'acide chlorhydrique N, et 10 cm3 d'eau. La phase dichlorométhane est séchée sur sulfate de sodium puis évaporée à sec. L'amide brut est séché sous vide à 600C puis recristallisé dans de l'éther isopropylique contenant un peu de méthanol. On obtient 130 mg d'aiguilles jaune pâle de N-éthyl [(tétrahydro-5,6,7,8 naphtyl)- carbonyl-6 naphtalène carboxamide-2 dont le point de fusion est de 1370 C. Elementary analysis
C22 H18 O3
Cal. % C: 79.98 H: 5.49 O: 14.53
Tr.% 80.18 5.52 14.24
EXAMPLE VIII
Preparation of N-ethyl [(tetrahydro-5,6,7,8 naphthyl) -2] carbonyl-6 naphthalene carboxamide-2
(Compound of formula II with R1 = R2 = R3 = R4 = H and R5 = -CONR C2H5)
A suspension of 165 g (0.5 mmol) of acid [(tetradydro-5,6,7,8 naphthyl) -2 carbonyl-6 naphthalene carboxylic-2, obtained in 11 Example VII, and of 97.5 mg (0 , 6 mmol) of N, N'-carbonyldiimidazole in 5 cm 3 of dry dichloromethane is stirred for 2 hours at room temperature. 0.04 cm3 (0.6 mmol) of anhydrous ethylamine is then added to the solution obtained. After 30 minutes of stirring, the reaction medium is diluted with 10 cm9 of water, washed successively with 10 cm3 of normal sodium hydroxide, 2 times 10 cm9 of water, 10 cm3 of hydrochloric acid N, and 10 cm3 of water. The dichloromethane phase is dried over sodium sulfate and then evaporated to dryness. The crude amide is dried under vacuum at 600C and then recrystallized from isopropyl ether containing a little methanol. 130 mg of pale yellow N-ethyl needles [(tetrahydro-5,6,7,8 naphthyl) - carbonyl-6 naphthalene carboxamide-2 are obtained, the melting point of which is 1370 C.
Les spectres R.M.N.1H 250 MHz et 13C sont conformes à la structure attendue. The R.M.N. 1H 250 MHz and 13C spectra conform to the expected structure.
Analyse élémentaire: : C24 H23 NO2
Cal. % C: 80,64 H: 6,49 N: 3,92 O: 8,95
Tr. % 80,49 6,55 3,86 8,75
EXEMPLE IX
Préparation du (tétrahydro-5,6,8,8 tétraméthyl-5,5,8,8 naphtyl)-2/ carbonyl-6 naphtalène carboxaldéhyde-2 (Composé de formule Il avec R1=R2=R3=RçCH3 et R5=-CH=O)
Ce composé est préparé en deux étapes à partir de l'acide [(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-27 carbonyl-6 naphtalène carboxylique-2 préparé à l'exemple II. Dans une première étape les fonctions carbonyle et acide carboxylique sont réduites en alcool.Dans une deuxième étape le (tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)- -1
(hydroxyméthyl-6 naphtyl)-2 -1 méthanol est oxydé en aldéhyde attendu.Elementary analysis:: C24 H23 NO2
Cal. % C: 80.64 H: 6.49 N: 3.92 O: 8.95
Tr.% 80.49 6.55 3.86 8.75
EXAMPLE IX
Preparation of (tetrahydro-5,6,8,8 tetramethyl-5,5,8,8 naphthyl) -2 / carbonyl-6 naphthalene carboxaldehyde-2 (Compound of formula II with R1 = R2 = R3 = RçCH3 and R5 = - CH = O)
This compound is prepared in two stages from the acid [(tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -27 carbonyl-6 naphthalene-carboxylic-2 prepared in Example II . In a first step the carbonyl and carboxylic acid functions are reduced to alcohol. In a second step the (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) - -1
(6-hydroxymethyl naphthyl) -2 -1 methanol is oxidized to the expected aldehyde.
a) Préparation du C( [(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 napthyl)-21-l p(hydroxyméthyl-6 naphtyl)-2j -1 méthanol. a) Preparation of C ([(tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -21-l p (hydroxymethyl-6 naphthyl) -2d -1 methanol.
A une suspension de 225 mg (6 mmoles) d'hydrure de lithium aluminium dans 10 cm3 de tétrahydrofuranne anhydre agitée à OOC, on ajoute en une fois 1,16 g (3 mmoles) d'acide préparé suivant l'exemple II. Après une heure, le milieu est agité à température ordinaire, la réaction étant suivie en C.C.M. To a suspension of 225 mg (6 mmol) of lithium aluminum hydride in 10 cm 3 of anhydrous tetrahydrofuran stirred with OOC, 1.16 g (3 mmol) of acid prepared according to Example II are added at once. After one hour, the medium is stirred at ordinary temperature, the reaction being followed by C.C.M.
Lorsque la totalité du produit de départ est transformée on ajoute lentement 100 cm3 d'acide chlorhydrique 0,1 N puis le mélange est extrait 4 fois par 25 cm3 d'éther éthylique. Les phases éthérées sont décantées, séchées sur sulfate de sodium et le solvant est éliminé par évaporation sous vide.When all of the starting material is transformed, 100 cm3 of 0.1N hydrochloric acid is slowly added, then the mixture is extracted 4 times with 25 cm3 of ethyl ether. The ethereal phases are decanted, dried over sodium sulfate and the solvent is removed by evaporation under vacuum.
Le diol brut obtenu est purifié par passage sur colonne de gel de silice et élué au mélange acide acétique-dioxanne-toluène (2-8-90). The crude diol obtained is purified by passage over a column of silica gel and eluted with an acetic acid-dioxane-toluene mixture (2-8-90).
Après évaporation de l'éluant on isole 0,9 g de p(tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-2c 0(hydroxyméthyl-6 naphtyl)-g-1 méthanol sous forme de cristaux blancs dont le point de fusion est de 1570C. After evaporation of the eluent, 0.9 g of p (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -2c 0 (hydroxymethyl-6 naphthyl) -g-1 methanol is isolated. form of white crystals with a melting point of 1570C.
Le spectre R.M.N1H 60 MHz est conforme à la structure attendue. The R.M.N1H 60 MHz spectrum conforms to the expected structure.
b) Oxydation du diol précédent
A une solution du diol préparé ci-dessus de 0,8 g (2,1 mmoles) dans 20 cm3 de dichlorométhane anhydre, agitée à la température ordinaire, on ajoute 0,55 g (2,5 mmoles) de chlorochromate de pyridinium. Après 45 mn on ajoute 30 g de gel de silice et I1 ensemble est filtré sur célite. Le filtre est lavé au dichlorométhane et la solution est concentrée sous pression réduite. Le produit obtenu est purifié par chromatographie sur gel de silice et élué au mélange acide acétique-dioxanne-toluène (2/8/90). Après concentration des phases d'élution, puis recristallisation dans l'hexane on obtient 0,52 g de (tétrahydro-5,6,7,8 tétraméthyl-5,5,8,8 naphtyl)-2 carbonyl-6 naphtalène carboxaldéhyde-2 sous forme de cristaux blancs dont le point de fusion est de 1310C.b) Oxidation of the previous diol
To a solution of the diol prepared above 0.8 g (2.1 mmol) in 20 cm 3 of anhydrous dichloromethane, stirred at room temperature, 0.55 g (2.5 mmol) of pyridinium chlorochromate is added. After 45 min, 30 g of silica gel are added and the whole is filtered through Celite. The filter is washed with dichloromethane and the solution is concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel and eluted with an acetic acid-dioxane-toluene mixture (2/8/90). After concentrating the elution phases, then recrystallization from hexane, 0.52 g of (tetrahydro-5,6,7,8 tetramethyl-5,5,8,8 naphthyl) -2 carbonyl-6 naphthalene carboxaldehyde is obtained. 2 in the form of white crystals with a melting point of 1310C.
Le spectre R.M.N. 1H 250 MHz est conforme à la structure attendue. The R.M.N. 1H 250 MHz conforms to the expected structure.
Analyse élémentaire: C26H2602
Calc. % C : 84,29 H : 7,07 0: 8,64
Tr. % 84,21 6,96 8,46
EXEMPLE X
Préparation du (tétraméthyl-5,5,8,8 tétrahydro-5 ,6,7,8 naphtyl)-i
carbonyl-6 hydroxyméthyl-2 naphtalène.Elementary analysis: C26H2602
Calc. % C: 84.29 H: 7.07 0: 8.64
Tr.% 84.21 6.96 8.46
EXAMPLE X
Preparation of (tetramethyl-5,5,8,8 tetrahydro-5, 6,7,8 naphthyl) -i
6-carbonyl-2-hydroxymethyl-naphthalene.
(Composé de formule Il avec R 1=R2=R3=R4=-CH3 et R5=-CH2OH)
A une solution de 0,3g de potasse à 85% dans 10cm3 de méthanol,
agitée à 600C, on ajoute 0,6g (1,6mmoles) de t(tétraméthyl-5,5,8,8
tétrahydro-5,6,7,8 naphtyl)-43 carbonyl-6 formyl-2 naphtalène et 0,16cm3
(1,9mmoles) de formaldéhyde en solution aqueuse à 37%. Après 2h d'agitation à
60-700C, le méthanol est distillé sous pression normale. On ajoute alors 10cm3
d'eau au résidu chaud et refroidit à température ambiante. Le précipité formé
est extrait par quatre fois 25cm d'éther éthylique. Les phases éthérées sont
lavées à l'eau puis séchées sur sulfate de sodium et évaporées à sec sous
pression réduite.Le produit brut est purifié par chromatographie sur gel de
silice 60 dans le mélange éluant acide acétique/dioxane/toluène 2/8/90 suivie
d'une recristallisation dans un mélange hexane/acétone. Après séchage, on
obtient 140mg de cristaux blancs de tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)-g carbonyl-6 hydroxyméthyl-2 naphtalène dont le point de fusion est de 1620C. Le spectre R.M.N.H correspond à la structure attendue.(Compound of formula II with R 1 = R2 = R3 = R4 = -CH3 and R5 = -CH2OH)
To a solution of 0.3 g of 85% potassium hydroxide in 10 cm 3 of methanol,
stirred at 600C, 0.6g (1.6mmol) of t (tetramethyl-5,5,8,8) is added
tetrahydro-5,6,7,8 naphthyl) -43 carbonyl-6 formyl-2 naphthalene and 0.16 cm3
(1.9 mmoles) of formaldehyde in 37% aqueous solution. After 2 hours of agitation at
60-700C, methanol is distilled under normal pressure. We then add 10cm3
of water to the hot residue and cools to room temperature. The precipitate formed
is extracted with four times 25cm of ethyl ether. The ethereal phases are
washed with water then dried over sodium sulphate and evaporated to dryness under
reduced pressure The crude product is purified by chromatography on
silica 60 in the eluent mixture acetic acid / dioxane / toluene 2/8/90 followed
recrystallization from a hexane / acetone mixture. After drying,
obtains 140 mg of white crystals of tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl) -g carbonyl-6 hydroxymethyl-2 naphthalene whose melting point is 1620C. The NMR spectrum corresponds to the expected structure.
EXEMPLE XI
Préparation du N-hydroxy-2 éthoxyéthyl [(tétraméthyl-5,5,8,8
tétrahydro-5,6,7,8 naphtyl)-i carbonyl-6 naphtalène carboxamide-2.EXAMPLE XI
Preparation of 2-hydroxy-ethoxyethyl [(tetramethyl-5,5,8,8
tetrahydro-5,6,7,8 naphthyl) -i carbonyl-6 naphthalene carboxamide-2.
(composé de formule II avec R1=R2=R3=R4=-CH3 et R5=-CONH(CH2) 20-(CH2) 2-OH)
A une suspension de 0,9g (2,33mmoles) d'acide[tétraméthyl-5,5,8,8
tétrahydro-5,6,7,8 naphtyl-2carbonyl-6 naphtalène carboxylique-2 dans 9cm9
de dichlorométhane anhydre, on ajoute 490mg (3,03mmoles) de
N,N'-carboxyldiimidazole. Après 1h d'agitation à température ambiante, on ajoute 0,27cm9 (2,57mmoles) de N-hydroxyéthoxy-2 éthylamine à la solution
obtenue. Le milieu réactionnel est agité 3h à température ambiante puis dilué par 25cm de dichlorométhane et lavé à l'eau et à l'acide chlorhydrique dilué.(compound of formula II with R1 = R2 = R3 = R4 = -CH3 and R5 = -CONH (CH2) 20- (CH2) 2-OH)
To a suspension of 0.9 g (2.33 mmol) of [tetramethyl-5,5,8,8 acid
tetrahydro-5,6,7,8 naphthyl-2carbonyl-6 naphthalene carboxylic-2 in 9cm9
of anhydrous dichloromethane, 490 mg (3.03 mmol) of
N, N'-carboxyldiimidazole. After 1 hour of stirring at room temperature, 0.27 cm 9 (2.57 mmol) of 2-hydroxyethoxy-ethylamine is added to the solution.
obtained. The reaction medium is stirred for 3 h at room temperature then diluted with 25 cm of dichloromethane and washed with water and dilute hydrochloric acid.
La phase dichlorométhane est séchée sur sulfate de sodium puis évaporée à sec.The dichloromethane phase is dried over sodium sulfate and then evaporated to dryness.
L'amide brut est purifié par chromatographie sur gel de silice 60 dans le mélange éluant dichlorométhane/tétrahydrofuranne 70/30. Après évaporation et
séchage, on obtient 0,65g de cristaux blancs de N-hydroxyéthoxy-2 éthyl [(tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2 carbonyl-6 naphtalène
carboxamide-2 de 800.The crude amide is purified by chromatography on silica gel 60 in the eluent mixture dichloromethane / tetrahydrofuran 70/30. After evaporation and
drying, 0.65 g of white crystals of N-hydroxyethoxy-2 ethyl [(tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2 carbonyl-6 naphthalene) are obtained
carboxamide-2 of 800.
Le spectre R.M.N.1H 250 MHz est conforme à la structure attendue. The R.M.N. 1H 250 MHz spectrum conforms to the expected structure.
Analyse élémentaire : C30H35N04
Calc. C 76,08 H 7,45 N 2,96 O 13,51
Tr. 76,04 7,52 3,00 13,62
EXEMPLE XII
Préparation du N-p-hydroxyphényl (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène carboxamide-2.Elementary analysis: C30H35N04
Calc. C 76.08 H 7.45 N 2.96 O 13.51
Tr. 76.04 7.52 3.00 13.62
EXAMPLE XII
Preparation of Np-hydroxyphenyl (tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2) carbonyl-6 naphthalene carboxamide-2.
(composé de formule II avec R1=R2=R3=R4=-CH3 et R5=-CONH C6H4 p OH)
A une suspension de 0,9g (2,33mmoles) d'acide (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène carboxylique-2 dans 9cm9 de dichlorométhane anhydre, on ajoute 490mg (3,03mmoles) de
N,N'-carbonyldiimidazole. Après 1h d'agitation à température ambiante, on ajoute lcm3 de N,N-diméthylformamide pur 0,31g (2,8mmoles) de p-aminophénol à la solution obtenue. Le milieu réactionnel est agité une nuit à température ambiante. L'acide de départ n'ayant pas totalement réagi, on ajoute O,lg de
N,N'-carbonyldiimidazole puis 0,lg de p-aminophénol et agite 2h à température ambiante.Le milieu réactionnel est alors dilué par 50cm3 de dichlorométhane lavé à l'acide chlorhydrique dilué puis à l'eau jusqu'à neutralité. La phase dichlorométhane est séchée sur sulfate de sodium puis concentrée sous pression réduite. L'amide brut est purifié par chromatographie sur gel de silice 60 dans un mélange toluène/dichlorométhane/acétate d'éthyle 5/3/2. Par recristallisation dans un mélange éther isopropylique/acétone, on obtient 0,33g de cristaux blancs de N-p-hydroxyphényl (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène carboxamide-2 dont le point de fusion est de 268-9 C. (compound of formula II with R1 = R2 = R3 = R4 = -CH3 and R5 = -CONH C6H4 p OH)
To a suspension of 0.9 g (2.33 mmol) of acid (tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2) carbonyl-6 naphthalene carboxylic-2 in 9cm9 of anhydrous dichloromethane , add 490mg (3.03mmol) of
N, N'-carbonyldiimidazole. After 1 hour of stirring at room temperature, lcm3 of pure N, N-dimethylformamide 0.31 g (2.8 mmol) of p-aminophenol is added to the solution obtained. The reaction medium is stirred overnight at room temperature. The starting acid not having completely reacted, O, lg of
N, N'-carbonyldiimidazole then 0.1 g of p-aminophenol and stirred for 2 h at room temperature. The reaction medium is then diluted with 50 cm 3 of dichloromethane washed with dilute hydrochloric acid and then with water until neutral. The dichloromethane phase is dried over sodium sulfate and then concentrated under reduced pressure. The crude amide is purified by chromatography on silica gel 60 in a toluene / dichloromethane / ethyl acetate 5/3/2 mixture. By recrystallization from an isopropyl ether / acetone mixture, 0.33 g of white crystals of Np-hydroxyphenyl (tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2) -carbonyl-6 naphthalene carboxamide are obtained. -2 with a melting point of 268-9 C.
Le spectre R.M.N.1H 250 MHz est conforme à la structure attendue. The R.M.N. 1H 250 MHz spectrum conforms to the expected structure.
Analyse élémentaire: : C H NO
32 32 3
Calc. C 80,47 H 6,54 N 2,93
Tr. 80,55 6,27 2,89
Au cours de la chromatographie sur silice, on isole également un deuxième produit qui par recristallisation dans un mélange acétone/méthanol fournit 0,3g de cristaux blancs de N,O-bis (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)-2 dicarbonyl-2,6 naphtyl amino-4 phénol dont le point de fusion est de 239-2400C. Elementary analysis:: CH NO
32 32 3
Calc. C 80.47 H 6.54 N 2.93
Tr. 80.55 6.27 2.89
During the chromatography on silica, a second product is also isolated which, by recrystallization from an acetone / methanol mixture, provides 0.3 g of white crystals of N, O-bis (tetramethyl-5,5,8,8 tetrahydro-5, 6,7.8 naphthyl) -2 dicarbonyl-2,6 naphthyl amino-4 phenol with a melting point of 239-2400C.
Le spectre R.M.N. H 250 MHz est conforme à la structure décrite. The R.M.N. H 250 MHz conforms to the structure described.
Analyse élémentaire: : C H NO
58 55 5
Calc. C 82,33 H 6,55 N 1,66 O 9,45
Tr. 82,13 6,73 1,65 9,25
Ce produit décondensé est saponifié par de la potasse 6N en milieu hydroalcoolique pendant 5h à 500C. Après dilution à l'eau, évaporation de l'alcool sous pression réduite, et acidification par de l'acide chlorhydrique
concentré, on obtient un mélange équimoléculaire de N-p-hydroxyphényl
(tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène
carboxamide-2 et d'acide (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2)
carbonyl-6 naphtalène carboxylique-2.Par chromatographie sur silice 60 dans
un mélange toluène/dichlorométhane/acétate d'éthyle 5/3/2, on isole ainsi une
deuxième fraction de 0,11g de N-p-hydroxyphényl (tétraméthyl-5,5,8,8
tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène carboxamide-2 dont le
point de fusion est identique à la précédente.Elementary analysis:: CH NO
58 55 5
Calc. C 82.33 H 6.55 N 1.66 O 9.45
Tr. 82.13 6.73 1.65 9.25
This uncondensed product is saponified with 6N potassium hydroxide in an alcoholic medium for 5 hours at 500C. After dilution with water, evaporation of the alcohol under reduced pressure, and acidification with hydrochloric acid
concentrated, an equimolecular mixture of Np-hydroxyphenyl is obtained
(tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2) carbonyl-6 naphthalene
carboxamide-2 and acid (tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2)
carbonyl-6 naphthalene carboxylic-2. By chromatography on silica 60 in
a toluene / dichloromethane / ethyl acetate 5/3/2 mixture, thus isolating a
second fraction of 0.11 g of Np-hydroxyphenyl (tetramethyl-5,5,8,8
tetrahydro-5,6,7,8 naphthyl-2) carbonyl-6 naphthalene carboxamide-2 whose
melting point is identical to the previous one.
EXEMPLE XIII
Préparation du N-(éthoxycarbonyl-l méthylthio-3 propyl) [(tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)-20 carbonyl-6 naphtalène
carboxamide-2.EXAMPLE XIII
Preparation of N- (ethoxycarbonyl-1 methylthio-3 propyl) [(tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl) -20 carbonyl-6 naphthalene
carboxamide-2.
(composé de formule II avec R1=R2"R3=R4=-CH3 et R5=-CONH-Cll-(CH2)2-5-CH3)
C02C2H5
On agite lh30 à 40-500C, une solution de 1,2g (3,lmmoles) d'acide Wtétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl-2) carbonyl-6 naphtalène
carboxylique-2 et de 605mg (3,72mmoles) de N,N'-carbonyldiimidazole dans 15cm3
de N,N-diméthyl formamide anhydre. On refroidit à 200C et ajoute 730mg
(3,41mmoles) de chlorhydrate de l'ester éthylique de la L-méthionine puis
0,48cm3 (3,41mmoles) de triéthylamine. Après 1h d'agitation à 200C puis 2h à
40-500C, le milieu réactionnel est versé sur 100cm9 d'eau acidulée.On agite
15mn puis filtre le précipité qu'on lave alors abondamment à l'acide
chlorhydrique dilué puis à l'eau. Après séchage sous vide à 700C, on purifie
par chromatographie sur silice 60 dans un- mélange
toluène/dichlorométhane/acétate d'éthyle 5/3/2. Après évaporation, on obtient
O,8g de N-(carbéthoxy-1 méthylthio-3 propyl) (tétraméthyl5,5,8,8
tétrahydro-5,6,7,8 naphtyl)-2 carbonyl-6 naphtalène carboxamide-2 sous la
forme d'une huile épaisse qui se transforme en produit vitreux après séchage
prolongé sous vide à 70-80 C. (compound of formula II with R1 = R2 "R3 = R4 = -CH3 and R5 = -CONH-Cll- (CH2) 2-5-CH3)
C02C2H5
Stirred for 1 h 30 at 40-500C, a solution of 1.2 g (3, lmmoles) of Wtetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl-2) carbonyl-6 naphthalene
carboxylic-2 and 605mg (3.72mmol) of N, N'-carbonyldiimidazole in 15cm3
anhydrous N, N-dimethyl formamide. Cool to 200C and add 730mg
(3.41 mmol) of hydrochloride of the ethyl ester of L-methionine then
0.48 cm3 (3.41 mmol) of triethylamine. After 1 hour of stirring at 200C then 2 hours at
40-500C, the reaction medium is poured onto 100cm9 of acidulated water.
15 minutes then filter the precipitate which is then washed thoroughly with acid
hydrochloric diluted then with water. After drying under vacuum at 700C, it is purified
by chromatography on silica 60 in a mixture
toluene / dichloromethane / ethyl acetate 5/3/2. After evaporation, we obtain
0.8g N- (1-carbethoxy-3-methylthio propyl) (tetramethyl5,5,8,8
tetrahydro-5,6,7,8 naphthyl) -2 carbonyl-6 naphthalene carboxamide-2 under the
form of a thick oil which turns into a glassy product after drying
extended under vacuum to 70-80 C.
Le spectre R.M.N.1H 60MHz correspond à la structure attendue. The R.M.N.1H 60MHz spectrum corresponds to the expected structure.
EXEMPLE XIV
Préparation du N-(carboxy-l méthylthio-3 propyl)
rtétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)- carbonyl-6 naphtalène
carboxamide-2.EXAMPLE XIV
Preparation of N- (carboxy-1 methylthio-3 propyl)
rtetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl) - carbonyl-6 naphthalene
carboxamide-2.
(composé de formule II avec R1=R2=R3=R4=-CH3 et
R5=-CONH-CH-(CH2)2-S-CH3)
CO2H
Une suspension de 0,58g (immole) de N-(éthoxycarbonyl-1 méthylthio-3
propyl) (tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)- carbonyl-6
naphtalène carboxamide-2 obtenu à l'exemple XIII est agitée 30mn dans un mélange de 5cm3 d'alcool et de 5cm3 de potasse aqueuse 6N chauffé à 500C.(compound of formula II with R1 = R2 = R3 = R4 = -CH3 and
R5 = -CONH-CH- (CH2) 2-S-CH3)
CO2H
A suspension of 0.58 g (immole) of N- (ethoxycarbonyl-1 methylthio-3
propyl) (tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl) - carbonyl-6
Naphthalene carboxamide-2 obtained in Example XIII is stirred for 30 minutes in a mixture of 5 cm 3 of alcohol and 5 cm 3 of aqueous 6N potassium hydroxide heated to 500 C.
Après addition de 50cm3, 11 alcool est éliminé par évaporation sous pression réduite à 40-450C. La phase aqueuse est alors acidifiée par 3cm3 d'acide chlorhydrique 12N. Le précipité obtenu est essoré, lavé abondamment à l'eau et séché sur potasse à 700C puis repris à l'éther isorpopylique tiède. Après refroidissement, filtration et séchage sous vide à 700C, on obtient 0,4g de cristaux blancs de N-(carboxy-1 méthylthio-3 propyl) tétraméthyl-5,5,8,8 tétrahydro-5,6,7,8 naphtyl)-2 carbonyl-6 naphtalène carboxamide-2 dont le point de fusion est de 171-20C.After adding 50 cm3, 11 alcohol is removed by evaporation under reduced pressure at 40-450C. The aqueous phase is then acidified with 3cm3 of 12N hydrochloric acid. The precipitate obtained is drained, washed with copious amounts of water and dried over potassium hydroxide at 700C and then taken up in lukewarm isorpopylic ether. After cooling, filtration and drying under vacuum at 700C, 0.4g of white crystals of N- (1-carboxy-3-methylthio-propyl) tetramethyl-5,5,8,8 tetrahydro-5,6,7,8 naphthyl is obtained. ) -2 carbonyl-6 naphthalene carboxamide-2 with a melting point of 171-20C.
Le spectre R.M.N.1H 250MHz est conforme à la structure attendue
Analyse élémentaire: C31H35NO4S 0,5H20
Calc. C 70,69 H 6,89 N 2,66 O 13,67 S 6,08
Tr. 70,95 6,87 2,59 13,55 5,98
EXEMPLES DE COMPOSITIONS :
A - VOIE ORALE
Exemple 1 - Comprimé de 0,2g
Composé de ltexemple II 0,001 g
Amidon 0,114 g
Phosphate bicalcique 0,020 g
Silice 0,020 g
Lactose 0,030 g
Talc 0,010 g
Stéarate de magnésium 0,005 g
Exemple 2 - Comprimé de 0,2g
Composé de l'exemple V 0,005 g
Amidon 0,114 g
Phosphate bicalcique 0,020 g
Silice 0,020 g
Lactose 0,030 g
Talc 0,010 g
Stéarate de magnésium 0,005 g
Exemple 3 - Suspension buvable
en ampoules 5ml
Composé de l'exemple III 0,001 g
Glycérine 0,500 g
Sorbitol à 70% 0,500 g
Saccharinate de sodium 0,010 g
Parahydroxybenzoate de méthyle 0,040 g
Arôme q.s.The 1 H NMR 250 MHz spectrum conforms to the expected structure
Elemental analysis: C31H35NO4S 0.5H20
Calc. C 70.69 H 6.89 N 2.66 O 13.67 S 6.08
Tr. 70.95 6.87 2.59 13.55 5.98
EXAMPLES OF COMPOSITIONS:
A - ORAL ROUTE
Example 1 - 0.2 g tablet
Compound of Example II 0.001 g
Starch 0.114 g
Dicalcium phosphate 0.020 g
Silica 0.020 g
Lactose 0.030 g
Talc 0.010 g
Magnesium stearate 0.005 g
Example 2 - 0.2g tablet
Compound of Example V 0.005 g
Starch 0.114 g
Dicalcium phosphate 0.020 g
Silica 0.020 g
Lactose 0.030 g
Talc 0.010 g
Magnesium stearate 0.005 g
Example 3 - Oral suspension
in 5ml ampoules
Compound of Example III 0.001 g
Glycerin 0.500 g
Sorbitol 70% 0.500 g
Sodium saccharin 0.010 g
Methyl parahydroxybenzoate 0.040 g
Aroma qs
Eau purifiée QSP 5,000 ml
B - VOIE TOPIQUE
Exemple 4 - Onguent
Composé de l'exemple I 0,020 g
Myristate d'isopropyle 81,700 g
Huile de vaseline fluide 9,100 g
Silice vendue par la société
Dégussa sous le nom de
"Aerosil 200" 9,180 g
Exemple 5 - Crème huile-dans-l'eau anionique
Composé de l'exemple II 0,010 g
Dodécyl sulfate de sodium 0,800 g
Glycérol 2,000 g
Alcool stéarylique 20,000 g
Triglycérides d'acides caprique/
caprylique vendus par la Société
Dynamit Nobel sous le nom de
"Miglyol 812" 20,000 g
Conservateurs qs
Eau déminéralisée 100,000 g
Exemple 6 - Gel
Composé de l'exemple V 0,050 g
Hydroxy-propyl cellulose vendue
par la société Hercules sous le
nom de "Klucel HF" 2,000 g
Eau/éthanol (50:50) QSP 100,000 g QSP purified water 5,000 ml
B - TOPICAL ROUTE
Example 4 - Ointment
Compound of Example I 0.020 g
Isopropyl myristate 81,700 g
Fluid petroleum jelly 9,100 g
Silica sold by the company
Disgusted under the name of
"Aerosil 200" 9.180 g
EXAMPLE 5 Anionic Oil-in-Water Cream
Compound of Example II 0.010 g
Dodecyl sodium sulfate 0.800 g
Glycerol 2,000 g
Stearyl alcohol 20,000 g
Capric acid triglycerides /
caprylic sold by the Company
Dynamit Nobel under the name of
"Miglyol 812" 20,000 g
Preservatives qs
Demineralized water 100,000 g
Example 6 - Gel
Compound of example V 0.050 g
Hydroxy-propyl cellulose sold
by the company Hercules under the
name of "Klucel HF" 2,000 g
Water / ethanol (50:50) QSP 100,000 g
Claims (16)
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8515106A FR2590566B1 (en) | 1985-10-11 | 1985-10-11 | CETO-NAPHTHALENIC DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THE PHARMACEUTICAL AND COSMETIC FIELDS |
ZA867705A ZA867705B (en) | 1985-10-11 | 1986-10-09 | Bicyclic naphthalene derivatives,process for their preparation and their use in human and veterinary medicine and in cosmetics |
IL80270A IL80270A0 (en) | 1985-10-11 | 1986-10-09 | Naphthalene derivatives,their preparation and pharmaceutical compositions containing them |
DK484886D DK171347B1 (en) | 1985-10-11 | 1986-10-10 | Derivatives of naphthalene which contain, in addition to a naphthalene ring system, an indane or 5,6,7,8-tetrahydronaphthalene ring system, their preparation, pharmaceutical and cosmetic preparations thereof and their use in the preparation of pharmaceutical preparations |
PT83521A PT83521B (en) | 1985-10-11 | 1986-10-10 | METHOD FOR PREPARING NEW NAFTALENIC BICYCLIC DERIVATIVES AND THEIR RESPECTIVE PHARMACEUTICAL AND COSMETIC COMPOSITIONS |
AU63859/86A AU588385B2 (en) | 1985-10-11 | 1986-10-10 | New bicyclic naphthalene derivatives, the process for the preparation of them and the use of them in human and veterinary medicine and in cosmetics |
IE267686A IE59829B1 (en) | 1985-10-11 | 1986-10-10 | Bicyclic naphthalene derivatives, a method for their preparation, and cosmetic and pharmaceutical compositions containing them |
NO864040A NO164971C (en) | 1985-10-11 | 1986-10-10 | PROCEDURE FOR THE PREPARATION OF NEW BICYCLE Naphthalene derivatives |
AT86402257T ATE71080T1 (en) | 1985-10-11 | 1986-10-10 | BICYCLIC NAPHTHALINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND COSMETICS. |
DK484886A DK484886A (en) | 1985-10-11 | 1986-10-10 | BICYCLIC NAPHTHALENDER DERIVATIVES, THEIR PREPARATION AND THEIR USE FOR MEDICAL AND COSMETIC PURPOSES |
DE8686402257T DE3683240D1 (en) | 1985-10-11 | 1986-10-10 | BICYCLIC NAPHTHALINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND COSMETICS. |
FI864106A FI87455C (en) | 1985-10-11 | 1986-10-10 | New Derivatives of Bicyclic Naphthalenes, Procedures for their Preparation and Their Use as Cosmetic Preparations |
CA000520279A CA1267420A (en) | 1985-10-11 | 1986-10-10 | Bicyclic naphthalenic derivatives, process for their preparation and use in human and veterinary medicine |
EP86402257A EP0220118B1 (en) | 1985-10-11 | 1986-10-10 | Bicyclic naphthalenic derivatives, process for their preparation and their use in human and veterinary medicine and cosmetics |
CA000520278A CA1270766A (en) | 1985-10-11 | 1986-10-10 | Cosmetic compositions containing as active ingredient at least one bicyclic naphtoic compound |
DE198686402257T DE220118T1 (en) | 1985-10-11 | 1986-10-10 | BICYCLIC NAPHTHALINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND COSMETICS. |
ES198686402257T ES2003065T3 (en) | 1985-10-11 | 1986-10-10 | NAFTALENIC BICYCLE DERIVATIVES, THEIR PREPARATION PROCEDURE AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND IN COSMETICS. |
JP61240222A JP2607485B2 (en) | 1985-10-11 | 1986-10-11 | Novel naphthalene-based bicyclic derivatives and pharmaceutical and cosmetic compositions containing the same |
US06/918,507 US4826969A (en) | 1985-10-11 | 1986-10-14 | Bicyclic naphthalenic derivatives, a process for preparing the same and human or veterinary medicines and cosmetic compositions containing said derivatives |
GR88300149T GR880300149T1 (en) | 1985-10-11 | 1988-12-16 | Bicyclic naphthalenic derivatives, process for their preparation and their use in human and veterinary medicine and cosmetics |
NO894197A NO166483C (en) | 1985-10-11 | 1989-10-20 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE BICYCLIC Naphthalene derivatives. |
FI914628A FI90528C (en) | 1985-10-11 | 1991-10-02 | Process for the preparation of new derivatives of therapeutic bicyclic naphthalenes |
GR920400040T GR3003598T3 (en) | 1985-10-11 | 1992-01-16 |
Applications Claiming Priority (1)
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FR8515106A FR2590566B1 (en) | 1985-10-11 | 1985-10-11 | CETO-NAPHTHALENIC DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THE PHARMACEUTICAL AND COSMETIC FIELDS |
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FR2590566A1 true FR2590566A1 (en) | 1987-05-29 |
FR2590566B1 FR2590566B1 (en) | 1987-12-31 |
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ZA (1) | ZA867705B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1917285A (en) * | 1932-03-16 | 1933-07-11 | Du Pont | Halogen derivative of alpha-naphthoyl-omicron-benzoic acid |
-
1985
- 1985-10-11 FR FR8515106A patent/FR2590566B1/en not_active Expired
-
1986
- 1986-10-09 ZA ZA867705A patent/ZA867705B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US1917285A (en) * | 1932-03-16 | 1933-07-11 | Du Pont | Halogen derivative of alpha-naphthoyl-omicron-benzoic acid |
Also Published As
Publication number | Publication date |
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FR2590566B1 (en) | 1987-12-31 |
ZA867705B (en) | 1987-06-24 |
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