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MXPA99003653A - Biphenyl derivatives substituted by an aromatic or heteroaromatic radical and pharmaceutical and cosmetic compositions containing same - Google Patents

Biphenyl derivatives substituted by an aromatic or heteroaromatic radical and pharmaceutical and cosmetic compositions containing same

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Publication number
MXPA99003653A
MXPA99003653A MXPA/A/1999/003653A MX9903653A MXPA99003653A MX PA99003653 A MXPA99003653 A MX PA99003653A MX 9903653 A MX9903653 A MX 9903653A MX PA99003653 A MXPA99003653 A MX PA99003653A
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MX
Mexico
Prior art keywords
tetrahydro
tetramethyl
naphthalen
carboxylic acid
terphenyl
Prior art date
Application number
MXPA/A/1999/003653A
Other languages
Spanish (es)
Inventor
Bernardon Jeanmichel
Nedoncelle Philippe
Original Assignee
Centre International De Recherches Dermatologiques Galderma (Cird Galderma)
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Filing date
Publication date
Application filed by Centre International De Recherches Dermatologiques Galderma (Cird Galderma) filed Critical Centre International De Recherches Dermatologiques Galderma (Cird Galderma)
Publication of MXPA99003653A publication Critical patent/MXPA99003653A/en

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Abstract

The invention concerns compounds of formula (I) in which:Ar represents an aromatic radical or a heteroaromatic radical optionally substituted in particular by an alkyl or a carboxylic group;R2 and R3, represent in particular H, alkyl, or R2 and R3, together form a cycle with 5 or 6 chains;R4 and R5 represent in particular H or halogen;R6 represents in particular H or lower alkyl, and the salts of the compounds of formula (I). Said compounds can be used in particular for treating dermatological diseases related to keratinization disorder, and to fight against skin ageing.

Description

BIFENILIC DERIVATIVES SUBSTITUTED BY AN AROMATIC RADICAL OR HETE OR OMAT CO AND COMPOS C ONES PHARMACEUTICALS AND COSMETICS CONTAINING THEM.
Field of Invention _ The invention relates, as both new and useful industrial products, to biphenyl derivatives substituted by an aromatic or heteroaromatic radical. 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 possess a marked activity in the fields of cell differentiation and proliferation and find applications more particularly in the "topical and systemic treatment of the dermatological conditions associated with a keratinization disorder, dermatological disorders. (or others) with inflammatory and / or immunoallergic component and of dermal or epidermal proliferations, whether benign or malignant. These REF .: 29958 compounds can also be used in the treatment of diseases of connective tissue degeneration, to combat skin aging, be it photo-induced or chronological, and treat healing disorders. Said compounds also find their 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.
Background of the Invention EP-382,077 have already described triaromatic derivatives whose structure consists essentially of two aromatic nuclei substituted and connected to each other by a 5- or 6-membered divalent heteroaryl radical comprising, as heteroatom, an oxygen atom, a sulfur atom and / or at least one nitrogen atom.
Description of the invention The compounds according to the present invention, which are also triaromatic derivatives, are distinguished, with respect to JLos of EP-382 077, essentially because, when they possess a heteroaryl radical, in particular a pyridyl, furyl or thienyl radical thereof ( s), this is at the end of the chain, thus giving these compounds a chemical structure totally different from that of the compounds of EP-382 077.
Although the compounds according to the invention are not limited to those containing a heteroaryl radical, it has been unexpectedly and surprisingly found that the compounds comprising said radical exhibited excellent pharmaceutical and cosmetic properties totally similar to those of the compounds of the invention. according to the invention, which comprise at the end of the chain a substituted phenyl radical (s).
On the other hand, it has been possible to demonstrate that the compounds according to the invention, even when exhibiting excellent activity, had virtually no side effects.
Therefore, the present invention has as its object new compounds that can be represented by the following general formula: wherein: Ar represents a aromatic or heteroaromatic radical selected from: being Z 0 or S, Ri represents -CH 3, -CH 2-0H, 0R 8 or -C0R 9, R 2 and R 3, identical or different, represent H, alkyl, linear or branched, in C 1 -C 15, cycloalkyl, -ZR 10 or a radical polyether, representing at least one of R2 or R3 an alkyl, linear or branched, in Ci-Cis, or R2 and 3A taken together, form a cycle with 5 or 6 links, optionally substituted by at least one methyl and / or optionally for an oxygen or sulfur atom or for an SO or S02 radical, R4 represents H, a halogen atom, alkyl, linear or branched, in C? -C2o, -OR10, OCORn or a polyether radical, R5 represents H , a halogen atom, alkyl, linear or branched, in C? -C2o, -OCORu, -OR12, mono- or polyhydroxy-alkyl, -N02, - (CH2) n -N (CH2) n-NHCOCH3, -CH0CH-COR? 3, - (CH2) nC0R? 3, where n "O to 6, -O- (CH2) mCORi3, -0- (CH2) mOH, where m is 12 optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, a polyether radical or a radical -CH2-polyether.Re represents H, lower alkyl or -OR10, R7 represents H, a halogen atom, alkyl, linear or branched at C1 -C20 / ~ OR? Ou -OCORn or a polyether radical, R.sub.8 represents H, lower alkyl or -CORn, R9 represents H, lower alkyl, -OR? 4 or -N -_ »' Rio represents H or lower alkyl, Rn represents lower alkyl, R12 represents H, alkyl, linear or branched, in C? -C2or mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, R13 represents H, lower alkyl, -OR10, .r 'aril or -N Ri 4 represents H, alkyl, linear or branched, in C 1 -C 2, alkenyl, mono- or polyhydroxyalkyl, aryl or optionally substituted aralkyl or a sugar moiety, r 'and r ", identical or different, represent H, OH, alkyl lower, mono- or polyhydroxyalkyl, optionally substituted aryl, an amino acid residue, a peptide moiety or else r 'and r ", taken together, form a heterocycle, and the salts of the compounds of formula (I) when Ri represents a function carboxylic acid as well as the optical and geometric isomers of said compounds of formula (I).
When the compounds according to the invention are in the form of a salt, they are preferably a salt of an alkali metal or alkaline earth metal or also zinc or an organic amine.
According to the present invention, lower alkyl means a radical in Ci-Ce, preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
By alkyl, straight or branched, in C1-C15, 'is meant in particular the methyl, ethyl, propyl, 2-yl-hexyl, octyl and dodecyl radicals. When the radical is in C? -C2o * - it is further understood the hexadecyl and octadecyl radicals.
By "cycloalkyl" is meant a mono- or polycyclic radical with 5 to 10 optionally substituted carbon atoms, in particular a cyclopentyl, cyclohexyl, 1-methylcyclohexyl or 1-adamantyl radical.
By "monohydroxyalkyl" is meant a radical preferably having 1 to 6 carbon atoms, in particular a hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
By "polyhydroxyalkyl" is meant a radical preferably having 3 to 6 carbon atoms and 2 to 5 hydroxyl groups such as 2, 3-dihydroxypropyl, 2,3,4-t-hydroxybutyl radicals, 2, 3, 4, 5 tetrahydroxipent ilo or the rest of pentaeri tritol.
By "polyether radical" is meant a radical with 2 to 6 carbon atoms interrupted by at least two oxygen atoms such as the methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.
By "-CH2-polyether radical" is meant a radical chosen preferably from the methoxymethoxymethyl, ethoxymethoxymethyl or methoxyethoxymethoxymethyl radicals.
By "aryl" is meant preferably a phenyl radical optionally substituted by at least one halogen, a lower alkyl, a hydroxyl, a C1-C3 alkoxy, a nitro function, a polyether radical or an amino function optionally protected by an acetyl group or optionally substituted by at least one lower alkyl or one alkoxy in Ci-Cd.
Aralkyl is preferably understood to mean the benzyl or phenethyl radical optionally substituted by at least one halogen, a lower alkyl, a hydroxyl, a C 1 -C 3 alkoxy, a nitro function, a polyether radical or an "amino function optionally protected by a acetyl group or optionally substituted by at least one lower alkyl or one alkoxy in Ci-Cß- By "heteroaryl radical" is meant preferably a pyridyl, furyl or thienyl radical optionally substituted by at least one halogen, a lower alkyl, a hydroxyl, a C1-C3 alkoxy, a nitro function, a polyether radical or an optionally protected amino function by an acetyl group or optionally substituted by at least one lower alkyl or a C? -C6 alkoxy.
By "alkenyl" is meant a radical preferably having 2 to 5 carbon atoms and having one or more ethylenic unsaturations, such as, more particularly, the allyl radical.
For the rest of sugar, it means a residue that derives particularly from glucose, galactose or mannose or also glucuronic acid.
By the amino acid residue is meant in particular a moiety derived from lysine, glycine or aspartic acid, and by peptide moiety is meant more particularly a dipeptide or tripeptide residue resulting from the amino acid combination.
By heterocycle, preference is given to a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4-position by a lower alkyl in Ci-Ce or a mono- or polyhydroxyalkyl, as defined above.
When R 4, R 5 and / or R 7 represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom.
According to a preferred embodiment, the compounds according to the invention correspond to the following general formulas (II) and (III): in which: Ar represents a radical of formula (a or (b) that follows: having Ri, R4, R5, Re, R and Z the same meanings as those given above for formula (I), i5 / Ri6 R17 and i8 / identical or different, represent H or -CH3, and t is 1 or 2.
Among the compounds of the formulas (I) to (III) mentioned according to the present invention, mention may be made in particular of the following: 4 - [4-hydroxy-3- (5,6,7,8-tetrahydro-5 , 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid and its methyl ester, - 4- [4- (5-hydroxypent-yloxy) -3- (5,6,7,8-tetrahydro-5, 5, 8, 8 -tetramethyl-2-naphthyl) phenyl] benzoic acid and its methyl ester, 4 - [4 - (6-hydroxyhexyloxy) -3- (5,6,7,8-tetrahydro-5,5,8) , 8-tetramet il-2-naphthyl) phenyl] benzoic acid and its methyl ester, - 4- [4- (7-hydroxyheptyloxy) -3- (5,6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid, 4- [4- (8-hydroxy-octyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ) phenyl] benzoic acid, 4- [4- (9-hydroxynyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8 -tetramet i 1-2 -naphthyl) phenyl] benzoic, -. 4- [4-methoxy-3- (5,6,7,8-hydroxy-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid, 4- [4-methoxyethoxymethoxy-3-acid] (5, 6, 7, 8-tetrahydro-5,5,8,8-tetramet-il-2-naphthyl) phenyl] benzoic acid - 4 - [4-benzyloxy-3- (5,6,7,8) tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid, - (2,3-dihydroxy-propoxy) -3 '- (5,5,8,8-tetramethyl-5,6) , 7, 8-tetrahydro-naphthalen-2-yl) biphenyl-4-carboxylic (racemic), - 4 '- (2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy)) - 3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) biphenyl-4-carboxylic acid (racemic), 4 '- (2-morpholin-4-yl- ethoxy) -3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthatalen-2-yl) -biphenyl-4-carboxylic acid, 2' - (5, 5 , 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] tetraphenyl-4" -'-carboxylic acid methyl ester; '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] tetraphenyl- 4 '' -carboxylic acid, 4 -me toxime toxi-2 '- (5, 5, 8, 8 -tetramethyl-5, 6, 7, 8-1e trahi dro -na ft a 1 en-2-i 1 ) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, 4-hydroxy-2 '- (5, 5, 8, 8 -tetramet-il-5, 6, 7, 8 -tetrahydro-naphthalen-2-yl) - [l, l '; 4', l "] terphenyl-4" -carboxylic acid, 4-methoxy-2 '- (5, 5, 8, 8-tetramethyl- 5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, - 3-methoxymethoxy-2 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1' '] terphenyl-4' '-carboxylic acid, 3-hydroxy-2' - (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, 3-methoxy-2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro) -naphthalen-2-il) - [1, 1 '; 4 ', 1"'] terphenyl-4" -carboxylic acid, 2-methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl) ) - [l, l '; 4', l ''] terphenyl-4"-carboxylic acid, 2-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6,7, 8- tetrahydro-naphthalen-2-yl) - [l, l '; 4 ', l' '] terphenyl-4' '-carboxylic acid, - 2-methoxy-2' - (5, 5, 8, 8-te tramethyl-5,6,1,8-tetrahydro-naphthalene-2) -yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2'-methoxymethoxy-5 '- (5, 5, 8, 8 -te rame il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2 '-me toxy-5' - (5, 5, 8, 8 -tet ramet il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -bi-phenyl-4-carboxylic acid, 2'-propyloxy-5 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro) -naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2'-hydroxy-5 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalene-2) -yl) -biphenyl-4-carboxylic acid, 4 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 tetrahydro-naphthalen-2-yl) - [1, l'; 2 ' , l ''] terphenyl-4"-carboxylic acid, 2'-methoxymethoxy-3 '- (5, 5, 8, 8 tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - biphenyl-4-carboxylic acid, 2'-hydroxy-3 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2'-methoxy-3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bi-phenyl-4-acid -carboxylic acid, 3 '-methoxymethoxymethyl-5' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 3-carboxylic acid '-hydroxymethyl-5' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2 '- (4, 4 - dimethyl-t-ochroman-7-yl) - [l, l '; 4', l "] terphenyl-4" -carboxylic acid, 2 '- (4, 4 -dimethyl-t-chichroman-6-yl) - [eleven'; 4 ', 1' '] terphenyl-4' '-carboxylic acid, 2' - (3, 5, 5, 8, 8 -pentamet-il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, - 2 '- (3-methoxymethoxy-5,5,8,8,8-tetramethyl-5,6,8,8-tetrahydro) -naphthalene-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2 '- (3-hydroxy-5, 5, 8, 8 -te tramet il- 5, 6, 7, 8 -tetrahydro-naphthalen-2-yl) - _ [l, l '; 4', l "] terphenyl-4" -carboxylic acid, 2 '- (3-methoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, - 2 'acid - (3-propyloxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l '; 4', l ''] terphenyl-4 ' '-carboxylic acid, 3' '-met-il-2' - (5, 5, 8, 8-tetramet-il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l '; 4 ', l' '] terphenyl-4"-carboxylic acid, 2" -hydroxy-2' - (5, 5, 8, 8-te t ramethyl-5, 6, 7, 8-tetrahydro-naphthalene -2-il) - [l, l '; 4', l ''] terphenyl-4"-carboxylic, 2 '' -methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1' 'acid ] terphenyl-4"-carboxylic acid, 2" -methoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2"-propoxy-2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2) -il) - [1, 1 '; 4 ', 1"'] terphenyl-4" -carboxylic acid, 3"-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2- il) - _ [1, 1 '; 4 ', 1"] terphenyl-4" -carboxylic acid, 6- [2- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4 -yl] -nicotinic acid, 5- [2- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] -pyridine- 2-carboxylic acid, 2 '- (5, 5, 8, 8 -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] terphenyl -4"-hydroxamic, 2 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [l, l'; 4 ', l' ' ] terphenyl-4 '' - ol, [2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', l ''] terphenyl-4 '' - il] -methanol, - '2' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 -te t rahydro-naphthalen-2-yl) - [ eleven'; 4 ', 1"] terphenyl-4" -carbaldehyde, 4' -methoxycarbonylmethoxy-3 '- (5, 5, 8, 8-tetramethyl-5,7,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 4 '-carboxymethoxy-3' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) ^ - biphenyl-4-carboxylic acid , - 4 '- (5-ethoxycarbonyl-pentyloxy) -3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-acid carboxylic, - '- (5-carboxy-pentyloxy) -3' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4- 'acid carboxylic, 2 '- (5, 5, 8, 8 -ethemethyl -5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1']; 4 ', 1' '] terphenyl-4' '-carboxamide, N-ethyl-2' - (5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl) ) - [eleven'; 4 ', 1' '] terphenyl-4' '-carboxamide, N, N-diethyl-2' - (5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-naphthalene-2- il) - [l, l '; 4', l ''] terphenyl-4"-carboxamide, morpholin-4-yl- [2 '- (5,5,8,8, -tetramethyl-5,6 , 7, 8-tetrahydro-naphthalen-2-yl) - [l, l '; 4', l "] terphenyl-4" -methanone, (4-hydroxy-phenyl) -2 '- (5,5 , 8.8, -ethemethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4 ', 1' '] terphenyl-4' '-carboxamide, 3- (5, 5, 8, 8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4 acid -carboxymethyl-4"-carboxylic acid, 3- (5, 5, 8, 8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4,4'-dicarboxylic acid, - 3 '-methoxymethoxy-5' - (5, 5, 8, 8, -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, - 3 'acid methoxy-5 '- (5, 5, 8, 8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 3'-propyloxy-5' - (5, 5, 8, 8, -tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 3 '-hydroxy-5' - (5, 5, 8, 8, -tetramethyl- ', 5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 4' - (5, 5, 8, 8, - tet ramethyl-5 , 6, 7, 8 -tetrahydro-naphthalen-2-yl) -terphenyl-4"-carboxylic acid, 4 '- (5-carboxamido-pentyloxy) -3' - (5,5,8,8, -tetramethyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -bife nyl-4-carboxylic acid, - 3 '-methoxycarbonyl-5' - (5, 5, 8, 8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid , 3 '-carboxyl-5' - (5, 5, 8, 8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2'-acid (4-hydroxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic , 2 '- (4-methoxy-5, 5, 8, 8-tetramethyl-5, 6, 1, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-carboxylic acid, 2 '- (4-propyloxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-carboxylic acid, 2' - (4-methoxymethoxy-5, 5, 8, 8-tet ramethyl-5,6,7,8-tetrahydro-naphthalene-2- il) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2- [2- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro) -naphthalen-2-yl) -biphenyl-4-yl] -thiophene-4-carboxylic acid.
The subject of the present invention is also the processes for the preparation of the compounds of formula (I) mentioned, according to the reactive schemes given in Tables A and B.
With reference to Table A, compounds of formula (la) can be obtained by Suzuki-type coupling reaction between a boronic derivative of formula (6) and a biaromatic brominated derivative of formula (7_). The boronic derivative of formula (6) is obtained from the halogenated derivative of formula (5_), preferably the brominated or iodinated derivative. The biaromatic brominated derivative of formula (7_) can be obtained by two different routes involving a Suzuki-type coupling reaction. The first consists of reacting a halogenated aromatic compound of formula (1_) with a brominated boronic derivative of formula (2_) and the "second one in reacting an aromatic boronic derivative of formula (3_) with a hydrobrominated aromatic derivative of formula (4). ).
The reaction conditions of these different stages are described fundamentally in: - N. MIYAURA Synthetic Communications 1981, 1 1 (7), 513-9, - A. SUZUKI Synlett 1990, 221, - AR MARTIN Acta Chemical Scandinavia 1993, 47 , 221-30, - G. MARCK Tetrahedron Letters 1994, vol. 35, No. 20, 3277-80, - T. WALLON J. Org. Chem. 1994, 59, 5034-7, - H. ZHANG Tetrahedron Letters 1996, vol. 37, No 7, 1043-4.
The boronic derivatives of the formulas (2_), (3) and (6_) can be prepared according to the following two methods: (a) either by reaction with the butyllithium, then with an alkyl borate, preferably the triisopropyl borate or of trimethyl, after hydrolysis with hydrochloric acid, (b) either by reaction with the pinacolic ester of diboronic acid according to the method described by T. ISIYAMA J. Org. Chem. 1995, 60, 7508-10.
From the compound of formula (la), the compounds of formulas (Ib) and (le) can be accessed.
The compounds of formula (Ib) can be obtained from the compounds of formula (Ia) (R5 = OH) by reaction of a halogenated derivative (9_) in the presence of a solvent such as acetone, methylacetone, DMF and a base such as potassium carbonate or sodium hydride.
Compounds of formula (le) can be obtained from the compounds of formula (Ia) (R5 = OH) by conventional acylation reaction from an acid (10).
The compounds of formula (Id) can be obtained from compounds of formula (la) "(R5 = OH) which are transformed in a first step into triflate derivatives of formula (8_), then in a second stage, subjected to reaction and either under Suzuki-type reaction conditions with an aromatic boronic derivative (12) or under Stille-type reaction conditions with an aromatic stannic derivative (-l) according to the method described by AM ECHAVARREN J. Am. Chem. Soc. 1987, 1 09, 5478-86.
Referring now to Table B_, the compounds of formulas (le), (If) and (Ig) can be obtained directly from the triflate derivatives of formula (8_) by carbonylation in the presence of a catalyst with palladium or respectively medium of an alcohol derivative, an amine or a trialkylsilane according to the methods described by JK STILLE, Angew Chem. Int., Ed. Engl. 1996, 508-524 and H. KOTSUKI, Synthesus 1996, 470-2.
The compounds of formula (Ih) can also be obtained from the triflate derivatives of formula (8) by reaction with an acrylic ester (13) in the presence of a catalyst with "palladium according to the method described in J. Med. Chem. 1990 , vol 33, No. 7, 1919 24. From the unsaturated compound of formula (Ih), the compound of formula (Ii) can be directly accessed by catalytic hydrogenation.
The compounds of formula (Ij) can always be obtained from the triflate derivatives of formula (8_) by reaction with stannic derivatives such as vinyltributyl or alumyltributyltin (1 4_) in the presence of a catalyst with. palladium. The intermediate compound obtained of formula (15) is then subjected to an oxidation reaction with osmium tetraoxide under the conditions described in J. Org. Chem. 1990, vol. 55, No. 3, 906-9 and J. Med. Chem. 1991, vol. 34, No. 5, 1614-23.
When in the compounds of formula (I) according to the invention, Ri represents the radical -COOH, these are prepared according to two different synthesis routes: (a) the first consists in protecting the carboxylic acid function by a protective group of type alkyl, allyl, benzyl or tert-butyl.
When the protecting group is an alkyl, deprotection is obtained by means of soda or lithium hydroxide in an alcohol solvent such as methanol or THF.
When the protecting group is an allyl radical, deprotection is carried out by means of a catalyst such as certain transition metal complexes in the presence of a secondary amine such as morpholine.
When the protecting group is a benzyl radical, deprotection is carried out in the presence of hydrogen by means of a catalyst such as palladium on carbon.
Finally, when the protecting group is a tert-butyl radical, deprotection is carried out by means of trimethylsilane iodide. (b) The second consists of starting from the corresponding phenolic compound that is transformed into triflate, then subjected to carbonylation in the presence of a catalyst with palladium.
When in the compounds of the formula (I) according to the invention Ri represents an alcohol function, these can be obtained: (a) either from the corresponding aldehyde derivatives by the action of an alkali metal hydride such as sodium borohydride. in an alcohol solvent such as methanol, (b) either from the acid derivatives of formula (le) (R? o = H) by reduction with the lithium and aluminum double hydride.
When in the compounds of formula (I) according to the invention, Ri represents an aldehyde function, these can be obtained by oxidation of the corresponding alcohols in the presence of manganese, dichromate, pyridinium oxide or Swern's reagent.
Finally, when in the compounds of formula (I) according to the invention, Ri represents an amide function, these can be obtained by reacting the acid chlorides, "obtained from the corresponding carboxylic acids, with aliphatic, aromatic amines, I heterocycled in the presence of dicyclohexylcarbodiimide or carbonyldiimidazole.
The subject of the present invention is also, as a medicament, the compounds of formula (I) as defined above. These compounds have an agonist or antagonist activity with respect to the expression of one or more biological markers in the test for the differentiation of the cells (F9) of the rat embryonic teratocinoma (Skin Pharmacol 3, pages 256-267, 1990) and / or on the differentiation of human keratinocytes in vitro (Skin Pharmacol 3, pages 70-85, 1990). These tests show the activities of the compounds in the fields of differentiation and proliferation. The activities can also be measured in cellular transactivation tests by means of recombinant receptors RARs according to the method B.A. Bernard et al., Biochemical and "Biophysical Research Communication, 1992, vol 186, 977-983.
The compounds according to the invention are particularly suitable for the fields of the following treatments: 1) for treating the dermatological conditions associated with a keratinization disorder referred to differentiation and proliferation, in particular for treating common, comedonic, polymorphs, rosacea, nodulocystic acnes, conglobata, senile acnes, secondary acnes such as solar acne, medicated or professional, 2) to treat other types of keratinization disorders, particularly ichthyosis, ichthyosiform states, Darrier's disease, palmoplantar keratoderma, leukoplakias and leukoplasiform states, cutaneous lichen or mucous (buccal), 3) to treat other dermatological conditions associated with a keratinization disorder with an inflammatory and / or immunoallergic component and especially all the forms of psoriasis, be it cutaneous, mucous or ungular, and even psoriatic rheumatism or also cutaneous atopy such as eczema or respiratory atopy or also gingival hypertrophy; the compounds can also be used in certain inflammatory conditions that do not present keratinization disorder, 4) to treat all dermal or epidermal proliferations whether they are benign or malignant, viral or non-viral, such as common warts, flat warts and the like. verruciform epidermodysplasia, oral or florid papillomatosis and proliferations that may be induced by ultraviolet rays, especially in the case of basal and spinocellular epithelioma, 5). to treat other dermatological disorders such as vesicular dermatoses and collagen diseases, 6) to treat certain ophthalmological disorders, particularly corneopathies, 7) to repair or combat skin aging, whether this is photo-included or chronological, or to reduce pigmentations and actinic keratosis or any type of pathology associated with chronological or actinic aging, "8) to prevent or cure the stigmata of epidermal and / or dermal atrophy induced by local or systemic corticosteroids or any other form of cutaneous atrophy, 9) to prevent or treat scarring disorders or to prevent or repair stretch marks, 10) to combat disorders of sebaceous function such as acne hyperseborrhea or simple seborrhea, 11) to treat or prevent conditions cancerous or precancerous, 12) to treat inflammatory conditions such as arthritis, 13) to treat class of viral origin affection at cutaneous or general level, 14) to prevent or treat alopecia, 15) to treat dermal or general conditions with immunological component, and 16) to treat conditions of the cardiovascular system such as arteriosclerosis s.
In the aforementioned therapeutic fields, the compounds according to the invention can be advantageously used in combination with other compounds of retinoid-like activity, with vitamins D or their derivatives, with corticosteroids, with free antiradicals, a- hydroxy or α-keto acids or their derivatives or also ion channel blockers Vitamins D or their derivatives, for example, are derivatives of vitamin D2 or D3 and in particular 1, 25-dihydroxyvitamin D. 3. By antiradicals free is understood, for example, as α-tocopherol, Super Oxide Dismutase or SOD, Ubiquinol or certain metal chelating agents. By α-hydroxy or α-ketoacids or their derivatives, it is meant, for example, lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid or ascorbic acid or its salts, amides or esters Finally, by ion channel blockers, it is Examples are Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives.
The subject of the present invention is also pharmaceutical 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 pharmaceutical compositions are intended in particular for the treatment of the aforementioned conditions and are characterized in that they contain a pharmaceutically acceptable support and compatible with the mode of administration retained, 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 enterally, parenterally, topically or ocularly.
By enteral route, the compositions may be in the form of tablets, dragees, capsules, syrups, suspensions, solutions, powders, granules, emulsions, micro-faeces or nanospheres or lipid or polymeric vesicles which they allow a controlled release. Parenterally, the compositions can be in the form of "solutions or suspensions for perfusion or injection.
The compounds according to the invention are generally administered at a daily dose of about 0.01 mg / kg to 100 mg / kg of body weight, in a ratio of 1 to 3 doses.
Topically, pharmaceutical compositions based on the compounds according to the with the invention they are particularly intended for the treatment of the skin and mucous membranes and can therefore be presented in the form of ointments, creams, milks, ointments, powders, embedded tampons, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymer patches and hydrogels that allow a controlled release of the active principle. These topical compositions can also be presented in anhydrous or aqueous form, according to clinical indication.
By ocular route, they are mainly eye drops These compositions for topical or ocular use contain at least one compound of formula (I) as defined above, or one of its optimal or geometric isomers or also one of its salts, in a concentration preferably comprised between 0.001% and 5%. % by weight with respect 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 the corporal and capillary hygiene and especially for the treatment of acne-prone skin, for hair growth, against its fall, to combat the oily appearance of the skin or hair, in the protection against the harmful aspects of the sun or in the treatment of physiologically dry skins, to prevent and / or fight photo-chronological or chronological aging.
In the cosmetic field, the compounds according to the invention can also be advantageously used in combination with other compounds of retinoid-like activity, with vitamins D or their derivatives, with corticosteroids, with free antiradicals, a-hydroxy or -ceto acids or their derivatives, or also with ion channel blockers, the latter being the compounds as defined above.
The object of the present invention is therefore a cosmetic composition characterized in that it contains, in a cosmetically acceptable support, at least one compound of formula (I) as defined above or one of its optical or geometric isomers or one of its its salts, said cosmetic composition being able to be presented specifically in the form of a cream, a milk, a lotion, a gel, micro-spheres or nanospheres or lipid or polymeric vesicles, a soap or a shampoo.
The concentration of the compound of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001 and 3% by weight with respect to the total weight of the composition.
The pharmaceutical and cosmetic compositions according to the invention can also contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and in particular: wetting agents, depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or acid kojic; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholine and its derivatives or urea; anti-seborrhoeic or antiacne agents, such as S-carboxymethylcisine, S-benzyl-cis-teamine, its salts or derivatives or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamisin and its esters, tetracyclines; antifungal agents such as ketoconazole or polymethylene-4,5-i-thiazolidones-3; agents that promote hair growth, such as Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro 3-methyl-1,2,4-benzothiadiazine 1, 1-dioxide) and Feniltoin (5,4-diphenyl-imidazolidine 2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and in particular ß-carotene; antipsoriatic agents such as anthralin and its derivatives, and finally the eicosa-5, 8, 11, 14-tetrainoic and eicosa 5, 8, 11-trinoic acids, their esters and amides.
The compositions according to the invention may also contain flavoring agents, preservatives such as parahydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, osmotic pressure regulating agents, emulsifying agents, UV-A filters and UV-B, antioxidants such as a-tocopherol, butylhydroxyanisole or butylhydroxy toluene.
In the following, various examples of preparation of the active compounds of formula (I) according to the invention, as well as various pharmaceutical and cosmetic formulations based on these compounds, will be given by way of illustration and without any limiting character.
Example 1 4- [4-Hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phehyl] benzoic acid, (a) 5, 6, 7, 8 -tetrahydro-5, 5, 8, 8 -tetramet il-2-naphthylboronic acid.
In a triple neck flask and under a stream of nitrogen, 21.38 g (80, Ominol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene and 50 ml are introduced. of THF. At -78 ° C, 38.4 ml (96.0 mmoles) of n-butyllithium (2.5M in hexane) are added dropwise and the mixture is stirred for one hour. At this same temperature, 27.7 ml (120.0 mmol) of triisopropylborate are added dropwise and the mixture is stirred for 2 hours. At -50 ° C, add 350 ml of hydrochloric acid (IN) and allow to resume at room temperature. The reaction medium is extracted with dichloromethane, the organic phase is separated out by settling, dried over magnesium sulphate and evaporated. 18.60 g (100%) of the expected boronic acid are recovered in the form of an oil which crystallizes slowly. Melting point 190-192 ° C. XH NMR (CDC13) d 1.34 (s, 6H), 1.39 (s, 6H), 1.75 (s, 4H), 4.88 (s, 2H), 7.47 (d, 1H, J = 7.9 Hz), 7.97 (d, 1H, J = 7.9 Hz), 8.21 (s, 1H). (b) 4 - (4-Hydroxyphenyl) benzoate methyl (or ethyl).
In a flask, 10.10 g (47.3 mmol) of 4- (4-hydroxyphenyl) benzoic acid are introduced.150 ml of ethanol (or ethanol) are added and 2.5 ml of concentrated sulfuric acid are added dropwise. The mixture is heated to reflux for twelve hours, the reaction medium is evaporated to dryness. The residue obtained is taken up with a mixture of water and ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulphate and evaporated. 10.60 g (98%) of the expected ester are taken up in the form of a colorless oil. 2H NMR (methyl ester) (CDC13) d 3.87 (s, 3H), 6.90 (d, 2H, J = 8.5 Hz), 7.59 (d, 2H, J = 8.6 Hz) , 7.74 (d, 2H, J = 8.4 Hz), 7.99 (d, 2H, J = 8.4 Hz), 9, 77 (s, 1H). (c) Methyl (or ethyl) 4 - (3-bromo-4-hydroxy phenyl) benzoate.
Into a flask, 9.35 g (41.0 mmol) of methyl 4- (4-hydroxyphenyl) benzoate (or ethyl), 125 ml of dioxane and 40 ml of THF are introduced. 12.19 g (49.1 mmol) of Br2 / dioxane complex are added and the mixture is stirred for 24 hours at room temperature. The reaction medium is evaporated to dryness, taken up with water and ethyl acetate, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of ethyl acetate and heptane (20/80). After evaporation of the solvents, 10.80 g (86%) of the expected product is taken up in the form of white crystals of melting point 145-146 ° C (methyl ester). XH NMR (methyl ester) (CDC13) d 3.94 (s, 3H), 5.74 (s, 1H), 7.11 (d, 1H, J = 8.5 Hz), 7.49 (dd, 1H, J = 8.5 / 2.1 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.74 (d, 1J, J = 2.1 Hz), 8.08 ( d, 2H, J = 8.5 Hz). (d) Methyl (or ethyl) 4- [4-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramet-il-2 -naphthyl) phenyl] benzoate.
In a triple-necked flask, 11.41 g (49.1 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylboronic acid, 0.06 g (32 g. , 7 mmoles) of methyl (or ethyl) 4- (3-bromo-4-hydroxyphenyl) benzoate, 640 ml of toluene and 39.3 ml (78.6 mmoles) of a potassium carbonate solution (2M). The reaction medium is degassed by bubbling nitrogen, 69 mg (0.06 mmol) of tetrakis triphenylphosphinates palladium (0) are added and the mixture is heated at 90 ° C for twenty hours. The reaction medium is evaporated to dryness, taken up with water and ethyl ether, acidified. The organic phase is decanted, dried over magnesium sulfate, evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. '11.57 g (85%) of the expected product are taken up in the form of a very light yellow solid of melting point 178-181 ° C (methyl ester). 1H NMR (methyl ester) (CDC1) d 1.32 (s, 6H), 1.33 (s, 6H), 1.73 (s, 4H), 3.93 (s, 3H), 5.52 ( s, 1H), 7.09 (d, 1H, J = 9.1 Hz), 7.26 (dd, 1H, J = 7.1 / 1.9 Hz), 7.42 to 7.44 (m , 2H), 7.47 to 7.55 (m, 2H), 7.64 (d, 2H, J = 8.4 Hz) 8.08 (d, 2H, J = 8.4 Hz). (e) 4 - [4-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-ethyl-2-naphthyl) phenyl] benzoic acid. 1.24 g (3.0 mmol) of the methyl (or ethyl) ester obtained in example 1 (d) and 7.5 ml of methanolic sodium hydroxide (4N) are introduced into a flask. The mixture is heated to reflux for four hours, the reaction medium is poured into the water, acidified, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on a short column of silica, eluted with ethyl ether. It is retaken. 1.00 g (83%) of 4- [4-hydroxy-3-5,6,7,8-tetrahydro-5, 5, 8, 8-te tramet il-2-naphthyl) phenyl] benzoic acid under the Form of white crystals of melting point 240-241 ° C. XH NMR (CDC13) d 1.33 (s, 6H), 1.34 (s, 6H), 1.74 (s, 4H), 7.1.0 (d, 1H, J = 8.7 Hz), 7 , 26 (dd, 1H, J = 7.2 / 1.8 Hz), 7.42 to 7.48 (m, 2H), 7.54 to 7.58 (m, 2H), 7.69 (d , 2H, J = 8.4 Hz), 8.16 (d, 2H, J = 8.4 Hz).
Example 2 4 - [4 - (5-Hydroxypenethyl oxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid (a) 4- [4- (5-Acetoxypentyloxy) -3- (5,6,7, tetrahydro-5, 5, 8, 8-tetramet-il-2-naphthyl) phenyl [methyl benzoate]. 1.66 g (4.0 mmol) of the methyl ester obtained in example 1 (d), 150 ml of acetone and 2.21 g (16.0 mmoles) of potassium carbonate are introduced into a flask. 2.67 ml (16.0 mmol) of 5-bromopentyl acetate is added and heated to reflux for eight hours. The reaction medium is evaporated to dryness, the residue is taken up in ethyl acetate and water, the organic phase is separated out, dried over magnesium sulphate and evaporated. 2.20 g (100%) of the expected product are recovered in the form of a colorless oil. XH NMR (CDC13) d 1.32 (s, 12H), 1.66 (s, 4H), 1.45 to 2.05 (m, 6H), 3.41 (t, 2H, J = 6.7 Hz), 3.93 (s, 3H), 4.04 (t, 2H, J = 6.7 Hz), 7.04 (d, 1H, J = 8.5 Hz), 7.38 (, 2H ), 7.52 to 7.58 (m, 2H), 7.62 (d, 1H, J = 2.4 Hz), 7.66 (d, 2H, J = 8.4), 7.87 ( d, 2H, J = 8, 3 Hz). (b) 4- [4- (5-hydroxypentyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid.
Analogously to example l (e), starting from 2.20 g (4.0 mmol) of the methyl ester obtained in example 2 (a), is obtained, after taking up in a mixture ethyl ether / hexane (10/90) and filtering, 1.45 g (74%) ) of 4- [4- (5-hydroxypentyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid, in the form of a white solid melting point 195-196 ° C. 1H NMR (CDC13) 'd 1.32 (s, 12H), 1.49 to 1.61 (m, 3H), 1.72 (s, 4H), 1.77 to 1.85 (m, 3H) ), 3.59 (t, 2H, J = 6.1 Hz), 4.03 (t, 2H, J = 6.4 Hz), 7.04 (d, 1H, J = 8.6 Hz), 7.30 to 7.38 (m, 2H), 7.54 (dd, 1H, J = 8.5 / 2.2 Hz), 7.58 to 7.62 (m, 2H), 7.65 ( d, 2H, J = 8.4 Hz), 8.10 (d, 2H, J = 8.3 Hz).
Example 3 4- [4- (6-Hydroxyhexyloxy) -3- (5, 6, 7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid. (a) Methyl 4- [4- (6-hydroxyhexyloxy) -3- (5, 6, 7, tetrahydro-5, 5, 8, 8-tetramethoxyl-2-naphthyl) phenyl] benzoate.
Analogously to example 2 (a), by reaction of 1.66 g of the methyl ester obtained in example 1 (d), with 2.1 ml (16.0 mmol) of 6-bromohexanol, 2.10 was obtained g (100%) of the expected product, in the form of a colorless oil. 1H NMR (CDC13) d 1.33 (s, 12H), 1.41 to 1.93 (m, 8H), 1.72 (s, 4H), 3.65 (t, 2H, J = 6.3 Hz) _, 3.93 (s, 3H), 4.02 (t, 2H, J = 6.4 Hz), 7.04 (d, 1H, J = 8.5 Hz), 7.30 to 7 , 38 (m, 2H), 7.54 (dd, 1H, J = 8.5 / 2.3 Hz), 7.59 to 7.62 (m, 2H), 7.66 (d, 2H, J = 8.4 Hz), 8.08 (d, 2H, J = 8.3 Hz). (b) 4- [4- (6-hydroxyhexyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8 -tetramethyl-2-naphthyl) phenyl] benzoic acid.
Analogously to example 1 (e), from 2.10 g (4.0 mmol) of the methyl ester obtained in example 3 (a), 1.70 g (86%) of acid 4 was obtained. 4- (6-hydroxyhexyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid, in the form of a white solid of melting point 200-201 ° C. 1R NMR (CDCI3) d 1.33 / s, 12H), 1.38 to 1.83 (m, 8H), 1.72 (s, 4H), 3.59 (t, 2H, J = 6.4 Hz), 4.03 (t, 2H, J = 6.5 Hz), 7.04 (d, 1H, J = 8.6 Hz), 7.30 to 7.38 (m, 2H), 7.54 (dd, 1H, J = 8.5 / 2.3 Hz), 7.60 to 7.62 ( m, 2H), 7.65 (d, 2H, J = 8.4 Hz), 8.10 (d, 2H, J = 8.4 Hz).
Example 4 4- [4- (7-Hydroxyheptyloxy) -3- (5,6,7,8-tetrahydro-5, 5, 8, 8 -tetramethyl-1-2-naphthyl) phenyl] -benzoic acid. (a) ethyl 4- [4- (7-hydroxyheptyloxy) -3- (5, 6, 7, tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoate.
Analogously to example 2 (a), by reaction of 1.50 g (3.5 mmol) of the ethyl ester in example l (d), with 1.06 g (5.4 mmol) of 7-bromoheptanol, 1.43 g (75%) of the expected product is obtained in the form of a colorless oil. XH NMR (CDC13) from 1.18 to 1.24 (m, 2H), 1.33 (s 12H), 1.41 (t, 3H, J = 7.1 Hz), 1.52 to 1.58 (m, 4H), 1.72 (s, 4H), 1.72 at 1.82 (m, 4H), 3.60 at 3.64 (m, 2H), 4.02 (t, 2H, J = 6.5 Hz), 4.39 (q, 2H, J = 7.1 Hz), 7.04 (d, 1H, J = 8.5 Hz), 7.32 to 7.38 (m, 2H), 7.54 (dd, 1H, J = 8.4 / 2.4 Hz), 7.59 to 7.63 (, 2H), 7.65 (d, 2H, J = 8.5 Hz), 8.09 (d, 2H, J = 8.4 Hz). (b) 4- [4- (7-hydroxyheptyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramet-il-2-naphthyl) phenyl] benzoic acid.
Analogously to example 1 (e), from 1.40 g (2.6 mmol) of the ethyl ester obtained in Example 4 (a), 1.15 g (87%) of acid 4 is obtained. 4- (7-hydroxyheptyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid, in the form of a white solid of melting point 168 -172 ° C. 1H NMR (CDC13) from 1.21 to 1.43 (m, 6H), 1.33 (s, 12H), 1.53 to 1.56 (m, 2H), 1.73 (s, 4H), 1.77 to 1.82 (m, 2H), 3.64 8t, 2H, J = 6.5 Hz), 4.02 (t, 2H, J = 6.5 Hz), 7.05 (d, 1H, J = 8.6 Hz), 7.31 to 7.38 (m, 2H), 7.55 (dd, 1H, J = 8.5 /2.4 Hz), 7.59 ^ (s, 1H), 7.64 (d, 1H, J = 2.4 Hz), 7.69 (d, 2H, J = 8.4 Hz), 8.16 (d, 2H, J = 8.4 Hz). 4- [4- (8-Hydroxyoctyloxy) -3- (5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-2-naphyl) phenyl] -iic acid. (a) Methyl 4- [4- (8-hydroxyoctyloxy) -3- (5,6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoate.
Analogously to example 2 (a), by reaction of 700 mg (1.7 mmol) of the methyl ester obtained in example 1 (d), with 1.15 ml (6.7 mmol) of 8-bromooctanol, they obtain 920 mg (100%) of the expected product, in the form of a colorless oil. XH NMR (CDC13) d 1.33 (s, 12H), 1.38 to 1.83 (m, 12H), 1.72 (s, 4H), 3.64 (t, 2H, J = 6.5 Hz), 3.93 (s, 3H), 4.02 ( t, 2H, J = 6.5 Hz), 7.05 (d, 1H, J = 8.6 Hz), 7.52 to 7.67 (m, 4H), 7.69 (d, 2H, J = 8.3 Hz), 8.15 (d, 2H, J = 8.3 Hz). (b) 4- [4- (8-Hydroxyoctyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8 -etheremethyl-2-naphthyl) phenyl] benzoic acid.
Analogously to example 1 (e), from 920 mg (1.7 mmol) of the methyl ester obtained in example 5 (a), 740 mg (83%) of 4- [4- (8 -hydroxyoctyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic, _ in the form of pale yellow crystals of melting point 155-160 ° C. XH NMR (CDC13) d 1.33 (s, 12H), 1.38 to 1.83 (m, 12H), 1.72 (s, 4H), 3.64 (t, 2H, J = 6.5 Hz), 4.03. (T, 2H, J = 6.5 hz), 7.05 (d, 1H, J = 8.6 Hz), 7.52 to 7.67 (m, 4H, 7.69 (d, 2H, J = 8.3 Hz), 8.15 (d, 2H, J = 8.3 Hz).
Example 6 4- [4- (9-Hydroxyinonyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid. (a) Methyl 4- [4- (9-hydroxynononyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoate.
Analogously to example 2 (a), by reaction of 680 mg (1.6 mmol) of the methyl ester obtained in example 18d), with 1.47 g (6.6 mmol) of 9-bromononanol, 920 are obtained mg (100%) of the expected product, in the form of a brown oil. 1ñ NMR (CDC13) d 1.33 (s, 12H), 1.38 to l._83 (m, 14H), 1.72 (s, 4H), 3.64 (t, 2H, J = 6.5 Hz), 3.93 (s, 3H), 4.02 (t, 2H, J = 6.5 Hz), 7.05 (d, 1H, J = 8.6 Hz), 7.52 to 7.67 (, 4H), 7.69 (d, 2H, J = 8.3 Hz), 8.15 (d, 2H, J = 8.3 Hz). (b) 4- [4- (9-Hydroxyinonyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid.
Analogously to example 1 (e), from 920 mg (1.6 mmol) of the methyl ester obtained in example 6 (a), 720 mg (81%) of 4- [4- (9 -hydroxy-inkyloxy) -3- (5, 6, 7, 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid, in the form of pale yellow crystals with a melting point of 147-150 ° C . XH NMR (CDCl 3) d 1.33 (s, 12H), 1.38 to 1.83 (m, 14H), 1.72 (s, 4H), 3.64 (t, 2H, J = 6.5 Hz), 4.03 (t, 2H, J = 6.5 Hz), 7.05 (d, 1H, J = 8.6 Hz), 7.52 to 7.67 (m, 4H), 7.69 (d, 2H, J = 8.3 Hz), 8.15 (d, 2H, J = 8.3 Hz).
Example 7 4- [Methoxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenylbenzoic acid. (a) Methyl 4- [4-methoxy-3- (5,6,7,8-tet rahydro-5, 5, 8, tetramethyl-2-naphthyl) phenyl] benzoate.
In a reactor and under a stream of nitrogen, 1.66 g (4.0 mmol) of the methyl ester obtained in example 1 (d) and 25 ml of DMF are introduced. 144 mg (4.8 mmol) of sodium hydride (80% in the oil) are added in small quantities and stirred until the gas evolution is stopped. Then 311 μl (5.0 mmol) of iodomethane are added and stirred for two hours. The reaction medium is poured into the water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 1.70 g (100%) of the expected product is taken up in the form of a crystalline white solid. 1 H NMR (CDCl 3) d 1.33 (s, 12 H), 1.72 (s, 4 H), 3.87 (s, 3 H), 3.93 (s, 3 H) ', 7.06 (d, 1 H, J = 8.4 Hz), 7.36 (s , 2H), 7.52 to 7.61 (m, 3H), 7.66 (d, _ 2H, J = 8.3 hz), 8.09 (d, 2H, J = 8.3 Hz). (b) 4- [4-methoxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid.
Analogously to example 1 (e), from 1.70 g (4.0 mmol) of the methyl ester obtained in Example 7 (a), 1.35 g (81%) of acid 4 is obtained. 4-methoxy-3- (5, 6,7, 8-tetrahydro-5, 5, 8, 8-tetramet-il-2-naphthyl) phenyl] benzoic melting point 251-255 ° C. 1 R NMR (CDCl 3) d 1.33 8 s, 12 H), 1.72 (s, 4 H), 3.88 (s, 3 H), 7.08 (d, 1 H, J = 8.4 Hz), 7.37 (s, 2 H), 7.53 to 7.62 (m , 3H), 7.70 (d, 2H, J = 8.2 hz), 8.17 (d, 2H, J = 8.2 Hz).
Example 8 4- [4-Methoxyethoxymethoxy-3- (5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-2-naphyl) phenyl] ben oric acid. (a) Methyl 4 - [4-methoxyethoxymethoxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoate.
From . Analogously to example 2 (a), by reaction of 1.66 g (4.0 mmol) of the methyl ester obtained in example 1 (d), with 571 μl (5.0 mmol) of methoxyethoxymethyl chloride, is obtained 1.99 g '(99%) of the expected product, in the form of a white crystalline solid. XH NMR (CDC13) d 1.32 8s, 12H), 1.72 (s, 4H), 3.37 (d, 3H, J = 0.5 Hz), 3.52 (t, 2H, J = 3.9 Hz), 3.77 (t, 2H, J = 3.9 Hz), 3.93 (s, 3H), 5.26 (s 2H), 7.30 a 7.37 (m, 3H, 7.51 to 7.60 (m, 3H), 7.65 (d, 2H, J = 8.2 Hz), 8.09 (d, 2H, J = 8.1 Hz). (b) 4 - [4-methoxyethoxymethoxy-3- (5,6,7,8-tetrahydro-5,5,8,8-ethyl-2-naphthyl) phenyl] benzoic acid.
Analogously to example 1 (e), from 1.99 g (4.0 mmol) of the methyl ester obtained in example 8 (a), 1.62 g (84%) of acid 4 was obtained. 4-methoxyethoxymethoxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid, _ in the form of a crystalline white solid of melting point 218-219 ° C. XH NMR (CDC13) d 1.32 (s, 12H), 1.72 8s, 4H), 3.37 (s, 3H), 3.52 (t, 2H, J = 3.9 Hz), 3.76 (t, 2H, J = 3.9 hz), 5.26 (s, 2H), 7.30 to 7.37 (m, 3H), 7.50 to 7.61 (m, 3H), 7.65 (d, 2H, J = 8.3 Hz), 8.11 (d, 2H, J = 8.3 Hz).
Example 9 4 - [4-benzyl] -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzyl acid. (a) ethyl 4- [4-benzyloxy-3- (5,6,7,8-tetrahydro-5,5,8,8,8 'tetramethyl-2 -naphthyl) phenyl] benzoate.
Analogously to example 2 (a), by reaction of 1.20 g (2.8 mmol) of the ethyl ester obtained in example l (d) with 400 μl (3.2 mmol) of benzyl bromide, 1.23 g (85%) of the expected product, in the form of a colorless oil. XH NMR (CDCl 3) d 1.23 (s, 6H), 1.32 (s, 6H), 1.41 (t, 3H, J = 7.1 Hz), 1.70 (s, 4H), 4.39 (q, 2H, J = 7.1 Hz) , 5.38 (s, 2H), 7.11 (d, 1H, J = 8 _5 Hz), 7.28 to 7.36 (m, 6H), 7.53 (dd, 1H, J = 8.5 / 2.4 Hz), 7.58 to 7.64 (m, 2H), 7.65 (d, 2H, J = 8.4 Hz), 8.09 (d, 2H, J = 8.4 Hz). (, b) 4 - [4-benzyloxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid.
Analogously to example 1 (e), from 1.20 g (2.3 mmol) of the ethyl ester obtained in example 9 (a), 970 mg (86%) of 4- [4- benzyloxy-3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid, in the form of a crystalline white solid of melting point 241-244 ° C. XH NMR (CDCl 3) d 1.23 (s, 6H), 1.32 (s, 6H), 1.70 (s, 4H), 5.13 (s, 2H), 7.12 (d, 1H, J = 8.6 Hz), 7.28 to 7.36 ( m, 6H), 7.54 (dd, 1H, J = 8.5 / 2.4 Hz), 7.58 (s, 1H), 7.64 (s, 1H), 7.66 (d, 2H, J = 8.4 Hz), 8.11 (d, 2H) , J = 8.4 Hz).
Example 10 4 '- (2,3-Dihydroxy -propoxy) -3' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-te trahidro -na phta l in -2-il) -bif acid enyl -4 -carboxy li co (ra cémi co). (a) 4-2,2-dimethyl- [1, 3] dioxolan-4-methylmethyl sulfonate (racemic) Into a flask, under an argon atmosphere, 5.29 g (40.0 mmol) of (2,2-dimethyl- [1,3] dioxolan-4-yl) methanol (Solketal®) and 10 ml of pyridine are introduced. . It is cooled to 0 ° C and 8.39 g are added (44.0 mmol) of paratholuensulonic acid and stir sixteen hours at room temperature. The reaction medium is poured into a mixture of IN HCl / ethyl ether, extracted with ethyl ether, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica, eluted with dichloromethane, after evaporation of the solvents, 9.70 g (85%) of the expected product are recovered in the form of yellow crystals of melting point. 45-47 ° C. 1 H NMR (CDCl 3) d 1.31 (s, 3 H), 1.34 (s, 3 H), 2.45 (s, 3H), 3.74 to 3.80 (m, 1H), 3.93 to 4.07 (m, 3H), 4. 23 to 4.32 (m, 1H), 7.35 (d, 2H, J = 8.1 Hz), 7.80 (d, 2H, J = 8.2 Hz). (b) 4 '- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene) -2-yl) -biphenyl-4-carboxylic acid ethyl ester (racemic).
Into a flask, under an argon atmosphere, 3.00 g (7.0 mmol) of the ethyl ester obtained in Example 1 (d), 2.41 g (8.4 mmol) of the tosylate obtained in Example 10 are introduced. (a), 1.10 g (7.7 mmol) of potassium carbonate and 35 ml of DMF. The reaction medium is heated for one hour at 100 ° C, cooled, poured into a water / ethyl ether mixture, extracted with ethyl ether, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture composed of 50% dichloromethane and 50% heptane. After evaporation of the solvents, 2.66 g (70%) of the expected product are recovered in the form of a colorless oil. 1R NMR (CDCI3) d 1.32 (s, 6H), 1.33 (s, 6H), 1.36 (s, 6H), 1.41 (t, 3H, J = 7.1 Hz), 1.72 (s, 4H), 3. 83 (dd, 1H, J = 8.4 / 6.0 Hz), 3.94 to 4.07 (m, 2H), 4.14 (dd, 1H, J = 9.5 / 4.9 Hz), 4.39 (q, 2H, J = 7.1 Hz), 4.40 (q, 1H, J = 5.1 Hz), 7J6 (d, 1H, J = 8.5 Hz), 7.28 (dd, 1H, J = 8.1 / 1.8 Hz), 7. 36 (d, 1H, J = 8.2 Hz), 7.53 (d, 1H, J = 1.8 hz), 7.55 8dd, 1H, J = 8.5 / 2.3 Hz), 7.61 (d, 1H, J = 2.4 Hz), 7.65 (d, 2H, J = 8.4 Hz), 8.09 (d, 2H, J = 8.4 Hz). (c) 4 '- (2,3-dihydroxy-propoxy) -3' - (5,5,8, tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylate of ethyl (racemic).
Into a flask, under an argon atmosphere, 1.66 g (3.2 mmol) of the ester obtained in example 10 (b), 6.12 g (32.2 mmol) of paratoluenesulfonic acid, 60 ml of dichloromethane are introduced. and 5 ml of THF. The mixture is stirred for sixteen hours at room temperature, the reaction medium is poured into a water / ethyl ether mixture, extracted with ethyl ether, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica cake, eluted with a mixture composed of 40% ethyl acetate and 60% heptane. After evaporation of the solvents, 1.16 g (72%) of the expected product is taken up in the form of a white powder with a melting point of -56 ° C. XH NMR (CDC13) d 1.33 (s, 12H), 1.41 (t, 3H, J = 7.1 Hz), 1.73 (s, 4H), 1.87 (t, 1H, J = 6.3 hz), 2.49 (d, 1H, J = 4.3 Hz), 3.60 to 3.80 (m, 2H), 4.03 to 4.16 (m, 3H), 4.40 (q, 2H, J = 7.1 Hz), 7. 07 (d, 1H, J = 8.4 Hz), 7.29 (d, 1H, J = 1.8 Hz), 7.38 (d, 1H, J = 8.1 hz) ', 7.48 8d, 1H, J = 1. 8 Hz), 7.54 to 7.60 (m, 2H), 7.65 (d, 2H, J = 8.4 hz), 8.10 (d, 2H, J = 8.5 Hz).
(D) 4 '- (2, 3-dihydroxy-propoxy) -3' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalene-2-yl) -biphenyl-4 -carboxylic (racemic).
Analogously to example 1 (e), from 1.16 g (2.3 mmol) of the ethyl ester obtained in Example 10 (c), 897 mg (82%) of 4 '- (2) acid are obtained. , 3-dihydroxy-propoxy) -3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a solid crystallized white of melting point 258 ° C.
XH NMR (CDCl3 + 2 drops of DMSO D6) d 1.12 (s, 12H), 1.52 (s, 4H), 3.38 to 3.53 (m, 2H) ', 3.79 to 3.94 (m, 3H), 6.91 (d, 1H , J = 8.4 Hz), 7.10 to 7.17 (m, 2H), 7.34 to 7.39 (m, 3H), 7.45 (d, 2H, J = 8.4 Hz), 7.88 (d, 2H, J = 8.4 Hz). _ Example 11 Acid 4 '- (2, 2-dimethyl) - [1, 3] dioxolan-4 -ilmetoxi) -3' - (5, 5, 8, 8 -tetramet yl-5, 6, 7,8-tetrahydro-naphthalen -2-yl) -bifenyl-4-carboxylic acid (racemic).
Analogously to example 1 (e), from 1.00 g (1.8 mmol) of the ester obtained in example 10 (b), 805 mg (85%) of 4 '- (2, 2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4 -carboxylic in the form of a crystallized white solid of melting point 206 ° C. 1 H NMR (CDCl 3) d 1.33 (s, 12 H), 1.36 (s, 6 H), 1.73 (s, 4 H), 3.84 (dd, 1 H, J = 8.4 / 6.0 Hz), 3.96 to 4.09 (m, 2 H), 4.15 (dd, 1H, J = 9.5 / 4.9 Hz), 4.42 (q, 1H, J = 5.1 Hz), 7.08 (d, 1H, J = 8.6 Hz), 7.29 (dd, 1H, J = 8.1 / 1.7 Hz ), 7.36 (d, 1H, J = 8.2 Hz), 7.54 8d, 1H, J = 1.6 hz), 7.57 (dd, 1H, J = 8.5 / 2.3 Hz), 7.63 (d, 1H, J = 2.3 hz), 7. 69 (d, 2H, J = 8.4 Hz), 8.17 8d, 2H, J = 8.4 Hz). _ Example 12. 4 '- (2-morpholin-2-yl-ethoxy) -3' - (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl -4-acid -carboxylic. (a) 4 '- (2-morpholin-4-i-1-ethoxy) -3' - (5,5,8,8-tetramethyl-5-6,7,8-tetrahydro-naphthalene-2-yl) -biphenyl-4-ethyl carboxylate.
Analogously to Example 2 (a), by reaction of 1.08 g (2.5 mmol) of the ethyl ester obtained in Example 1 (d) with 1.39 g (7.5 mmol) of 4-hydrochloride (2 - "chloroethyl) morpholine, 500 mg (37%) of the expected product are obtained in the form of a colorless oil XH NMR (CDC13) d 1.32 (s, 12H), 1.41 (t, 3H, J = 7.1 Hz ), 1.72 (s, 4H), 2.45 (t, 2H, J = 4.6 Hz), 2.77 8t, 2H, J = 5.8 Hz), 3.64 (t, 2H), J = 4.7 hz), 4.16 (t, 2H) , J = 5.8 Hz), 4.40 (q, 2H, J = 7.2 Hz), 7.05 (d, 1H, J = 8.5 Hz), 7.34 (s, 2H), 7. 52 • (s, 1H), 7.56 (dd, 1H, J = 8.4 / 2.4 Hz), 7. 61 (d, 1H, J = 2.3 Hz), 7.65 (d, 2H, J = 8.4 hz), 8.09 (d, 2H, J = • 8.4 Hz). (b) 4 '- (2-morpholin-4-yl-ethoxy) -3' - (5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-naphthalen-2-yl) - biphenyl-4-carboxylic acid.
Analogously to example 1 (e), from 500 mg (0.92 mmol) of the ethyl ester obtained in example 12 (a), 320 mg (70%) of 4 '- (2 -morpholine is obtained. - 4 -i-1-ethoxy) -3 '- (5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a crystallized white solid of melting point 270-272 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 1.31 (s, 12H), 1.73 (s, 4H), 2.58 to 2.61 (m, 2H), 3.23 (d, 2H, J = 11.9 Hz), 3.38 (br s 2H), 3.67 (d, 2H, J = 12.6 Hz), 4.02 (t, 2H, J = 11.9 Hz), 4.61 (br s, 2H), 7.08 (d, 1H, J = 8.3 Hz), 7.22 ( dd, 1H, J = 8.'1 / 1.6 Hz), 7.35 (d, 1H, J = 8.1 Hz), 7.47 8s, 1H), 7.55 (s, 1H), 7.61 (dd, 1H, J = 8.1 / 2.4 Hz), 7.64 (d, 2H, J = 8.4 Hz), 8.09 (d, 2H, J = 8.3 Hz).
Example 13 2 r - (5, 5, 8, 8 -tetramet il-5, 6,7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1 ',] terphenyl-4-r' -carboxylate of methyl. (a) 3 '- (5,5,8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -4'-trifluoromethanesulfonyloxy-biphenyl-4-carboxylic acid methyl ester.
In a triple neck flask and under a stream of nitrogen, 1.66 g (4.0 mmol) of the methyl ester obtained in example 1 (d), 1.56 g (12.8 mmol) of 4-dimethylaminopyridine are introduced. and 40 ml of dichloromethane. Cool to 0 ° C, add 701 μl (4.2 mmol) of trifluoromethanesulfonic anhydride and stir at room temperature for one hour. The reaction mixture is poured into a mixture of hydrochloric acid (IN) and dichloromethane, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (40/60). 1.90 g (87%) of the expected product is recovered in the form of a colorless oil. XH NMR (CDC13) d 1.31 (s, 6H), 1.32 (s, 6H), 1.73 (s, 4H), 3.95 (s, 3H), 7.23 (dd, 1H, J = 8.2 / 1.8 Hz), 7.39 to 7.48 (m, 3H), 7.60 to 7.70 (m ^ 2H), 7. 72 (d, 2H, J = 8.5 Hz), 8.13 (d, 2H, J = 8.3 Hz). (b) 2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-methylcarboxylate.
In a triple neck flask, 469 mg (3.8 mmol) of phenylboronic acid, 1.91 g (3.5 mmol) of 4 - [4 -tri fluoromethanesulphonate-3- (5, 6, 7, Methyl 8-tetrahydro-5, 5, 8, 8 -tetramethyl-2-naphthyl) phenyl] benzoate, 4.54 ml (9.1 mmol) of a sodium carbonate solution (2M), 296 mg of chloride of lithium and 30 ml of DF The reaction medium is degassed by bubbling nitrogen, 129 mg (0.11 mmol) of tetrakis triphenyl phosphinopalladium (0) are added and the mixture is heated at 90 ° C for twenty hours. The reaction medium is evaporated to dryness, taken up with water and ethyl ether, acidified. The organic phase is decanted, dried over magnesium sulfate, evaporated. The residue obtained is purified by. chromatography on a silica column, eluted with a mixture of ethyl ether and heptane (5/95). 480 mg (30%) of the expected product is taken up in the form of a yellow oil. XH NMR (CDC13) d 1.90 (s, 6H), 1.26 (s, 6H), 1.55 to 1.63 (m, 4H), 3.90 (s, 3H), 6.90 (d, 1H, J = 1.7 Hz), 7.14 a 7.28 (m, 7H), 7.49 (d, 1H, J = 8.0 Hz), 7.62 (dd, 1H, J = 8.0 / 1.9 Hz), 7.70 to 7.73 (m, 1H), 7.71 (d, 2H, J = 8.4 Hz), 8.11 8d, 2H, J = 8.4 Hz).
Example 14 Acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [!,! '; 4 ', 1' '] terphenyl-4' '-carboxylic acid.
Analogously to example 1 (e), from 950 mg (2.0 mmol) of the methyl ester obtained in Example 13 (b), 820 mg (89%) of Acid 2 '- (5.5 , 8,8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l '; 4', l ''] terphenyl-4"-carboxylic acid, in the form of a powder white melting point 287-288 ° C. XH NMR (CDCl 3) d 0.91 (s, 6H), 1.27 (s, 6H), 1.56 to 1.64 (m, 4H), 6.89 (d, 1H, J = 1.8 Hz), 7.14 to 7.33 (m, 7H), 7.52 (d, 1H, J = 7.9 Hz) ,. 1.6 (dd, 1H, J = 8.0 / 1.9 Hz), 7.72 to 7.73 (m, 1H), 7.75 (d, 2H, J = 8.6 Hz), 8.15 (d, 2H, J = 8.4 Hz).
Example 15 Acid 4 - (methox imet oxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 -tetrahydro-naph' talen -2-11) - [1, 1 '; 4', 1 ''] terphenyl-4 '' -carboxylic. (a) 4-methoxymethoxy-bromobenzene Analogously to example 7 (a), by reaction of 48.84 g (282.3 mmol) of 4-bromophenol with 25.0 ml (310.5 mmol) of methyl chloromethyl ether, 63.85 g are obtained. (100%) of the expected product, in the form of a beige oil. X H NMR (CDCl 3) d 3.46 (s, 3 H), 5.14 (s, 2 H), 6.92 (d, 2 H, J = 9.0 Hz), 7.38 (d, 2 H, J = 9.0 Hz). (b) 4-methoxymethoxy-phenylboronic acid.
Analogously to example 1 (a), from 63.81 g (293.0 mmol) of 4-methoxymethoxy-bromobenzene, 35.42 g (80%) of the expected product are obtained, in the form of a white solid of melting point 122 ° C. XH NMR (CDC13) d 3.52 (s, 3H), 5.27 (s, 2H), 7.15 (d, 2H, J = 8.6 Hz), 8.16 (d, 2H, J = 8.6 Hz). (c) 4-methoxymethoxy-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' ' ] ethyl terphenyl-4"-carboxylate.
Analogously to example 13 (b), by reaction of 357 mg (2.0 mmol) of the compound obtained in Example 15 (b) with 1.00 g (1.8 mmol) of the analogue (ethyl ester) of the compound obtained in Example 13 (a), 880 mg "(13%) of the expected product are obtained in the form of a colorless oil XH NMR (CDCl 3) d 0.94 (s, 6H), 1.28 (s, 6H), 1.42 ( t, 3H, J = 7.1 Hz), 1.58 to 1.63 (m, 4H), 3.46 (s, 3H), 4.41 (q, 2H, J = 7.1 Hz), 5.14 (s, 2H), 6.90 (d, 1H , J = 1.8 Hz), 3.91 (d, 2H, J = 8.7 Hz), 7.08 (d, 2H, J = 8.7 Hz), 7.17 (dd, 1H, J = 8.1 / 1. 9 Hz), 7.29 (d, 1H, J = 8.1 Hz), 7.50 (d, 1H, J = 7.9 Hz), 7.64 (d, 1H, J = 8.0 / 2.0 Hz), 7.72 (d, 1H, J = 1.9 Hz), 7.74 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.4 Hz). (d) 4-methoxymethoxy-2 '- (5, 5, 8, 8-tetramet-il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] terphenyl-4 '' -carboxylic.
Analogously to example 1 (e), starting from 870 mg (1.6 mmol) of the ethyl ester obtained in example 15 (c), 750 mg (91%) of 4-mexy-oximetoxy-2 'is obtained. - (5,5,8,8-tetrame-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid , in the form of a white powder of melting point 249-251 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 0.94 (s, 6H), 1.28 (s, 6H), 1.54 to 1.66 (m, 4H), 3.45 (s, 3H) 5.14 (s, 2H), 6.89 ( d, 1H, J = 1.9 Hz), 6.91 (d, 2, J = 8.6 Hz), 7.08 (d, 2H, J = 8.6 Hz), 7.17 (dd, 1H, J = 8.1 / 1.7 hz), 7.31 ( d, 1H, J = 8.1 Hz), 7.28 (d, 1H, J = 8.1 Hz), 7.50 (d, 1H, J = 7.9 Hz), 7.65 (dd, H, J = 8.0 / 1.8 hz), 7.71 ( d, 1H, J = 1.9 Hz), 7.74 8d, 2H, J = 8.3 Hz), 8.14 (d, 2H, J = 8.3 Hz).
Example 16 4-Hydr oxy-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1' '] acid Terfenyl-4"-carboxylic acid. (a) 4-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] terphenyl -4"ethyl-carboxylate.
In a 250 ml triple neck flask and under a stream of nitrogen, 3.81 g (5.5 mmol) of the compound obtained in the example are introduced. (c), 100 ml of ethanol and 50 ml of THF. 3.5 ml of concentrated sulfuric acid are added dropwise.
The reaction medium is heated for fifteen minutes at 60 ° C, then water is added, it is extracted with ethyl ether, the organic phase is washed with water until neutral pH, dried over magnesium sulfate, filtered and the solvents are evaporated. .
The residue obtained is purified by chromatography on a silica column, eluted with heptane, then with a mixture composed of 20% ethyl acetate and 80% heptane. After evaporation of the solvents, 2.60 g (74%) of the expected compound are taken up in the form of a white powder with a melting point of 177-179 ° C. 1H NMR (CDC13) d 0.98 (s, 6H), 1.27 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 1.58 to 1.65 (m, 4H), 4.41 (q, 2H, J = 7.1 Hz), 4.91 (s, 1H), 6.71 (d, 2H, J = 8.6 hz), 6.94 (d, 1H, J = 1.8 Hz), 7.03 (d, 2H, J = 8.6 Hz), 7.13 (dd) , 1H, J = 8.1 / 1.9 Hz), 7.27 (d, 2H, J = 7.4 Hz), 7.49 (d, 1H, J = 8.0 Hz), 7.64 (dd, 1H, J = 8.0 / 1.9 Hz), 7.71 (d, 1H, J = 1.9 Hz), 7.73 (d, 2H, J = 8.5 Hz), 8.13 (d, 2H, J = 8.4 Hz). (b) 4-hydroxy-2 '- (5, 5, 8, 8-tet ramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] terphenyl-4 '' -carboxylic.
Analogously to example 1 (e), starting from 980 mg (1.9 mmol) of the ethyl ester obtained in example 16 (a), 790 mg (80%) of 4-hydroxy-2'-acid are taken up again. (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; ', 1"] terphenyl-4" -carboxylic acid, in the form of a white powder of melting point 262-266 ° C. 2 H NMR (CDCl 3) d 0.99 (s, 6H), 1.27 (s, 6H), 1.55 to 1.67 (m, 4H), 6.72 (d, 2H, J = 8.5 Hz), 6.97 (d, 1H, J = 1.7 Hz), 6.98 (d, 2H, J = 8.5 Hz) + 7.12 (dd, 1H , J = 8.0 / 1.6 Hz), 7.25 (d, 1H, J = 8.1 Hz), 7.49 (d, 1H, J = 7.9 Hz), 7.64 (dd, 1H, J = 8.0 / 1.6 Hz), 7.69 (d , 1H, J = 1.7 Hz), 7.73 (d, 2H, J = 8.3 Hz), 8.13 (d, 2H, J = 8.3 Hz).
Example 17 4-methoxy-2 '- (5, 5, 8, 8-tetramt-il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 f, 1"'] terf nyl-4" -carboxylic. (a) 4-methoxy -2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naph alen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-ethylcarboxylate.
Analogously to example 7 (a), by reaction of 1.40 g (2.8 mmol) of the compound obtained in example 16 (a) with 250 μl (4.2 mmol) of methyl iodide, 1 is obtained. , 35 g (96%) of the expected product, in the form of a yellow solid of melting point 112-115 ° C. 1ti NMR (CDC13) d 1.27 (s, 12H), 1.42 (t, 3H, J = 7.1 Hz), 1.58 to 1.65 (m, 4H), 3.78 (s, 3H), 4.41 (q, 2H, J = 7.1 Hz), 6.78 (d, 2H, J = 8.7 Hz), 6.93 (d, 1H, J = 1.9 Hz), 7.08 (d, 2H, J = 8.7 Hz), 7.14 (dd) , 1H, J = 8.1 / 1.9 Hz), 7.27 (d, 1H, J = 7.0 Hz), 7.50 (d, 1H, J = 7.9 Hz), 7.64 (dd, 1H, J = 8.0 / 4.0 Hz), 7.71 (d, 1H, J = 1.9 Hz), 7.74 (d, 2H, J = 8.5 Hz), 8.12 (d, 2H, J = 8.4 Hz). (b) 4-methoxy -2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' ' ] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 1.30 g (2.7 mmol) of the ethyl ester obtained in Example 17 (a), 960 mg (74%) of the "4-methoxy-2 'acid are taken up again. - (5, 5, 8, 8-tet ramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid , in the form of a white powder of melting point 262-266 ° C. XH NMR (CDCI3) d 0.96 (s, 12H), 1.27 (s, 6H), 1.55 to 1.67 (m, 4H), 3.78 (s) , 3H), 6.79 (d, 2H, J = 8.7 Hz), 6.93 (d, 1H, J = 1.6 Hz), 7.08 (d, 2H, J = 8.6 Hz), 7.14 (dd, 1H, J = 8.2 / 1.7 Hz), 7.27 (d, 1H, J = 8.1 Hz), 7.50 (d, 1H, J = 8.0 Hz), 7.65 (d, 1H, J = 8.0 / 1.8 Hz), 7.72 (d, 1H, J = 1.6 Hz), 7.75 (d, 2H, J = 8.4 Hz), 8.17 (d, 2H, J = 8.3 Hz).
Example 18 Acid 3 -metox imet oxy -2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1' '] terphenyl-4"-carboxylic acid. (a) 3-methoxymethoxy-bromobenzene.
Analogously to example 7 (a), by reaction of 100.00 g (577.9 mmol) of 3-bromophenol with 48.28 g (635.8 mmol) of methyl chloromethyl ether, 135.32 g are obtained "(100%) of the expected product, in the form of a light beige oil, XH NMR (CDC13) d 3.46 (s, 3H), 5.15 (s, 2H), 6.92 to 7.00 (m, 1H), 7.10 a 7.14 (m, 2H), 7.18 to 7.22 (m, 1H). (b) 3-methoxymethoxy-phenylboronic acid.
Analogously to example 1 (a), starting from 125.00 g (575.8 mmol) of 3-methoxymethoxy-bromobenzene, 86.00 g (100% of the expected product, in the form of an oil, are obtained. yellow that will be used directly in the next stage. (c) 3-methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"] terphenyl-4" -ethylcarboxylate.
Analogously to example 13 (b), by reaction of 3.50 g (19.3 mmol) of the compound obtained in example 18 (b) with 9.00 g (16.1 mmol) of the analogue (ethyl ester) of the compound obtained in example 13 (a), 7.70 g are obtained (87%) of the expected product, in the form of a "white solid of melting point 103-104 ° C. XH, NMR (CDC13) d 0.96 (s, 6H), 1.27 (s, 6H), 1.42 (f , 3H, J- 7.1 Hz), 1.58 to 1.65 (m, 4H), 3.36 (s, 3H), 4.41 (q, 2H, J = 7.1 Hz), 4.89 (s, 2H), 6.76 (t, 1H, J = 2.1 Hz), 6.85 (dd, 1H, J = 8.2 / 2.4 Hz), 6.91 (m, 1H), 6.93 (d, 1H, J = 1.6 Hz), 7.13 to 7.30 (m, 3H), 7.54 ( d, 1H, J = 7.9 Hz), 7.65 (dd, 1H, J = 8.0 / 1.9 Hz), 7.72 (s, 1H), 7.74 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.4 Hz). (d) 3-methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 1.20 g (2.2 mmol) of the ethyl ester obtained in example 18 (c), 1.03 g (90%) of 3-methoxymethoxy acid is taken up again -2 '- (5,5,8, 8-tet ramet il-5, 6,7,8-tetrahydro-naphthalen-2-yl) - [l, l'; 4 ', l' '] terphenyl-4 '-carboxylic, in the form of a white powder of melting point 212 ° C. XH NMR (CDC13) d 0.96 (s, 6H), 1.27 (s, 6H), 1.56 to 1.66 (m, 4H), 3.37 (s, 3H), 4.90 (s, 2H), 6.77 (d, 1H, J = 1.9 Hz), 6.85 (dd, 1H, J = 8.2 / 1.9 Hz), 6.91 to 6.94 (m, 2H), 7.16 (dd, 1H, J = 8.1 / 1.8 * Hz), 7.17 to 7.23 (m, 1H ), 7.29 (d, 1H, J = 8.1 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.68 (dd, 1H, J = 8.0 / 1.9 Hz), 7.74 (d, 1H, J = 1.8 Hz ), 7.78 (d, 2H, J = 8.4 Hz), 8.21 (d, 2H, J = 8.4 Hz).
Example 19 3-hydroxy-2r - (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4r acid '-carboxylic, (a) 3-hydroxy-2 '- (5,5,8,8-tetramethi, 1-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-ethylcarboxylate.
Analogously to example 168 (a), from 6.26 g (11.4 mmol) of the compound obtained in example 18 (c), 5.63 g (98%) of the expected product are obtained, under the form of a white solid with a melting point lower than 70 ° C. 1H NMR (CDC13) d 0.95 (s, 6H), 1.27 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 1.58 to 1.65 (m, 4H), 4.41 (q, 2H, J = 7.1 Hz), 4.95 (s, 1H), 6.63 to 6.76 (m, 3H), 6.94 (d, 1H, J = 1.8 Hz), 7.11 (t, 1H, J = 7.9 Hz), 7.15 (dd, 1H, J = 8.2 / 1.9 Hz), 7.28 (d, 1H, J = 8.1 Hz), 7.49 (d, 1H, J = 7.9 Hz), 7.63 (dd, 1H, J = 8.2 / 1.9 Hz), 7.71 to 7.73 (m , 1H), 7.73 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.4 Hz). (b) 3-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1" ] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 1.05 g (2.1 mmol) of the ethyl ester obtained in example 19 (a), 820 mg (83%) of 3-hydroxy-2 acid are taken up '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [l, l'; 4 ', l' '] terphenyl-4"-carboxylic acid , in the form of a white powder with a melting point of 260-263 ° C. XH NMR (CDC13) d 0.96 (s, 6H), 1.27 (s, 6H), 1.57 to 1.64 (m, 4H), 6.58 (d, 1H, J = 7.7 Hz), 6.69 (dd, 1H, J = 8.0 / 2.0 Hz), 6.75 (d, 1H, J = 2.0 Hz), 6.98 (d, 1H, J = 1.7 Hz), 7.03 (t, 1H, J = 7.8 Hz), 7.16 (dd, 1H, J = 7.9 / 1.8 Hz), 7.26 (d, 1H, J = 8.1 Hz), 7.49 (d, 1H, J = 7.9 Hz), 7.63 (dd, 1H, J = 8.0 / 1.9 Hz), 7.71 (d, 1H, J = 1.9 Hz), 7.73 (d, 2H, J = 8.4 Hz), 8.14 (d, 2H, J = 8.4 ^ Hz).
Example 20 Acid 3 -metox i -2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4f, 1 ''] terphenyl-4"-carboxylic acid. (a) 3-methoxy-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' ' ] ethyl terphenyl-4"-carboxylate.
Analogously to example 7 (a), by reaction of 1.20 g (2.4 mmol) of the compound obtained in example 19 (a) with 190 μl (3.1 mmol) of methyl iodide, 1 is obtained. , 08 g (87%) of the expected product, in the form of a white solid with a melting point of 116-118 ° C. XH NMR (CDC13) d 0.96 (s, 6H), 1.27 (s, 6H), 1.42 (t, 3H, J «= 7.1 Hz), 1.58 to 1.66 (m, 4H), 3.49 (s, 3H), 4.41 (q, 2H, J = 7.1 Hz), 6.53 (d, 1H, J = 1.3 Hz), 6.74 (dd, 1H, J = 7.6 / 2.5 Hz), 6.89 (d, 1H, J = 7.6 Hz), 6.95 (d, 1H, J = 1.6 Hz), 7.12 to 7.30 (m, 3H), 7.56 (d, 1H, J = 8.0 Hz), 7.67 (dd, 1H, J = 8.0 / 1.8 Hz), 7.72 to 7.74 ( m, 1H), 7.74 (d, 2H, J = 8.3 Hz), 8.13 (d, 2H, J = 8.3 Hz), (b) 3-methoxy-2 '- (5, 5, 8, 8-tetramethyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4 ', 1' '] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 1.07 g (2.1 mmol) of the ethyl ester obtained in example 208 (a), 930 mg (92%) of the 3-methoxy acid 2 '- (5%) are obtained. , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; ', 1' '] terphenyl-4"-carboxylic acid, in the form of a white powder of melting point 258-259 ° C. XH NMR (CDC13) d 0.96 (s, 6H), 1.27 (s, 6H), 1.58 to 1.65 (m, 4H), 3.49 (s, 3H), 6.54 (d, 1H, J = 1.6 Hz), 6.72 ( dd, 1H, J = 7.6 / 2.1 Hz), 6.89 (d, 1H, J = 7.6 Hz), 6.94 (d 1H, J = 1.7 Hz), 7.14 (d, 1H, J = 7.8 Hz), 7.21 (d , 1H, J = 7.9 Hz), 7.28 (d, 1H, J = 8.1 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.68 (dd, 1H, J = 8.0 / 1.9 Hz), 7.68 to 7.70 (m, 1H), 7.74 (d, 2H, J = 8.3 Hz), 8.14 (d, 2H, J = 8.3 ^ Hz).
Example 21 Acid 2 -metox im t oxi -2 '- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] terphenyl-4 '' -carboxylic. _ (a) 2-methoxymethoxy-bromobenzene.
Analogously to example 7 (a), by reaction of 15.00 g (86.7 mmol) of 2-bromophenol with 8.40 g (104.0 mmol) of methyl chloromethyl ether, 18.80 g (100%) of the expected product are obtained, shape of a beige oil. 1ñ NMR (CDC13) d 3.53 (s, 3H), 5.52 (s, 2H), 6.89 (dt, 1H, J = 7.5 / 1.6 Hz), 7.15 (dd, 1H, J = 8.3 / 1.6 Hz), 7.25 (dt, 1H, J = 7.3 / 1.6 Hz), 7.54 (dd, 1H, J = 7.9 / 1.6 Hz). (b) 2-methoxymethoxy-phenylboronic acid.
Analogously to example 1 (a), from 19.00 g (8.7 mmol) of 2-methoxymethoxy-bromobenzene, 11.00 g (70%) of the expected product are obtained, in the form of a white solid of melting point. -66 ° C. X H NMR (CDCl 3) d 3.51 (s, 3 H), 5.31 (s, 2 H), 6.21 (s, 2 H), 7.07 (d, 1 H, J = 7.3 Hz), 7.14 (d, 1 H, J = 8.8 Hz) , 7.43 (dt, 1H, J = 8.6 / 1.9 Hz) _, 7.87 • (dd, 1H, J = 7.3 / 1.8 Hz). (c) 2-methoxymethoxy-2 '- (5,5,8,8-tetramet-il-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"'] terphenyl-4" -ethylcarboxylate.
Analogously to example 13 (b), by reaction of 2.73 g (15.0 mmol) of the compound obtained in example 21 (b) with 7.00 g (12.5 mmol) of the analogue (ethyl ester) of the compound obtained in example 13 ( a), 1.50 g (22%) of the expected product is obtained, in the form of a white solid of melting point 132-135 ° C. XH NMR (CDCl 3) d 0.91 (br s, 6H), 1.24 (s, 6H) 1.42 (t, 3H, J = 7.1 Hz), 1.54 to 1.63 (m, 4H), 3.10 (s, 3H), 4.41 ( q, 2H, J = 7.1 Hz), 4.40 to 4.80 (br s, 2H), 6.96 (d, 1H, J = 1.8 Hz), 7.02 to 7.29 (m, 7H), 7.47 (d, 1H, J = 8.7 Hz), 7.65 (dd, 1H, J = 7.9 '/ 1.9 Hz), 7.74 (s, 1H), 7.76 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.4 Hz). (d) 2-methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1' '] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), starting from 470 mg (0.86 mmol) of the ethyl ester obtained in Example 21 (c), 360 mg (81%) of 2-methoxymethoxy-2'-acid are taken up again. (5,5,8,8 -tetramet-il-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1' '] terphenyl-4"-carboxylic acid, in the form of a white powder of melting point 218-221 ° C. XH NMR (CDC1) d 0.91 (br s, 6H), 1.24 (s, 6H), 1.52 to 1.64 (m, 4H), 3.10 (s, 3H), 4.40 to 4.80 (br s, 2H), 6.97 (d , 1H, J = 1.8 Hz), 7.02 to 7.28 (m, 6H), 7.47 (d, 1H, J = 7.9 Hz) 7.67 (dd, 1H, J = 7.9 / 1.9 Hz), 7.75 (d, 1H, J = 1.8 Hz), 7.80 (d, 2H, J = 8.4 Hz), 8.21 (d, 2H, J = 8.3 Hz).
Example 22 2-Hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] terphenyl ester -4"-carboxylic (a) 2-hydroxy-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', l' '] ethyl terphenyl- "-carboxylate.
In a manner analogous to Example 16 (a), from 1.10 g (2.0 mmol) of the compound obtained in Example 21 (c), 1.00 g (99%) of the expected product is obtained, in the form of a white solid of melting point 161-163 ° C. XH NMR. (CDC13) d 0.93 (s, 6H), 1.25 (s, 6H), 1.43 (t, 3H, J = 7.2 Hz), 1.55 to 1.65 (m, 4H), 4.41 (q, 2H, J = 7.1 hz) , 6.81 (d, 1H, J = 8.1 Hz), 6.90 (t, 1H, J = 7.5 Hz), 6.99 (d, 1H, J = 1.9 Hz), 7.10 to 7.20 (m, 3H), 7.28 (d, 1H, J = 8.7 Hz), 7.50 (d, 1H, J = 7.9 Hz), 7.69 (dd, 1H, J = 7.9 / 1.9 Hz), 7.75 (d, 2H, J = 8.5 hz), 7.78 (d, 1H, J = 1.9 Hz), 8.15 (d, 2H, J = 8.4 Hz). (b) 2-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-carboxylic acid.
Analogously to example l (e), starting from 390 mg (0.77 mmol) of the ethyl ester obtained in example 22 (a), 315 mg (86%) of 2-hydroxy-2 '- (5,5,8,8-tetramethyl-5,6, 7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a white powder of melting point 265-269 ° C . XH NMR (CDC13 + 2 drops of DMSO D6) d 0.93 (s_, 6H), 1.25 (s, 6H), 1.55 to 1.62 (m, 4H), 6.77 to 6.85 (m, 2H, 7.02 to 7.13 (m, 3H ), 7.18 to 7.27 (m, 2H), 7.51 (d, 1H, J = 7.9 Hz), 7.66 (dd, 1H, J = 7.9 / 1.9 Hz), 7.73 (d, 1H, J = 7.9 Hz), 7.74 (d, 2H, J = 8.3 Hz), 8.14 (d, 2H, J = 8.3 Hz).
Example 23 2-Methoxy-2 '- (5, 5, 8, 8-tetramet-il-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-carboxylic. (a) 2-methoxy -2 '- (5,5,8,8 -tetramethyl-5,6,7, tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"Jterphenyl -4"ethyl-carboxylate.
Analogously to example 7 (a), by reaction of 580 mg (1.2 mmol) of the compound obtained in example 22 (a) with 110 μl (1.5 mmol) of methyl iodide, 530 mg (89%) of the expected product, in the form of a white solid of 133-136CC melting point. 1E NMR (CDCl 3) d 0.93 (br s, 6H), 1.24 (s, 6H), 1.42, (t, 3H, J = 7.1 Hz), 1.56 to 1.63 (m, 4H), 3.27 (s, 3H), 4.40 (q, 2H, J = 7.1 Hz), 6.- 1 (d, 1H, J = 8.0 Hz), 6.94 (d, 1H, J = 1.8 Hz), 6.98 (d, 1H, J = 7.3 Hz) , 7.12 (dd, 1H, J = 8.1 / 1.9 Hz), 7.19 to 7.26 (m, 3H), 7.47 (d, 1H, J = 7.9 Hz), 7.64 (dd, 1H, J = 7.9 / 1.9 Hz), 7.71 (d, 1H, J = 1.9 Hz), 7.75 (d, 2H, J = 8.6 Hz), 8.12 (d, 2H, J = 8.4 Hz). (b) 2-methoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), starting from 530 mg (1.0 mmol) of the ethyl ester obtained in example 23 (a), 435 mg (87%) of 2-methoxy-2 '- (5) are taken up again. , 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1"] terphenyl-4" -carboxylic acid, in the form of "a white powder of melting point 239-243 ° C. XH NMR (CDCl 3) d 0.93 (s, 6H), 1.25 (s, 6H) , 1.54 to 1.63 (m, 4H), 3.28 (s, 3H), 6.71 (d, 1H, J = 8.1 Hz), 6.95 to 7.01 (m, 2H), 7.14 (d, 1H, J = 8.1 Hz), 7.20 to 7.25 (m, 3H), 7.49 (d, 1H, J = 7.9 Hz), 7.67 (d, 1H, J = 7.9 Hz), 7.74 (d, 1H, J = 1.8 Hz), 7.79 (d, 2) », J = 8.2 Hz), 8.21 (d, 2H, J = 8.2 Hz).
Example 24 2'-Metho-imet oxy-5 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifenyl-4-carboxylic acid. (a) 4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenol.
Analogously to example 1 (d), by reaction of 53.00 g (230.3 mmol) of boronic acid obtained in example 1 (a) with 23.10 g (133.6 mmol) of 4-bromophenol, 60.00 'g (70%) are obtained ) of the expected compound, in the form of a white solid of melting point 137-140 ° C. 1H NMR (CDC13) d 1.31 (s, 6H), 1.33 (s, 6H), 1.71 (s, 4H), 4.77 (s, 1H), 6.89 (d, 2H, J = 8.86 Hz), 7.30 (d, 1H, J = 8.2 / 1.9 Hz), 7.36 (d, 1H, J = 8.1 Hz), 7.45 (d, 1H, J = 1.9 Hz), 7.46 (d, 2H, J = 8.6 Hz). (b) 2-bromo-4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenol.
Into a flask are introduced 39.00 (139.0 mmol) of the compound obtained in example 24 (a) and 350 ml of dichloromethane. 23.40 g (146.0 mmol) of bromine in solution in 50 ml of dichloromethane are added dropwise and the mixture is stirred at room temperature for thirty minutes. The reaction medium is evaporated to dryness, the residue is taken up in water and ethyl acetate, the organic phase is separated out, washed with an aqueous solution of sodium metabisulfite, dried over magnesium sulfate, filtered and evaporated. 40.60 g (80%) of the expected product are recovered, in the form of a yellow oil. XH NMR (CDC13) d 1.31 (s, 6H), 1.34 (s, 6H), 1.71 '(s, 4H), 5.49 (s, 1H), 7.07 (d, 1H, J = 8.4 Hz), 7.27 (dd) , 1H, J = 7.7 / 2.0 Hz), 7.36 (d, 1H, J = 8.2 Hz), 7.43 (dd, 1H, J = 7.8 / 2.0 Hz), 7.51 (d, 1H, J = 2.1 Hz), 7.65 (d, 1H, J = 2.1 Hz).OU. (c) 6- (3-Bromo-4-methoxymethoxy-phenyl) -1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene.
Analogously to example 7 (a), 45.00 g (98%) were obtained by reacting 40.60 g (113.1 mmol) of the compound obtained in example 24 (b) with 10.65 ml (135.0 mmol) of methyl chloromethyl ether. of the expected product, in the form of a brown oil. XH NMR (CDC13) d 1.31 (s, 6H), 1.33 (s, 6H), 1.71 (s, 4H), 3.55 (s, 3H), 5.28 (s, 2H), 7.20 (d, 1H, J = 8.5 Hz), 7.27 (dd, 1H, J = 8.2 / 1.9 Hz), 7.36 (d, 1H, J = 8.2 Hz), 7.43 (dd, 1H, < J = 7.8 / 2.0 Hz), 7.51 (d, 1H , J = 2.1 Hz), 7.75 (d, 1H, J = 2.2 Hz). (d) 2-methoxymethoxy-5- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -phenylboronic acid.
Analogously to example 1 (a), from 45.00 g (112.0 mmol) of the compound obtained in Example 24 (c), 41.50 g (100%) of the expected product are obtained in the form of a brown oil which will be used directly in the next stage. (e) Ethyl 2-methoxymethoxy-5 '- (5,5,8,8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylate.
Analogously to example l (d) _, by reaction of 41.20 g (112.0 mmol) of the compound obtained in example 24 (d) with 30.90 g (112.0 mmol) of ethyl 4-iodobenzoate, 18.00 g (34 g) were obtained. %) of the expected product, in the form of a yellow oil. XH NMR (CDC13) d 1.31 (s, 6H), 1.33 (s, 6H), 1.41 (t, 3H, J = 7.1 Hz), 1.72 (s, 4H), 3.04 (s, 3H), 4.40 (q, 2H, J = 7.1 Hz), 5.15 (s, 2H), 7.23 to 7.39 (m, 3H), 7.44 to 7.59 (m, 3H), 7.65 (d, 2H, J = 8.1 Hz), 8.12 (d, 2H) , J = 8.2 Hz). (f) 2 '-methoxymethoxy-5' - (5, 5, 8, 8 -tethramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
Analogously to example 1 (e), starting from 1.00 g (2.1 mmol) of the ester obtained in example 24 (e), 660 mg (70%) of 2'-methoxymethoxy-5 '- (5 , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of beige crystals of melting point 183-185 ° C. XH NMR (CDCl 3) d 1.32 (s, 6H), 1.34 (s, 6H), 1.72 (s, 4H), 3.42 (s, 3H), 5.18 (s, 2H), 7.28 to 7.40 (m, 3H), 7.49 to 7.56 (m, 3H), 7.70 (d, 2H, JL = 8.2 Hz), 8.19 (d, 2H, J = 8.2 Hz).
Example 25 2'-Methoxy-5 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifenyl-4-carboxylic acid. (a) Ethyl 2'-hydroxy-5 '- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylate.
Analogously to example 16 (a), from 17.00 g (36.0 mmoles) of the compound in example 24 (e), 15.10 g (98%) of the expected product are obtained, in the form of a beige-colored solid. melting point 148-152 ° C. XH NMR (CDCl 3) d 1.31 (s, 6H), 1.33 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 1.72 (s, 4H), 4.41 (q, 2H, J = 7.2 Hz), 5.29 (br s, 1H), 7.04 (d, 1H, J = 8.1 Hz), 7.31 to 7.39 (m, 2H), 7.46 to 7.52 (m, 3H), 7.63 (d, 2H, J = 8.3 Hz), 8.17 (d, 2H, J = 8.3 Hz). ' (b) 2 '-methoxy-5' - (5, 5, 8, 8 -tetramethyl-5, _6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid ethyl ester.
Analogously to example 7 (a), by 1.53 g (3.6 mmol) of the compound obtained in Example 25 (a) with 330 μl (5.4 mmol) of methyl iodide, 1.40 g (88%) of the expected product, in the form of a brown oil. XH NMR (CDC13) d 1.31 (s, 6H), 1.33 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 3.86 (s, 3H), 1.72 (s, 4H), 4.41 (q, 2H, J = 7.2 Hz), 5.29 (br s, 1H), 7.04 (d, 1H, J = 8.1 Hz), 7.31 to 7.39 (m, 2H), 7.46 to 7.52 (m, 3H), 7.63 (d, 2H, J = 8.3 Hz), 8.17 (d, 2H, J = 8.3 Hz). (c) 2'-methoxy-5 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
Analogously to example 1 (e), from 1.40 g (3.6 mmol) of the ester obtained in Example 25 (b), 1.07 g (72%) of 2'-methoxy-5 '- (5) acid is obtained. , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxy HcO, in the form of a crystallized white solid of melting point 233-235 ° C . XH NMR (CDC13) d 1.32 (s, 6H), 1.34 (s, 6H), 1.72 (s, 4H), 3.86 (s, 3H), 7.07 (d, 1H, J = 8.4 Hz), 7.32 to 7.39 ( m, 2H), 7.49 to 7.58 (m, 3H), 7.65 (d, 2H, J = 8.3 Hz), 8.11 (d, 1H, J = 8.3 Hz).
Example 26 2'-Propyloxy-5 '- (5,5,8,8-tetramethyl) acid , 6, 7, 8-tetrahydro-naphthalen-2-yl) -bifenyl-4-carboxylic acid. (a) 2'-propyloxy-5 '- (ethyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylate.
Analogously to example 7 (a), by reaction of 1.34 g (3.1 mmol) of the compound obtained in Example 25 (a) with 460 μl (4.7 mmol) of propyl iodide, 1.30 g (88%) of the expected product, in the form of a colorless oil. XH NMR (CDC13) d 0.98 (t, 3H, J = 7.3 Hz), 1.32 (s, 6H), 1.33 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz)? 1.72 • a 1.77 (m, 2H), 1.72 (s, 4H), 3.98 (t, 2H, J = 6.4 Hz), 4.41 (q, 2H, J = 7.1 Hz), 7.04 (d, 1H, J = 9.1 Hz), 7.31 to 7.39 (m, 2H), 7.49 to 7.54 (m, 3H), 7.67 (d, 2H, J = 8.4 Hz), 8.09 (d, 2H, J = 8.4 Hz). (b) 2'-Propyloxy-5 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
Analogously to example 1 (e), starting from 1.30 g (3.1 mmol) of the ester obtained in Example 26 (a), 850 mg (61%) of 2'-propyloxy-5 '- (5%) acid are obtained. , 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a crystallized white solid of melting point 199-204 ° C. X H NMR (CDCl 3) d 0.98 (t, 3 H, J = 7.3 Hz), 1.71 to 1.81 (m, 2 H), 1.72 (s, 4 H), 3.99 (t, 2 H, J = 6.4 Hz), 7.05 (d, 1H, J = 9.2 Hz), 7.35 to 7.40 (m, 2H), 7.49 to 7.56 (m, 3H), 7.72 (d, 2H, J = 8.4 Hz), 8.17 (d, 2H, J = 8.4 Hz).
Example 27 -Hydroxy-5 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifinyl-4-carboxylic acid.
Analogously to example 1 (e), from 1.00 g (2.3 mmol) of the ester obtained in example 25 (a), 800 mg (86%) of 2'-hydroxy-5 '- (5) acid are obtained. , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-carboxylic acid, in the form of a crystalline white solid of melting point 264-267 ° C. XH NMR (CDC13) d 1.31 (s, 6H), 1.33 (s, 6H), 1.71 (s, 4H), 7.07 (d, 1H, J = 8.3 Hz), 7.34 to 7.37 (m, 2H), 7.41 ( dd, 1H, J = 8.4 / 2.3 Hz), 7.47 to 7.49"(m, 2H), 7.72 (d, 2H, J = 8.3 Hz), 8.11 (d, 2H, J = 8.4 Hz).
Example 28 4 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naph such in -2 -yl) - [1, 1 1' '] ter phenyl-4"-carboxylate li co (a) 5 '- (5, 5, 8, 8 -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -2'-trifluoromethanesulfonyloxy-biphenyl-4"-ethylcarboxylate.
In a triple-necked flask under a stream of nitrogen, 2.00 g (4.7 mmol) of the ethyl ester obtained in Example 25 (a), 1.30 g (4.9 mmol) of 4-nitrophenol triflate, 1.30 g (9.3 mmol) are introduced. ) of potassium carbonate and 30 ml of N, N-dimethylformamide. The mixture is stirred at room temperature for sixteen hours, the reaction medium is poured into a water / ethyl ether mixture, washed with water, dried over magnesium sulfate, evaporated and 2.60 g (100%) of the expected product are taken up again. in the form of yellow crystals with a melting point of 110-113 ° C. XH NMR (CDC13) d 1.32 (s, 6H), 1.34 (s, 6H), 1.43 (t, 3H, J = 7.1 Hz), 1.73 (s, 4H), 4.42 (t, 2H, J = 7.2 Hz), 7.34 (dd, 1H, J = 8.2 / 1.9 Hz), 7.39 to 7.50 (m, 3H), 7.59 (d, 2H, J = 8.4 Hz), 7.60 to 7.65 (m, 2H), 8.17 (d, 2H, J = 8.4 Hz). (b) 4 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 2 ', 1"] terphenyl-4 The ethyl carboxylate.
Analogously to example 13 (b), by reaction of 2.60 g (4.6 mmol) of the compound obtained in Example 28 (a) with 626 mg (5.1 mmol) of phenylboronic acid, 1.10 g is obtained. (47%) of the expected product, in the form of yellow crystals of melting point 233-235 ° C.
XH NMR (CDC13) d 1.21 (t, 3H, J = 7.1 Hz), 1.32 (s, 6H), 1.35 (s, 6H), 1.68 (s, 4H), 4.29 (q, 2H, J = 7.0 Hz) , 7.25 to 7.32 (m, 5H), 7.44 (d, 2H, J = 8.2 Hz), 7.54 to 7.70 (m, 3H), 7.89 to 7.914 (m, 3H), 8.06 (d, 2H, J = 8.2 Hz ). (c) 4 '- (5, 5, 8, 8 -tetramet-il-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 2 ', 1' '] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 1.00 g (2.0 mmol) of the ester obtained in example 28 (b), 700 mg (77%) of 4 '- (5,5,8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 2', l "] terphenyl-4" -carboxylic acid, in the form of beige crystals of melting point 258-262 ° C. _ XH NMR (CDC13) d 1.28 (s, 6H), 1.32 (s, 6H), 1.68 (s, 4H), 7.11 to 7.15 (m, 2H), 7.25 to 7.28 (m, 3H), 7.32 (d, 2H, J = 8.2 Hz), 7.43 (d, 1H, J = 8.2 Hz), 7.46 (d, 1H, J = 1.8 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.62 to 7.64 (m, 2H), 7.74 (dd, 1H, J = 8.0 / 1.8 Hz), 7.81 (d, 2H, J = 8.3 Hz).
Example 29 2 '-methoxymethoxy-3' - (5, 5, 8, 8-tetramethyl 5, 6, 7, 8-tetrahydro-naph talen-2-yl) -bifenyl-4-carboxylic acid. (a) 1,3-dibromo-2-methoxymethoxy-benzene Analogously to example 7 (a), by reaction of 19.16 g (76.1 mmoles) of 2,6-dibromophenol with 7.35 g (91.3 mmoles) of methyl chloromethyl ether, 22.50 g (100%) of the expected product are obtained, in the form of a colorless oil. X H NMR (CDCl 3) d 3.73 (s, 3 H), 5.18 (s, 2 H), 6.88 (t, 1H, J = 8.1 Hz), 7.52 (d, 2H, J = 8.0 Hz). _ (b) 6- (3-boron-2-methoxymethoxy-phenyl) -1,4,4-tetramethyl-1, 2, 3, 4-tetrahydro-naphthalene.
Analogously to example l (d9), by reaction of 21.72 g (73.4 mmol) of the compound obtained in example 29 (a) with 18.74 g (80.7 mmol) of boronic acid obtained in example 1 (a), 4.04 are obtained g (14%) of the expected product, in the form of a white solid of melting point 74 ° C. XH NMR (CDCl 3) d 1.30 (s, 12H), 1.71 (s, 4H), 3.11 (s, 3H) , 4.73 (s, 2H), 7.04 (t, 1H, J = 7.8 Hz), 7.23 (dd, 1H, J = 8.1 / 1.8 Hz), 7.28 (dd, 1H, J = 7.9 / 1.6 Hz), 7.34 ( d, 1H, J = 8.1 Hz), 7.45 (d, 1H, J = 1.8 Hz), 7.53 (dd, 1H, < J = 7.9 / 1.6 Hz). (c) 2-methoxymethoxy-3- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenylboronic acid.
Analogously to example 1 (a), from 4.04 g (10.0 mmoles) of the compound obtained in example 29 (b), 3.82 g (100%) of the expected product are obtained, in the form of a colorless oil. XH NMR (CDC13) d 1.30 (s, 6H), 1.32 (s, 6H), 1.72 (s, 4H), 3.26 (s, 3H), 4.58 (s, 2H), 6.13 (s, 2H), 7.12 a 7.27 (m, 3H), 7.31 to 7.40 (m, 1H), 7.44 to 7.52 (, 1H), 7.80 (dd, 1H, J = 7.3 / 1.8 Hz). (d) ethyl 2 '-methoxymethoxy -3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylate.
Analogously to example 1 (d), 3.82 g (10.4 mmol) of the compound obtained in Example 29 (c) were obtained with 2.20 g (8.0 mmol) of ethyl 4-iodobenzoate, 3.28 g (87%) were obtained. ) of the expected product, in the form of a white crystalline solid of melting point 75 ° C. XH NMR (CDCl 3) d 1.32 (s, 6H), 1.33 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 1.72 (s, 4H), 2.60 (s, 3H), 4.33 (s, 2H), 4.41 (q, 2H, J = 7.2 Hz), 7.29 to 7.53 (m, 6H), 7.70 (d, 2H, J = 8.4 Hz), 8.11 (d, 2H, J = 8.4 Hz). (e) 2'-methoxymethoxy-3 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
Analogously to example 1 (e), starting from 1.00 g (2.1 mmol) of the ester obtained in Example 29 (d), 500 mg (53%) of 2'-methoxymethoxy-3 '- (5) acid are obtained. , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bi-phenyl-carboxylic acid, in the form of a crystallized white solid of melting point 176 ° C. XH NMR (CDC13) d 1.31 (s, 6H), 1.33 (s, 6H), 1.72 (s, 4H), 2.61 (s, 3H), 4.35 (s, 2H), 7.24 to 7.35 (m, 4H), 7.41 (dd, 1H, J = 7.3 / 2.3 Hz), 7.54 (s, 1H), 7.75 (d, 2H, J = 8.4 Hz), 8.19 (d, 2H, J = 8.4 Hz).
Example 30 3-Hydroxy-3 '- (5,5,8,8-tetramet-il-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifenyl-4-carboxylic acid. (a) 2'-hydroxy-3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-ethylcarboxylate.
Analogously to Example 16 (a), from 2.28 g (4.82 mmol) of the compound obtained in Example 29 (d), 1.59 g (77%) of the expected product is obtained, in the form of a white solid of melting point 121 ° C. XH NMR. (CDC13) d 1.31 (s, 6H), 1.33 (s, 6H), 1.41 (t, 3H, J = 7.1 Hz), 1.73 (s, 4H), 4.40 (q, 2H, J = 7.1 Hz), 5.53 (s, 1H, 7.07 (t, 1H, J = 7.6 Hz), 7.24 to 7.32 (m, 3H), 7.42 to 7.45 (m, 2H), 7.69 (d, 2H, J = 8.4 Hz). (b) 2'-Hydroxy-3 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
Analogously to example 1 (e), from 700 mg (1.6 mmol) of the ester obtained in example 30 (a), 526 mg (81%) of 2'-hydroxy-3 '- (5) acid are obtained. , 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a crystallized white solid of melting point 232 ° C. XH NMR (CDCl 3) d 1.31 (s, 6H), 1.33 (s, 6H), 1.73 (s, 4H), 5.58 (br s, 1H), 7.08 (t, 1H, J = 7.6 Hz), 7.24 to 7.35 (m, 3H), 7.43 to 7.46 (irt ^ 2H), 7. 74 (d, 2H, J = 8.4 Hz), 8.20 (d, 2H, J = 8.3 Hz).
Example 31 Acid-methoxy -3 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifenyl-4-carboxylic acid. (a) 2 '-methoxy-3' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-ethylcarboxylate.
Analogously to example 7 (a), by reaction of 890 mg (2.1 mmol) of the compound obtained in example 30 (a) with 192 μl (3.1 mmol) of methyl iodide, 800 mg are obtained (87%) of the expected product, in the form of a colorless oil.
XH NMR (CDCl 3) d 1.32 (s, 12H), 1.42 (t, 3H, J = 7.1 Hz), 1.72 (s, 4H), 3.20 (s, 3H), 4.41 (q, 2H, J = 7.1 Hz) , 7.23 to 7.35 (m, 4H), 7.39 (dd, 1H, J = 8.4 / 2.1 Hz), 7.56 (d, 1H, j = 1.4 Hz), 7.69 (d, 2H, "= 8.3 Hz), 8.11 ( d, 2H, J = 8.4 Hz. (b) 2'-methoxy-3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
Analogously to example 1 (e), from 800 mg (1.8 mmol) of the ester obtained in example 31 (a), 502 mg (67%) of 2'-methoxy-3 '- (5) acid are obtained. , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a white crystalline solid of melting point 205 ° C. XH NMR (CDCl 3) d 1.33 (s, 12H), 1.73 (s, 4H), 7.25 to 7.36 (m, 4H), 7.41 (dd, 1H, J = 7.4 / 2.0 Hz), 7.57 (d, 1H, J = 1.2 Hz), 7.74 (d, 2H, J = 8.4 Hz), 8.11 (d, 2H, J = 8.4 Hz).
Example 32 3 '-met-ox-imet or imet-5' - (5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-naphthalen-2-yl) -bifenyl-4-carboxylic acid. _ (a) methyl 3-bromo-5- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) benzoate.
Analogously to example 1 (d), by reacting 7.35 g (21.6 mmol) of methyl 3-bromo-5-iodobenzoate with 7.44 g (32.4 mmol) of boronic acid obtained in example 1 (a), obtain 5.12 g (59%) of the expected product, in the form of a powder with a melting point of 88 ° C. XH NMR (CDC13) d 1.32 (s, 6H), 1.35 (s, 6H), 1.72 (s, 4H), 1.72 (s, 4H), 3.95 (s, 3H), 7.34 (dd, 1H, J =. 8.2 / 1.9 Hz), 7.40 (d, 1H, J = 8.2 Hz), 7.48 (d, 1H, J = 1.7 Hz), 7.87 (t, 1H, J = 1.8 Hz) / 8.11 (t, 1H, J = 1.6 Hz), 8.16 (t, 1H, J = 1.5 Hz,). (b) 3-bromo-5- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -benzoic acid.
Analogously to example 1 (e), from 4.92 g (12.3 mmoles) of the ester obtained in example 32 (a), 3.26 g (70%) of the expected product are obtained, in the form of a white powder of melting point 165 ° C. _ XH NMR (CDC13) d 1.33 (s, 6H), 1.36 (s, 6H), 1.73 (s, 4H), 7.35 (d, 1H, J = 8.2 / 1.8 Hz), 7.39 (d, 1H, J = 8.2 Hz), 7.50 (d, 1H, J = 1.7 Hz), 7.94 (t, 1H, J = 1.7 Hz), 8.20 (t, 1H, J = 1.6 Hz), 8.24 (t, 1H, J = 1.5 Hz ). (c) 3-bromo-5- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -benzyl alcohol. 2.76 g (0.87 mmol) of the compound obtained in example 32 (b) and 60 ml of THF are introduced into a flask. The solution obtained is cooled to 0 ° C and 13.75 ml (13.7 mmol) of a borane solution (1M) in the THF are added dropwise and it is stirred for sixteen hours at room temperature, then at 50 ° C for two hours. Methanol is added slowly, then it is taken up with water and ethyl ether, the organic phase is separated out, extracted with ethyl ether, dried over magnesium sulfate, filtered and evaporated. 2.92 g (100%) of the expected product is recovered, in the form of a colorless oil. XH NMR (CDCl 3) d 1.30 (s, 6H.), 1.33 (s, 6H), 1.71 (s, 4H), 2.60 (br s, 1H), 4.68 (s, 2H), 7.28 (dd, 1H, J = 8.2 / 1.9 Hz), 7.36 (d, 1H, J = 8 ^ 2 Hz), 7.45 to 7.47 (m, 3H), 7.60 (s, 1H). (d) 3-methoxymethoxymethyl-5- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bromobenzene.
Analogously to example 7 (a), 2.92 g (7.8 mmol) of the bromoalcohol obtained in example 32 (c) were obtained with 650 μl (8.6 mmol) with methyl chloromethyl ether to obtain 2.52 g (77%). of the expected product, in the form of a yellow oil. XH NMR (CDCl 3) d 1.31 (s, 6H), 1.34 (s, 6H), 1.72 (s, 4H), 3.43 (s, 3H), 4.62 (s, 2H), 4.73 (s, 2H), 7.31 ( dd, 1H, J = 8.2 / 1.9 Hz), 7.38 (d, 1H, J = 8.2 Hz), 7.43 to 7.48 (m, 3H), 7.62 (m, 1H, J = 1.9 Hz). (e) 3-methoxymethoxymethyl-5- (5, 5, 8, 8 'tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -phenylboronic acid.
Analogously to example 1 (a), from 2.52 g (6.0 mmoles) of the compound obtained in example 32 (d), 2.60 g (100%) of the expected product are obtained, in the form of a yellow oil that will be used as-is in the next stage. (f) 3 '-methoxymethoxymethyl-5' - (5,5,8,8-tetramethoxy-1,5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid ethyl ester.
Analogously to example l (d), by reaction of 2.60 g (6.8 mmol) of the compound obtained in Example 32 (e) with 2.81 g (6.2 mmol) of ethyl 4-iodobenzoate, 1.48 g (45%) is obtained. ) of the expected product, in the form of a yellow oil. XH NMR (CDC13) d 1.33 (s, 6H), 1.35 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 1.73 (s, 4H), 3.46 (s, 3H) 4.41 (q, 2H , J = 7.1 Hz), 4.73 (s, 2H), 4.78 (s, 2H), 7.40 (d, 1H, J = 0.8 Hz), 7.55 to 7.58 (m, 3H), 7.71 (d, 2H, J = 8.4 Hz), 7.73 (s, 1H), 8.14 (d, 2H, J = 8.4 Hz). (g) 3 '-methoxymethoxymethyl-5' - (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
Analogously to example 1 (e), from 600 mg (1.2 mmol) of the ester obtained in example 32 (f), 560 mg (99%) of 3'-methoxymethoxymethyl-5 '- (5) acid are obtained. , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-carboxylic acid, in the form of a white crystalline solid of melting point 165 ° C. XH NMR (CDC13) d 1.33 (s, 6H), 1.36 (s, 6H), 1.74 (s, 4H), 3.47 (s, 3H), 4.75 (s, 2H), 4.79 (s, 2H), 7.41 ( s, 2H), 7.56 to 7.60 (m, 3H), 7.74 to 7.78 (m, 3H), 8.22 (d, 2H, J = 8.3 Hz).
Example 33 3 '-hydroxymethyl-5' - (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid. (a) 3 '-hydroxymethyl-5' - (5,5,8,8-tetramethi-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid ethyl ester.
Analogously to example 16 (a), from 670 mg (1.4 mmol) of the compound obtained in example 32 (f), 380 mg (62%) of the expected product are obtained, in the form of a yellow oil. XH NMR (CDC13 + 2 drops of DMSO D6) d 1.33 (s, 6H), 1.36 (s, 6H), 1.73 (s, 4H), 4.79 (s, 2H), 7.40 to 7.43 (m, 3H), 7.56 (s, 1H), 7.61 (d, 1H, J = 7.4 Hz), 7.69 (s, 1H), 7.73 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.3 Hz). (b) 3'-Hydroxymethyl-5 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bi-phenyl-4-carboxylic acid.
Analogously to example 1 (e), from 380 mg (0.86 mmol) of the ester obtained in example 33 (a), 260 mg (73%) of 3 '-hydroxymethyl-5' - (5) acid are obtained. , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bi-phenyl-4-carboxylic acid, in the form of a crystallized white solid of melting point 213 ° C. H NMR (DMSO D6) d 1.33 (s, 6H), 1.36 (s, 6H), 1.73 (s, 4H), 4.79 (s, 2H), 7.40 to 7.43 (m, 3H), 7.56 (s, 1H) , 7.61 (d, 2H, J = 7.3 Hz), 7.69 (s, 1H), 7.73 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.3 Hz).
Example 34 Acid (4,4-dimethyl-thiochroman-7-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid a) • ethyl methoxymethoxy-biphenyl-4-carboxylate Analogously to example 1 (d), by reaction of 85.00 g (566.7 mmoles) of the compound obtained in example 18 (b) with 104.30 g (377.8 mmoles) of ethyl 4-iodobenzoate, 162.4 g (100 g) are obtained. %) of the expected product, in the form of a dark brown oil. XH NMR (CDC13) d 1.42 (t, 3H, J = 7.2 Hz), 3.51 (s, 3H), 4.40 (q, 2H, J = 7.1 Hz), 5.24 (s, 2H), 7.08 ^ (dt, 1H , J = 8.1 / 1.0 Hz), 7.25 to 7.42 (m, 3H), 7.65 (d, 2H, J = 8.5 Hz), 8Z10 (d, 2H, J = 8.5 Hz) '. (b) 3 '-hydroxy-biphenyl-4-carboxylate ethyl Analogously to Example 16 (a), from 162.00 g (566.7 mmol) of the compound obtained in Example 34 (a), 133.41 g (97%) of the expected product are obtained, in the form of a colored powder Beige melting point 76 ° C. XH NMR (CDC13) d 1.26 (s, 12H9, 1.41 (t, 3H, J = 7.1 Hz), 4.39 (q, 2H, J = 7.1 Hz), 6.88 to 6.91 (m, 1H), 7.09 to 7.13 (m , 2H), 7.25 to 7.33 (m, 1H), 7.64 (m, 2H, J = 8.3 Hz), 8.08 (d, 2H, J = 8.3 Hz), 8.77 (br s, 1H). (c) 3'-Hydroxy-bi-phenyl-4-carboxylic acid.
Analogously to example 1 (e), from 130.00 g (536.6 mmoles) of the ester obtained in example 34 (b), 40.00 g (35%) of the expected product are obtained, in the form of a beige powder clear of melting point 180 ° C. XH NMR (DMSO D6) d 6.50 (dd, 1H, J = 7.2 / 1.5 Hz), 6.71 to 6.74 (m, 2H), 7.22 to 7.31 (m, 1H), 7.30 (d, 2H, J = 8.3 Hz) , 7.71 (d, 2H, J = 8.3 Hz). (d) 4 '-iodo-3'-hydroxy-biphenyl-4-carboxylic acid.
In a two-liter triple necked flask and under a stream of nitrogen, 40.00 g are introduced. (186.7 mmoles) of the compound obtained in example 34 (c), 7.47 g (186.7 mmoles) of soda in pellets, 27.98 g (186.7 mmoles) of sodium iodide and 800 ml of methanol. The mixture is cooled to 0 ° C and 111.00 g (186.7 mmol) of an aqueous solution of sodium hypochlorite at 12.5% are added dropwise in one hour and fifty minutes. The reaction medium is stirred for five hours at 0 ° C, then a solution of sodium thiosulfate is added, acidified to pH 5, extracted with ethyl ether, the organic phase is washed with water until neutral pH, dried over Magnesium sulfate is filtered and the solvents are evaporated. 54.00 g (85%) of the expected compound are taken up in the form of an oxide-colored powder of melting point 174 ° C. XH NMR (DMSO D6) d 6.83 to 6.89 (m, 1H), 7.11 to 7.24 (m, 1H), 7.38 to 7.41 (m, 1H), 7.60 to 7.76 (m, 2H), 8.06 to 8.17 (m, 2H). (e) Methyl 4 '-iodo-3' -hydroxy-biphenyl-4-carboxylate.
Analogously to example 1 (b), from 54.00 g (158.8 mmol) of the compound obtained in example 34 (d), 27.16 g (48%) of the expected product are obtained, in the form of a beige-colored powder clear melting point 192. ° C. XH NMR (DMSO D6) d 3.44 (s, 3H), 6.37 (dd, 1H, J = 8.1 / 2.1 Hz), 6.70 (d, 1H, J = 2.0 Hz), 7.13 (d, 2H, J = 8.5 Hz ), 7.26 (d, 1H, J = 8.1 Hz), 7.58 (d, 2H, J = 8.4 Hz), 9.45 (br s, 1H). (f) 2 '-hydroxy- [1,1'; 4 ', 1"] terphenyl-4" -methylcarboxylate.
Analogously to example l (d), by reaction of 27.16 g (76.6 mmoles) of the compound obtained in example 34 (e) with 14.03 g (115.0 mmoles) of phenylboronic acid, 2.90 g (12%) of the product are obtained. expected, in the form of a yellow oil. XH NMR (DMSO D6) d 3.88 (s, 3H), 7.25 to 7.45 (m, 6H), 7.61 (d, 2H, J = 7.1 Hz), 7.79 (d, 2H, J = 8.3 Hz), 9.85 (br s, 1H). (g) 2 '-trifluoromethanesulfonyloxy- [1, 1'; 4 ', 1' '] terphenyl-4"-methylcarboxylate.
Analogously to example 13 (a), from 2.90 g (9.5 mmol) of the compound obtained in Example 34 (d), 3.62 g (87%) of the expected product are obtained, in the form of a beige-colored powder of melting point 95 ° C. XH NMR (CDC13) d 3.96 (s, 3H), 7.41 to 7.72 (m, 10H), 8.16 (d, 2H, J = 8.5 Hz). (h) 1-bromo-3- (3-methyl-but-2-enyl sulfane) -benzene. .00 g (132.0 mmoles) of 3-bromothiophenol, 200 ml of DMF and 18.23 g (138.0 mmoles) of potassium carbonate are introduced into a flask. 18.0 ml (157.0 mmoles) of 1-bromo-3-methyl-2-butene are added dropwise and the mixture is stirred at room temperature for five hours. The reaction medium is poured into the water, extracted with ethyl acetate, the organic phase is separated out, washed with water, dried over magnesium sulphate and evaporated. 33.00 g (97%) of the expected compound are taken up in the form of a yellow oil.
X H NMR (CDCl 3) d 1.62 (s, 3 H), 1.73 (s, 3 H), 3.54 (d, 2H, J = 7.7 Hz), 3.54 (d, 2H, J = 1. 1 Hz), . 28 (t, 1H, J = 7.7 Hz), 7.09 to 7.15 (m, 1H), 7.22 to 7.31 (m, 2H), 7.45 (s, 1H)? (i) 7-bromo-4, 4-dimethyl-t-iochroman. .00 g (97.0 mmoles) of l-bromo-3- (3-methyl-but-2-enylsulfane) -benzene, 200 ml of toluene and 27.75 g (146.0 mmoles) of paratoluene sulfonic acid are introduced into a flask. It is heated to reflux for four hours and the reactive medium is evaporated to dry. It is taken up with an aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, the organic phase is separated out after settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with heptane. 22.57 g (90%) of the expected compound are taken up in the form of a yellow oil. XH NMR (CDCl 3) d 1.23 (s, 6H), 1.84 to 1.89 (m, 2H), 2.92 to 2.97 (m, 2H), 7.03 (dd, 1H, J = 8.5 / 2.0 Hz), 7.13 (d, 1H) , J = 8.5 Hz), 7.15 (d, 1H, J = 2.0 Hz). (j) 7-bromo-4,4-dimethyl thiochromate boronic acid.
Analogously to example 1 (a), from 5.00 g (20.4 mmol) of the compound obtained in Example 34 (i), 2.63 g (61% of the expected product, in the form of a light beige solid are obtained. melting point 242 ° C. XH NMR (CDC13) d 1.37 (s, 6H), 1.98 to 2.02 (m, 2H), 3. 05 to 3.10 (m, 2H), 7.48 (d, 1H, J = 7.9 Hz), 7..82 (dd, 1H, J = 7.9 / 1.2 Hz), 7.89 (d, 1H, J = 1.0 Hz). (k) 2 '- (4,4-dimethyl-thiochroman-7-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-methylcarboxylate.
Analogously to example 13 (b), by reaction of 1.81 g (4.1 mmol) of the compound obtained in example 34 (g) with 1.04 g (5.0 mmol) of the boronic acid obtained in example 34 (j), 570 mg (30%) of the expected product, in the form of a white solid of melting point 172 ° C. XH NMR (CDCl 3) d 1.29 (s, 6H), 1.96 (t, 2H, J = 5.9 Hz), 3.02 (t, 2H, J = 5.9 Hz), 3.95 (s, 3H), 6.69 (dd, 1H, J = 8.1 / 1.8 Hz), 7.04 (d, 1H, J = 1.8 Hz), 7.14 (d, 1H, J = 8.2 Hz), 7.19 to 7.26 (m, 5H), 7.50 (d, 1H, J = 8.5 Hz), 7.65 to 7.67 (m, 2H), 7.73 (d, 2H, J = 8.4 Hz), 8.12 (d, 2H, J = 8.3 Hz). (1) 2 '- (4, 4-dimethyl-t-chloro-7-yl) - [l, l'; 4 ', l "] terphenyl-4" -carboxylic acid.
In an analogous manner to example 1 (e), from 570 mg (1.2 mmol) of the ester obtained in example 34 (k), 500 mg (90%) of 2 '- (4,4-dimethyl) acid are obtained. thiochroman-7-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a crystallized white solid of melting point 261 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 0.64 (s, 6H), 1.53 (t, 2H, J = 5.9 Hz), 2.65 (t, 2H, J = 6.0 Hz), 6.63 (d, 1H, J = 1.6 Hz), 6.71 (d, 1H, J = 8.0 Hz), 6.77 (dd, 1H, J = 8.1 / 1.7 Hz), 6.84 to 6.97 (, 5H), 7.19 (d, 1H, J = 8.6 Hz) , 7.32 to "7.36 (m, 2H), 7.42 (d, 2H, J = 8.3 Hz), 7.81 (d, 2H, J = 8.3 Hz).
Example 35 Acid (4, 4 -dimethyl-thioc-ornan-6-yl) - [I r l] phenyl-4-carboxylic acid (a) 1-bromo-4- (3-methyl-but-2-enylsulfañil) -benzene Analogously to example 34 (h), 37.40 g (93%) were obtained by reacting 30.00 g (159.0 mmol) of 4-bromothiophenol with 26.00 g (175.0 mmol) of 1-bromo-3-methyl-2-butene. ) of the expected product, in the form of a yellow oil. XH NMR (CDC13) d 1.59 (s, 3H), 1.71 (s, 3H), 3.51 (d, 2H, J = 7.7 Hz), 5.27 (t, 1H, J = 7.7 Hz), 7.19 (d, 2H, J = 8.5 Hz), 7.38 (d, 2H, J = 8.5 Hz). (b) 6-bromo-4,4-dimethyl-triochroman.
Analogously to example 34 (i), from 34.00 g (132.0 mmol) of the compound obtained in Example 35 (a), 21.80 g (64%) of the expected product are obtained, in the form of a dark brown solid of melting point 51 ° C. XH NMR (CDCl 3) d 1.31 (s, 6H), 1.93 (t, 2H, J = 6.0 Hz), 3.01 (t, 2H, J = 6.1 Hz), 6.94 (d, 1H, J = 8.4 Hz), 7.13 (dd, 1H, J = 8.4 / 2.2 Hz), 7 ^ 5 (d, 1H, J = 2.1 Hz). (c) 6-bromo-4,4-dimethyl-thiochroman boronic acid.
Analogously to example l (a), from . 00 g (20.4 mmoles) of the compound obtained in example 35 (b), 2.28 g (53%) of the expected product are obtained, in the form of a white solid of melting point 242 ° C. XH NMR (CDCl 3) d 1.43 (s, 6H), 1.98 to 2.04 (m, 2H), 3.06 to 3.11 (m, 2H), 7.21 (d, 1H, J = 7.8 Hz), 7.81 (dd, 1H, J = 7.8 / 1.1 Hz), 8.20 (d, 1H, J = 1. 1 Hz). (d) 2 '- (4,4-dimethyl-thiochroman-6-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-methylcarboxylate.
Analogously to example 13 (b), by reaction of 1.81 g (4.1 mmol) of the compound obtained in example 34 (g) with 1.04 g (5.0 mmol) of the boronic acid obtained in example 35 (c), 680 mg (35%) of the expected product, in the form of a colorless oil. XH NMR (CDC13) d 1.27 (s, 6H), 1.83 to 1.88 (m, 2H), 2.94 to 2.99 (m, 2H), 3.94 (s, 3H), 6.69 (d, _lH, J = 1.4 Hz), 7.04 to 7.25 (m, 7H), 7.51 (d, 1H, J = 7.9 Hz), 7.65 (dd, 1H, J = 7.9 / 2.0 Hz), 7.69 (d, 1H, J = 1.8 Hz), 7.73 (d , 2H, J = 8.5 Hz), 8.13 (d, 2H, J = 8.5 Hz). (e) 2 '- (, 4-dimethyl-thiochroman-6-yl) - [1, 1'; 4 ', 1"] terphenyl-4" -carboxylic acid.
Analogously to Example 1 (e), from 680 mg (1.5 mmol) of the ester obtained in example 35 (d), 280 mg (42%) of 2 '- (4,4-dimethyl) acid are obtained. thiochronan-6-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a crystallized white solid of melting point 279 ° C. XH NMR (CDCl 3) d 1.29 (s, 6H), 1.95 (t, 2H, J = 5.9 Hz), 3.01 (t, 2H, J = 5.9 Hz), 6.70 (dd, 1H, J = 8.2 / 1.9 Hz) , 7.01 (d, 1H, J = 1.9 Hz), 7.15 (d, 1H, J = 8.3 Hz), 7.17 to 7.42 (m, 5H), 7.50 (d, 1H, J = 8.7 Hz), 7.65 to 7.69 ( m, 2H), 7.73 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.4 Hz).
Example 36 2 '- (3,5, 5, 8,8-pentyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1' '] terphenyl-4' '-carboxylic. (a) 6-bromo-l, 1,4,4,7-pentamethyl-l, 2,3,4-tetrahydro-naphthalene.
In a triple neck flask, under an argon atmosphere, 18.31 g (100.0 mmol) of dichloro-2,5-dimethyl-2,5-hexane, 17.10 g (100.0 mmol) of 2-bromo-toluene and 200 ml of 1: 1 are introduced. , 2-dichloroethane. 1.33 g (10.0 mmol) of aluminum chloride is added quickly and once and the reaction medium is stirred for thirty minutes at room temperature. The reaction medium is poured into the water, extracted with dichloromethane, washed with water, the organic phase is decanted, dried over magnesium sulphate, evaporated, taken up after recrystallization from the residue in methanol, 17.78 g. (63%) of the expected compound, in the form of fine white crystals of melting point 73 ° C.
X H NMR (CDCl 3) d 1.25 (s, 12 H), 1.65 (s, 4 H), 2.33 (s, 3 H), 7.14 (s, 1 H), 7.42 (s, 1 H). (b) 5, 6, 7, 8-tetrahydro-3,5,5,8,8-pentamet-il-2-naphthylboronic acid. _ Analogously to example l (a), from 14. 00 g (49.8 mmoles) of the compound obtained in example 36 (a), 7.36 g (60%) of the expected product are obtained, in the form of a colorless oil. XH NMR (CDCl 3) d 1.32 (s, 6H), 1.34 (s, 6H), 1.72 (s, 4H), 2.81 (s, 3H), 7.21 (s, 1H), 8.28 (s, 1H). (c) ethyl 4- [4-hydroxy-3- (5,6,7,8 -tetrahydro-3,5,5,8,8-pentyl-ethyl-2-naphthyl) phenyl] benzoate.
Analogously to example 1 (d), by reaction of 2.26 g (7.0 mmol) of the compound obtained in Example 1 (c) with 2.08 g (8.4 mmol) of the boronic acid obtained in example 36 (b), 1.00 g (32%) of the expected product, in the form of a colorless oil. XH NMR (CDCl 3) d 1.27 (s, 6H), 1.33 (s, 6H), 1.41 (t, 3H, J = 7.1 Hz), 1.71 (s, 4H), 2.17 (s, 3H), 4.39 (q, 2H, J = 7.1 Hz), 5.05 (s, 1H), 7.09 (d, 1H, J = 8.4 Hz) (7.21 (s, 1H), 7.25 (s, 1H), 7.45 (d, 1H, J = 2.3 Hz), 7.56 (dd, 1H, J = 8.4 / 2.3 Hz), 7.64 (d, 2H, J- = 8.4 Hz), 8.08 (d, 2H, J = 8.4 Hz). (d) 3 '- (3, 5,5,8, 8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -4't -difluoromethanesulfonyloxy -biphenyl-4-carboxylic acid ethyl ester.
Analogously to example 13 (a), 1.30 g (100%) of the expected product are obtained, in the form of a yellow oil. XH NMR (CDC13) d 1.26 (d, 6H, J = 6.8 Hz), 1.31 (d, 6H, J = 6.5 Hz), 1.42 (t, 3H, J- = 7.1 Hz), 1.71 (s, 4H), 2.15 (s, 3H), 4.40 (q, 2H, J = 7.1 Hz), 7.16 (s, 1H), 7.21 (s, 1H), 7.43 to 7.47 (m, 1H), 7.64 to 7.68 (, 2H), 7.67 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.4 Hz). (e.) 2 '- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1' '] ethyl terphenyl-4"-carboxylate.
Analogously to example 13 (b), by reaction of 1.00 g (1.7 mmol) of the compound obtained in Example 36 (d) with 254 mg (2.1 mmol) of benzene boronic acid, 770 mg (88%) of the expected product, under the form - of a colorless oil that will be used directly in the next stage. (f) 2 '- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, l'; 4 ', l' '] Terfenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 770 mg (1.5 mmol) of the ester obtained in Example 36 (e), 150 mg (21%) of 2 '- (3.5.5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a powder beige color of 'fusion 217 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 1.20 (s, 6H), 1.26 (s, 6H), 1.63 (s, 3H), 2.11 (s, 3H), 6.28 (br s, 1H), 6.83 a 7.16 (m, 5H), 7.23 (s, 1H), 7.37 (d, 1H, J = 2.2 Hz), 7.47 (dd, 1H, J = 8.4 / 2.4 Hz), 7.57 (d, 2H, J = 8.4 Hz ), 8.02 (d, 2H, J = 8.3 Hz).
Example 37 2 '- (3-methoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terf acid enyl -4 '' -carboxylic. _ (a) 3-bromo-5, 5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ol.
Analogously to example 36 (a), by reaction of 67.14 g (388.0 mmoles) of 2-bromophenol with 71.10 g (388.0 mmoles) of 2,5-dichloro-2,5-dimethylhexane, 86.13 g (78%) are obtained. ) of the expected product, in the form of a white solid with a melting point of 90-94 ° C. XH NMR (CDC13) d 1.16 (s, 6H), 1.17 (s, 6H), 1.57 (s, 4H), 5.21 (s, 1H), 6.87 (s, 1H), 7.26 (s, 1H). (b) 6-bromo-7-methoxymethoxy-1, 1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene.
Analogously to example 7 (a), by reaction of 8.00 g (28.2 mmol) of the compound obtained in example 37 (a) with 2.36 ml (31.1 mmol) of methyl chloromethyl ether, 9.49 g (100%) are obtained. of the expected product, in the form of a beige-colored oil. XH NMR (CDC13) d 1.24 (s, 6H), 1.26 (s, 6H), 1.65 (s, 4H), 3.53 (s, 3H), 5.20 (s, 2H), 7.06 (s, 1H), 7.42 ( s, 1H). _ (c) 3-methoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylboronic acid.
Analogously to example 1 (a), from 9.49 g (29.0 mmoles) of the compound obtained in example 37 (b), 8.21 g (97%) of the expected product are obtained, in the form of a yellow oil . XH NMR (CDCl 3) d 1.12 (s, 12H), 1.51 (s, 4H), 3.34 (s, 3H), 5.10 (s, 2H), 6.40 (s, 2H), 6.88 (s, 1H), 7.64 (s, s, 1H). (d) Ethyl 4- [4-hydroxy-3- (3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8 -ethermethyl-2-naphthyl) phenyl] benzoate .
In a manner analogous to Example 1 (d), by reaction of 8.10 g (25.2 mmol) of the compound obtained in Example 1 (c) with 6.15 g (21.0 mmol) of the boronic acid obtained in example 37 (c), 5.26 g (51%) of the expected product, in the form of a light yellow oil. XH NMR (CDC13) d 1.21 (s, 6H), 1.25 (s, 6ti) _ 1.33 (t, 3H, J = 7.1 Hz), 1.63 (s, 4H), 3.31 (s, 3H), 4.31 ( q, 2H, J = 7.1 Hz), 5.06 (s, 2H), 6.31 (s, 1H), 7.00 (d, H, J = 8.3 Hz), 7.09 (s, 1H), 7.20 (s, 1H), 7.45 to 7.48 (dd, 1H, J = 8.3 / 2.3 Hz), 7.51 (d, 1H, J = 2.3 Hz), 7.57 (d, 2H, J = 8.4 Hz), 8.01 (d, 2H, J = 8.4 Hz ). (e) 3 '- (3-methoxymethoxy-5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -4'-trifluoromethanesulfonyloxy-bi-phenyl-4-carboxylate of ethyl.
Into a flask and under a stream of nitrogen, 4.76 g (9.7 mmol) of the ethyl ester obtained in example 37 (d), 2.64 g (9.7 mmol) of 4-nitrophenol triflate, 2.64 g (1.9 mmol) are introduced. potassium carbonate and 100 ml of 1,2-dimethoxyethane. It is stirred at room temperature for three hours, the reaction medium is poured into a mixture of water and ethyl ether, the organic phase is separated out, extracted with ethyl ether, washed with water until the disappearance of the 4-nitrophenol from the phase aqueous, dried over magnesium sulfate, evaporated. 6.05 g (100%) of the expected product are recovered, in the form of a beige oil. XH NMR (CDC13) d 1.26 (t, 3H, J = 7.1 Hz), 1.27 (s, 6H), 1.32 (s, 6H), 1.72 (s, 4H), 3.37 (s, 3H), 3.41 (q, 2H, J = 7.1 Hz), 5.10 (s, 2H), 7.17 (s, 1H), 7.19 (s, 1H), 7.42 (d, 1H, J = 8.5 Hz), 7.62 to 7.71 (m, 4H), 8.13 (d, 2H, J = 8.4 Hz). (f) 2 '- (3-methoxymethoxy-5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"'" terphenyl-4"-ethylcarboxylate.
Analogously to example 13 (b), by reaction of 6.59 g (10.6 mmol) of the compound obtained in example 37 (e) with 1.55 g (12.7 mmol) of benzene boronic acid, 5.30 g (91%) of the product are obtained. Expected, in the form of a colorless oil XH NMR (CDCl 3) d 1.26 (s, 6H), 1.27 (s, 6H), 1.30 (t, 3H, J = 7.1 Hz), 1.60 to 1.64 (m, 4H) , 3.22 (s, 3H), 4.41 (q, 2H, J = 7.1 Hz), 4.75 (br s, 2H), 6.93 (s, 1H), 7.02 (s, 1H), 7.16 to 7.19 (m, 2H), -7.44 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8. 0 Hz), 7.62 to 7.77, (m, 6H), 8.13 (d, 2H, J = 7.6 Hz). (g) 2 '- (3-methoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, l'; 4 ', l' '] terphenyl-4"-carboxylic acid.
In a manner analogous to example 1 (e), from 1.00 g (1.8 mmol) of the ester obtained in Example 37 (f), 540 mg (57%) of 2 '- (3-methoxymethoxy) -3- 5, 5.8, 8 -tetrame ti 1-5, 6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a crystallized white solid of melting point 219-222 ° C. XH NMR (CDC13) d 1.03 (br s, 6H), 1.26 (d, 6H), 1.58 to 1.66 (m, 4H), 3.21 (s, 3H), 4.75 (br s, 2H), 6.93 (s, 1H ), 7.01 (s, 1H), 7.16 to 7.21 (m 5H), 7.55 (d, 1H, J = 8.0 Hz), 7.68 (dd, 1H, J = 8., 0 / 1.9 Hz), 7.72 (s, 1H), 7.74 (d, 2H, J = 8.4 Hz '), 8.14 (d, 2H, < J = 8.4 Hz).
Example 38 2 '- (3-Hydroxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-carboxylic (a) 2 '- (3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, l'; 4 ', l' '] terphenyl-4"-ethylcarboxylate.
Analogously to Example 16 (a), from 4.30 g (7.8 mmol) of the compound obtained in Example 37 (f), 1.65 g (42%) of the expected product is obtained, in the form of a white powder of melting point 145 ° C. XH NMR (CDC13) d 0.98 (s, 6H), 1.24 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 1.56 1 1.64 (m, 4H), 4.41 (q, 2H, J = 7.1 Hz), 4.76 (s, 1H), 6.80 (d, 2H, J = 7.1 Hz), 7.13 to 7.23 (m, 5H), 7.62 (d, 1H, J = 7.9 ^ Hz), 7.72 to 7.23 (m, 1H), 7.74 (d, 2H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.4 Hz). (b) 2 '- (3-hydroxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, l'; 4 ', l' '] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 600 mg (1.1 mmol) of the ester obtained in example 38 (a), 400 mg (70%) of 2 '- (3-hydroxy-5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a white crystallized solid of melting point 273 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 0.96 (s, 6H), 1.23 (s, 6H), 1.53 to 1.61 (m, 4H), 6.70 (s, 1H), 6.79 (s, 1H), 7.13 at 7.18 (m, 5H), 7.54 (d, 1H, J = 8.0 Hz), 7.66 (dd, 1H, J = 8.0 / 1.9 Hz), 7.74 (d, 2H, J = 8.3 Hz), 7.82 (d, 1H, J = 1.8 Hz), 8.10 (d, 2H, J = 8.3 Hz), 8.18 (br s, 1H).
Example 39 2 '- (3-methoxy-5, 5, 8, 8-te trame t -tyl, 5, 6, 7, 8 -tetrahydro-naphtal in -2-yl) - [1, 1'; 4 ', 1' '] terphenyl -4' '-carboxy I co. (a) 2 '- (3-methoxy-5, 5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' ' ] ethyl terphenyl-4"-carboxylate.
Analogously to example 78 (a), by reaction of 530 mg (1.1 mmol) of the compound obtained in Example 38 (a) with 71 μl (1.1 mmol) of methyl iodide, 544 mg (100%) of the expected product, in the form of a colorless oil. XH NMR (CDC13) d 1.04 (s, 6H), 1.27 (s, 6H), 1.42 (t, 3H, J = 7.1 Hz), 1.59 to 1.67 (m, 4H), 3.48 (s, 3H), 4.40 ( q, 2H, J = 7.1 Hz), 6.68 (s, 1H), 6.94 (s, 1H), 7.10 to 7.19 (m, 5H), 7.54 (d, 1H, J = 8.0 Hz), 7.67 (dd, 1H , J = 8.0 / 2.0 Hz), 7.73 to 7.74 (m, 1H), 7.75 (d, 2H, J = 8.4 Hz), 8.12 (d, 2H, J = 8.4 Hz). (b) 2 '- (3-methoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, l'; 4 ', l' '] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 544 mg (1.0 mmol) of the ester obtained in example 39 (a), 490 mg (95%) of 2 '- (3-methoxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1"') terphenyl-4" -carboxylic acid, in the form of a crystallized white solid of melting point 248 ° C.
XH NMR (CDCl 3 + 2 drops of DMSO D6) d 1.04 (s, 6H), 1.27 (s, 6H), 1.59 to 1.67 (m, 4H), 3.48 (s, 3H), 6.67 (s, 1H), 6.93 (s, 1H), 7.10 to 7.18 (m, 5H), 7.54 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 8.0 / 2.0 Hz), 7.73 (d, 2H, J = 8.3 Hz), 7.74 (s? 1H), 8.13 (d, 2H, J = 8.3 Hz).
Example 40 2 '- (3-propyl oxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] acid terfenyl-4 '' -carboxylic (a) 2 '- (3-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] ethyl terphenyl- "-carboxylate.
Analogously to example 7 (a), by reaction of 450 mg (8.3 mmol) of the compound obtained in Example 38 (a) with 89 μl (9.2 mmol) of propyl iodide, 450 mg (92%) of the expected product, in the form of a yellow solid of melting point 163 ° C, which will be used directly in the next stage. (b) 2 '- (3-propyloxy-5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1" ] terphenyl-4"-carboxylic acid.
Analogously to example 18e), from 450 mg (0.8 mmol) of the ester obtained in Example 40 (a), 400 mg (94%) of 2 '- (3-propyloxy-5, 5, 8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a solid crystallized white of melting point 234 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 0.85 (t, 3H, J = 7.5 Hz), 0.95 (br s, 6H), 1.27 (s, 6H), 1.54 to 1.70 (m, 6H), 3.72 ( t, 2H, J = 6.6 Hz), 6.73 (s, 1H), 6.82 (s, 1H), 7.11 to 7.17 (m, 5H), 7.53 (d, 1H, J = 8.0 Hz), 7.66 (dd, 1H , J = 8.0 / 1.9 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.79 (d, 1H, J = 1.8 Hz), 8.13 (d, 2H, J = 8.3 Hz).
Example 41 Acid -methyl-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 -tetrahydro-naph talen-2-yl) - [1, 1'; 4 ', 1"] terphenyl -4"-carboxylic (a) 2-bromo-4-nitrophenol.
In a triple neck flask, under an argon atmosphere, 139.40 (64.7 mmol) of 4-nitrophenol and 130 ml of dichloromethane are introduced. It is cooled to 0 ° C and 3.31 ml (67.7 mmol) of bromine are added dropwise. The reaction medium is stirred for one hour at 0 ° C, then 360 mg (6.5 mmol) of powdered iron are added and it is stirred for sixteen hours at room temperature. The reaction medium is poured into water, a saturated solution of sodium thiosulfate is added, it is extracted with dichloromethane, washed with water, the organic phase is separated out, dried over magnesium sulphate and the solvents are evaporated. 13.50 g (96%) of the expected compound are recovered in the form of a beige-colored powder of melting point 105-107 ° C. XH NMR (CDC13) d 6.34 (br s, 1H), 7.13 (d, 1H, J = 9.0 Hz), 8.16 (dd, 1H, J = 9.1 / 2.7 Hz), 8.44 (d 1H, J = 2.7 Hz) . (b) '4-nitro-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenol.
Analogously to example 1 (d), by reaction of 160.00 g (672.0 mmol) of boronic acid obtained in example 1 (a) with 100.00 g (459.0 mmol) of the compound obtained in example 41 (a), 81.70 g (55%) of the expected compound, in the form of a yellow oil. XH NMR (CDC13) d 1.25 (s, 6H), 1.26 (s, 6H), 1.67 (s, 4H), 5.89 (br s, 1H), 7.00 (d, 1H, J = 9.7 Hz), 7.13 (dd) , 1H, J = 8.1 / 1.9 Hz), 7.28 (d, 1H, J = 1.9 Hz), 7.41 (d, 1H, J = 8.1 Hz), 8.07 to 8.11 (m, 2H). (c) tri-fluoro-methansulphonate 4-nitro-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -phenyl ester.
Analogously to example 13 (a), from 78.50 g (241.0 mmol) of the compound obtained in example 41 (b), 81.40 g (73%) of the expected product are obtained, in the form of a gray powder of melting point 87-89 ° C. XH NMR (CDCl 3) d 1.31 (s, 6H), 1.32 (s, 6H), 1.73 (s, 4H), 7.21 (dd, 1H, J = 8.2 / 2.0 Hz), 7.39 (d, 1H, J = 1.9 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.56 (d, 1H, J = 9.0 Hz), 8.27 (dd, 1H, J = 9.0 / 2.9 Hz), 8.37 (d, 1H, J = 2.8 Hz). (d) 1,1,4,4, -tetramethyl-6- (4-nitro-biphenyl-2-yl) -1,2,3,4-tetrahydro-naphthalene. _ Analogously to example 13 (b), by reaction of 81.00 g (177.0 mmol) of the compound obtained in Example 41 (c) with 32.20 g (265.0 mmol) of phenyl boronic acid, 62.20 g (91%) of the product are obtained expected, in the form of a beige-colored powder of melting point 181-183 ° C. XH NMR (CDC13) d 0.90 (s, 6H), 1.26 (s, 6H), 1.56 to 1.64 (m, 4H), 6.84 (d, 1H, J = 1.9 Hz), 7.09 to 7.15 (m, 3H), 7.25 to 7.30 (m, 4H), 7.56 (d, 1H, J = 8.4 Hz), 8.21 (dd, 1H, J = 8.5 / 2.4 Hz), 8.32 (d, 1H, J = 2.4 Hz). (e) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) biphenyl-4-ylamine.
In a two-liter hydrogenator, 62.00 g (160.0 mmol) of the compound obtained in Example 41 (d9 and one liter of methanol) are introduced, purged with nitrogen, 1.85 g of 5% palladium on carbon are added, Hydrogen and the reactive medium is stirred for six hours at 60 ° C under a pressure of seven bars of hydrogen.After cooling the reactive medium and filtering on Celite®, the solvents are evaporated and the product is purified by column chromatography. of silica is eluted with a mixture composed of 80% heptane and 20% ethyl acetate.After evaporation of the solvents, 43.00 g (75%) of the expected compound are taken up in the form of an orange oil. XH NMR (CDC13) d 1.25 (s, 12H), 1.53 to 1.63 (m, 4H), 3.74 (br s, 2H), 6.72 (dd, 1H, J = 8.1 / 2.5 Hz), 6.79 (d, 1H, J = 2.4 Hz), 6.86 (d, 1H, J = 1.9 Hz), 7.04 to 7.24 (m, 8H). (f) 6- (4-iodo-biphenyl-2-yl) -l, l, 4, 4-te tramethi, 1-1, 2, 3, 4-tetrahydro-naphthalene. 500.00 g (113.0 mmol) of the compound obtained in example 41 (e) and 113 ml (113 mmol) of a 1M diiodomethane solution are introduced into a 500 ml flask under an argon atmosphere. 45.5 ml of isoamyl nitrile is left to drip off and the reaction medium is heated for twenty minutes at 60 ° C. After evaporating to dryness, the product is purified by chromatography on a silica column, eluted with a mixture composed of 90% heptane and 10% ethyl acetate. After the. After evaporation of the solvents, 21.00 g (40%) of the expected compound are taken up in the form of a white powder with a melting point of 120-122 ° C. XH NMR (CDC13) d 0.89 (s, 6H), 1.25 (s, 6H), 1.54 to 1.62 (m, 4H.), 6.80 (d, 1H, J = 1.9 Hz), 7.03 to 7.24 (m, 8H) , 7.70 (dd, 1H, J = 8.1 / 1.9 Hz), 7.80 (d, 1H, J = 1.8 Hz). (g) 3- (5, 5, 8, 8-tet ramethyl-5, 6, 7, 8 tetrahydro-naphthalen-2-yl) -4-phenyl-benzene boronic acid.
Analogously to example 1 (a), from 18.00 g (38.0 mmol) of the compound obtained in example 41 (f), 11.90 g (81%) of the expected product are obtained, in the form of a pink white solid melting point 257-259 ° C. XH NMR (CDCl 3) d 0.93 (s, 6H), 1.28 (s, 6H), 1.58 to 1.63 (m, 4H), 6.92 (d, 1H, J = 1.7 Hz), 7.20 to 7.31 (m, 7H), 7.56 (d, 1H, J = 7.6 Hz), 8.28 (dd, 1H, J = 8.7 / 1.1 Hz), 8.34 (s, 1H). (h) 3"-methyl-2 '- (5,5,8,8-tetramethyl-5,6,7, tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-methylcarboxylate.
Analogously to example 1 (d), by reaction of 700 mg (1.8 mmol) of the compound obtained in Example 41 (g) with 380 mg (1.7 mmol) of methyl 2-methyl-4-bromobenzoate, 740 are obtained mg (91%) of the expected product, in the form of a white solid of melting point 130-132 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.27 (s, 6H), 1.54 to 1.64 (m, 4H), 2.68 (s, 3H), 3.92 (s, 3H), 6.89 (d, 1H, J = 7.1 Hz), 7.15 to 7.29 (m, 7H), 7.50 to 7.56 (m, 3H), 7.65 (dd, 1H, J = 7.9 / 1.8 Hz), 7.72 (d, 1H, J = 1.7 Hz), 8.02 (d, 1H, J = 8.7 Hz). (i) 3"-methyl-2 '- (5, 5, 8, 8-tet ramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; , l ''] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 700 mg (1.4 mmol) of the ester obtained in Example 41 (h), 537 mg (79%) of 3"-methyl-2 '- ( 5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1"] terfeni 1-4" - carboxylic acid, in the form of a crystallized white solid of melting point 237-239 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.27 (s, 6H), 1.57 to 1.65 (m, 4H), 2.75 (s, 3H), 6.90 (d, 1H, J = 1.8 Hz), 7.15 a 7.30 (m, 7H), 7.53 (d, 1H, J = 7.9 Hz), 7.59 to 7.61 (m, 2H), 7.66 (d, 1H, J = 8.0 / 1.9 Hz), 7.74 (d, 1H, J = 1.8 Hz), 8.19 (d, 1H, J = 8.7 Hz).
Example 42 Acid-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] terphenyl- 4 '' -carboxylic (a) 3-hydroxy-4-iodo-benzoic acid.
In a one liter triple necked flask under a stream of nitrogen, introduce 25.00 g (180.0 mmol) of 3-hydroxybenzoic acid, 7.20 g (180.0 mmol) of soda into tablets, 27.13 g (180.0 mmol) of sodium iodide. and 500 ml of methanol. It is cooled to 0 ° C and 374.30 g (180.0 mmoles) of an aqueous solution of sodium hypochlorite are added dropwise in one hour and fifty minutes. The reaction medium is stirred for two hours at 0 ° C, then a solution of sodium thiosulfate is added, acidified to pH 5, extracted with ethyl ether, the organic phase is washed with water until neutral pH, dried over sulphate of magnesium, it is filtered and the solvents are evaporated. 43.80 g (92%) of the expected compound are taken up in the form of a beige powder of melting point 198 ° C. XH NMR (DMSO D6) d 7.13, (dd, 1H, J = 8.1 / 1.9 Hz), 7.43 (d, 1H, J = 1.8 Hz), 7.80 (d, 1H, J = 8.1 Hz), 10.69 (br s) , 1H), 12.98 (br s, 1H). (b) methyl 3-hydroxy-4-iodo-benzoate Analogously to example 1 (b), from 43.80 g (166.0 mmol) of the acid obtained in example 42 (a), 43.54 g (94%) of methyl 3-hydroxy-4-iodo-benzoate are obtained , in the form of a beige powder of melting point 153 ° C.
X H NMR (CDCl 3) d 3.89 (s, 3 H), 7.25 (dd, 1 H, J = 8.2 / 1.9 Hz), 7.58 (d, 1 H, J = 1.9 Hz), 7.77 (d, 1 H, J = 8.2 Hz) 8.79 (br s, lH). (c) 2"-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, _6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] methyl terphenyl-4 '' -carboxylate.
Analogously to example 1 (d), by reaction of 2.80 g (7.3 mmol) of the boronic acid obtained in example 41 (g) with 1.84 g (6.6 mmol) of the compound obtained in example 42 (b), 2.0 g (62%) of the expected product, in the form of a white solid of melting point 183-185 ° C. XH NMR (CDCl 3) d 0.89 (s, 6H), 1.26 (s, 6H), 1.56 to 1.64 (m, 4H), 3.94 (s, 3H), 5.51 (s, 1H), 6.89 (d, 1H, J = 1.9 Hz), 7.18 to 7.26 (m, 7H), 7.42 (d, 1H, J = 8.3 Hz), 7.53 to 7.55 (m, 2H), 7.59 to 7.60 (m, 1H), 7.68 to 7.71 (m, 2H). (d) 2"-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', l ''] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 500 mg (1.0 mmol) of the ester obtained in example 42 (c), 480 mg (99%) of 2"-hydroxy-2 '- acid are obtained ( 5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1' '] terphenyl-4' '- carboxylic acid, in the form of a crystallized white solid of melting point 282-284 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 0.90 (s, 6H), 1.25 (s, 6H), 1.55 to 1.63 (m, 4H), 6.88 (d, 1H, J = 1.5 -Hz), 7.12 a 7.25 (m, 7H), 7.43 (d, 1H, J = 8.1 Hz), 7.47 (d, 1H, J = 8.7 Hz), 7.61 (s, 1H9, 7.65 to 7.67 (m, 1H), 7.71 (d, 2H, J = 7.6 Hz).
E emplo 43 Acid 2 '' -me tox imet oxy -2 '- (5,5,8,8-tetramethyl 5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] terphenyl-4 '' -carboxylic. (a) 2"-methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-methylcarboxylate.
Analogously to example 7 (a), by reaction of 580 mg (1.2 mmol) of the compound obtained in example 42 (c) with 103 μl (1.3 mmol) of methyl chloromethyl ether, 630 mg (100%) are obtained of the expected product, in the form of an orange oil. XH NMR (CDC1) d 0.91 (s, 6H), 1.26 (s, 6H), -1.56 to 1.63 (m, 4H), 3.48 (s, 3H), 3.94 (s, 3H), 5.26 (s, 2H) , 6.91 (d, 1H, J = 1.8 Hz), 7.10 (dd, 1H, J = 7.9 / 1.9 Hz), 7.19 to 7.25 (m, 6H), 7.46 to 7.51 (m, 2H), 7.61 (dd, 1H , J = 7.8 / 1.7 Hz), 7.65 (d, 1H, J = 1.7 Hz), 7.79 (dd, 1H, J = 7.9 / 1.8 Hz), 7.89 (d, 1H, • J = 1.5 Hz). (b) 2"-methoxymethoxy-2 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1; 4 ', 1"] terphenyl-4" -carboxylic.
In a manner analogous to example 1 (e), from 620 mg (1.2 mmol) of the ester obtained in the example 43 (a), 556 mg (92%) of the 2"-methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl acid are obtained. ) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, in the form of a crystallized white solid of melting point 204-206 ° C. XH NMR (CDCl 3) d 0.92 (s, 6H), 1.26 (s, 6H), 1.56 to 1.64 (m, 4H), 3.49 (s, 3H), 5.28 (s, 2H), 6.92 (d, 1H, J = 1.7 Hz), 7.12 (dd, 1H, J = 7.9 / 1.8 Hz), 7.18 to 7.7.26 (m, 6H), 7.49 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 8.0 Hz), 7.62 (dd, 1H, J = 8.0 / 1.8 Hz), 7.67 (d, 1H, J = 1.6 Hz), 7.88 (dd, 1H, J = 7.9 / 1.8 Hz), 7.99 (d, 1H, J = 1.4 Hz). _ Example 44 Acid-methoxy-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"] terphenyl- 4 '' -carboxylic. (a) 2 '' -me toxy -2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] methyl terphenyl-4 '' -carboxylate.
Analogously to example 7 (a), by reaction of 500 mg (1.0 mmol) of the compound obtained in example 42 (c) with 70 μl (1.1 mmol) 'of methylene iodide, 510 mg (99%) are obtained of the expected product, in the form of a beige powder of melting point '144-146 ° C. XH NMR (CDC13) d 0.90 (s, 6H), 1.26 (s, 6H), 1.56 to 1.63 (m, 4H), 3.93 (s, 3H), 3.95 (s, 3H), 6.90 (d, 1H, J = 1.8 Hz), 7.14 to 7.26 (m, 7H), 7.46 (s, 1H), 7.49 (s, 1H), 7.61 (dd, 1H, J = 7.9 / 1.8 Hz), -7.66 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 1.3 Hz), 7.73 (d, 1H, J = 7.8 Hz). (b) 2"-methoxy-2 '- (5, 5, 8, 8 -ethamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; ', 1' '] terphenyl-4' '-carboxylic.
Analogously to example 1 (e), from 500 mg (1.0 mmol) of the ester obtained in Example 44 (a), 420 mg (86%) of 2"-methoxy-2 '- ( 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1"] terphenyl-4" -carboxylic acid, in the form of a crystalline white solid of melting point 272-274 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 0.91 (s, 6H) , 1.26 (s, 6H), 1.55 to 1.63 (m, 4H), 3.92 (s, 3H), 6.90 (d, 1H, J = 1.8 Hz), 7.13 to 7.25 (m, 7H), 7.45 (d, 1H) , J = 1.4 Hz), 7.49 (d, 1H, J = 1.3 * Hz), 7.62 (dd, 1H, J = 7.9 / 1.8 Hz), 7.65 (d, 1H, J. = 1.6 Hz), 7.71 (s) , 1H), 7.75 (d, 1H, J = 8.1 Hz ').
Example 45 2 '' - Propyloxy-2 '- (5,5,8,8-tetramethyl) acid , 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid. (a) 2 '' - propyloxy-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1 ''] methyl terphenyl-4 '' -carboxylate.
Analogously to example 7 (a), by reaction of 500 mg (1.0 mmol) of the compound obtained in example 42 (c) with 110 μl (1.1 mmol) of propyl iodide, 530 mg (98%) of the expected product, in the form of a dark brown oil. XH NMR (CDC13) d 0.91 (s, 6H), 1.03 (t, 3H, J = 7.5 Hz), 1.25 (s, 6H), 1.55 to 1.63 (m, 4H), 1.86 (sext, 2H, J = 6.8 Hz), 3.94 (s, 3H), 4.06 (t, 2H, J = 6.5 Hz), 6.90 (d, 1H, J = 1.8 Hz), 7.12 (dd, 1H, J = 8.0 / 1.8 Hz), 7.17 a 7.26 (m, 6H), 7.47 (d, 1H, J = 7.9 Hz), 7.50 (d, 1H, J = 7.9 Hz), 7.64 to 7.69 (m, 4H). (b) 2"-propyloxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', l ''] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 520 mg (1.0 mmol) of the ester obtained in example 45 (a), 385 mg (77%) of 2"-propyloxy-2 '- acid are obtained ( 5, 5, 8, 8 -tetramet-il-5, 6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, the form of a crystallized white solid of melting point 216-218 ° C. XH NMR (CDC13) d 0.92 (s, 6H), 1.04 (t, 3H, J = 7.5 Hz), 1.26 (s, 6H), 1.56 to 1.64 (m, 4H), 1.87 (sext, 2H, J = 6.9 Hz), 4.08 (t, '2H, J = 6.5 Hz), 6.92 (d, 1H, J = 1.8 Hz), 7.14 to 7.25 (m, 7H), 7.48 (d, 1H , J = 7.9 Hz), 7.55 (d, 1H, J = 7.9 Hz), 7.66 to 7.74 (m, 3H), 7.82 (d, 1H, J = 8.0 Hz).
Example 46 3 '' -hydroxy-2 '- (5,5,8,8-tetramethyl) acid , 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1' '] terphenyl-4"-carboxylic (a) 3" -hydroxy-2' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2) -il) - [1, 1 '; 4', 1"Jphenylphenyl-4" methyl-carboxylate.
Analogously to example l (d) _, by reaction of 700 mg (1.8 mmol) of the boronic acid obtained in example 41 (g) with 420 mg (1.5 mmol) of methyl 4-yodosalicylate, 550 mg are obtained ( 75%) of the expected product, in the form of yellow crystals with a melting point of 134-136 ° C.
XH NMR (CDC13) d 0.91 (s, 6H), 1.27 (s, 6H), 1.55 to 1.65 (m, 4H), 3.98 (s, 3H), 6.88 (d, 1H, J = 1.9 Hz), 7.14 a 7.31 (m, 9H), 7.51 (d, 1H, J = 7.9 Hz), 7.65 (dd, 1H, J = 7.9 / 2.0 Hz), 7.72 (d, 1H, J = 1.9 Hz), 7.91 (d, 1H , J = 8.0 Hz), 10.82 (s, 1H). (b) 3"-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', l ''] terphenyl-4"-carboxylic acid.
Analogously to example 1 (e), from 550 mg (1.1 mmol) of the ester obtained in Example 46 (a), 277 mg (52%) of 3"-hydroxy-2 '- acid are obtained ( 5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, form of a crystallized white solid of melting point 266-268 ° C. XH NMR (CDCl 3) d 0.91 (s, 6H), 1.27 (s, 6H), 1.56 to 1.64 (m, 4H), 6.89 (d, 1H, J = 1.7 Hz), 7.14 to 7.25 (m, 9H), 7.28 (d, 1H, J = 2.9 Hz), 7.50 (d, 1H, J = 8.0 Hz), 7.65 (d, 1H, J = 8.0 / 1.8 Hz), 7.72 (d, 1H, J = 1.7 Hz), 7.95 (d, 1H, J = 8.2 Hz).
Example 47 6- [2- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifinyl-4-yl] nicotinic acid. (a) 6- [2- (5,5,8, 8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] -nicotinate ethyl.
Analogously to example 1 (d), by reaction of 700 mg (1.8 mmol) of the boronic acid obtained in Example 41 (g) with 460 mg (1.7 mmol) of ethyl 6-iodonotinate, 650 mg (80 mg) are obtained. %) of the expected product, in the form of a white solid of melting point 105-107 ° C.
XH NMR (CDCl 3) d 0.92 (s, 6H), 1.28 (s, 6H), 1.45 (t, 3H, J = 7.1 Hz), 1.57 to 1.65 (m, 4H), 4.44 (q, 2H, J = 7.1 Hz), 6.89 (d, 1H, J = 1.8 Hz), 7.18 to 7.30 (m, 6H), 7.57 (d, 1H, J = 7.9 Hz), 7.89 (d, 1H, J = 8.3 Hz), 8.10 a 8.15 (m, 2H, 8.36 (dd, 1H, J = 8.3 / 2.2 Hz), 9.31 (d, 1H, J = 2.1 Hz). (b) 6- [2- (5, 5, 8, 8-Tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] -nicotinic acid.
Analogously to example 1 (e), from 650 mg (1.3 mmol) of the ester obtained in Example 47 (a), 490 mg (80%) of 6- [2- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] -nicotinic acid, in the form of a white solid crystallized in fine needles, melting point 319- 321 ° C. XH NMR (CDCl 3) d 1.04 (s, 6H), 1.26 (s, 6H), 1.57 to% 1.63 (m, 4H), 7.21 to 7.41 (m, 7H), 7.58 (s, 1H), 7.65 (d, 1H, J = 8.1 Hz), 8.15 (d, 1H, J = 8.3 Hz), 8.41 (dd, 1H, J = 8.1 / 1.9 Hz), 8.59 (d, 1H, J = 1.8 Hz), 8.69 (d, 1H, J = 2.2 Hz), 9.82 (d, 1H, J = 1.9 Hz).
Example 48 - [2- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifinyl-4-yl] -pyridine-2-carboxylic acid, (a) 5- [2- (5,5,8,8-ethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] -pyridine-2-carboxylic acid.
Analogously to example 1 (d), by reaction of 700 mg (1.8 mmol) of the boronic acid obtained in example 41 (g) with 430 mg (1.7 mmol) of methyl 5-iodopyridine-2-carboxylate, 600 mg (77%) of the expected product, in the form of a white solid of melting point 160-162 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.27 (s, 6H), 1.55 to 1.65 (m, 4H), 4.05 (s, 3H), 6.90 (d, 1H, J = l.β 'Hz) , 7.16 to 7.30 (m, 7H), 7.57 (d, 1H, J = 7.9 Hz.), 7.67 (dd, 1H, J = 8.0 / 1.9 Hz), 7.72 (d, 1H, J '= 1.9 Hz), 8.10 (dd, 1H, J = 8.2 / 2.2 Hz), 8.24 (d, 1H, J = 8.2 Hz), 9.06 (d, 1H, J = 2.1 Hz). (b) 5- [2- (5, 5, 8, 8-Tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] -pyridine-2-carboxylic acid.
Analogously to example 1 (e), from 600 mg (1.3 mmol) of the ester obtained in the example 48 (a), 490 mg (84%) of 5- [2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl- acid are obtained. 4 -yl] -pyridine-2-carboxylic acid, in the form of a beige powder of melting point 222-224 ° C. XH NMR (CDC13) d 0.92 (s, 6H), 1.27 (s, 6H), 1.57 a 1. 65 (m, 4H), 6.89 (d, 1H, J = 1.6 Hz), 7.13 to 7.30 (m, 7H), 7.58 (d, 1H, J = 7.9 Hz), 7.68 (dd, 1H, J = 8.0 / 1.5 Hz), 7.73 (s, 1H).
Example 49 Acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naph talen-2-yl) - [1,1] ter-phenyl-4"-hydroxamic acid In a triple neck flask and under a stream of nitrogen, 2.00 g (4.3 mmol) of the acid obtained in example 14, 30 ml of ethanol and 290 mg (5.2 mmol) of powdered potash are successively introduced. The reaction medium is stirred for thirty minutes at room temperature, then evaporated to dryness. The residue is taken up in 80 ml of dichloromethane and 673 mg (4.8 mmol) of 0- (trimethylsilyl) hydroxylamine and 645 mg (4.8 mmol) of 1-hydroxybenzotriazole (HOBT) are added. After cooling the reaction medium to 0 ° C, 915 mg are added (4.8 mmol) of l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), the obtained solution is stirred for one hour at 0 ° C, then for sixteen hours at room temperature. The reaction medium is poured into a water / dichloromethane mixture, extracted with dichloromethane, the organic phase is washed with water until neutral pH, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of 20% ethyl acetate and "80% heptane." After evaporation of the solvents, 530 mg (22%) of the expected product, in the form of a beige solid of melting point 105-108 ° C. XH NMR (CDC13) d 0.90 (s, 6H), 1.26 (s, 6H), 1.55 to 1.63 (m, 6H), 4.70 to 5.20 (m, 2H), 6.88 (s, 1H), 7.12 to 7.27 (m, 7H), 7.49 (d, 1H, J = 7.9 Hz), 7. 60 (d, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 1.3 Hz), 7.73 (d, 2H, J = 8.2 Hz), 7.84 (d, 2H, J = 8.1 Hz).
Example 50 2 '- (5,5,8, 8 -tetramet-il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"] terphenyl-4" -ol.
Analogously to example 1 (d), by reaction of 700 mg (1.8 mmol) of the boronic acid obtained in example 41 (g) with 287 mg (1.7 mmol) of 4-bromophenol, 560 mg (89%) are obtained of 2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-ol, in the form of a colorless oil. XH NMR (CDC13) d 0.91 (s, 6H), 1.26 (s, 6H), 1.56 to 1.64 (m, 4H), 4.88 (s, 1H), 6.90 to 6.94 (m, 3H) 7.14 to 7.22 (m, 7H), 7.47 (d, 1H, J = 7.9 Hz), 7.57 (d, 2H, J = 8.0 Hz), 7.57 to 7.59 (m, 1H), 7.65 (d, 1H, J = 1.9 Hz).
Example 51 [2 '- (5, 5, 8, 8 -tetramet il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"] terphenyl-4' '-yl] -methanol.
In a two-liter three-neck flask and under a stream of nitrogen, 1.80 g (3.7 mmol) of the ester obtained in example 13 (b) and 30 ml of toluene are introduced. The solution obtained is cooled to -78 ° C and 14.7 ml (14.7 mmol) of a solution (1M in toluene) of diisobutylaluminum hydride are allowed to run dropwise. The reaction medium is stirred for one hour at -78 ° C, hydrolysed by INN hydrochloric acid and filtered. The organic phase is washed with water until neutral pH, dried over magnesium sulfate, filtered and the solvents are evaporated, after evaporation of the latter, 1.31 g "(79%) of [2 '- ( 5, 5, 8, 8-te-t -methyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l '; 4', l "] terphenyl-4" -il] -methanol, in the form of an orange solid of melting point 134-136 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.27 (s, 6H), 1.57 to 1.64 (m, 4H), 1.72 (br s, 1H), 4.75 (d, 2H, J = 3.4 Hz), 6.90 (d, 1H, J = 1.9 Hz), 7.14 to 7.28 (m, 7H), 7.44 to 7.51 (m, 3H), 7.63 (dd, 1H, J = 8.0 / 1.9 Hz), 7.67 to 7.71 (m, 3H) ).
Example 52 2 '- (5, 5, 8, 8 - te trame t i l -5, 6, 7, 8 - te trahidro -na f tal en -2 -íl) - [1, 1'; 4 ', 1' '] terphenyl -4' '-c'a rb to the dehi do.
Into a 500 ml flask, 640 mg (1.4 mmol) of the alcohol obtained in example 51, 2.50 g (28.7 mmol) of manganese oxide and 50 ml of dichloromethane are mixed. The reaction medium is stirred for twenty hours at room temperature, then the manganese oxide is filtered off and the dichloromethane is evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture composed of 80% heptane and "20% ethyl acetate." After evaporation of the solvents, 90 mg (14%) is taken up again. of the expected compound, under the form of a white powder of melting point 120-122 ° C. XH NMR (CDC1) d 0.91 (s, 6H), 1.27 (s, 6H), 1.56 to 1.64 (m, 4H) , 6.90 (d, 1H, J = 1.8 Hz), 7.14 to 7.29 (m, 7H), 7.54 (d, 1H, J = 8.0 Hz), 7.66 (dd, 1H, J = 7.9 / 2.0 Hz), 7.74 ( d, 1H, J = 1.9 Hz), 7.84 (d, 2H, J = 8.3 Hz), 7.97 (d, 2H, J = 8.3 Hz), 10.07 (s, 1H).
Example 53 4 '-methyl and carbon 4-methoxy-3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifenyl-4-carboxylic acid. (a) 4- [4-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8, tetramethyl-2-naphthyl) phenyl] benzyl benzoate.
In a flask and under current. of nitrogen, 6.00 g (15.0 mmol) of the compound obtained in example 1 (e) and 140 ml of DMF are introduced. It is cooled to 0 ° C, 502 mg (15.7 mmol) of sodium hydride (80% in the oil) is added in small quantities and stirred until the gas emission is stopped, then 1.87 ml (15.7 mmol) is added. of benzyl bromide and stirred for one hour at 0 ° C, then sixteen hours at room temperature.The reaction medium was poured into a mixture 2N HCl / ethyl acetate, extracted with ethyl acetate, the organic phase was decanted, it is dried over magnesium sulphate, evaporated, the residue obtained is purified by chromatography on a silica column, eluted with a mixture composed of 20% ethyl acetate and 80% heptane, after evaporation of the solvents, 5.21 g (71%) of the expected product are recovered in the form of a crystallized yellow solid of melting point 90-91 ° C. XH NMR (CDC13) d 1.34 (s, 6H), 1.36 (s, 6H), 1.76 (s, 4H), 5.40 (s, 2H), 5.47 (s, 1H), 7.11 (d, 1H, J = 8.8 Hz), 7.27 to 7.30 (m, 1H), 7.38 to 7.56 (m, 9H) , 7.66 (d, 2H, J = 8.4 Hz) , 8.14 (d, 2H, J = 8.4 Hz). (b) 4 '-methoxy carbonyl lmetoxy -3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-benzylcarboxylate.
Analogously to Example 2 (a), by reaction of 1.20 g (2.44 mmol) of the compound obtained in example 53 (a) with 280 μl (2.9 mmol) of methyl bromoacetate, 950 mg (70%) of the expected product, in the form of a white solid of melting point 104-106 ° C.
XH NMR (CDCl 3) d 1.27 (s, 6H), 1.33 (s, 6H), 1.72. (s, 4H), 3.80 (s, 3H), 4.67 (s, 2H), 5.38 (s, 2H), 6. 95 (d, 2H, J = 8.5 Hz), 7.37 to 7.54 (m, 8H), 7. 60 to 7.62 (, 2H), 7.64 (d, 2H, J = 8.5 Hz), 8.12 (d, 2H, J = 8.5 Hz). _ (c) 4'-methoxycarbonylmethoxy-3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid.
In a triple-necked flask under a stream of argon, 300 mg (0.53 mmol) of the compound obtained in example 53 (b), 20 ml of methanol and 10 ml of THF are introduced. The medium is degassed with argon and 60.0 mg (15% palladium on charcoal), purged with hydrogen and the reaction medium is stirred under a hydrogen atmosphere (slight overpressure) for 22 hours. Celite®, the solvents are evaporated, the product obtained is crystallized in a mixture composed of 10% ethyl ether and 90% heptane and 142 mg (57%) of the expected product are taken up in the form of a crystallized white solid of melting point 234-238 ° C.
X H NMR (CDCl 3) d 1.33 (s, 12 H), 1.72 (s, 4 H), 3.80 (s, 3 H), 4.68 (s, 2 H), 6.95 (d, 1 H, J = 8.5 Hz), 7. 33 to 7.40 (m, 2H), 7.53 (dd, 1H, J = 8.5 / 2.3 Hz), 7.60 to 7.66 (m, 4H), 8.11 (br s, 2H, J = 7.8 Hz). _ Example 54 4 '-carbox imet oxy-3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naph talen-2-yl) -biphenyl-4'-carboxylic acid.
Analogously to example 1 (e), from 650 mg (1.2 mmol) of the diester obtained in Example 53 (b), 470 mg (88%) of 4 '-carboxymethoxy-3' - (5%) acid are obtained. , 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a crystallized white solid of melting point 279-281 ° C. XH NMR (CDC13 + 2 drops of DMSO D6) d 1.33 (s, 12H), 1.72 (s, 4H), 4.65 (s, 2H), 6.99 (d, 1H, J = 8.6 Hz), 7.38 (d, 1H , "J = 7.3 Hz), 7.41 (d, 1H, J = 8.2 Hz), 7.53 (dd, 1H, J = 8.5 / 2.4 Hz), 7.60 to 7.62 (m, 2H), 7.64 (d, 2H, J = 8.4 Hz), 8.09 (d, 2H, J = 8.4 Hz).
Example 55 4 '- (5-ethoxycarbonyl-pentyloxy) -3' acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid. (a) 4 '- (5-ethoxycarbonyl-pentyloxy) -3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylate of benzyl.
Analogously to example 2 (a), by reaction of 1.20 g (2.4 mmol) of the compound obtained in Example 53 (a) with 520 μl (2.9 mmol) of ethyl 6-bromohexane, 1.52 g (100%) is obtained ) of the expected product, in the form of a yellow oil. XH NMR (CDC13) d 1.24 (t, 3H, J = 7.1 Hz), 1.32 (s, 6H), 1.33 (s, 6H), 1.42 to 1.49 (m, 2H), 1.64 (quint, 2H, J = 8.0 Hz), 1.72 (s, 4H), 1.78 (quint, 2H, J = 7.1 Hz), 2.27 (t, 2H, J = 7.6 Hz), 4.02 (t, 2H, J = 6.5 Hz), 4.11 (q, 2H, J = 7.1 Hz), 5.38 (s, 2H), 7.03 (d, 1H, J = 8.6 Hz), 7.32 to 7.57 (m, 8H), 7.57 (d, 1H, J = 1.5 Hz), 7.61 ( d, 1H, J = 2.4 Hz), 7.65 (d, 2H, J = 8.5 Hz), 8.12 (d, 2H, J = 8.5 Hz). (b) 4 '- (5-ethoxycarbonyl-pentyloxy) -3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-acid carboxylic Analogously to Example 53 (c), from 620 mg (1.0 mmol) of the diester obtained in Example 55 (a), 420 mg (80%) of 4 '- (5-ethoxycarbonyl-pentyloxy) are obtained -3 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a crystalline white solid of melting point 177 ° C. XH NMR (CDC13) d 1.25 (t, 3H, J = 7.2 Hz), 1.32 (s, 6H), 1.33 (s, 6H), 1.41 to 1.49 (m, 2H), 1.59 to 1.68 (, 2H), 1.73 (s, 4H), 1.78 to 1.83 (m, 2H), 2.27 (t, 1H, J = 7.6 Hz), 4.03 (t, 2H, J = 6.5 Hz), 4.12 (q, 2H, J = 7.1 Hz), 7.04 (d, 1H, J = 8.6 Hz), 7.30 to 7.38 (m, 2H), 7.53 (d, 1H, J = 2.1 Hz), 7.58 (d, 1H, J = 1.4 Hz), 7.63 (d, 1H, J = 2.3 Hz), 7.69 (d, 2H, J = 7.9 Hz), 8.16 ( br d, 2H, "J = 6.7 Hz).
Example 56 Acid (5-carboxy -pentyloxy) -3 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 -tetrahydro-naph' talen-2-11) -bifinyl-4-carboxylic acid.
Analogously to example 1 (e), from 750 mg (1.2 mmol) of the diester obtained in example 55 (a), 610 mg (100%) of 4 '- (5-carboxy-pentyloxy) are obtained -3 '- (5,5,8, 8-te tramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, in the form of a white solid crystallized from a fusion 245 ° C. XH NMR (DMSO D6) d 1.28 (s, 12H), 1.36 to 1.44 (m, 2H), 1.46 to 1.55 (s, 2H), 1.68 (s, 4H), 1.69 a 1. 73 (m, 2H), 2.18 (t, 2H, J = 7.0 Hz), 4.04 (t, 2H, J = 6.0 Hz), 7.20 (d, 1H, J = 8.6 Hz), 7.30 (dd, 1H, J = 8.0 / 1.2 Hz), 7.37 (d, 1H, J = 8.2 Hz), 7.56 (d, 1H, J = 1.1 Hz), 7.61 (d, 1H, J = 2.2 Hz), 7.66 (d, 1H, J = 8.6 / 2.1 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.99 (d, 2H, J = 8.3 Hz).
Example 57 2 '- (5, 5, 8, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] -terphenyl-4" -carboxamide. (a) 2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l'; 4 ', l' '] chloride - terphenyl-4"-carbonyl.
In a triple neck flask and under a stream of nitrogen, 6.00 g (12.9 mmol) of the acid obtained in example 14 and 240 ml of dichloromethane are introduced. 2.63 ml (13.5 mmol) of dicyclohexylamine are allowed to run dropwise and the solution is stirred for ten minutes at room temperature. 984 [mu] l (13.5 mmol) of thionyl chloride are allowed to run off and the solution obtained is stirred for fifteen minutes at room temperature. The reaction medium is evaporated to dryness, taken up in ethyl ether, filtered and the filtrate is evaporated to dryness. The acid chloride thus obtained is used directly in the next step. (b) 2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] -terphenyl- 4 '' -carboxamide.
Dissolve 1.03 g (2.1 mmol) of the acid chloride obtained in the preceding step in 100 ml of THF. The solution thus obtained is allowed to run dropwise in a solution composed of 2.6 ml (43.0 mmoles) of a 32% ammonia solution and 20 ml of THF. The reaction medium is stirred for one hour at room temperature, poured into the water and extracted with ethyl ether. The organic phase is washed with water until neutral pH, dried over magnesium sulfate, filtered and the solvents are evaporated. The residue obtained is triturated in heptane, filtered and dried. 940 mg (95%) of 2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] -terphenyl-4" -carboxamide, in the form of a "beige powder of melting point 220 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.26 (s, 6H), 1.56 a 1. 64 (m, 4H), 6.20 (br s, 2H), 6.89 (d, 1H, J = 1.3 Hz), 7.14 to 7.29 (m, 7H), 7.51 (d, 1H, J = 7.9 Hz), 7.64 ( dd, 1H, J = 7.9 / 1.5 Hz), 7.72 (s, 1H), 7.74 (d, 2H, J = 8.2 Hz), 7.91 (d, 2H, J 8.2 Hz).
Example 58 N-ethyl-2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-carboxamide In a manner analogous to example 57 (b), starting from 1.30 g (2.7 mmol) of the acid chloride obtained in example 57 (a) and 4.4 ml (54.3 mmol) of a 70% ethylamine aqueous solution, obtains 1.20 g (91%) of N-ethyl-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', .1' '] terphenyl-4"-carboxamide, in the form of a beige powder of melting point 183 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.27 (s, 6H), 1.28"(t, 3H, J = 5.7 Hz), 1.56 to 1.63 (m, 4H), 3.53 (q, 2H, J = 5.3 Hz), 6.18 (br s, 1H), 6.89 (d, 1H, J = 1.9 Hz), 7.14 to 7.29 (m, 7H), 7.51 (d, 2H, J = 7.9 Hz), 7.64 (dd, 1H) , J = 7.9 / 1.9 Hz), 7.71 (s, 1H), 7.73 (d, 2H, J = 8.4 Hz), 7.86 (d, 2H, J = 8.4 Hz).
Example 59 N, N-diethyl-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] ter phenyl 4"-carboxamide.
Analogously to example 57 (b), from 1.30 g (2.7 mmol) of the acid chloride obtained in example 57 (a) and 5.6 ml (54.0 mmol) of diethylamine, 930 mg (67%) of N, N-diethyl-2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-carboxamide, in the form of a beige powder of melting point 113 ° C. XH NMR (CDC13) d 0.85 (s, 6H), 1.25 (m, 6H), 1.27 (m, 6H), 1.56 to 1.64 (m, 4H), 3.35 (br s, 2H), 6.90 (s, 1H) , 7.14 to 7.28 (m, 7H), 7.47 (d, 2H, J = 8.2 Hz), 7.52 (s, 1H), 7.63 (dd, 1H, J = 8.0 / 1.4 Hz), 7.68 to 7.71 (m, 3H ).
Example 60 Morpholin-4-yl- [2 '- (5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-yl] -metanone.
Analogously to example 57 (b), from 1.03 g (2.1 mmol) of the acid chloride obtained in Example 57 (a) and 945 μl (43.0 mmol) of morpholine, 900 mg (80%) of morpholin-4 -yl- [2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4' '-yl] -methanone, in the form of a white powder of melting point 223 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.27 (s, 6H), 1.56 to 1.64 (m, 4H), 3.60 to 4.00 (m, 8H), 6.90 (d, 1H, J = 1.7 Hz), 7.13 to 7.26 (m, 9H), 7.49 (s, 1H), 7.50 (d, 2H, J = 8.4 Hz), 7.63 (d, 1H, J = 7.9 / 1.8 Hz), 7.72 (d, 2H, J = 8.4 Hz).
Example 61 (4-hydroxy-phenyl) -2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1' '] terphenyl-4"-carboxamide.
Analogously to Example 57 (b), from 1.04 g (2.2 mmol) of the acid chloride obtained in example 57 (a), 260 mg (23.9 mmol) of 4-aminophenol and 362 μl (2.7 mmol) of triethylamine, 1.15 g (95%) of (4-hydroxy-phenyl) -2 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) are obtained. [ eleven '; 4 ', 1' '] terphenyl-4' '-carboxamide, in the form of a gray powder of melting point 231 ° C. XH NMR (CDC13) d 0.91 (s, 6H), 1.26 (s, 6H), _ 1.56 to 1.64 (m, 4H), 6.84 (d, 2H, J = 8.5 Hz), 6.89 (d, 1H, J = 1.2 Hz), .7.14 to 7.28 (m, 7H), 7.41 to 7.44 (m, 3H), 7.51 (d, 1H, J = 7.8 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.72 ( s, 1H), 7.75 (d, 2H, J = 8.0 Hz), 7.95 (d, 2H, J = 8.0 Hz), 8.06 (s, 1H).
Example 62 3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naph 'such en- 2- i 1) -bifinyl -4 -carboxymethyl-4'-carboxylic acid. 2 '- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -4-trifluoromethanesulfonyloxy - [1,1'; 4 ', 1' '] terphenyl-4' '-carboxylic acid benzyl ester Analogously to example 13 (a), from 2.0 g (4.1 mmol) of the compound obtained in Example 53 (a), 2.33 g (90%) of the expected product are obtained, in the form of a yellow oil. XH NMR (CDCl 3) d 1.31 (s, 6H), 1.32 (s, 6H), 1.73 (s, 4H), 5.39 (s, 2H), 7.24 to 7.26 (m, 2H), 7.37 to 7.48 (m, 6H) ), 7.60 to 7.69 (m, 2H), 7.66 (d, _2H, J = 8.3 Hz), 8.16 (d, 2H, J = 8.3 Hz). (b) 3- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -bifeni 1-4 -carboxymethyl-4'-benzylcarboxylate.
Into a hydrogenating pump, 1.80 g (2.9 mmol), of the triflate obtained in Example 62 (a), 120 mg (0.29 mmol) of 1,3-bis (diphenyl fos) propane (DPPP), 32 mg are successively introduced. (0.14 mmol) of palladium acetate, 50 ml of methanol, 800 μl (5.8 mmol) of triethylamine and 5 ml of THF. The reaction medium is confined under a pressure of six bars of carbon monoxide and heated under stirring at 70 ° C for seven hours. The mixture is cooled, evaporated to the maximum, taken up in a saturated solution of sodium chloride, extracted with ethyl acetate, washed with a dilute solution of hydrochloric acid, then with water, the organic phase is dried over sodium sulfate. magnesium and evaporates. The residue obtained is purified by chromatography. on a column of silica and eluted with heptane. After evaporation of the solvents, 1.36 g (88%) of the expected compound is taken up in the form of a yellow oil. XH NMR (CDC13) d 1.21 (s, 6H), 1.25 (s, 6H), 1.64 (s, 4H), 3.58 (s, 3H), 5.32 (s, 2H), 7.09 (dd, 1H, J = 8.1 / 2.0 Hz), 7.18 (d, 1H, J = 2.2 Hz), 7.27 to 7.38 (m, 6H), 7.53 to 7.56 (m, 2H), 7.62 (d, 2H, J = 8.5 Hz), 7.79 (d , 1H, J = 7.6 Hz), 8.08 (d, 2H, J = 8.5 Hz). (c) 3- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxymethyl-4'-carboxylic acid.
Analogously to example 53 (c), from 450 mg (0.84 mmol) of the benzylester obtained in example 62 (b), 330 mg (89%) of 3- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxymethyl-4'-carboxylic acid, in the form of a white powder of melting point 258-261 ° C.
XH NMR (DMSO D6) d 1.25 (s, 6H), 1.29 (s, 6H), 1.67 (s, 4H), 3.64 (s, 3H), 7.23 (dd, 1H, J = 8.0 / 1.8 Hz), 7.25 (s, 1H), 7.74 (s, 1H), 7.80 (s, 1H), 7. 92 (d, 2H, J = 8.4 Hz), 8.05 (d, 2H, J = 8.4 Hz). _ Example 63 3- (5, 5, 8, 8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -bifenyl-4,4'-carboxylic acid.
Analogously to example 1 (e), from 850 mg (1.6 mmol) of the diester obtained in example 62 (b), 600 mg (88%) of 3- (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4,4'-carboxylic acid, in the form of a crystallized white solid of melting point 343 ° C. XH NMR (DMSO D6) d 1.27 (s, 6H); 1.28 (s, 6H), 1.67 (s, 4H), 7.25 (dd, 1H, J = 7.9 / 1.9 Hz), 7.31 (s, 1H), 7.69 (s, 1H), 7.78 (s, 1H), 7.91 (d, 2H, J = 8.4 Hz), 8.04 (d, 2H, J = 8.4 Hz).
In the following examples, various pharmaceutical and cosmetic formulations based on the compounds according to the invention have been illustrated. • _ A - ORAL VIA, (a) 0.2 g tablet - Compound prepared in example 2 10,001 g - Starch 0.114 g - Dicalcium phosphate 0.020 g - Sillice 0.020 g - Lactose 0.030 g - Alkal 0.010 g - Magnesium stearate 0.005 g In this example, the compound according to example 2 can be replaced by the same amount of one of the compounds of example 4, "8, 14, 17, 29 and 34. (b) Drinkable suspension in 5 ml vials-Compound prepared in example 1 20,001 g -Glycerin 0.005 g -Sorbitol 70% 0.500 g -Saccharide sodium 0.010 g -p-hydroxybenzoate methyl 0.040 g -Aroma cs -Purified water csp 5 ml (c) 0.8 g tablet - Compound of example 4 0.500 g - Pregelatinised starch 0.100 g - Microcrystalline cellulose 0.115 g - Lactose 0.075 g - Magnesium stearate 0.010 g In this example, the compound according to example 4 can be replaced by the same amount of one of the compounds of examples 11, 18, 21, 24, 39 and 48. (d) Drinkable suspension in 10 ml vials-Compound of Example 5 0.200 g-Glycerin 1,000 g-70% Sorbitol 1,000 g-Sodium saccharinate 0.010 g-methyl-p-hydroxybenzoate 0.080 g -Aroma is -purified water csp 10 ml B - TOPICAL (a) Ointment - Compound of example 3 20.020 g - Isopropyl insulin 81,700 g - Liquid petrolatum oil 9.100 g - Silica ("Aerosil 200" sold by Degussa 9.180 g In this example, the compound according to example 3 can be replaced by the same amount of one of the compounds of examples 7, 14, 27, 36 and 53. (b) Ointment-Compound of example 6 0.300 g -Vaselina white codex 100 g (c) Cream water in non-ionic oil r-Compound of example 2 0.100 g-Blend of lanolin alcohols emulsifiers, waxes and oils ("Eucérine anhydre" sold by BDF) 39,900 g-methyl p-hydroxybenzoate 0.075 g Propyl-p-hydroxybenzoate 0.075 g - Sterile demineralized water csp100 g (d) Lotion _-Compound of example 3 0.100 g -Polyethylene glycol (PEG 400) 69,900 g -95% Ethanol 30,000 g In this example, the compound according to example 3 can be replaced by the same amount of one of the compounds of examples 8, 18, 24, 32, 35, 43 and 46. (e) Hydrophobic ointment - Compound of example 1 0.300 g - Isopropyl ruby 36,400 g - Silicone oil ("Rhodorsil 47V300" sold by Rhóne-Poulenc) .36,400 g - Bee-time 13,600 g - Silicone oil ("Abil 300,000 cst "sold by Goldschmidt) 100 g (f) Oil cream in non-ionic water - Compound of example 5 1,000 g - Cetyl alcohol 4,000 g - Glycerol monostearate 2,500 g - PEG 50 stearate 2,500 g - Shea butter 9,200 g - Propylene glycol 2,000 g-methyl p-hydroxybenzoate 0.075 g propyl-p-hydroxybenzoate 0.075 g Sterile demineralized water 100 g In this example, the compound according to example 5 can be replaced by the same amount of one of the compounds of examples 29, 49, 51, 52, 58 and 62. < TABLE B It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.

Claims (27)

Claims
1. Biphenyl compounds substituted by an aromatic or heteroaromatic radical, characterized in that they correspond to the following general formula (I): wherein: Ar represents a heteroaromatic aromatic radical chosen from: where ZO or S, Ri represents -CH3, -CH2-OH, OR8 or -COR9, R2 and R3 identical or different, represent H, alkyl, linear or branched, in C1-C15, cycloalkyl, -ZR? 0 or a radical polyether, representing at least one of R2 or R3 an alkyl, linear or branched, in C1-C15, or R2 and R3, taken together, form a 5 or 6-membered ring, optionally substituted by at least one methyl and / or optionally by an oxygen or sulfur atom or by a radical SO or S02, R4 represents H, a halogen atom, alkyl, linear or branched, in C1-C20 / -OR? o, OCORn or a polyether radical, R5 represents H, a halogen atom, alkyl, linear or branched, in C1-C20-OCORn, -OR12, mono- or polyhydroxy-alkyl, -NO2, - (CH2) n -N (CH2) n-NHCOCH3, -CHOCH-COR13, - (CH2) nCORi3, where n O to 6, -O- (CH2) mCOR? 3, -0- (CH2) mOH, where m is 12, aryl if any substituted, optionally substituted aralkyl, optionally substituted heteroaryl, a polyether radical or a radical -CH2-polyether, Re represents H, lower alkyl or -OR10, R7 represents H, a halogen atom, alkyl, linear or branched at C1-C20 '-OR10 or -OCORn or a polyether radical, Rs represents H, lower alkyl or -CORn, .r ' R9 represents H, lower alkyl, -ORi or -N Rio represents H or lower alkyl, Rn represents lower alkyl, R12 represents H, alkyl, linear or branched, in C? -C20r mono- or polyhydroxyalkyl, aryl or optionally substituted aralkyl, R13 represents H, lower alkyl, -OR? 0, aril or -N • t "r" R 4 represents H, alkyl, linear or branched, in C 1 -C 20 alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl or a sugar moiety, r 'and r ", identical or different, represent H, OH, alkyl lower, mono- or "polyhydroxyalkyl, optionally substituted aryl, an amino acid residue, a peptide residue or r 'and r", taken together, form a heterocycle, and the salts of the compounds of formula (I) when Ri represents a carboxylic acid function as well as the optical and geometric isomers of said compounds of formula (I).
2. The compounds according to claim 1, characterized in that they occur in the form of a salt of an alkaline or alkaline-earth metal, or also of zinc or of an organic amine.
3. . The compounds according to one of claims 1 or 2, characterized in that the lower alkyl radical is chosen from the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
4. The compounds according to any of the preceding claims, characterized in that the alkyl radical, straight or branched, when it is C1-C15, is chosen from the group "consisting of the methyl, ethyl, propyl, 2-ethylhexyl radicals, octyl and dodecyl, and when in C1-C20 is also chosen between the hexadecyl and octadecyl radicals.
5. The compounds according to any of the preceding claims, characterized in that the monohydroxyalkyl radical is selected from the group consisting of the hydroxymethyl, 2-hydroxyethyl, 2-hydroxyphenyl or 3-hydroxypropyl radicals.
6. The compounds according to any of the preceding claims, characterized in that the polyhydroxyalkyl radical is selected from the group consisting of the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl radicals or rest of the pentaeri tritol.
7. The compounds according to any of the preceding claims, characterized in that the polyether radical is chosen from the group consisting of the methoxymethoxy, methoxyethoxy or methoxyethoxymethoxy radicals.
8. The compounds according to any of the preceding claims, characterized in that the -CH2-polyether radical is chosen from the group consisting of the methoxymethoxymethyl, ethoxymethoxymethyl and methoxyethoxymethoxymethyl radicals.
9. The compounds according to any of the preceding claims, characterized in that the aryl radical is a phenyl radical optionally substituted by at least one halogen, a hydroxyl, a nitro function, a polyether radical or an amino function optionally protected by an acetyl group or optionally substituted by at least one lower alkyl or one alkoxy in Ci-Ce.
10. The compounds according to any of the preceding claims, characterized in that the aralkyl radical is chosen from the group consisting of benzyl or phenethyl radicals optionally substituted by at least one halogen, a hydroxyl, a nitro function, a polyether radical or a functional group. amino optionally protected by an acetyl group or optionally substituted by at least one lower alkyl or an alkoxy at Ci-Cß-
11. The compounds according to any of the preceding claims, characterized in that the heteroaryl radical is chosen from the group " constituted by the pyridyl, furyl or thienyl radicals, optionally substituted by at least one halogen, an unsubstituted alkyl, a hydroxyl, a C1-C3 alkoxy, a nitro function, a polyether radical or an amino function optionally protected by an acetyl group or optionally substituted by at least one lower alkyl or one alkoxy in Ci-Cß-
12. The compounds according to any of the preceding indications, characterized in that the alkenyl radical is selected from the group consisting of radicals containing from 2 to 5 carbon atoms and having one or two ethylenic unsaturation (s), in particular the allyl radical.
13. The compounds according to any of the preceding claims, characterized in that the sugar moiety is chosen from the group consisting of the glucose, galactose, mannose or glucuronic acid moieties.
14. The compounds according to any of the preceding claims, characterized in that the amino acid residue is chosen from the group consisting of the residues derived from lysine, glycine or aspartic acid.
15. The compounds according to any of the preceding claims, characterized in that the peptide moiety is chosen from the group consisting of the dipeptide or tripeptide moieties.
16. The compounds according to any of the preceding claims, characterized in that when r 'and r "form a heterocycle, it is chosen in the group consisting of the piperidino, morpholino, pyrrolidino or piperazino radicals, optionally substituted in position 4 by a alkyl in Ci-Cß or a mono- or a polyhydroxyalkyl.
17. The compounds according to any of the preceding claims, characterized in that the halogen atom is chosen from the group consisting of fluorine, chlorine and bromine.
18. The compounds according to any of the preceding claims, characterized in that they correspond to the general formulas (II) and (III) which follow: in which: Ar represents a radical of formula (a) or (b) which follows: having Rx, R, R5, R6, R7 and Z the same meanings as those given above for formula (I), Ri5 »- Rie» - R17 and Rid identical or different, represent H or -CH3, and t is 1 or 2 .
19. The compounds according to any of the preceding claims, characterized in that they are selected from the group consisting of: 4 - [4 - hydroxy - 3- (5, 6, 7, 8 - tet rahydro - 5, 5, 8, 8 - tetramethyl-2-naphthl) phenyl] benzoic acid and its methyl ester, - 4- [4- (5-hydroxypentyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl) -2-naphthyl) phenyl] benzoic acid and its methyl ester, 4 - [4 - (6-hydroxyhexyloxy) -3- (5,6,7,8-tetrahydro-5, 5, 8, 8-tetramet i1-2) -naphthyl) phenyl] enzoic acid and its methyl ester, - 4- [4- (7-hydroxyheptyloxy) -3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ) phenyl] benzoic, 4- [4- (8-hydroxyoctyloxy) -3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid, 4- [4- (9-hydroxynynyloxy) -3- (5,6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) phenyl] benzoic acid, 4- [4-methoxy-3- (5 , 6, 7, 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid, 4 - [4-methoxyethoxymethoxy-3- (5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-2-naphthyl) phenyl] benzoic acid, 4- [4-benzyloxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ) phenyl] benzoic acid, 4 '- (2,3-dihydroxy-propoxy) -3' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) biphenyl -4-carboxylic (racemic), - 4 '- (2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy)) -3' - (5,5,8,8-tetramethyl-5,6) , 7,8-tetrahydro-naphthalen-2-yl) bi-phenyl-4-carboxylic acid (racemic), 4 '- (2-morpholin-4-yl-ethoxy) -3' - (5, 5, 8, 8 -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carb oxime, 2 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] methyl tetraphenyl-4" -carboxylate, 2' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [ 1, 1 '; 4', 1"'] tetraphenyl-4" -carboxylic acid, - 4-methoxymethoxy-2' - (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro- naphthalen-2-yl) - [1, 1 ', 4', 1"] terphenyl-4" -carboxylic acid, 4-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" '-carboxylic acid, 4-methoxy-2' - (5, 5, 8 , 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1' '] terphenyl-4' '-carboxylic acid, 3-methoxymethoxy-2' - (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) ) - [l, l '; 4', l ''] terphenyl-4"-carboxylic acid, 3-hydroxy-2 '- (5, 5, 8, 8 -tetramethyl-5, 6,7, 8- tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1' '] terphenyl-4' '-carboxylic acid, 3-methoxy-2' - (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [l, l '; 4', l ''] terphenyl-4"-carboxylic acid, - 2-methoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8- tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2-hydroxy-2 '- (5, 5, 8, 8-tetramethyl-5 , 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2-methoxy-2 '- (5, 5, 8, 8 -tetramet il-5, 6,7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', l' '] terphenyl-4' '-carboxylic acid, 2'-methoxymethoxy-5' - (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2) il) -bi-phenyl-4-carboxylic acid, 2'-methoxy-5 '- (5, 5, 8, 8-tetramethyl-5,6,8,8-tetrahydro-naphthalen-2-yl) -biphenyl- 4-carboxylic acid, 2'-propyloxy-5 '- (5, 5, 8, 8 -tetramet-il-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid; '-hydroxy-5' - (5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 4 '- (5, 5) , 8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 2', 1"] terphenyl-4" -carboxylic acid, 2'-methoxymethoxy- 3 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2'-hydroxy-3' - (5, 5) , 8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2'-methoxy-3 '- (5, 5, 8, 8-tetramethyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, - 3 '-methoxymethoxymethyl-5' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, - 3 '-hydroxymethyl acid -5 '- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2' - (4, 4-dimethyl-thiochroman) -7-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2 '- (4, 4 -dime-t-yl-t-ochroman-6-yl) - [1 , 1'; 4 ', 1' '] terphenyl-4' '-carboxylic acid, - 2' - (3, 5, 5, 8, 8 -pentamet il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 ', 4', 1 '' Jterphenyl-4 '' -carboxylic, - 2 '- (3-methoxymethoxy-5, 5, 8, 8-tet ramethyl-5, 6,7, 8- tetrahydro-naphthalen-2-yl) - [l, l '; 4', l "] terphenyl-4" -carboxylic acid, 2 '- (3-hydroxy-5, 5, 8, 8-tetramethyl-5,6) , 7, 8-tetrahydro-naphthalen-2-yl) - [1 ', 4', 1"] terphenyl-4" -carboxylic acid, 2 '- (3-methoxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - _ [l, l '; 4', l "] terphenyl-4" -carboxylic acid, 2 '- (3- propyloxy-5, 5, 8, 8 -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" '-carboxylic acid , - 3"-methyl-2 '- (5, 5, 8, 8 -ethemethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1 ''] terphenyl-4 '' -carboxylic acid, 2"-hydroxy-2 '- (5, 5, 8, 8-te t ramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) ) - [1, 1 ', 4', 1 ''] terphenyl-4"-carboxylic acid, 2" -m ethoxymethoxy-2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l'; 4 ', l' '] terphenyl-4' '-carboxylic acid, 2"-methoxy-2' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1"] terphenyl-4" -carboxylic acid, 2"-propoxy-2' - (5, 5, 8, 8 -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l '; 4 ', l' '] terphenyl-4"-carboxylic acid, 3" -hydroxy-2' - (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2) -yl) - [1, 1 '; 4', 1"] terfenyl-4" -carboxylic acid, 6- [2- (5, 5, 8, 8 -tetramet il-5, 6, 7, 8 -tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] - _ nicotinic acid, 5- [2- (5, 5, 8, 8 -tetramet-il-5, 6, 7, 8 -tetrahydro-naphthalene- 2-yl) -biphenyl-4-yl] -pyridine-2-carboxylic acid, - 2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [ eleven '; ', 1' '] terphenyl-4"-hydroxamic, -2' - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) - [1, 1] '; 4', l ''] terphenyl-4 '' - ol, - [2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [eleven'; 4 ', 1"] terphenyl-4" -yl] -methanol, 2' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, l '; 4', l ''] terphenyl-4 '' - carbaldehyde, 4 '- methoxycarbonylmethoxy-3' - (5, 5, 8, 8-tetramethyl-5, 6,, 8-tetrahydro-naphthalene-2) -yl) -biphenyl-4-carboxylic acid, 4 '-carboxymethoxy-3' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalene-2-ii) -biphenyl-4 -carboxylic acid, 4 '- (5-ethoxycarbonyl-pentyloxy) -3' - (5,5,8,8-tet-ramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl ester -4-carboxylic acid, 4 '- (5-carboxy-pentyloxy) -3' - (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl- 4-carboxylic, 2 '- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1'; 4 ', 1"] terphenyl-4" -carboxamide, N-ethyl-2' - (5,5,8,8, -tetramethyl-5,6,7,8-tetra idro-naphthalen-2-yl) - [1, 1 ', 4', 1 ''] terphenyl-4 '' -carboxamide, N, N-diethyl-2 '- (5,5,8,8, -tetramethyl-5, 6,7,8 -tetrahydro-naphthalen-2-yl) - [l, l '; 4', l "] terphenyl-4" -carboxamide, morpholin-4-yl- [2'- (5,5,8, 8, -tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-2-yl) - [1, 1 '; 4', 1"] terphenyl-4" -metanone, (4-hydroxy-phenyl) -2 '- (5,5,8,8, -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1, 1'; 4 ', 1"] terphenyl-4" -carboxamide, 3- (5, 5, 8, 8, -tetramethyl-5, 6, 7, 8 tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxymethyl-4"-carboxylic acid, 3- ( 5, 5, 8, 8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4,4'-dicarboxylic acid, 3'-methoxymethoxy-5 '- (5, 5, 8, 8, -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 3'-methoxy-5 '- (5, 5, 8, 8, -tetramet il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -bi phenyl -4- carboxylic acid, 3'-propyloxy-5 '- (5, 5, 8, 8, -te tramet il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, - 3 '-hydroxy-5' - (5, 5, 8, 8, - tet ramet il-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, acid - (5, 5, 8, 8, -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -terphenyl-4"-carboxylic acid, 4 '- (5-carboxamido-pentyloxy) - 3 '- (5,5,8,8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 3'-methoxycarbonyl-5' - ( 5, 5, 8, 8, -tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 3-carboxyl-5 '- (5, 5, 8, 8, -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, 2 '- (4-hydroxy-5, 5, 8, 8-tetramethyl- 5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4 ', 1' '] terphenyl-4"-carboxylic acid, 2' - (4-methoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -[eleven'; 4 ', 1"] terphenyl-4" -carboxylic acid, 2' - (4-propyloxy-5, 5, 8, 8-tet ramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [l, l '; 4', l ''] terphenyl-4 '' -carboxylic acid, - 2 '- (4-methoxymethoxy-5, 5, 8, 8-te t ramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) - [1,1 '; 4', 1"] terphenyl-4" -carboxylic acid, 2- [2- (5, 5, 8, 8 -tetramethyl) -5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -biphenyl-4-yl] -thiophene-4-carboxylic acid.
20. The compounds according to any of the preceding claims, characterized in that they are for use as a medicine.
21. The compounds according to any of claim 20, characterized in that they are for use as a medicament for the treatment of dermatological conditions, of dermatological conditions with inflammatory and / or immunoallergic components of the rheumatic or respiratory type, of cardiovascular diseases and of Ophthalmological disorders.
22. The use of at least one of the compounds as defined in any of claims 1 to 19 for the preparation of a medicament for the treatment of dermatological conditions, of dermatological conditions with an inflammatory and / or immunoallergic component of rheumatic type "or respiratory, cardiovascular diseases of ophthalmological disorders.
23. A pharmaceutical composition, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound as defined according to any of claims 1 to 19.
24. The composition according to claim 23, characterized in that the concentration in at least one compound according to any of claims 1 to 19 is comprised between 0.001% and 5% by weight with respect to the total weight of the composition.
25. A cosmetic composition, characterized in that it contains, in a cosmetically acceptable support, at least one compound as defined according to any of claims 1 to 19.
26. The composition according to claim 25, characterized in that the concentration in at least one compound according to any of claims 1 to 19 is comprised between 0.001 and 3% by weight with respect to the total weight of the composition.
27. The use of a cosmetic composition as defined in any of claims 25 or 26 for body or hair hygiene.
MXPA/A/1999/003653A 1997-08-21 1999-04-20 Biphenyl derivatives substituted by an aromatic or heteroaromatic radical and pharmaceutical and cosmetic compositions containing same MXPA99003653A (en)

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Application Number Priority Date Filing Date Title
FR97/10552 1997-08-21

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MXPA99003653A true MXPA99003653A (en) 2000-05-01

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