FR2724654A1 - NOVEL DERIVATIVES OF GALLIC ACID, PROCESS FOR THE PREPARATION THEREOF, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS COMPRISING THEM - Google Patents

Abstract

Products of formula (ID), in which R1 is hydrogen, carboxy, formyl, alkyl, hydroxyalkyl, alkoxyalkyl, carbamoyl, N-alkyl-carbamoyl, NNdialkylcarbamoyl, alkoxycarbothioate or alkylcarbonyl, V1 is oxygen or -NH-, V2 is -V1H or hydrogen and A is optionally substituted alkyl or aryl, the products of formula (ID) being in all the possible isomeric forms. The invention also concerns the acid addition salts and bases of the products of formula (ID).

Description

 The present invention relates to novel gallic acid derivatives, process for their preparation, novel intermediates obtained, their use as medicaments and pharmaceutical compositions containing them.

dans laquelle R1 représente - l'atome d'hydrogène - le radical formyle - un radical alkyle éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle, alcoxy, aryle, carboxy libre, salifié, estérifié ou amidifié, carbonyle, amino, amino substitué, carbamoyle et carbamoyle substitué, - un radical aryle éventuellement substitué, - les radicaux mercapto, alkylthio, arylthio, - les radicaux alkylcarbonyloxy ou phénylcarbonyloxy, - le radical carboxy libre ou salifié, - le radical

dans lequel X représente un atome d'oxygène ou de soufre et
R7 représente un radical alkyle, alcoxy, phényle ou amino éventuellement substitué par un ou deux radicaux alkyl, tous ces radicaux alkyl, alcoxy et phényle étant éventuellement substitués,
R3, R4 et R5 sont tels que ou bien identiques ou différents, ils sont choisis parmi a) l'atome d'hydrogène, b) le radical hydroxyle éventuellement substitué par un radical alkyle, aryle ou A-sulfonyl- dans lequel le radical A représente un radical alkyle ou aryle, tous les radicaux alkyle et aryle étant éventuellement substitués, c) le radical amino éventuellement substitué par un ou deux radicaux choisis parmi les radicaux alkyle, alkylcarbonyle, arylcarbonyle et A-sulfonyl- tel que défini ci-dessus, ou bien l'un de R3 et R5 est choisi parmi les valeurs indiquées ci-dessus et les deux autres forment ensemble le radical

dans lequel n représente un entier de 1 à 2, ou le radical

The subject of the present invention is, as medicaments, the products of formula (I)

in which R1 represents - the hydrogen atom - the formyl radical - an alkyl radical optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, aryl, free carboxy, salified, esterified or amidified radicals; , carbonyl, amino, substituted amino, carbamoyl and substituted carbamoyl, - an optionally substituted aryl radical, - mercapto, alkylthio, arylthio radicals, - alkylcarbonyloxy or phenylcarbonyloxy radicals, - free or salified carboxy radical, - radical

wherein X represents an oxygen or sulfur atom and
R7 represents an alkyl, alkoxy, phenyl or amino radical optionally substituted by one or two alkyl radicals, all these alkyl, alkoxy and phenyl radicals being optionally substituted,
R3, R4 and R5 are as either identical or different, they are chosen from a) the hydrogen atom, b) the hydroxyl radical optionally substituted by an alkyl, aryl or A-sulphonyl- radical in which the radical A represents an alkyl or aryl radical, all the alkyl and aryl radicals being optionally substituted, and c) the amino radical optionally substituted with one or two radicals chosen from alkyl, alkylcarbonyl, arylcarbonyl and A-sulphonyl radicals as defined above, or one of R3 and R5 is chosen from the values indicated above and the two others together form the radical

in which n represents an integer of 1 to 2, or the radical

R 2 and R 61, which are identical to or different from each other and from R 5, are chosen from the values indicated above for R 5 and the nitro, carboxy free, salified, esterified or amidified radicals and the alkyl radicals optionally substituted by a hydroxyl, alkoxy or aryl radical; , said products of formula (I) being in all the isomeric forms racemic, enan tiomers and diastereoisomers possible as well as the addition salts with inorganic and organic acids or with the mineral and organic bases pharmaceutically acceptable of said products of formula (I) .

tels que définis ci-dessus, lesdits produits de formule (I) étant sous toutes les formes isomères racémiques, énantiomè- res et diastéréoisomêres possibles ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques pharmaceutiquement acceptables desdits produits de formule (I).The products of formula (I) as defined above are preferably such that at least two of R 2, R 3, R 4, R 5 and R 6 or else, which are identical or different, are chosen from hydroxyl and amino radicals, these hydroxyl radicals. and amino being optionally substituted as indicated above, or together form one of the radicals

as defined above, said products of formula (I) being in all possible racemic isomeric, enantiomeric and diastereoisomeric forms as well as addition salts with mineral and organic acids or with pharmaceutically acceptable inorganic and organic bases said products of formula (I).

 The alkyl, alkoxy and aryl radicals as defined above and hereinafter are optionally substituted with, preferably, one or more substituents chosen from halogen atoms and hydroxyl radicals; alkyl; alkoxy cyano; nitro; carbamoyl; trifluoromethyl; trifluoromethoxy; free, salified, esterified or amidified carboxy; amino optionally substituted with one or two alkyl acylamino radicals; arylcarbonyl; alkylcarbonyl; pyridinyl, isoxazolyl and phenyl optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy, free carboxy, salified, esterified or amidified radicals and phenyl itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy, cyano, nitro, carbonyl, trifluoromethyl, trifluoromethoxy and free carboxy, salified, esterified or amidified radicals.

 In the products of formula (I) and in the following, the term "alkyl" denotes a linear or branched alkyl radical containing from 1 to 6 carbon atoms and preferably denotes methyl, ethyl, propyl, isopropyl, butyl or isobutyl radicals, sec-butyl and tert-butyl and also pentyl, hexyl, isopentyl and isohexyl, the term halogen atom preferably denotes the chlorine atom, but may also represent a fluorine, bromine or iodine atom, the term "alkoxy" denotes a linear or branched alkoxy radical containing from 1 to 6 carbon atoms and preferably denotes the methoxy, ethoxy, propoxy or isopropoxy radicals, and also linear, secondary or tertiary butoxy radicals, the acyl radical preferably denotes a radical; having from 1 to 6 carbon atoms such as, for example, the formyl, acetyl, propionyl, butyryl or benzoyl radical, and also the pentanoyl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical; ryl denotes a monocyclic radical comprising 5, 6 or 7 members or a radical consisting of fused rings comprising 8 to 14 members, carbocyclic or heterocyclic, it being understood that the heterocyclic radicals may contain one or more heteroatoms chosen from oxygen atoms, d nitrogen or sulfur and that when these heterocyclic radicals comprise more than one heteroatom, the heteroatoms of these heterocyclic radicals may be the same or different.

 Examples of such a monocyclic aryl radical include phenyl, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyridyl such as 2-pyridyl and 3-pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, tetrazolyl saline, diazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl; examples of carbocyclic or heterocyclic condensed groups containing at least one heteroatom selected from sulfur, nitrogen and oxygen, mention may be made of naphthyl and benzothienyl radicals such as 3-benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl and thionaphthyl, indolyl, indolinyl, quinolyl or isoquinolyl, purinyl, - the term arylalkyl or aryl-substituted alkyl means radicals in which the alkyl and aryl radicals respectively may take the values defined above for these radicals; examples of such arylalkyl radicals include benzyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, indenylmethyl, thienylmethyl such as 2-thienylmethyl, furylmethyl such as furfuryl, pyridylmethyl, pyridylethyl, pyrimidylmethyl or pyrrolylmethyl, it being understood that in the non-exhaustive list examples of radicals as mentioned above, the alkyl radical may be represented by methyl as well as by ethyl, propyl or butyl radicals such as, for example, in phenylalkyl radicals such as phenylethyl, phenylpropyl or phenylbutyl - the term "arylthio radical" preferably denotes radicals in which the aryl radical represents the radicals as defined above, for example in phenylthio, pyridylthio or pyrimidylthio, imidazolylthio or N-methylimidazolylthio, the term alkylthio radical preferably denotes radicals in which the alkyl radical is as defined above: mention may be made, for example, of methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, isopentylthio or isohexylthio, optionally substituted by one or more radicals chosen for example from those defined above; among these substituents, mention may be made, by way of example and in a non-exhaustive manner, of halogen atoms, hydroxyl, amino, alkoxy and aryl radicals, such as, for example, in the trifluoromethylthio, trifluoroethylthio or pentafluoroethylthio, benzylthio or phenethylthio radicals.

 In all the radicals defined above, the sulfur atoms may not be oxidized as in the alkylthio and arylthio radicals, or on the contrary be oxidized to give the alkylsulfinyl, arylsulfinyl, alkylsulfonyl or arylsulfonyl radicals in which the alkyl and aryl radicals the values given above. Mention may be made, for example, of methylsulfinyl, ethylsulfinyl, methylsulfonyl or ethylsulfonyl, phenylsulfinyl or phenylsulfoacyl radicals.

 When the alkyl radical as defined above is substituted with one or more radicals chosen for the halogen atoms and the hydroxyl, alkoxy, alkylthio and carbamoyl radicals as defined above, it may represent, for example, the bromoethyl radicals, trifluoromethyl, trifluoroethyl, pentafluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethoxymethyl, propyloxypropyl, propylthiopropyl, propylthioethyl, methylthiomethyl, carbamoylmethyl or carbamoylethyl.

 The carbonyl radical denotes the alkylcarbonyl and arylcarbonyl radicals in which the alkyl and aryl radicals are as defined above and optionally substituted.

Mention may therefore be made, for example, of methylcarbonyl, ethylcarbonyl, benzylcarbonyl, phenylethylcarbonyl and phenylcarbonyl radicals, which may be substituted, for example in nitrophenylcarbonyl.

The substituted hydroxyl radical may be, for example, the aryloxy radical which preferably represents the radicals in which the aryl radical is as defined above, for example in phenoxy, the arylalkoxy radical which preferably designates the radicals in which the radical aryl and the alkoxy radical represent the radicals as defined above, for example in benzyloxy or phenylethoxy, the acyloxy radical, which for example denotes a radical in which the acyl radical has the values indicated above, preferably denotes a formyloxy radical; acetyloxy, propionyloxy, butyryloxy or benzoyloxy, the alkoxy radical as defined above, optionally substituted as for example in hydroxyalkoxy and especially hydroxyethoxy; the haloalkoxy radical refers to radicals in which the alkoxy radical is as defined above and may contain one or more halogen atoms as defined above such as for example in bromoethoxy, trifluoromethoxy, trifluoroethoxy or pentafluoroethoxy,
The hydroxyl radical may also be substituted by a protective group known to those skilled in the art of phenol chemistry and, in particular, those cited in the reference work "Protective Groups in Organic Synthesis of Th. Green." (John Wiley and Ed Sounds).

 The carbamoyl and amino radicals that may represent or carry one or more of the possible substituents of the radicals defined in the products of formula (I) and in what follows, denote radicals which are unsubstituted or substituted in particular by the alkyl radicals as defined. above to give the monoalkyl- or dialkylamino or -carbamoyl radicals in which the alkyl radicals are optionally substituted and as defined above and hereinafter.

 By way of example and non-exhaustively - the substituted carbamoyl radical denotes N-monoalkyl groups such as N-methylcarbamoyl, N-ethylcarbamoyl; N, N-dialkyl carbamoyl, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl; N- (hydroxyalkyl) carbamoyl, such as N (hydroxyethyl) carbamoyl, phenylcarbamoyl, pyridylcarbamoyl, benzylcarbamoyl, N-methyl-N-phenylcarbamoyl pyridylmethylcarbamoyl;

the substituted amino radical denotes the methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino or methylethylamino radicals, these radicals being optionally substituted as indicated above, for example in hydroxyalkylamino or alkoxyalkylamino such as methoxymethylamino, methoxyethylamino or ethoxyethylamino.

 The substituted amino radical may also be an alkoxycarbonylamino radical, such as in particular tert-butyloxycarbonylamino or benzyloxycarbonylamino, or an acylamino radical in which the acyl radical represents an alkylcarbonyl or arylcarbonyl radical such as in particular in the acetylamino or benzoylamino radicals.

 The amino and carbamoyl radicals may in particular be substituted by one or two amino acids chosen from 20 natural amino acids such as in particular proline or for example glycine, alanine, leucine, isoleucine, valine or phenylalanine. or one of the other natural amino acids known to those skilled in the art.

 The hydroxyl, amino and carbamoyl radicals can in particular be substituted by alkenyl radicals such as allyl, alkanoyl such as pivaloyl, aryl, arylalkyl and asulfonyl as defined above and hereinafter.

 Mention may in particular be made of arylsulphonyloxy and arylsulphonylamino radicals in which the arylsulphonyl radical represents, for example, the para-toluenesulphonyl radical.

 The carbocyclic or heterocyclic radicals which may constitute substituents of the hydroxyl, amino or carbamoyl radicals and also alkyl and alkoxy radicals may be the aryl radicals as defined above, but also partially or completely saturated radicals, these radicals being optionally substituted.

 Among such substituents, mention may in particular be made of phenyl, benzyl, phenethyl, naphthyl, indolyl, indolinyl, thienyl, furyl, pyrrolyl, pyridyl, pyrrolidinyl, piperidino, morpholino and piperazinyl radicals, these radicals possibly being substituted with one or more radicals such as as defined above, such as, for example, in methylpiperazinyl, fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl.

 The carboxyl group (s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which mention may be made, for example, of the salification compounds obtained with mineral bases, mention may be made of for example, one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or with organic bases, for example, methylamine, propylamine, trimethylamine, diethylamine or triethylamine may be mentioned; , N, N-dimethylethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine, - among the esterification compounds, the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being able to be substituted by radicals chosen by exe among the halogen atoms, the hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for example, in the chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.

 The addition salts with the mineral or organic acids of the products of formula (I) may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic or benzoic acids, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as, for example, methanesulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and the like. aryldisulphonic acids.

dans laquelle R1A représente - l'atome d'hydrogène - le radical formyle - un radical alkyl éventuellement substitué par un radical hydroxyle ou alcoxy, - le radical phényle, pyridyle, pyrimidyle, imidazole, oxazolyle ou oxazolinyle, - le radical carboxy libre ou salifié, - un radical

dans lequel X représente un atome d'oxygène ou de soufre et
R7A représente un radical alkyle, alcoxy ou amino éventuellement substitués par un ou deux radicaux alkyl
R3A, R4A et R5A sont tels que deux d'entre eux soit sont identiques et représentent le radical hydroxyle, soit consécutifs, forment ensemble un radical

soit sont choisis parmi les radicaux hydroxyle et amino éventuellement protégés ainsi qu'il est défini ci-après et l'autre de R3A, R4A et R5A est choisi parmi l'atome d'hydrogène, le radical amino et le radical hydroxyle éventuellement substitué pour former les radicaux suivants - Q-alkyle-Aa - Q-Aa, - Q-S02-Aa, dans lesquels Q représente -O- ou -NR8- avec R8 représente un atome d'hydrogène ou un radical alkyle et Aa représente un radical alkyle ou aryle éventuellement substitués par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux hydroxyle ; alkyl ; alcoxy ; cyano ; nitro ; carbamoyle ; trifluorométhyle ; trifluorométhoxy ; carboxy libre, salifié, estérifié ou amidifié ; amino éventuellement substitué par un ou deux radical alkyl ; acylamino ; arylcarbonyle ; alkylcarbonyle ; pyridinyl, isoxazolyl et phényl éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle, alkyl, alcoxy1 carboxy libre, salifié, estérifié ou amidifié et phényle lui-même éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle, alkyl, alcoxy, cyano, nitro, carbonyle, trifluorométhyle, trifluorométhoxy et carboxy libre, salifié, estérifié ou amidifié,
R2A et R6A identiques ou différents sont choisis parmi l'atome d'hydrogène et les radicaux arylalkyle et arylsulfonyloxy dans lesquels le radical aryle est éventuellement sub stitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux hydroxyle, alkyl, alcoxy, cyano, nitro, trifluorométhyle, trifluorométhoxy, carboxy libre, salifié, estérifié ou amidifié, phényl et amino éventuellement substitué par un ou deux radicaux alkyl, lesdits produits de formule (IA) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques pharmaceutiquement acceptables desdits produits de formule (IA). The subject of the invention is in particular as medicaments the products of formula (I) as defined above corresponding to formula (IA)

in which R1A represents - the hydrogen atom - the formyl radical - an alkyl radical optionally substituted by a hydroxyl or alkoxy radical, - the phenyl, pyridyl, pyrimidyl, imidazole, oxazolyl or oxazolinyl radical, - the free or salified carboxy radical , - a radical

wherein X represents an oxygen or sulfur atom and
R7A represents an alkyl, alkoxy or amino radical optionally substituted by one or two alkyl radicals
R3A, R4A and R5A are such that two of them are identical and represent the hydroxyl radical, or consecutive, together form a radical

or are chosen from hydroxyl and optionally protected amino radicals as defined below and the other of R3A, R4A and R5A is chosen from hydrogen, amino and hydroxyl radicals optionally substituted for to form the following radicals - Q-alkyl-Aa-Q-Aa, - Q-SO2-Aa, in which Q is -O- or -NR8- with R8 is a hydrogen atom or an alkyl radical and Aa is a radical alkyl or aryl optionally substituted by one or more substituents selected from halogen atoms and hydroxyl radicals; alkyl; alkoxy; cyano; nitro; carbamoyl; trifluoromethyl; trifluoromethoxy; free, salified, esterified or amidified carboxy; amino optionally substituted with one or two alkyl radicals; acylamino; arylcarbonyl; alkylcarbonyl; pyridinyl, isoxazolyl and phenyl optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy-free, salified, esterified or amidified radicals and phenyl itself optionally substituted with one or more radicals chosen from halogen atoms and the hydroxyl, alkyl, alkoxy, cyano, nitro, carbonyl, trifluoromethyl, trifluoromethoxy and free carboxy, salified, esterified or amidified radicals,
R 2 A and R 6 A identical or different are chosen from the hydrogen atom and the arylalkyl and arylsulphonyloxy radicals in which the aryl radical is optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl, alkyl or alkoxy radicals; cyano, nitro, trifluoromethyl, trifluoromethoxy, free, salified, esterified or amidified carboxy, phenyl and amino optionally substituted by one or two alkyl radicals, said products of formula (IA) being in all the racemic isomeric forms, enantiomers and possible diastereoisomers, the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (IA).

 The subject of the invention is, as medicaments, the products of formula (I), as defined above, in which R 1, R 2, R 3, R 4 and R 5 have the meanings indicated above and at least one R2 and R6 represent a hydrogen atom, said products of formula (I) being in all isomeric forms racemic, enan tiomers and diastereoisomers possible as well as addition salts with mineral and organic acids or with mineral bases and pharmaceutically acceptable organic compounds of said products of formula (I).

dans laquelle R1B représente - l'atome d'hydrogène - le radical formyle - le radical méthyle, hydroxyméthyle ou méthoxyméthyle, - le radical carboxy libre, estérifié par un radical alkyl, salifié ou amidifié en radical carbamoyle éventuellement substitué sur le radical amino par un ou deux radicaux alkyl, - un radical alkylcarbonyle, - le radical

dans lequel R7A représente un radical alcoxy,
R3B et R4B sont tels que soit R3B et R4B sont identiques et représentent le radical hydroxyle, soit R3B et R4B forment ensemble le radical

soit R3B et R4B différents sont choisis parmi l'atome d'hydrogène et les radicaux amîno et hydroxyle éventuellement substitués par un radical choisi parmi les radicaux alkyle, phénylsulfonyl et benzyl, les radicaux alkyl et phényl étant eux-mêmes éventuellement substitués par un radical hydroxyle ou alcoxy et le radical phényle étant éventuellement substitué par un radical alkyle,
R5B représente i) l'atome d'hydrogène, ii) le radical hydroxyle éventuellement substitué en radical alcoxy ou arylsulfonyloxy dans lequel le radical aryle est choisi parmi - le radical phényl éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux hydroxyle ; alkyl ; alcoxy ; cyano ; nitro ; trifluorométhyle ; trifluorométhoxy ; carboxy libre, salifié, estérifié ou amidifié ; amino éventuellement substitué par un ou deux radicaux alkyl ; acylamino ; arylcarbonyle ; alkylcarbonyle ; pyridinyl, isoxazolyl et phényl eux-mêmes éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle, alkyl, alcoxy, carboxy libre, salifié, estérifié ou amidifié et phényle lui-même éventuellement substitué par les atomes d'halogène et les radicaux hydroxyle, alkyl, alcoxy, cyano, nitro, carbonyle, trifluorométhyle, trifluorométhoxy et carboxy libre, salifié, estérifié ou amidifié - le radical quinolyle - le radical isoxazolyl éventuellement substitué par un ou plusieurs radicaux choisis parmi les radicaux alkyle et thiényl - le radical pyrazolyle éventuellement substitué sur un atome de carbone ou d'azote par un ou plusieurs radicaux choisis parmi les radicaux alkyle et les atomes d'halogène ;; - le radical thiényle éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux nitro, pyridinyl et isoxazolyl - le radical naphtyl iii) le radical amino éventuellement substitué par un radical phénylsulfonyl ou benzoyl dans lesquels le radical phényl est éventuellement substitué par un radical alkyl,
R2B est choisi parmi l'atome d'hydrogène et le radical phénylsulfonyloxy dans lequel le radical phényle est éventuellement substitué par un radical alkyl, lesdits produits de formule (zig) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques pharmaceutiquement acceptables desdits produits de formule (1B >
L'invention a encore plus particulièrement pour objet à titre de médicaments, les produits de formule (I), telle que définie ci-dessus dans laquelle R1, R2, R5 et R6 ont les significations indiquées ci-dessus et R3 et R4 identiques représentent le radical hydroxyle, lesdits produits de formule (I) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques pharmaceutiquement acceptables desdits produits de formule (I).The invention more particularly relates, as medicaments, to the products of formulas (I) and (IA) as defined above and corresponding to formula (zig):

in which R 1B represents - the hydrogen atom - the formyl radical - the methyl, hydroxymethyl or methoxymethyl radical, - the free carboxy radical, esterified with an alkyl radical, salified or amidated to a carbamoyl radical optionally substituted on the amino radical by a or two alkyl radicals, an alkylcarbonyl radical, the radical

in which R7A represents an alkoxy radical,
R3B and R4B are such that either R3B and R4B are identical and represent the hydroxyl radical, or R3B and R4B together form the radical

or R3B and R4B are chosen from the hydrogen atom and the amine and hydroxyl radicals optionally substituted with a radical selected from alkyl, phenylsulfonyl and benzyl radicals, the alkyl and phenyl radicals themselves being optionally substituted with a hydroxyl radical; or alkoxy and the phenyl radical being optionally substituted by an alkyl radical,
R5B represents i) the hydrogen atom, ii) the hydroxyl radical optionally substituted in the alkoxy or arylsulphonyloxy radical in which the aryl radical is chosen from - the phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and hydroxyl radicals; alkyl; alkoxy; cyano; nitro; trifluoromethyl; trifluoromethoxy; free, salified, esterified or amidified carboxy; amino optionally substituted with one or two alkyl radicals; acylamino; arylcarbonyl; alkylcarbonyl; pyridinyl, isoxazolyl and phenyl themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy, free carboxy, salified, esterified or amidified radicals and phenyl itself optionally substituted by the halogen atoms; halogen and the hydroxyl, alkyl, alkoxy, cyano, nitro, carbonyl, trifluoromethyl, trifluoromethoxy and free carboxy, salified, esterified or amidified radicals - the quinolyl radical - the isoxazolyl radical optionally substituted with one or more radicals chosen from alkyl radicals and thienyl - the pyrazolyl radical optionally substituted on a carbon or nitrogen atom with one or more radicals chosen from alkyl radicals and halogen atoms; the thienyl radical optionally substituted by one or more radicals chosen from halogen atoms and the nitro, pyridinyl and isoxazolyl radicals; the naphthyl iii radical; and the amino radical optionally substituted by a phenylsulfonyl or benzoyl radical in which the phenyl radical is optionally substituted by an alkyl radical,
R2B is chosen from the hydrogen atom and the phenylsulfonyloxy radical in which the phenyl radical is optionally substituted by an alkyl radical, said products of formula (zig) being in all the racemic isomeric forms, enantiomers and possible diastereoisomers as well as the salts of addition with the inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (1B>
The invention even more particularly relates to medicaments, the products of formula (I), as defined above in which R1, R2, R5 and R6 have the meanings indicated above and R3 and R4 identical represent the hydroxyl radical, said products of formula (I) being in all the possible isomeric racemic, enantiomeric and diastereoisomeric forms as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula ( I).

 The invention particularly relates, as medicaments, to the products of formula (I), as defined above, corresponding to the following formulas - 2 - (((2,3-dihydroxy-5- (methoxycarbonyl) phenyl) methyl oxy) sulfonyl) benzoate; methyl 3,4-dihydroxy-5- (((2- (trifluoromethyl) phenyl) sulfonyl) oxy) benzoate; 3,4-dihydroxy-5 - (((2-thienyl) sulfonyl ) methyl oxy) benzoate, - methyl 3-O-tosyl gallate, - propyl 3-O-tosyl gallate, - (2,3-dihydroxyphenyl) -4-methylbenzenesulfonate.

The subject of the invention is also the products of formula (IN) corresponding to the products of formula (I) as defined above except for (a) products in which R1 represents an alkoxycarbonyl radical, R2 and R6 represent an atom hydrogen,
R4 represents a hydroxyl radical optionally substituted by a methyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl and alkylphenylsulfonyl radical and R3 and R5 are identical and represent a hydroxyl radical optionally substituted by the benzyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl, alkylphenylsulfonyl or methyl radical comprising at least two substituents, b) and products in which two of R3, R4, R5 and R6, consecutive on the ring which carries them, represent a hydroxyl radical, the other two of R3, R4, R5 and R6 are such that one represents a hydrogen atom and the other represents a hydroxyl radical, optionally protected and
R1 is selected from: - the hydrogen atom, - the unsubstituted alkyl radical, - the formyl radical and - the free or esterified carboxy radical, said products of formula (IN) being in all racemic isomeric, enantiomeric and diastereoisomeric forms as well as the addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (IN).

dans laquelle R1 représente l'atome d'hydrogène ou le radical carboxy libre ou estérifié, formyle, alkyle, hydroxyalkyle, alcoxyalkyle, carbamoyle, N alkylcarbamoyle, NNdialkylcarbamoyle, alcoxycarbothioate ou alkylcarbonyle, V1 représente un atome d'oxygène ou le radical -NH- et V2 représente -V1H ou un atome d'hydrogène et A a la signification indiquée cidessus, lesdits produits de formule (ID) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques desdits produits de formule (ID).The subject of the invention is particularly the products of formula (I), as defined above, and corresponding to the formula (ID)

in which R 1 represents the hydrogen atom or the free or esterified carboxy, formyl, alkyl, hydroxyalkyl, alkoxyalkyl, carbamoyl, N alkylcarbamoyl, N, N-dialkylcarbamoyl, alkoxycarbothioate or alkylcarbonyl radical, V 1 represents an oxygen atom or the radical -NH- and V 2 represents -V 1 H or a hydrogen atom and A has the meaning indicated above, said products of formula (ID) being in all the racemic isomeric forms, enantiomers and diastereoisomers possible as well as the addition salts with the mineral acids and organic or with the inorganic and organic bases of said products of formula (ID).

 The subject of the invention is more particularly the products of formula (I), as defined above, in which R5 represents an arylsulphonyloxy radical, optionally substituted by one or more radicals chosen from halogen atoms and alkyl or alkoxy radicals. , cyano, amino, nitro, free or esterified carboxy, trifluoromethoxy, trifluoromethyl, phenyl, pyridinyl and isoxazolyl, said products of formula (I) being in all the racemic isomeric forms, enantiomers and diastereoisomers possible as well as the addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

 The subject of the invention is particularly the following products: methyl 2- (((2, 3-dihydroxy-5- (methoxycarbonyl) phenyl) oxy) sulfonyl) benzoate, 3,4-dihydroxy 5 - ((2- Methyl (trifluoromethyl) phenyl) sulfonyl) oxy) benzoate, methyl 3,4-dihydroxy-5- (((2-thienyl) sulfonyl) oxy) benzoate.

The products of formula (I) which are not products of formula (IN) or (ID) can be prepared as indicated in particular in EP 0491600 or BF 2.001.654
The products of formula (IN) or (ID) can be prepared as follows.

dans laquelle R'1 a la signification indiquée ci-dessus pour
R1 dans laquelle les éventuelles fonctions réactives sont éventuellement protégées, Z'1 et Z'2 représentent deux des radicaux R2, R3, R4, R5 et R6 tels que définis ci-dessus dans lesquelles les éventuelles fonctions réactives sont éventuellement protégées et Z représente un radical hydroxyle ou un atome d'hydrogène.The invention thus also relates to a process for preparing the products of formulas (IN) and (ID), as defined above, characterized in that either a polyphenol of formula (II) is treated

in which R'1 has the meaning indicated above for
R1 in which the possible reactive functions are optionally protected, Z'1 and Z'2 represent two of the radicals R2, R3, R4, R5 and R6 as defined above in which the possible reactive functions are optionally protected and Z represents a hydroxyl radical or a hydrogen atom.

dans laquelle alc, R'1, Z, Z'1 et Z'2 sont définis comme précédemment soit par le composé de formule (IV) ou (IV')

Hal-(CH2)n-Hal (IV') dans lesquelles Hal représente un atome d'halogène et n représente 1 à 3 pour obtenir le produit de formule (I2) ou (I2,) : :

dans lesquelles R'1, Z, Z'lt n et Z'2 ont les significations indiquées ci-dessus, produits de formules (III), (I2) et (121) que lorsque Z représente un radical hydroxyle l'on traite éventuellement in situ par un réactif susceptible d'introduire un substituant W sur le radical hydroxy, pour obtenir respectivement le produit correspondant de formule (V), (I3) ou (I3,) ::

dans laquelle W, Z'11 Z'2 alc, n et R'1 ont les significations indiquées ci-dessus, que l'on peut si désiré, hydrolyser en produit de formule (I1)

dans laquelle Z'11 Z'2 et R'1 ont les significations indiquées ci-dessus et W représente un substituant du radical hydroxyle, soit par un agent salifiant pour salifier l'un des radicaux hydroxyle libre du produit de formule (II) et traiter ensuite in situ pour introduire un substituant sur le radical hydroxyle salifié, produit ainsi obtenu ou produit de formule (II) que l'on traite éventuellement in situ sur l'un ou, le cas échéant, plusieurs des radicaux hydroxyle libres pour introduire un substituant sur l'un ou, le cas échéant, plusieurs des radicaux hydroxyle libre, ou bien l'on traite un composé de formule (VI)

dans laquelle Z' représente un atome d'hydrogène ou un radical hydroxyle substitué et R'1, Z'1 et Z'2 ont les significations indiquées ci-dessus, par un agent réducteur pour obtenir le produit de formule (14)

dans laquelle R'1, Z', Z'1 et Z'2 ont les significations indiquées ci-dessus que l'on traite éventuellement in situ pour introduire un substituant sur le radical hydroxy ou le radical amino pour obtenir les produits correspondants de formule (Ig) et (I6)

dans lesquelles R'1, Z', Z'1 et Z'2 ont les significations indiquées ci-dessus et W1 et W2 identiques ou différents, représentent des substituants des radicaux hydroxyle et amino, produit de formules (I4), (Ig) et (I6) que lorsque Z' représente un radical hydroxyle substitué l'on peut hydrolyser sur
Z' pour obtenir les produits de formule (I7) :

dans laquelle R'1, Z'1 et Z'2 ont les significations indi quées ci-dessus et S1 et S2 représentent tous les deux un atome d'hydrogène ou bien l'un un atome d'hydrogène et l'autre le substituant W1 ou W2 tel que défini ci-dessus, produits de formules (I1), (12), (13), (14), (in)' (I6) et (I7) qui peuvent être des produits de formule (IN) ou (ID) et que, pour obtenir des ou d'autres produits de formule (IN) ou (ID), l'on peut soumettre, si désiré et si nécessaire, à l'une ou plusieurs des réactions de transformations suivantes, dans un ordre quelconque a) une réaction d'estérification de fonction acide, b) une réaction de saponification de fonction ester en fonction acide, c) une réaction de transformation de radical hydroxyalkyle en radical alkyle d) une réaction de transformation de fonction ester en fonction acyle, e) une réaction de transformation de la fonction cyano en fonction acide, f) une réaction de transformation de fonction acide en fonction amide, puis éventuellement en fonction thioamide, g) une réaction de réduction de la fonction carboxy en fonction alcool, h) une réaction de réduction du radical nitro en radical amino i) une réaction de transformation de fonction alcoxy en fonction hydroxyle, ou encore de fonction hydroxyle en fonction alcoxy, j) une réaction d'oxydation de fonction alcool en fonction aldéhyde, acide ou cétone, k) une réaction de transformation du radical formyle en radical carboxy estérifié 1) une réaction de transformation du radical formyle en radical carbamoyle, m) une réaction de transformation du radical carbamoyle en radical nitrile, n) une réaction de transformation de radical nitrile en tétrazolyle, o) une réaction de transformation de fonction oxo en fonction thioxo, p) une réaction de transformation de fonction acide en fonction

q) une réaction de transformation de la fonction p-céto- sulfoxyde en fonction a-céto thio ester, r) une réaction d'élimination des groupements protecteurs que peuvent porter les fonctions réactives protégées, s) une réaction de salification par un acide minéral ou organique ou par une base pour obtenir le sel correspondant, t) une réaction de dédoublement des formes racémiques en produits dédoublés, lesdits produits de formules (IN) et (ID) ainsi obtenus étant sous toutes les formes isomères possibles racémiques, énan tiomères et diastéréoisomères.or by at least two equivalents of a base under aprotic and anhydrous conditions to give the corresponding dianion, which is treated with a trialkyl borate of formula B (Oalc) 3, in which alc represents an alkyl radical containing 1 to 6 carbon atoms, to obtain a product of formula (III)

wherein alc, R'1, Z, Z'1 and Z'2 are defined as above either by the compound of formula (IV) or (IV ')

Hal- (CH2) n-Hal (IV ') wherein Hal represents a halogen atom and n represents 1 to 3 to obtain the product of formula (I2) or (I2):

in which R'1, Z, Z'lt n and Z'2 have the meanings indicated above, products of formulas (III), (I2) and (121) that when Z represents a hydroxyl radical is optionally treated in situ by a reagent capable of introducing a substituent W on the hydroxyl radical, to obtain respectively the corresponding product of formula (V), (I3) or (I3,) ::

in which W, Z'll Z'2 alk, n and R'1 have the meanings indicated above, which can be, if desired, hydrolyzed to the product of formula (I1)

in which Z'11 Z'2 and R'1 have the meanings indicated above and W represents a substituent of the hydroxyl radical, or by a salifying agent for salifying one of the free hydroxyl radicals of the product of formula (II) and then treat in situ to introduce a substituent on the salified hydroxyl radical, thus obtained product or product of formula (II) which is optionally treated in situ on one or, where appropriate, more free hydroxyl radicals to introduce a substituent on one or, where appropriate, several free hydroxyl radicals, or a compound of formula (VI) is treated

in which Z 'represents a hydrogen atom or a substituted hydroxyl radical and R'1, Z'1 and Z'2 have the meanings indicated above, with a reducing agent to obtain the product of formula (14)

in which R'1, Z ', Z'1 and Z'2 have the meanings indicated above which is optionally treated in situ to introduce a substituent on the hydroxyl radical or the amino radical to obtain the corresponding products of formula (Ig) and (I6)

in which R'1, Z ', Z'1 and Z'2 have the meanings indicated above and W1 and W2 identical or different, represent substituents of hydroxyl and amino radicals, product of formulas (I4), (Ig) and (I6) that when Z 'represents a substituted hydroxyl radical, it is possible to hydrolyze on
Z 'to obtain the products of formula (I7):

in which R'1, Z'1 and Z'2 have the meanings indicated above and S1 and S2 both represent a hydrogen atom or one a hydrogen atom and the other substituent W1 or W2 as defined above, products of formulas (I1), (12), (13), (14), (in) '(I6) and (I7) which may be products of formula (IN) or (ID) and that, to obtain or of other products of formula (IN) or (ID), one can undergo, if desired and if necessary, one or more of the following transformation reactions, in any order a) an esterification reaction of an acid function, b) a saponification reaction of an ester function as an acid function, c) a conversion reaction of a hydroxyalkyl radical to an alkyl radical d) an ester function conversion reaction as a function acyl, e) a conversion reaction of the cyano function to an acid function, f) an acid functional conversion reaction to an amide function, and then ntiellement thioamide function, g) a reduction reaction of the carboxy function in alcohol function, h) a reduction reaction of the nitro radical to amino radical i) a conversion reaction of alkoxy function hydroxyl function, or hydroxyl function in alkoxy function, j) an oxidation reaction of alcohol function as a function of aldehyde, acid or ketone, k) a conversion reaction of the formyl radical to esterified carboxy radical 1) a conversion reaction of the formyl radical to carbamoyl radical, m) a conversion reaction of the carbamoyl radical to nitrile radical, n) a conversion reaction of nitrile radical to tetrazolyl, o) an oxo function conversion reaction to thioxo function, p) an acid function transformation reaction to function

q) a conversion reaction of the β-ketosulfoxide function according to α-keto thio ester, r) an elimination reaction of the protective groups that can be carried by the protected reactive functions, s) a salification reaction with a mineral acid or organic or with a base to obtain the corresponding salt, t) a resolving reaction of the racemic forms into split products, said products of formulas (IN) and (ID) thus obtained being in all possible isomeric forms racemic, enan tiomers and diastereoisomers.

 Under preferred conditions of implementation of the invention, the process described above can be carried out in the following manner.

 W, W1 and W2 represent substituents of the hydroxyl radical as defined above and in particular protective groups.

 The process of reacting the product of formula (II) as defined above with a borate to obtain the product of formula (III) as defined above can be carried out in the presence of a base such as hydride sodium or an organometallic such as in particular an alkyl lithium in a solvent such as tetrahydrofuran or dimethylformamide with a borate such as in particular trimethyl and triethyl borates or tripropyl, trisopropyl or tributyl.

 In the products of formula (IV) and (II '), the halogen atoms preferably represent bromine or chlorine atoms.

 The reaction of the product of formula (II) as defined above with the compounds of formulas (IV) or (IV ') can be carried out hot, for example in toluene or dimethylformamide or in the absence of solvent.

 The introduction of a substituent on the hydroxyl radical which may represent Z in the products of formulas (III), (I2) and (121) may be carried out in a solvent such as, for example, preferably anhydrous methylene chloride or dimethylformamide in the presence of a base such as for example triethylamine or pyridine.

 The substituent to be introduced may be in the form of a halogenated derivative such as in particular a chloride or bromide of alkyl, aryl, arylalkyl of alkylsulfonyl or arylsulfonyl as defined above by the radical A-sulfonyl: By way of example, mention may be made of tosyl chloride and benzyl bromide or those used in the examples described below.

 The products of formulas (V), (I3) and (I'3), as defined above, thus obtained, may, if desired, be hydrolyzed to a product of formula (I1) as defined above for the products of formula (I3) or (131) for example in a mixture of acetic acid and water and then refluxed or in 6N hydrochloric acid while hot, or trifluoroacetic acid at room temperature or for the products of formula (I3) in a solvent such as tetrahydrofuran or methanol under hydrogenation conditions such as for example in the presence of palladium on activated charcoal.

 In particular, the hydrolysis of the product of formula (V) can be carried out by an acid such as hydrochloric acid.

 The product of formula (II) may be salified under the usual conditions known to those skilled in the art such as in particular with sodium hydroxide or potassium hydroxide in a solvent such as, for example, ethanol, the introduction of a substituent on the thus salified hydroxyl radical may be carried out in a solvent such as for example dimethylformamide with a halogenated derivative as indicated above.

 The reduction of the product of formula (VI) to a product of formula (I4) can be carried out under the usual conditions known to those skilled in the art, such as, for example, by hydrogenation in the presence of palladium in tetrahydrofuran or ethanol.

 The introduction of a substituent on the hydroxyl radical of the compound of formula (I4) to obtain the product of formula (Ig) can be carried out as indicated above and the introduction of a substituent on the amino radical of the compound of formula (I4) to obtain the product of formula (I6) can be carried out under the same conditions.

 The hydrolysis of the products of formulas (in), (I5) and (I6) to the product of formula (I7) for liberating the hydroxyl group can be carried out in the usual manner in a solvent such as, for example, dichloroethane in the presence of sodium chloride. 'aluminum.

 The products of formulas (I1), (12), (13), (14), (in) '(I6) and (17) can give products of formula (IN) or (ID), or be converted into d other products of formula (IN) or (ID) being subjected to one or more of reactions a) to t) indicated above.

 Thus, the various reactive functions that certain compounds of the reactions defined above may carry may, if necessary, be protected: for example, they are hydroxyl, acyl, free carboxy or amino and monoalkylamino radicals which may be protected by the groups appropriate protectors.

 The following non-exhaustive list of examples of protection of reactive functions can be cited: the hydroxyl groups can be protected for example by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl the amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl or phthalimido radicals; the acyl groups such as the formyl group may be protected, for example, in the form of cyclic or non-cyclic ketals or thioketals; such as dimethyl or diethylketal or ethylene dioxyketal, or diethylthioketal or ethylenedithiocetal, the acid functions of the products described above can be, if desired, amidated by a primary or secondary amine for example in methylene chloride in the presence for example, 1-ethyl-3- (dimethylaminopropyl) carbod hydrochloride The acid functions can be protected, for example, in the form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry.

 The reactions to which the products of formulas (I1), (I2), (13), (14) (I5), (16) and (I7) as defined above may be subjected, if desired or necessary, may be realized, for example, as indicated below.

a) The products described above may, if desired, be subjected, on the possible carboxy functions, to esterification reactions which may be carried out according to the usual methods known to those skilled in the art.

b) The possible acid-functional ester function transformations of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in an alcoholic medium such as, for example, in methanol or in hydrochloric or sulfuric acid.

c) the reaction of conversion of hydroxyalkyl radical to alkyl radical can be carried out in the usual manner, note by halogenation then reduction in the presence of lithium hydride and aluminum for example.

dans laquelle E1 peut représenter un radical alkyle ou aryle éventuellement substitué et éventuellement protégé en fonction acyle

peut être réalisée notamment par action de l'anion carboné

dans lequel E2, E3 et E4, identiques ou différents sont choisis parmi l'atome d'hydrogène, les radicaux alkyl, alkylthioaryle, alkylsulfoxyde, arylsulfoxyde, alkylsulfone, arylsulfone, acyle, carboxy libre, salifié, estérifié ou amidifié, les radicaux alkyle, alkylthio et aryle étant éventuellement substitués et éventuellement protégés ainsi qu'il est indiqué ci-dessus.d) the addition reaction on the ester function

in which E1 may represent an optionally substituted alkyl and aryl radical and optionally protected acyl function

can be carried out in particular by the action of the carbon anion

in which E2, E3 and E4, which are identical or different, are chosen from hydrogen, alkyl, alkylthioaryl, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, acyl, free carboxy, salified, esterified or amidified alkyl radicals, alkylthio and aryl being optionally substituted and optionally protected as indicated above.

 Such a reaction is carried out according to the usual methods known to those skilled in the art.

e) The possible cyano functions of the products described above may, if desired, be converted into an acidic function under the usual conditions known to those skilled in the art, for example by a double hydrolysis carried out in an acidic medium such as, for example, in a mixture of sulfuric acid, glacial acetic acid and water, these three compounds preferably being in equal proportions, or in a mixture of sodium hydroxide, ethanol and refluxing water.

f) the reaction of conversion of acid function to amide function may in particular be carried out by first forming an acid chloride according to the usual conditions known to those skilled in the art and for example by the action of SOCl2 then amidification hereinafter above, or by direct amidification of the acid above.

The amide thus obtained can then, if desired, be converted into thioamide by the action, in particular, of the reagent of
LAWESSON in toluene, g) The optional free or esterified carboxy functions of the products described above can be, if desired, reduced in alcohol function by the methods known to those skilled in the art: the possible esterified carboxy functions can be, if desired, reduced in alcohol function by methods known to those skilled in the art and in particular by lithium hydride and aluminum in a solvent such as for example tetrahydrofuran or dioxan or ethyl ether.

 The optional free carboxy functions of the products described above may, if desired, be reduced in particular alcohol function by boron hydride.

h) the reduction reaction of the nitro radical to the amino radical can be carried out as indicated above by hydrogenation on palladium or by the action of tin chloride in ethanol.

i) The optional alkoxy functions, such as in particular the methoxy compounds of the products described above, may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as methylene chloride, for example, with hydrobromide or pyridine hydrochloride or with aluminum chloride in dichloroethane or chlorobenzene.

j) The possible alcohol functions of the products described above can be, if desired, converted to an aldehyde or acid function by oxidation under the usual conditions known to those skilled in the art, such as, for example, by the action of manganese oxide in order to obtain the aldehydes or Jones reagent to access the acids.

k) the conversion reaction of the formyl radical esterified carboxy radical can be carried out in the usual manner such as for example in methanol or ethanol in the presence of manganese oxide and sodium cyanide.

1) m) Formyl radical conversion reactions to carbamoyl radical and carbamoyl radical to nitrile radical, are carried out according to the usual conditions known to those skilled in the art, such as for example by passage through the keto nitrile and displacement by a amine (Chem.

1971, p. 733).

n) The optional nitrile functions of the products described above may, if desired, be converted into tetrazolyl under the usual conditions known to those skilled in the art, such as, for example, by cycloaddition of a metal azide such as, for example, sodium azide or a trialkyltin azide on the nitrile function as indicated in the method described in the referenced article as follows
J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S. et al.

o) the oxo function conversion reaction in thioxo function can be carried out in particular by the reagent of
LAWESSON under the conditions defined above.

que l'on peut transformer en radical

par exemple par action du composé Sn(Bu)3N3 dans le toluène, q) la réaction de transformation de la fonction B céto sulfoxyde en fonction a céto thioester, peut être réalisée par bromation en a du cétosulfoxyde par exemple par action du NBS dans par exemple le chlorure de méthylène puis par une réac tion de PUMMERER réalisée dans un mélange d'acide trifluoroacétique et de chlorure de méthylène ou encore un mélange d'acide sulfurique et de dioxanne.p) The reaction of conversion of acid function to tetrazolylcarboxy function can be carried out for example by preliminary conversion of the acid function to acid chloride as indicated above, then by action of Cu-C-N, according to the usual conditions known to those skilled in the art on the acid chloride thus obtained, the radical is thus obtained.

that we can transform into radical

for example, by the action of the compound Sn (Bu) 3N 3 in toluene, q) the conversion reaction of the function B keto sulphoxide as a function of a keto thioester, can be carried out by bromination in a ketosulfoxide for example by the action of NBS in by For example, methylene chloride and then a PUMMERER reaction carried out in a mixture of trifluoroacetic acid and methylene chloride or a mixture of sulfuric acid and dioxane.

r) The removal of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art including acid hydrolysis performed with an acid such as hydrochloric acid, benzene sulfonic or para-toluenesulphonic, formic or trifluoroacetic or catalytic hydrogenation.

 The phthalimido group may be removed by hydrazine.

 A list of different protective groups used can be found, for example, in the patent FR 2,499,995.

s) The products described above can, if desired, be the subject of salification reactions for example by a mineral or organic acid or a mineral or organic base according to the usual methods known to those skilled in the art.

t) The possible optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art.

 Illustrations of such reactions defined above are given in the preparation of the examples described below.

 The compounds of formula (I) as defined above and their addition salts with acids have interesting pharmacological properties.

 The products of formula (I) as defined above, have endothelin receptor antagonistic properties and are thus particularly inhibitors of the effects of endothelin, including endothelin-induced vasoconstrictor and hypertensive effects. In particular, there is an anti -ischemic effect, the vasoconstrictor activity of endothelin being abolished.

 The products of formula (I) are also able to oppose the stimulating effects of endothelin in all cell types, including smooth muscle cells, neuronal cells and bone cells.

 These properties justify their application in therapeutics and the subject of the invention is also, as medicaments, the products as defined by the formula (I) above, the said products of formula (I) being in all isomeric forms possible racemic or optically active, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I).

dans laquelle R1 représente l'atome d'hydrogène ou le radical carboxy libre ou estérifié, formyle, alkyle, hydroxyalkyle, alcoxyalkyle, carbamoyle, N alkylcarbamoyle, NNdialkylcarba moyle, alcoxycarbothioate ou alkylcarbonyle, V1 représente un atome d'oxygène ou le radical -NH- et V2 représente -V1H ou un atome d'hydrogène et A a la signification indiqué cidessus, lesdits produits de formule (ID) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques pharmaceutiquement acceptables desdits produits de formule (ID) et tout particulièrement ceux dans laquelle R5 représente un radical arylsulfonyloxy, éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux alkyl, alcoxy, cyano, amino, nitro, carboxy libre ou estérifié, trifluorométhoxy, trifluo rométhyle, phényle, pyridinyl et isoxarzolyl, lesdits produits de formule (I) étant sous toutes les formes isomères racémiques, énantiomères et diastéréoisomères possibles ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques pharmaceutiquement acceptables desdits produits de formule (I).The invention is particularly concerned, as medicaments, with the products of formulas (IA) and (zig) as defined above, said products of formulas (IA) and 1B being in all isomeric forms possible racemic or optically as well as the addition salts with inorganic or organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formulas (IA) and
The subject of the invention is, as medicaments, the products of formula (IN) and (ID) as defined above.
The invention more particularly relates, as medicaments, to the products of formula (I) as defined above and corresponding to the formula (ID)

in which R 1 represents the hydrogen atom or the free or esterified carboxy, formyl, alkyl, hydroxyalkyl, alkoxyalkyl, carbamoyl, N alkylcarbamoyl, NNdialkylcarba moyle, alkoxycarbothioate or alkylcarbonyl radical, V1 represents an oxygen atom or the radical -NH and V 2 represents -V 1 H or a hydrogen atom and A has the meaning indicated above, said products of formula (ID) being in all the racemic isomeric forms, enantiomers and diastereoisomers possible as well as the addition salts with mineral acids; and organic or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (ID) and very particularly those in which R5 represents an arylsulphonyloxy radical, optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy radicals cyano, amino, nitro, free or esterified carboxy, trifluoromethoxy, trifluoromethyl, phenyl, pyridinyl and isoxarzolyl, said products of formula (I) being in all the racemic isomeric forms, enantiomers and diastereoisomers possible as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula ( I).

 The invention more particularly relates, as medicaments, to the products described hereinafter in the examples and in particular the following products - 2 - (((2,3-dihydroxy-5- (methoxycarbonyl) phenyl) oxy) sulfonyl) Methyl benzoate, methyl 3,4-dihydroxy-5- (((2- (trifluoromethyl) phenyl) sulfonyl) oxy) benzoate, 3,4-dihydroxy-5 - (((2-thienyl) sulfonyl) oxy) benzoate of methyl.

 The medicinal products which are the subject of the invention find, for example, their use in the treatment of all vascular spasms, in the treatment of post-cerebral hemorrhages, in the treatment of coronary spasms, peripheral vascular spasms and in treatment. kidney failure. These drugs can also be used in the treatment of myocardial infarction, congestive heart failure, prevention of post-angioplasty restenosis, treatment of atherosclerosis, certain forms of hypertension such as pulmonary hypertension, as well as in the treatment of asthma.

 The medicaments, object of the invention, can also find an application in the treatment of osteoporosis, prostatic hypertrophy and as neural protectors.

 The invention extends to pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.

 These pharmaceutical compositions may be administered orally, rectally, parenterally or locally by topical application to the skin and mucous membranes or by intravenous or intramuscular injection.

 These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, single or coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.

 The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 1 to 300 mg per day in the adult, orally or from 1 to 100 mg per day per day. intravenous.

 Examples of the starting materials of the formulas (II), (IV), (IV ') and (VI) are given in the preparation of the examples described hereinafter.

 Some starting materials of formulas (II) and (VI) are commercially available such as in particular methyl gallate in Fluka, methyl 3,5 dihydroxybenzoate in Janssen or nitrovaniline in Aldrich, from which can be prepared from other starting materials of formula (VI) by usual methods.

 Among the products of formula (II), analogs or derivatives of gallic acid are described in, for example, the following references: G. J. Kapadia et al. J. Pharm.

Sci. 58 n09 (1969) p.1157, or Y. Takuma et al. Mitsubishi Chemical. "An efficient synthesis of contamine1 Congress
Kyoto IUPAC 29/05 / -03 / 06/1988 or Y. Kato. Synth.

Comm. 172 (1980).

 Examples of commercial products of formula (11) are given in EP 0491600 or BF 2 001 654.

 It is also possible in particular to prepare certain products of formulas (II) from other products of formula (II) by subjecting them to one or more reactions customary to those skilled in the art, such as, for example, to one or more of the reactions described above in a) to t), performed under the usual conditions or described above.

 The starting materials of formula (IV) and (IV ') are commercial, such as in particular biphenylmethyl dichloride or ethyl dibromide.

 The present invention finally has as its object as new industrial products, certain compounds of formulas (III) and (IV) in which Z, Z'11 Z'2 and R'1 are chosen from the meanings indicated above for radicals R2, R3, R4, R5 and R6 in which the possible reactive functions are optionally protected and may be deprotected.

 The present invention finally relates to the use of the products of formulas (I), (IA) and (IB) and more particularly the use of the products of formulas (IN) and (ID) as defined above, for the preparation of pharmaceutical compositions for the treatment of conditions resulting from abnormal stimulation of the lendothelin receptors.

 The subject of the invention is therefore particularly the use of the products of formulas (I), (IA), (IB), (IN) and (ID) as defined above, for the preparation of pharmaceutical compositions intended for the treatment disorders resulting from abnormal stimulation of endothelin receptors and in particular for the treatment of endothelin-induced hypertension, all vascular spasms, treatment of cerebral post-hemorrhages, renal insufficiency, myocardial infarction and the prevention of post-angioplasty restenosis.

 The following examples illustrate the invention without limiting it.

EXAMPLE 1: methyl 2,2-diphenyl-7 - (((5- (dimethylamino) -1-naphthyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
STAGE 1: 2, 2-diphenyl-7-hydroxy-1,3-benzodioxole-5-methyl carboxylate
10 g of methyl gallate are introduced into 10.2 ml of dichlorodiphenylmethane and stirred for 5 minutes at 1800C.

 It is allowed to cool to ambient temperature, solubilized in 100 ml of toluene, filtered, 150 ml of hexane are added and the mixture is stirred for 1 hour. The crystals are drained, washed with hexane and dried.

 18.7 g of expected product (white crystals) F = 1650 ° C. are thus obtained.

1714-1438
Aromatique 1642-1617-1586-1514-1504
STADE 2 : 2,2-diphényl-7-( ( (5-(diméthylamino)-l-naphtyl) sulfonyl)oxy)-1,3-benzodioxole-5-carboxylate de méthyle
On introduit 2 g du produit obtenu du stade 1 ci-dessus dans 100 ml de chlorure de méthylène, ajoute 0,95 ml de triéthylamine et 1,53 g de chlorure de dansyle. On agite deux heures à température ambiante.ANALYZES
IR CHC13 (cal) -OH 3576 + associated

1714-1438
Aromatic 1642-1617-1586-1514-1504
STAGE 2: Methyl 2,2-diphenyl-7- (((5- (dimethylamino) -1-naphthyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
2 g of the product obtained of Stage 1 above are introduced into 100 ml of methylene chloride, 0.95 ml of triethylamine and 1.53 g of dansyl chloride are added. Stirred for two hours at room temperature.

 It is poured into 500 ml of water and extracted three times with 120 ml of methylene chloride.

Purified on silica eluting with cyclohexane 7 / ethyl acetate 3 and 2.3 g of expected product (oil)
EXAMPLE 2 Methyl 3,4-dihydroxy-5 - (((5- (dimethylamino) -1-naphthyl) sulfonyl) oxy) benzoate
2.1 g of the product of Example 1 are introduced into 100 μl of a 80% acetic acid / water mixture and the mixture is refluxed overnight.

 It is poured into 300 ml of water and extracted with three times 100 ml of isopropyl ether. The organic phase is washed with water and dried.

 After chromatography on silica with cyclohexane 7 / ethyl acetate 3 eluent mixture, 0.5 g of expected product (yellow foam) F = 740C is obtained.

ANALYZES
IR CHC13 cm 1
OH - 3550
= 0 1724
Aromatic 1620-1602-1592-1575-1501
EXAMPLE 3 Methyl 3,4-dihydroxy-5 - ((phenylsulfonyl) oxy) benzoate
3 g of methyl gallate are introduced into 90 ml of anhydrous dimethylformamide.

 The solution is cooled to 15 0C. Without adding the temperature above 20 ° C., 1.56 g of 50% sodium hydride in the oil is added.

 It is stirred for one hour at room temperature, 2.7 ml of triethylborate are added and the mixture is stirred for 30 minutes.

 A solution of 2.04 ml of benzene sulphonyl chloride in 30 ml of anhydrous dimethylformamide is added over one hour and stirred for 4 hours at room temperature.

 The reaction medium is poured into 500 ml of water + ice containing 36 ml of a 2N hydrochloric acid solution.

 The aqueous phase is extracted with three times 150 ml of ethyl acetate. The organic phase is washed with water and dried.

 It is purified on silica with cyclohexane 7 / ethyl acetate eluent and 3 g of product of which 2.5 g are recrystallized from 65 ml of ethyl acetate and 10 ml of cyclohexane.

 1.65 g of expected product (white crystals) are thus obtained.

ANALYZES
IR NUJOL cm-l
OH 3420-3340
C = O 1708
Aromatic 1620-1602-1590-1537
EXAMPLE 4 Methyl 3,5-dihydroxy-4 - (((4-methylphenyl) sulfonyl) owyl) benzoate
STAGE 1: Methyl 3,4,5-trihydroxybenzoate, mono potassium salt
5 g of methyl gallate are introduced into 40 ml of 99.9% anhydrous ethanol.

 4 ml of 5N potassium hydroxide solution in ethanol are added during 30 minutes and the mixture is stirred for ten minutes at room temperature.

 The crystals are dewatered and dried.

5.5 g of expected product (yellow crystals) are obtained
STAGE 2: Methyl 3,5-dihydroxy-4 - (((4-methylphenyl) sulfonyl) oxy) benzoate
1 g of the potassium salt obtained in Step 1 above is introduced into 15 ml of anhydrous dimethylformamide.

 0.86 g of tosyl chloride are added and the mixture is stirred for one hour at room temperature.

 The reaction medium is poured into 75 ml of water. The aqueous phase is extracted with three times 50 ml of ethyl acetate. The organic phase is washed with 100 ml of water and dried.

 On silica, the mixture is purified with cyclohexane 7 / ethyl acetate 3 and then recrystallized from 40 ml of methylene chloride.

 0.4 g of expected product (white crystals) F = 1900 ° C. is obtained.

ANALYZES
IR NUJOL (cal)
Absorption complex OH / NH 1700 region
Aromatic 1620-1598-1542
EXAMPLE 5 3,4-dihydroxy-5 - (((4-methylphenyl) sulfonyl) oxy) benzoic acid
0.6 g of the product obtained in Example 1 from
EP 0491600 in 40 ml of dioxane.

 6 ml of a 6N hydrochloric acid solution are added and the reaction medium is heated for approximately three days at a temperature of 600 ° C.

 The reaction medium is cooled to room temperature, poured into 150 ml of water, with three times 50 ml of ethyl acetate and dried.

 The crude product obtained is recrystallized from 25 ml of acetonitrile to give 0.45 g of the expected product (white crystals), mp = 225.degree.

ANALYZES
IR NUJOL cm-1
Absorption region OH / NH
Max 3452} + general absorption
Max 3322}
# = 0 1701-1681
Aromatic 1605-1596-1536-1497
EXAMPLE 6: (2,3-Dihydroxy-5- (hydroxymethyl) phenyl) -4-methylbenzenesulfonate
4 g of the product obtained in Example 1 of
EP 0491600 in 40 ml of anhydrous tetrahydrofuran and slowly added 11.8 ml of a solution of lithium aluminum hydride at 1 M at room temperature. Reflux was maintained for one hour and stirred at room temperature for about 13 hours.

 It is poured into 100 ml of ice + 3 ml of concentrated hydrochloric acid, stirred for 30 minutes in OOC and 300 ml of water (pH 2) are added. The aqueous phase is extracted with three times 100 ml of ethyl acetate. The organic phase is washed with 500 ml of water and dried.

 After purification by recrystallization from acetonitrile, 0.75 g of expected product (white crystals) are obtained:> 2200 ° C.

ANALYZES
IR NUJOL cm 1
Absorption complex OH / NH region
Aromatic 1620-1603-1595-1537 -OSO2- 1356-1182-1166
EXAMPLE 7 Methyl 3,4-dihydroxy-5- ((((2,4,6-tris (1-methylethyl) phenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 3 starting from 1.5 g of methyl gallate in 45 ml of anhydrous dimethylformamide, 0.76 g of 50% sodium hydride in oil, 1.35 ml of triethylborate and 2.4 g of triisopropyl benzene sulphonyl chloride in 15 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 8 ml of a 2N hydrochloric acid solution.

Purified on silica with cyclohexane 7 / ethyl acetate eluent and obtained 3.5 g of pink crystals in 500 ml of methylene chloride, added carbon black and stirred for one hour at room temperature, dried, purified on silica with the eluent mixture cyclohexane 8 / ethyl acetate 2 and obtains 1.4 g of expected product (white crystals)
ANALYZES
IR CHC13 cm-1 -OH - 3550 cm 1 + associated - 3390

Aromatic 1620-1602-1568-1552-1510 -S02 - 1168
EXAMPLE 8 Methyl 3-hydroxy-5 - (((4-methylphenyl) sulfonyl) oxy) benzoate
3 g of methyl 3,5-dihydroxybenzoate are introduced into 35 ml of anhydrous acetone.

 4.9 g of potassium carbonate and 2.6 g of tosyl chloride are added and the mixture is stirred overnight at room temperature and then heated at reflux for 24 hours.

 The suspension is poured into 100 ml of water. The aqueous phase is acidified with a 2N hydrochloric acid solution and then extracted with three times 50 ml of ethyl acetate. The organic phase is washed with 500 ml of water and dried.

 After purification on silica with cyclohexane 6 / ethyl acetate 4 eluent mixture, 3.67 g of expected product (white crystals) F = 1500 ° C. are obtained.

aromatique 1600-1495 -S02 1375-1190-1180
EXEMPLE 9 : 3,4-dihydroxy-5(((4-methoxyphenyl)sulfonyl)oxy)- benzoate de méthyle
On procède comme à l'exemple 3 à partir de 1,5 g de gallate de méthyle dans 45 ml de diméthylformamide anhydre, 0,76 g d'hydrure de sodium à 50 % dans l'huile, 1,35 ml de triéthylborate et 2,4 g de chlorure de 4-méthoxy benzene sulfonyle dans 15 ml de diméthylformamide anhydre.ANALYZES
IR CHCl 3 (cl 1) -OH 3590-3440

aromatic 1600-1495 -S02 1375-1190-1180
EXAMPLE 9 Methyl 3,4-dihydroxy-5 - (((4-methoxyphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 3 starting from 1.5 g of methyl gallate in 45 ml of anhydrous dimethylformamide, 0.76 g of 50% sodium hydride in oil, 1.35 ml of triethylborate and 2.4 g of 4-methoxy benzene sulfonyl chloride in 15 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 8 ml of a 2N hydrochloric acid solution.

 It is purified on silica with cyclohexane / ethyl acetate eluent and then recrystallized from 15 ml of ethyl acetate and 5 ml of cyclohexane.

 0.195 g of expected product (beige crystals) are thus obtained, F = 1700 ° C.

ANALYZES
IR NUJOL cm 1 - General Absorption OH / NH -C = O 1685
Aromatic 1613-1598-1580-1535-1500 -S02 - 1320-1170
EXAMPLE 10 5 - ((((1,1'-Biphenyl) -4-yl) sulfonyl) oxy) -3,4-dihydro-benzoate
The procedure is as in Example 3 starting from 1.5 g of methyl gallate in 45 ml of anhydrous dimethylformamide, 0.76 g of 50% sodium hydride in oil, 1.35 ml of triethylborate and a solution of 2.02 g of 4-biphenylsulfonyl chloride in 15 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 8 ml of a 2N hydrochloric acid solution.

 The mixture is purified on silica with cyclohexane / ethyl acetate eluent and 3.1 g of white crystals are obtained, 2.7 g of which are recrystallized from 120 ml of ethyl acetate and 20 ml of cyclohexane.

2.3 g of expected product (white crystals) are obtained
ANALYZES
IR NUJOL cm 1
Absorptions OH / NH region
= 0 1698
Aromatic 1620-1550
EXAMPLE 11 Ethyl 3,4-dihydroxy-5 - (((4-methylphenyl) sulfonyl) oxy) benzoate
STAGE 1: ethyl gallate
5 g of gallic acid monohydrate are introduced into 45 ml of 99% ethanol, 0.5 ml of sulfuric acid and 20 ml of 1,2-dichloroethane are added and the mixture is stirred overnight under reflux.

 It is cooled to ambient temperature and dried and then solubilized in 200 ml of ethyl acetate. The organic phase is washed with a 0.1 N sodium hydroxide solution and dried.

 5.03 g of expected product (white crystals) are obtained.

ANALYZES
IR NUJOL cm 1
OH / NH Complex Absorption
-O 1700
Aromatic 1620-1534
STAGE 2: Ethyl 3,4-dihydroxy-5 - (((4-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 3 starting from 2 g of the product obtained in Step 1 above in 60 ml of anhydrous dimethylformamide, 0.97 g of 50% sodium hydride in oil, 1.7 ml. of triethylborate and 1.9 g of tosyl chloride in 15 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 11 ml of a 2N hydrochloric acid solution. It is filtered, washed with isopropyl ether and dried.

 3.15 g of expected product (white crystals) are obtained, mp = 1420 ° C.

ANALYZES
IR NUJOL (cal) -OH 3430 + general uptake -C = O 1682 -aromatic 1615-1600-1532-1495 -S 2 - 1335-1180
EXAMPLE 12 Methyl 3,4-dihydroxy-5 - (((4- (1-methylethyl) phenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 3 starting from 1.5 g of methyl gallate in 45 ml of anhydrous dimethylformamide, 0.76 g of 50% sodium hydride in oil, 1.35 ml of triethylborate and a solution of 1.75 g of isopropyl benzene sulfonyl chloride in 15 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 8 ml of a 2N hydrochloric acid solution.

 The mixture is purified on silica with cyclohexane / ethyl acetate eluent 5 and then recrystallized from 50 ml of ethyl acetate and 20 ml of cyclohexane to give 0.7 g of expected product (white crystals). F = 1850C.

ANALYZES
IR NUJOL cm 1
Region OH / NH max 3480-3300
= 0 1710
Aromatic 1615-1602-1537-1497 -OSO, 1308-1176
EXAMPLE 13: Methyl 3,5-dihydroxy-4- (phenylmethoxy) benzoate
The procedure is as in Example 4 starting from 0.5 g of the potassium salt obtained in Step 1 of Example 4 in 15 ml of anhydrous dimethylformamide and 0.26 ml of benzyl bromide.

 Purified on silica with cyclohexane 7 / ethyl acetate 3 eluent and 0.6 g of expected product (white crystals) F = 140 ° C.

ANALYZES
IR NUJOL (cal) -OH - 3510 cm 1 + 3320 + general absorption -C = O 1685 -Aromatic 1605-1545-1530
EXAMPLE 14 Methyl 3-amino-4 - (((4-methylphenyl) sulfonyl) oxy) benzoate
2 g of methyl 3-amino-4-hydroxybenzoate are introduced into 20 ml of methyl chloride, 1.4 ml of triethylamine are added and the mixture is stirred for 15 minutes.

 2.28 g of tosyl chloride dissolved in 15 ml of methylene chloride are added dropwise, the mixture is stirred for two hours at room temperature and left to stand overnight.

 The reaction medium is poured into 300 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 75 ml of methylene chloride. The organic phase is washed with 500 ml of water and dried.

 The crude product is crystallized in 20 ml of ethyl acetate and 3 ml of methanol and 2 g of expected product (white crystals) are obtained, mp = 14 ° C.

ANALYZES
IR NUJOL (cm-1)
Absorption OH / NH2 = max - 3496-3400
= 0 1722
NH2 def + Aromatic 1629-1608-1592-1506-1498
EXAMPLE 15 Methyl 4-hydroxy-3-methoxy-5 - (((4-methylphenyl) sulfonyl) amino) benzoate
STAGE 1: methyl t4-hydroxy-3-methoxy] nitrotbenzoate
4 g of 5-nitrovaniline are introduced into 150 ml of anhydrous methanol, 6.4 g of sodium cyanide are added and the mixture is stirred for ten minutes at room temperature.

 30 g of manganese oxide are added and the mixture is stirred for 24 hours at room temperature.

 Filtered, the manganese oxide is washed with ethyl acetate, and the filtrate evaporated to dryness and solubilized in 100 ml of ethyl acetate. The organic phase is washed with 150 ml of a 2N hydrochloric acid solution and evaporated to dryness.

 After purification by filtration on celite and on silica with ethyl acetate, 2.5 g of expected product (yellow crystals) are obtained.

ANALYZES
IR NUJOL (cal)
General OH / NH absorption
= 0 1710
Aromatic + NH2 def 1610-1568-1540
STAGE 2: (4-hydroxy-3-methoxy-5-amino methyl benzoate)
2.4 g of the product obtained in Step 1 above is introduced into 120 ml of methanol, 0.1 g of 18% activated palladium-on-charcoal is added and maintained under a hydrogen atmosphere for 4 hours.

 The suspension is filtered, the catalyst washed with ethyl acetate and the filtrate evaporated.

 Purified on silica with cyclohexane 1 / ethyl acetate eluent mixture 9 and 1.4 g of expected product.

ANALYZES
IR CHCl3 (cal) -OH 3544-3474-3394
NH2
= 0 1711
NH2 def + Aromatic 1629-1609-1594-1516
STAGE 3: methyl 4-hyroxy-3-methoxy-5 - (((4-methylphenyl) sulfonyl) amino) benzoate
To a solution of 0.5 g of the product obtained in Stage 2 above in 20 ml of anhydrous methylene chloride is added to OOC, 0.31 ml of pyridine is stirred for 15 minutes and to OOC is added in portions 0.47 g of chloride. of tosyl.

 The reaction medium is poured into 100 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 50 ml of methylene chloride. The organic phase is washed with 100 ml of water and evaporated to dryness.

 Chromatography on silica with cyclohexane / ethyl acetate eluent gives 0.8 g of yellow crystals which are purified by recrystallization from 30 ml of ethyl acetate and 5 ml of methylene chloride.

 This gives 0.4 g of expected product (yellow crystals) F = 1480C.

ANALYZES
IR CHCl 3 (cm 1) -OH 3531
NH 3354
= 0 1715
Aromatic 1619-1599-1514-1498
EXAMPLE 16 Methyl 3-amino-5-methoxy-4 - (((4-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 14 starting from 0.5 g of the product obtained in Step 2 of Example 15 in 20 ml of anhydrous methylene chloride, 0.31 ml of triethylamine and 0.47 g of chloride. of tosyl.

 The reaction medium is poured into 100 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 50 ml of methylene chloride. The organic phase is washed with 100 ml of water and evaporated to dryness.

 It is purified on silica with cyclohexane / ethyl acetate eluent and then recrystallized from 30 ml of ethyl acetate and 5 ml of methylene chloride. 0.45 g of expected product (yellow crystals) F = 1580 ° C. are thus obtained.

ANALYZES = C-NH2 3494-3406
= 0 1719
NH2 def + Aromatic 1626-1599-1499
EXAMPLE 17 Methyl 4-hydroxy-3 - (((4-methylphenyl) sulfonyl) ino-benzoate
2 g of methyl 3-amino-4-hydroxybenzoate are introduced into 20 ml of anhydrous methylene chloride.

 To OOC, 1.4 ml of pyridine is slowly added and the mixture is stirred for 15 minutes.

 2.28 g of tosyl chloride dissolved in 15 ml of methylene chloride are added dropwise and the mixture is stirred for two hours at room temperature.

 The reaction medium is poured into 300 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 75 ml of methylene chloride. The organic phase is washed with 500 ml of water and evaporated to dryness. It is impasted in 75 ml of isopropyl ether and 3.56 g of white crystals are obtained, of which 3 g are purified by recrystallization from 60 ml of ethyl acetate and 1 ml of cyclohexane. 1.2 g of expected product (white crystals) are obtained, mp 165 ° C.

ANALYZES
IR NUJOL (cal) -Absorptions OH / NH + general absorption
= 0 1680
Aromatic 1610-1520-1492
EXAMPLE 18 2 - Methyl (((2,3-dihydroxy-5- (methoxycarbonyl) phenyl) oxy) sulfonyl) benzoate
The procedure is as in Example 3 starting from 2 g of methyl gallate in 90 ml of anhydrous dimethylformamide, 0.96 g of 50% sodium hydride in oil, 1.75 ml of triethylborate and a solution of 2.3 g of 2-carbomethoxy benzene sulfonyl chloride in 15 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 11 ml of a 2N hydrochloric acid solution.

 The aqueous phase is extracted with three times 150 ml of ethyl acetate. The organic phase is washed with water and evaporated to dryness.

 Purification on silica with the eluent mixture methylene chloride 8 / ethyl acetate 2 and then recrystallization in 8 ml of ethyl acetate and 2 ml of cyclohexane.

 0.26 g of the expected product (crystals) F = 1690 ° C. are thus obtained.

ANALYZES
IR CHCl 3 cm 1 -OH - 3543 -CO 2 Me 1714-1438
Aromatic 1622-1604-1590-1575-1515 502 - 1171
EXAMPLE 19 Methyl 3 - (((4-butyloxyphenyl) sulfonyl) oxy) -4,5-dihydroxybenzenecarboxylate
The procedure is as in Example 3 starting from 3 g of methyl gallate in 90 ml of anhydrous dimethylformamide, 1.56 g of 50% sodium hydride in oil, 2.7 ml of triethylborate and a solution of 3.98 g of 4- (n-butoxy) benzene sulfonyl chloride in 30 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 16 ml of a 2N hydrochloric acid solution.

 The aqueous phase is extracted with three times 150 ml of ethyl acetate. The organic phase is washed and concentrated to dryness.

 The mixture is purified on silica with cyclohexane / ethyl acetate eluent and then recrystallized from ethyl acetate (120 ml) and cyclohexane (20 ml).

3.6 g of expected product are obtained (white crystals).
ANALYZES
IR NUJOL (cm-1)
Absorption OH / NH - 3419
= 0 1686
Aromatic 1615-1596-1575-1525-1498
EXAMPLE 20 Methyl 3,4-dihydroxy-5 - (((4-methylphenyl) sulfonyl) amino) -benzenecarbolrylate
0.3 g of the product of Example 15 is introduced into 75 ml of 1,2-dichloroethane.

 0.42 g of aluminum chloride is added, the mixture is refluxed for 4 hours and the reaction medium is poured into 100 ml of water. The aqueous phase is extracted with three times 50 ml of ethyl acetate. The organic phase is washed with 100 ml of water and dried.

 It is purified on silica with cyclohexane / ethyl acetate eluent 5 and then by hot solubilization in 7 ml of ethyl acetate. Carbon black is added, the solution is filtered and the filtrate is cooled.

0.090 g of expected product is obtained (gray crystals)
Mp 2120C.

ANALYZES
IR NUJOL (cal)
Absorption OH / NH - 3343
= 0 1686
Aromatic 1610-1595-1525
EXAMPLE 21 Methyl 4-hydroxy-3 - (((4-methylphenyl) sulfonyl) oxy) benzoate
1 g of methyl 3,4-dihydroxybenzoate are introduced into 70 ml of anhydrous dimethylformamide and then 0.56 g of 50% sodium hydride in oil at room temperature. After stirring for two hours, 1.13 g of tosyl chloride in solution in 30 ml of dimethylformamide are added dropwise and the mixture is stirred for one hour at room temperature.

 The suspension is poured into 100 ml of water. The aqueous phase is acidified with a 2N hydrochloric acid solution and then extracted with three times 50 ml of ethyl acetate. The organic phase is washed with 500 ml of water and evaporated to dryness.

 The mixture is purified on silica with cyclohexane / ethyl acetate eluent and then recrystallized from 50 ml of ethyl acetate and 10 ml of cyclohexane.

 0.6 g of expected product (white crystals) are obtained, mp = 1400 ° C.

ANALYZES
IR CHC13 (cm 1) -C-OMe 1719-1439
#
O-OH 3559
Aromatic 1613-1598-1511 -OS02 1380-1178
EXAMPLE 22: (2,3-Dihydro-17-yl) formylphenyl-4-methylbenzenesulphonate
The procedure is as in Example 3 starting from 1 g of 3,4,5, trihydroxy benzaldehyde hydrate in 35 ml of anhydrous dimethylformamide, 0.83 g of 50% sodium hydride in oil, 1 ml of triethylborate and a solution of 1.1 g of tosyl chloride in 30 ml of anhydrous dimethylformamide.

 The reaction medium is poured into 500 ml of water + ice containing 16 ml of a 2N hydrochloric acid solution.

 It is purified on silica with cyclohexane / ethyl acetate eluent and then recrystallized from 20 ml of ethyl acetate and 10 ml of cyclohexane.

 0.43 g of expected product (white crystals) F = 125.degree.

ANALYZES
IR NUJOL (cal)
OH / NH Complex Absorption
= 0 1694-1650
Aromatic 1598-1543-1494 - S 2 - 1310-1180
EXAMPLE 23 Methyl 2,2-diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
7 g of the product obtained in Stage 1 of Example 1 are introduced into 320 ml of anhydrous methylene chloride, 4.8 ml of triethylamine are added and the mixture is stirred for 15 minutes.

 3.8 g of tosyl chloride in solution in 150 ml of methylene chloride are added dropwise and the mixture is stirred at room temperature.

 The reaction medium is poured into 500 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 120 ml of methylene chloride. The organic phase is washed with 500 ml of water, dried and evaporated to dryness.

 10.08 g of white foam are obtained, 3 g of which are purified by recrystallization from 60 ml of ethyl ether and 40 ml of isopropyl ether.

 2.1 g of expected product (white crystals) F = 1300 ° C. are thus obtained.

ANALYZES
IR CHC13 (cm 1)
Absence of OH -C-OMe 1718-1441
#
O - S 2 1301-1179
Aromatic 1627-1617-1599-1499
EXAMPLE 24 Methyl 3-hydroxy-4- (phenylmethoxy) -5 - (((4-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 14 starting from 0.5 g of the product of Example 13 in 120 ml of anhydrous methylene chloride, 0.22 ml of triethylamine with OOC and 0.34 g of tosyl chloride in solution. in 35 ml of methylene chloride.

 The reaction medium is poured into 100 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 50 ml of methylene chloride. The organic phase is washed with 100 ml of water, dried and evaporated to dryness.

 Purified on silica with the eluent mixture of methylene chloride 9 / ethyl acetate 1 and 0.160 g of expected product (white crystals) F = 125 ° C.

ANALYZES
IR CHC13 cm 1 -OH - 3527 -C = O 1723-1437 #
OMe -Aromatic 1620-1598-1587-1502 -S 2 1380-1193-1180
EXAMPLE 25 Methyl 3- (2-hydroxyethoxy) -5 - (((4-methylphenyl) sulfonyl) -4- (phenylmethoxy) benzoate
1.4 g of the product of Example 24, 0.3 g of ethylene carbonate, 0.2 g of tetraethylammonium bromide and heated at 1400C for one hour are introduced.

 The reaction medium is poured into 100 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 50 ml of ethyl acetate. The organic phase is washed with 100 ml of dried water and evaporated to dryness.

 It is purified on silica with the cyclohexane / ethyl acetate eluent mixture, crystallizes the oil obtained in 20 ml of isopropyl ether and gives 0.180 g of white crystals of which 0.150 g are recrystallized from 2 ml of ethyl acetate. 1 ml of cyclohexane and 2 ml of isopropyl ether.

0.1 g of expected product (white crystals) are thus obtained. F = 1150C
ANALYZES
IR CHC13 (cal)
OH complex - 3610
= 0 1721
Aromatic 1599-1584-1501
EXAMPLE 26 Methyl 4-hydroxy-3- (2-hydroxyethoxy) -5 - (((4-methylphenyl) sulfonyl) oxy) -bensoate
0.5 g of the product of Example 25 are introduced into 100 ml of tetrahydrofuran, 0.05 g of 5% activated palladium on carbon and hydrogen for two hours.

 It is filtered, washed with ethyl acetate and the filtrate is evaporated.

 The residue is recrystallized from 15 ml of ethyl acetate to give 0.32 g of expected product (white crystals).

F = 1900C
ANALYZES
IR NUJOL (cm 1)
OH / NH absorption
= 0 1709-1694
Aromatic 1612-1598-1520
EXAMPLE 27 Methyl 2,2-diphenyl-7 - ((ethylsulfonyl) oxy) -1,3-b-n-dioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 1 g of the product obtained in Step 1 of Example 1 in 60 ml of methylene chloride with 0.8 ml of triethylamine and 0.26 ml of chloroform. ethylsulfonyl.

1.25 g of expected product (oil) are thus obtained.
ANALYZES
IR CHC13 (cal)
Absence of OH -OS02- 1304-1173 -C-OMe 1720
#
O
Aromatic 1627-1620-1580-1500
EXAMPLE 28 Methyl 3,4-dihydroxy-5 - ((ethylsulfonyl) oxy) benzoate
1.2 g of the product of Example 27 are introduced into 120 ml of tetrahydrofuran. 0.5 g of 18% activated palladium on charcoal and hydrogen are added overnight. Wash with ethyl acetate and the filtrate is evaporated.

 It is purified on silica with a cyclohexane / ethyl acetate mixture and then recrystallized from 35 ml of ethyl acetate and 10 ml of cyclohexane.

 0.4 g of expected product (white crystals) F = 1460C are thus obtained.

ANALYZES
IR NUJOL (cal)
Max - 3492 OH / NH
= 0 1688
Aromatic 1612-1604-1532
EXAMPLE 29: (2,2-Diphenyl-6- (methoxymethyl) -1,3-benzodioxol-4-ol) 4-methylbenzenesulfonate
STAGE 1: 2,2-diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-hydroxymethyl
2.8 g of the product of Example 23 are introduced into 280 ml of anhydrous tetrahydrofuran.

After cooling to 5.5 ° C., 5.5 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran are added dropwise, without the temperature exceeding 80.degree. C. and stirring for 30 minutes.
To 50C, 2 ml of 80/20 solution of tetrahydrofuran / water and then 1 ml of saturated solution of sodium tartrate of potassium are added. The mixture is filtered off with suction, washed with 50 ml of ethyl acetate, dried and then solubilized in 200 ml of ethyl acetate. The organic phase is washed with 300 ml of water and evaporated to dryness.

2.3 g of expected product are obtained
ANALYZES
IR CHC13 (cal)
Absence of # = 0
OH 3610
Aromatic 1631-1602-1503 -OS02- 1380-1180
STAGE 2: (2,2-Diphenyl (methoxymethyl) -1,3-benzodioxol-4-ol) 4-methylbenzenesulfonate
4.5 g of the product obtained in Step 1 above is introduced into 80 ml of anhydrous tetrahydrofuran.

 It is cooled to -50 ° C., 6.8 ml of 1.4 molar butyl lithium solution is added to the hexane, the temperature is allowed to rise to 0 ° C. and 1.2 ml of methyl iodide are added dropwise and the mixture is stirred overnight. at room temperature.

 It is poured into 300 ml of water. The aqueous phase is extracted with three times 100 ml of ethyl acetate. The organic phase is washed with 300 ml of water and evaporated to dryness.

Purified on silica with cyclohexane 8 / ethyl acetate 2 eluent and 1.4 g of expected product (pale yellow crystals)
ANALYZES
IR CHC13 (cm 1)
Absence of OH
Aromatic 1628-1597-1502
EXAMPLE 30: 1- (4-methylbenzenesulfonate) 5-ethyl-1,2,3-benzenetriol
The procedure is as in Example 28 starting from 0.5 g of the product of Example 29 in 120 ml of tetrahydrofuran, 0.1 g of 18% activated palladium on charcoal and hydrogenation.

 Purified on silica with cyclohexane 5 / ethyl acetate 5 and 0.150 g of expected product (white crystals).

IR NUJOL (cm 1)
Absorptions OH / NH area - 3450-3305
Aromatic 1610-1598-1520-1498
EXAMPLE 31: (2,3-Dihydroxy-5- (methoxymethyl) phenyl) -4-methyl-benzenesulfonate
STAGE 1: 3 - Methyl ((((4-methylphenyl) sulfonyl) oxy) -4,5-bis (phenylmethoxy) benzoate
3 g of the product of Example 1 of EP 0491,600 are introduced into 120 ml of anhydrous dimethylformamide.

 0.85 g of 50% sodium hydride in oil is added, the mixture is stirred for one hour at room temperature and 2.1 ml of benzyl chloride in solution in 20 ml of dimethylformamide are added and the mixture is stirred overnight at room temperature. room.

 It is poured into 300 ml of water, the aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with 3 times 75 ml of ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness.

It is purified on silica with the cyclohexane 7 / ethyl acetate 3 eluent mixture and then recrystallized from isopropyl ether to give 3.3 g of expected product (white crystals).
ANALYZES
IR CHC13 (cal)
Absence of OH
-O 1720
Aromatic 1599-1585-1501
STAGE 2: 3- ((((4-methylphenyl) sulfonyl) oxy) -4,5-bis (phenylmethoxy) -benzenemethanol
3.2 g of the product obtained in Step 1 above is introduced into 210 ml of anhydrous tetrahydrofuran.

 It is cooled to 50 ° C., and 6.2 ml of 1 × solution of lithium aluminum hydride in tetrahydrofuran are added, keeping the temperature at 60 ° C. and stirring for 30 minutes at 50 ° C.

 1.5 ml of 80/20 solution of tetrahydrofuran / water and then 1 ml of saturated sodium and potassium potassium tartrate solution are added at 50 ° C. and the mixture is stirred for 2 hours with OOC and then filtered off, washed with 50 ml of acetate of ethyl and dry. It is solubilized in 200 ml of ethyl acetate and the organic phase is washed with 300 ml of water, dried and evaporated to dryness.

3.2 g of expected product (white crystals) are obtained
ANALYZES
IR CHCl 3 (cl 1) -OH - 3608
Aromatic 1599-1588-1502
STAGE 3: 5- (Methoxymethyl) -2,3-bis (phenylmethoxy) -phenyl-3-methylbenzenesulfonate
2.85 g of the product obtained in Step 2 above are introduced into 140 ml of anhydrous tetrahydrofuran.

 It is cooled to -50 ° C., and 5.8 ml of 1M butyllithium solution in hexane are added, the temperature is allowed to rise to 0 ° C. and 1.08 ml of methyl iodide are added and the mixture is refluxed for 4 hours.

 It is poured into 300 ml of water, the aqueous phase is extracted with three times 100 ml of ethyl acetate and the organic phase is washed with 300 ml of water, dried and evaporated to dryness.

Purified on silica with cyclohexane 7 / ethyl acetate eluent 3 and 1.3 g of expected product (crystals)
ANALYZES
IR CHC13 (cal) -OMe-2830 -OH 3525
STAGE 4: (2,3-Dihydroxy-5 (methoxymethyl) phenyl) -4-methyl-benzenesulfonate
The procedure is as in Example 26 from 1 g of the product obtained in Step 3 above in 80 ml of tetrahydrofuran, 0.1 g of 5% palladium on activated charcoal and hydrogen under 400 mbar pressure.

 Filtered, washed with ethyl acetate. The filtrate is evaporated.

Purified on silica with cyclohexane 5 / ethyl acetate mixture 5 and then pasted in isopropyl ether and 0.42 g of expected product (white crystals) F = 1300C
ANALYZES
IR NUJOL (cal)
OH - 3505 + general absorption
Aromatic 1609-1600-1513
EXAMPLE 32 Methyl 7 - (((4-cyanophenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 1 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 0.8 ml of triethylamine and 0.58 g of chloroform. cyanobenzene sulfonyl.

1.4 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHC13 (cm 1)
Absence of OH C = -N - 2236 0 1720
Aromatic 1620-1586-1500
EXAMPLE 33 5 - Methyl ((((4-cyanophenyl) sulfonyl) oxy) -3,4-dihydroxybenzoate
The procedure is as in Example 2 starting from 1.4 g of the product of Example 32 in the acetic acid mixture 140 ml / water 30 ml.

 It is heated at 110 ° C. for 8 hours.

 The solution is poured into 500 ml of water and the crystals obtained are drained and washed with 30 ml of isopropyl ether and then purified by recrystallization from 25 ml of ethyl acetate and 5 ml of cyclohexane.

0.4 g of expected product (white crystals) is obtained
F = 2000C.

ANALYZES
IR NUJOL (cm-1)
Absorptions OH / NH - 3465-3310 C = -N 2240
= 0 1694
Aromatic 1620-1610-1552-1490
EXAMPLE 34 2,2-Diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxamide
Ammonia is solubilized for 10 minutes at -30 ° C. in 120 ml of anhydrous methylene chloride, then 3.9 ml of a solution of trimethylaluminium in 2M solution in hexane and stirred for 45 minutes are added to OOC. allowing to rise to room temperature.

 2 g of the product of Example 23 in solution in 50 ml of methylene chloride are added and the mixture is stirred for three hours at room temperature and then heated under reflux overnight.

 It is poured into 200 ml of water containing 50 ml of a 2N hydrochloric acid solution. The aqueous phase is extracted with three times 100 ml of methylene chloride. The organic phase is washed with 200 ml of water, dried and evaporated to dryness.

 It is purified on silica with cyclohexane / ethyl acetate eluent and gives 1.6 g of expected product (white crystals).

ANALYZES
IR CHCl3 (cm-1) = C-NH2 3530-3414
= 0 1678
Aromatic + NH2 def 1626-1599-1587-1502
EXAMPLE 35 Methyl 2,2-diphenyl-7 - (((phenylmethyl) sulfonyl) oxy-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 1 g of the product obtained in Step 1 of Example 1 in 60 ml of methylene chloride with 0.8 ml of triethylamine and 1.5 ml of alpha-toluenesulphonyl chloride. .

 1.2 g of expected product (white crystals) are thus obtained.

1H NMR NMR (CDCl3, 200MHz) NMR spectra: ppm 7.6-7.3 Ar (m, 17H), 4.6 CH2SO2 (s, 2H); 3.85 CO2CH3 (s, 3H)
EXAMPLE 36 Methyl 3,4-dihydroxy-5 - (((phenylmethyl) sulfonyl) oy) benzoate
The procedure is as in Example 2 starting from 1.45 g of the product of Example 35 in 100 ml of a mixture of acetic acid 80 / water 20.

 The reaction mixture is heated at 1500C for 10 hours.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and then dried and evaporated to dryness.

 It is purified by recrystallization in 30 ml of ethyl acetate and 15 ml of cyclohexane and then in 10 ml of ethyl acetate and 5 ml of cyclohexane to obtain 0.205 g of the expected product (beige crystals) mp 1720 ° C.

EXAMPLE 37 Methyl 7 - (((4-carboxyphenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.25 g of acid. chlorosulfonyl benzoic acid.

1.7 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHC13 (cal)
Region -OH - 3505 + general absorption
-O 1718-1708
Aromatic 1616-1603-1558-1499
EXAMPLE 38 Methyl 3,4-dihydroxy-5 - (((4- (methoxycarbonyl) phenyl) sulfonyl) oxy) benzoate
3 g of the product of Example 37 are introduced into 400 ml of methanol. Stirred 15 minutes at room temperature, added 1.7 ml of thionyl chloride and stirred for about three hours.

 The solution is evaporated. Purified on silica with the eluent mixture methylene chloride 8 / methanol 2 and then by recrystallization in 100 ml of a mixture of acetic acid 80 / water 20.

 0.8 g of expected product (white crystals) are thus obtained, mp = 2150 ° C.

ANALYZES
IR NUJOL cm 1
Region OH / NH - 3465-3400
= 0 1721-1698
Aromatic 1614-1580-1540
EXAMPLE 39 Methyl 2,2-diphenyl-7 - (((2-nitrophenyl) sulfonyl) oxy-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.26 g of chloride of 2. nitrobenzene sulfonyl.

3 g of expected product (crystals) are thus obtained
ANALYZES
IR CHC13 (cal)
Absence of OH
-O 1722
Aromatic 1st band NO2 1621-1597-1551-1501 -OS02- 1304-1195
EXAMPLE 40 Methyl 3,4-dihydroxy-5-t ((2-nitrophenyl) sulfonyl) owyl) benzoate
The procedure is as in Example 2 starting from 3 g of the product of Example 39 in 100 ml of a mixture of acetic acid 80 / water and left for 12 hours under reflux.

 Poured into 300 ml of water, the crystals are drained, washed with 30 ml of isopropyl ether.

 It is purified by recrystallization from 30 ml of ethyl acetate and 1 ml of cyclohexane and gives 1.43 g of the expected product (white crystals) mp 185 ° C.

ANALYZES
IR NUJOL (cm-1)
Region OH / NH: max 3460-3280
= 0 1690
Aromatic 1619-1597-1555
EXAMPLE 41 Ethyl 2,2-diphenyl-4 - (((pentafluorophenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 0.72 g of pentafluorobenzene chloride. sulfonyl.

 2.8 g of expected product are obtained after crystallization under isopropyl ether.

ANALYZES
IR CHC13 (cal)
Absence of OH
= 0 1722
Aromatic 1646-1624-1522-1505 -OS02- 1304-1195
EXAMPLE 42 Methyl 3,4-dihydroxy-5 - (((pentafluorophenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.7 g of the product of Example 41 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed overnight.

 The solution is poured into 300 ml of water and extracted with three times 100 ml of isopropyl ether. The organic phase is washed with water, dried and evaporated to dryness.

 Purified on silica with cyclohexane 7 / ethyl acetate eluent 3 and then recrystallized from 25 ml of ethyl acetate and 10 ml of cyclohexane.

0.63 g of expected product (white crystals) is thus obtained.
ANALYZES
IR NUJOL (cal)
Region OH / NH: max 3470-3290
= 0 1692
Aromatic 1648-1620-1542-1520-1503
EXAMPLE 43 3,4-Dihydroxy-5 - (((4-methylphenyl) sulfonyl) oxy) benzamide
The procedure is as in Example 2 starting from 1.6 g of the product of Example 34 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 9 hours.

 The solution is poured into 300 ml of water and the crystals are drained and washed with 75 ml of water. After chromatography on silica with the eluent mixture methylene chloride 98 / methanol 2, it is purified by recrystallization in 30 ml of ethyl acetate.

 0.43 g of expected product (white crystals) are thus obtained, mp = 2200 ° C.

ANALYZES
IR NUJOL (cm-1)
Absorptions OH / NH max 3575-3430
= 0 1691
Aromatic + NH2 def 1660-1620-1592-1522
EXAMPLE 44: N, N-dimethyl-2,2-diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxamide
The procedure is as for Example 34 by solubilizing for 10 minutes, at -300, dimethylamine in 120 ml of anhydrous methylene chloride by adding to OOC, 3.9 ml of a 2M solution of trimethylaluminium in hexane and allowing to return to room temperature in 45 minutes, 2 g of the product of Example 23 dissolved in 50 ml of methylene chloride.

2.2 g of expected product are obtained (white crystals).
ANALYZES
IR CHC13 ass 1
Absence of

= 0 Aromatic amide 1632-1619
EXAMPLE 45 3,4-Dihydroxy-N, N-dimethyl-5 - (((4-methylphenyl) sulfonyl) oxy) benzenecarboxamide
The procedure is as in Example 2 starting from 2.1 g of the product of Example 44 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 12 hours.

 The solution is poured into 150 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is evaporated to dryness.

It is recrystallized from 40 ml of ethyl acetate and 0.9 g of expected product (white crystals) are obtained. F = 1900C
ANALYZES
IR NUJOL (cm-1)
Region OH / NH max 3420 + general absorption
= 0 1580-1492
EXAMPLE 46 2,2-Diphenyl-N-methyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxamide
The procedure is as in Example 34, using a solution of methylamine in 120 ml of anhydrous methylene chloride, bubbled for 10 minutes at -300 ° C., 3.9 ml of a solution of trimethylaluminum in solution 2 × in hexane and from 2 g of product of Example 23 in solution in 50 ml of methylene chloride.

 0.8 g of expected product is thus obtained.

ANALYZES
IR CHCl3 (cal) = C-NH- - 3470
= 0 1665
Aromatic amide II 1623-1601-1535-1492
EXAMPLE 47 3,4-Dihydroxy-N-methyl-5 - (((4-methylphenyl) sulfonyl) oxy) benzenecarboxamide
The procedure is as in Example 2 starting from 0.8 g of the product of Example 46 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 24 hours.

 The solution is poured into 150 ml of water and the crystals are drained, washed with 30 ml of isopropyl ether and then purified by recrystallization in 20 ml of ethyl acetate.

0.3 g of expected product (white crystals) is obtained
F = 2400C
ANALYZES
IR NUJOL (cm-1)
Absorptions OH / NH Max - 3428
= 0 1648
Aromatic + amide II 1616-1606-1558-1532-1492
EXAMPLE 48: 1- (2,2-Diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxol-5-yl) -ethanone
STAGE 1: 2, 2-diphenyl-7-benzyloxy-1,3-benzodioxole-5-methyl carboxylate
8.1 g of the product obtained in Step 1 of Example 1 are introduced into 160 ml of anhydrous dimethylformamide, 6.2 g of potassium carbonate are added, the mixture is stirred for 5 minutes, 2.9 ml of benzoyl bromide is added and the mixture is stirred for 24 minutes. hours at room temperature.

 The reaction medium is poured into 300 ml of water, the aqueous phase neutralized with a 2N hydrochloric acid solution and then extracted with three times 100 ml of ethyl acetate. The organic phase is washed with 3 ml of water and dried.

10 g of expected product (white crystals) are obtained
ANALYZES
IR CHC13 (cm - Absence of OH - CO2Me 1713 - Aromatic 1634-1605-1585-1507-1497
STAGE 2: [2,2-Diphenyl-7-benzyloxy-1,3-benzodioxole-5-carboxylic acid
10 g of the product obtained in Step 1 above are introduced into 150 ml of concentrated sodium hydroxide and heated at 1000 ° C. for 2 hours.

 The reaction medium is poured into 150 ml of concentrated hydrochloric acid and 200 ml of ice and the suspension is stirred for 2 hours at 0.degree.

 The crystals are dewatered, washed with water, dried.

 9.2 g of expected product (pink crystals) are obtained, mp 1700 ° C.

ANALYZES
IR CHCl 3 (cal) -OH-3520 + general absorption type acid -c = O 1718-1687 -Aromatic 1632-1603-1577-1508-1496
STAGE 3: 2,2-Diphenyl-7-benzyloxy-1,3-benzodioxole-5-carboxylic acid chloride
5 g of the product obtained in Stage 2 above are introduced into 150 ml of anhydrous toluene, 3.2 ml of oxalyl chloride are slowly added without exceeding 50.degree. C., the temperature is allowed to rise, the mixture is stirred overnight at room temperature and the mixture is evaporated at room temperature. dry.

 5.1 g of expected product (white crystals) F = 1350 ° C. are obtained.

ANALYZES
IR CHCl3 (cl 1) -C = O - 1807-1746
Aromatic - 1628-1601-1586-1503-1496
STAGE 4: 2,2-diphenyl-7-benzyloxy-1,3-benzodioxole-5-yl) -1-ethanone
5.2 g of the product obtained in Step 3 above are introduced into 85 ml of anhydrous hexamethyl phosphotriamide, 1.62 ml of tetramethyltin and then 0.052 mg of chloro (benzyl) bis (triphenylphosphine) palladium II are added and the mixture is heated for four hours at 60.degree.

 It is left overnight at room temperature and then poured into 150 ml of water. The aqueous phase is extracted with three times 50 ml of ethyl acetate. The organic phase is washed with water and evaporated to dryness.

After purification on silica with the cyclohexane 7 / ethyl acetate 3 eluent mixture, 2.5 g of expected product (white crystals) are obtained.
ANALYZES
IR CHCl3 (cal)
-O 1678
Aromatic 1628-1605-1589-1510-1499
STAGE 5: 2,2-diphenyl-7-hydroxy-1,3-benzodioxol-5-yl) 1-ethanone
2.5 g of the product obtained in Step 4 above are introduced into 120 ml of tetrahydrofuran, 0.05 g of 5% palladium on activated charcoal and hydrogen are added at 60 mbar for two hours.

 The suspension is filtered, the catalyst washed with ethyl acetate and the filtrate evaporated.

 After purification on silica with the cyclohexane 7 / ethyl acetate 3 eluent mixture, 0.9 g of expected product (white crystals) are obtained.

ANALYZES
IR CHCl3 (cl 1) -OH-3580 + associated-3350 -C = O-1677 -Aromatic 1638-1610-1590-1518-1505
STAGE 6: 2,2-diphenyl-7-tosyl-1,3-benzodioxol-5-yl) -1-ethanone
0.9 g of the product obtained in Step 5 above is introduced into 70 ml of methylene chloride, 0.51 ml of triethylamine is added, the mixture is stirred for 15 minutes and 0.51 g of tosyl chloride dissolved in 5 ml are added dropwise. of methylene chloride and stirred for two hours at room temperature.

 The reaction medium is poured into 200 ml of water, the aqueous phase neutralized with a 2N hydrochloric acid solution and then extracted with three times 50 ml of methylene chloride. The organic phase is washed with 200 ml of water and evaporated to dryness.

 After purification on silica with the cyclohexane 7 / ethyl acetate 3 eluent mixture, 1.01 g of expected product (white crystals) is obtained.

ANALYZES
NMR CDCl3 (300 MHz) 2.36 (s) and 2.45 (s): CH3 and -COCH3; 7.21 and 7.76 J = 8 Hz
AA'BB and 7.30 to 7.50 the other aromatics.

EXAMPLE 49 4-Methyl-benzenesulfonate (5-acetyl-2,3-dihydro-phenyl)
0.7 g of the product of Example 48 are introduced into 170 ml of dioxane. 15 ml of a 6N hydrochloric acid solution are added.

 Refluxed overnight.

 The solution is poured into 300 ml of water, extracted with three 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 It is purified on silica with cyclohexane / ethyl acetate eluent and then recrystallized from 15 ml of ethyl acetate.

Is impasted in 20 ml of isopropyl ether and 0.18 g of expected product (yellow crystals) F = 2150C
ANALYZES
IR NUJOL (cal)
= 0 1660
Aromatic 1612-1590-1544
EXAMPLE 50 5 - Methyl ((((2-aminophenyl) sulfonyl) oxy) -3,4-dihydroxybenzoate
The procedure is as in Example 28 starting from 0.52 g of the product of Example 40 in 40 ml of tetrahydrofuran, adding 0.05 g of 18% palladium on activated charcoal and hydrogenating for one hour.

 Filtered, the catalyst is washed with ethyl acetate and the filtrate evaporated.

 It is purified on silica with cyclohexane / ethyl acetate 5 and then recrystallized from 20 ml of ethyl acetate to give 0.205 g of expected product (white crystals) mp = 1600 ° C.

ANALYZES
IR NUJOL (cal)
= 0 1674
Aromatic -NH2 1625-1615-1603-1570-1534-1490
EXAMPLE 51 Methyl 2,2-diphenyl-7 - (((2- (trifluoromethyl) phenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.39 g of chloride of 2. trifluorobenzene sulfonyl.

2.3 g of expected product (crystals) are thus obtained
ANALYZES
IR CHCl3 (cm-1)
Absence of OH -C-OMe 1721
#
O
Aromatic 1624-1621-1502
EXAMPLE 52 Methyl 3,4-dihydroxy-5 - (((2- (trifluoromethyl) phinyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.1 g of the product of Example 51 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 20 hours.

 The solution is poured into 300 ml of water, the crystals are drained, washed with 30 ml of isopropyl ether.

It is purified by recrystallization in 15 ml of ethyl acetate and 0.6 g of expected product (white crystals) are obtained. F = 1900C
ANALYZES
IR NUJOL (cm-1)
Region OH / NH max - 3460-3300
= 0 1693
Aromatic 1620-1541
EXAMPLE 53 Methyl 2,2-diphenyl-7 - (((4- (trifluoromethyl) phenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.05 g of chlorine chloride. trifluorobenzene sulfonyl.

This gives 2.4 g of expected product (gum)
ANALYZES
IR CHCl3 (cal)
Absence of OH
-O 1720
Aromatic 1625-1617-1588-1501
EXAMPLE 54 Methyl 3,4-dihydroxy-5 - (((4-trifluoromethyl) phenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.1 g of the product of Example 53 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 8 hours.

 The solution is poured into 300 ml of water, the crystals are drained, washed with 30 ml of isopropyl ether.

 It is purified by recrystallization from 15 ml of ethyl acetate and 8 ml of cyclohexane to give 0.78 g of the expected product (white crystals) mp 2180 ° C.

ANALYZES
IR NUJOL (cal)
Absorptions region OH / NH 3265-3310
= 0 1698
Aromatic 1618-1544
EXAMPLE 55: Methyl (- (((2,5-dimethoxyphenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carbo-methylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of anhydrous methylene chloride with 1.6 ml of triethylamine and 1.4 g of sodium chloride. 2,5-dimethoxybenzene sulfonyl.

2.9 g of expected product are obtained (white gum which crystallizes).
EXAMPLE 56 Methyl 3,4-dihydroxy-5 - (((2,5-dimethoxyphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.9 g of the product of Example 55 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 12 hours.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 After chromatography on silica with cyclohexane 7 / ethyl acetate mixture 3 and purification by recrystallization from cyclohexane 1 / ethyl acetate 4, 0.43 g of expected product (white crystals) are obtained.

ANALYZES
IR NUJOL (cm 1)
Absorptions OH / NH region - 3430
= 0 1690
Aromatic 1618-1606-1580-1536-1504-1490
EXAMPLE 57 Methyl 2,2-diphenyl-7 - (((3,5-bis (trifluorosethyl) phenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.78 g of chloride of 3. Trifluoromethane benzene sulfonyl.

3.22 g of expected product (gum) is thus obtained.
ANALYZES
IR CHCl3 (cal)
Absence of OH
-O 1726
Aromatic 1630-1502
EXAMPLE 58: Methyl 5- (((3,5-bis (trifluoromethyl) phenyl) sulfonyl) oxy) -3,4-dihydroxybenzoate
The procedure is as in Example 2 starting from 3 g of the product of Example 57 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 15 hours.

 The suspension is poured into 300 ml of water, extracted with three times 150 ml of isopropyl ether and the organic phase is washed with water and dried.

 After chromatography on silica with cyclohexane 7 / ethyl acetate 3, then purification by recrystallization in 40 ml of ethyl acetate and 10 ml of cyclohexane, 0.5 g of expected product (white crystals) are obtained. = 1800C.

ANALYZES
IR tIUJOL (cm-1)
Region OH / NH max - 3490-3340
= 0 1697
Aromatic 1620-1610-1541
EXAMPLE 59 Methyl 2,2-diphenyl-7 - (((8-quinolinyl) sulfonyl) oxy-1,3-bensodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.3 g of chloride of 8. quinoline sulfonyl.

1.9 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHCl3 (cal)
Absence of OH
-O 1720
Aromatic + heterocycle 1620-1600-1568-1499
EXAMPLE 60 Methyl 3,4-dihydroxy-5 - (((8-quinolinyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from the 1.8 g of the product of Example 59 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 18 hours.

 The suspension is poured into 300 ml of water and the crystals are drained and washed with 80 ml of isopropyl ether.

1.2 g of expected product (white crystals) are obtained
F:> 2600C ANALYZES
IR NUJOL (cal)
Absorption OH / NH - 3420
-O 1702
Aromatic + Heterocycle 1604-1570-1530-1498
EXAMPLE 61 Methyl 7 - (((3,5-dimethyl-4-isoxazolyl) sulfonyl) oxy) -2,2-diphenyl) 1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.1 g of chloride of 3. 5-dimethyl isoxazol-4-sulfonyl.

2.9 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHCl3 (cal)
Absence of OH
-O 1722
Aromatic Heteroatom 1620-1593-1502
EXAMPLE 62 Methyl 3,4-dihydroxy-5 - (((3,5-dimethyl-4-isoxazolyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.8 g of the product of Example 61 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 15 hours.

 The suspension is poured into 300 ml of water, extracted with three times 150 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 It is purified by recrystallization from 60 ml of ethyl acetate to give 1.3 g of the expected product (white crystals) mp 210 ° C.

ANALYZES
IR NUJOL (cal)
-O 1786-1712-1690
Aromatic Heteroatom 1602-1538-1505
EXAMPLE 63 7 - (((5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate methyl
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.5 g of sodium chloride. chloro 1,3-dimethyl pyrazol-4-sulphonyl.

2.2 g of expected product (crystals) are thus obtained.
ANALYZES
IR NUJOL (cal)
-O 1720-1704
Aromatic heteroatom 1620-1583-1503 -S02- possible
EXAMPLE 64: Methyl 5- (((5-chloro-1,3-dimethyl-1H-pyrasol-4-yl) sulfonyl) oxy) -3,4-dihydroxybenzoate
The procedure is as in Example 2 starting from 2.2 g of product of Example 63 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 18 hours.

 The solution is poured into 300 ml of water, extracted with three times 150 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 It is purified by recrystallization from 40 ml of ethyl acetate to give 1.2 g of expected product (white crystals) mp = 207 ° C.

ANALYZES
IR NUJOL (cal)
-O 1703-1688
Aromatic Heteroatom 1613-1538-1503
EXAMPLE 65 Methyl 2,2-diphenyl-7 - (((2-methylphenyl) sulfonyl) osy-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.08 g of chlorine chloride. orthotoluene sulfonyl.

This gives 3.2 g of expected product (oil)
ANALYZES
IR CHCl3 (cm-1)
-O 1720
Aromatic 1624-1601-1502
EXAMPLE 66 Methyl 3,4-dihydroxy-5 - (((2-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.8 g of product of Example 65 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 1 night.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and dried.

 After chromatography on silica with cyclohexane 7 / ethyl acetate 3 eluent mixture, 1.8 g of expected product (white crystals) = 1750 ° C. are obtained.

ANALYZES
IR NUJOL (cal)
Absorption region OH / NH - 3405
-O 1726
Aromatic 1618-1604-1536
EXAMPLE 67: Methyl 7 - (((2,6-dinitro-4-methylphenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 1 g of the product obtained in Step 1 of Example 1 in 70 ml of methylene chloride with 0.6 ml of triethylamine and 0.7 g of chloride of 3. 5-dinitro p toluene sulfonyl.

1.5 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHCl3 (cal)
\ = 0 1722
Aromatic + NO2 1642-1620-1549-1502
EXAMPLE 68 Methyl 3,4-dihydroxy-5- (((2,6-dinitro-4-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.4 g of the product of Example 67 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 12 hours.

 The solution is poured into 300 ml of water and the crystals are drained, washed with water and then with 40 ml of isopropyl ether.

 It is purified by recrystallization from 25 ml of ethyl acetate and 6 ml of cyclohexane to give 0.31 g of the expected product (white crystals) F = 1920 ° C.

ANALYZES
IR NUJOL (cm-1
-O 1693
Aromatic 1620-1572-1540
EXAMPLE 69 Methyl 2,2-diphenyl-7 - (((2,2,2, -trifluoroethyl) sulfonyl) oxy-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 0.64 ml of chloride of 2. trifluoroethyl sulfonyl.

2.2 g of expected product (gum) is thus obtained.
ANALYZES
IR CHCl3 (cm-1)
Absence of OH
-O 1723
Aromatic 1623-1502 -OS02 1304-1185
EXAMPLE 70 Methyl 3,4-dihydroxy-5 - (((2,2,2-trifluoroethyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.4 g of the product of Example 69 in 100 ml of an acetic acid mixture 80 / water 20.

 Refluxed overnight.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 Purified on silica with cyclohexane 7 / ethyl acetate eluent 3 and then recrystallized from 40 ml of ethyl acetate and 10 ml of cyclohexane to give 0.8 g of expected product (white crystals) mp = 1550 ° C.

ANALYZES
IR NUJOL (cal)
Region OH / NH: max: 3420 + general absorption
-O 1688
Aromatic 1620-1604-1533
EXAMPLE 71 Methyl 7 - {((3-carboxyphenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 4 g of the product obtained in Step 1 of Example 1 in 120 ml of methylene chloride with 3.4 ml of triethylamine and 2.53 g of acid. -chlorosulfonyl benzoic acid.

5.5 g of expected product are obtained (white gum).
ANALYZES
IR CHCl3 (cm-1)
-O 1722
Aromatic 1620-1605-1569-1502
EXAMPLE 72 Methyl 3,4-dihydroxy-5 - (((3-carboxyphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.8 g of the product of Example 71 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 20 hours.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

After recrystallization from 40 ml of ethyl acetate, 1.1 g of expected product (white crystals) are obtained
Mp = 2460C.

ANALYZES
IR NUJOL (cal)
OH / NH region: max: 3460-3310 + general absorption
-O 1696
Aromatic Heteroatom 1619-1606-1592
EXAMPLE 73 Methyl 3,4-dihydroxy-5 - (((3-methoxycarbonyl) phenyl) sulfonyl) oxy) benzoate
3.2 g of product of Example 71 are introduced into 400 ml of methanol and stirred for 15 minutes at room temperature. 3.1 ml of thionyl chloride are added and the mixture is stirred at room temperature overnight and heated for 3 hours under reflux.

 The solution is evaporated. Purified on silica with the eluent mixture methylene chloride 8 / methanol 2 and then recrystallized from 80 ml of ethyl acetate and 5 ml of cyclohexane to obtain 0.9 g of expected product (white crystals) F = 2050C.

ANALYZES
IR NUJOL (cal)
Region OH / NH: max: 3480-3265
-o 1721-1692
Aromatic 1616-1538
EXAMPLE 74: Methyl 7 - (((5-bromo-2-methoxyphenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2.5 g of the product obtained in Step 1 of Example 1 in 120 ml of methylene chloride with 2.1 ml of triethylamine and 2.05 g of chloride. 5-bromo-2-methoxy sulfonyl.

3 g of expected product (crystals) are thus obtained
ANALYZES
IR CHCl3 (cal)
-O 1720
Aromatic 1622-1590-1570-1502
EXAMPLE 75 Methyl 5 - (((5-bromo-2-methoxyphenyl) sulfonyl) oxy) -3,4-dihydroxybenzoate
The procedure is as in Example 2 starting from 3 g of the product of Example 74 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed overnight.

 The suspension is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 After chromatography on silica with cyclohexane / ethyl acetate eluent 5 and purification by recrystallization from ethyl acetate, 0.36 g of expected product (white crystals) = 1670 ° C. are obtained.

ANALYZES
IR NUJOL (cal)
Absorptions OH / NH 3414-3380
-O 1692
Aromatic 1622-1608-1590-1570-1528
EXAMPLE 76 Methyl 3,4-dihydroxy-5 - (((2-methoxyphenyl) sulfonyl) olry) -benzoate
1 g of the product of Example 75 is introduced into 25 ml of methanol and 6 ml of water, 0.8 ml of triethylamine and 15 mg of 5% palladium on barium sulfate are added.

 It is hydrogenated for one hour at ambient temperature under 300 mbar of pressure.

 Filtered, the catalyst is washed with methanol and the filtrate is evaporated. It is solubilized in 75 ml of ethyl acetate, the organic phase is washed with water with 100 ml and evaporated to dryness.

 Purified on silica with cyclohexane / ethyl acetate eluent 5 and then recrystallized from 35 ml of ethyl acetate and 5 ml of cyclohexane to give 0.29 g of expected product (white crystals). .

ANALYZES
IR NUJOL (cm-1)
OH / NH region: max 3400 + general absorption
-O 1695
Aromatic 1624-1607-1592-1580-1525-1487
EXAMPLE 77 Methyl 2,2-diphenyl-7 - (((4-nitrophenyl) sulfonyl) oxy-1,3-bensodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 120 ml of methylene chloride with 1.6 ml of triethylamine and 1.27 g of chloroform. nitrobenzene sulfonyl.

2.6 g of expected product (crystals) are thus obtained
ANALYZES
IR CHCl3 (cm-1)
Absence of OH C = O 1721 #
OMe -Aromatic 1657-1621-1609-1587 -NO2 1537-1500-1480 -S02 1301-1131
EXAMPLE 78 Methyl 3,4-dihydroxy-5 - (((4-nitrophenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 2.5 g of the product of Example 77 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 15 hours.

 The suspension is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 After chromatography on silica with cyclohexane 5 / ethyl acetate eluent 5, is impasted in 30 ml of isopropyl ether and 0.55 g of expected product (white crystals) F = 220 ° C.

ANALYZES
IR NUJOL (cm 1)
Region OH / NH: max: 3459-3307
= 0 1696
Aromatic 1617-1608-1531
EXAMPLE 79 Methyl 2,2-diphenyl-7 - (((3-nitrophenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 120 ml of methylene chloride with 1.6 ml of triethylamine and 1.27 g of chloroform. nitrobenzene sulfonyl.

2.6 g of expected product (crystals) are thus obtained
ANALYZES
IR CHCl3 (cal)
-O 1720 -NO2 1540-1354
Aromatic 1620-1610-1502
EXAMPLE 80 Methyl 3,4-dihydroxy-5 - (((3-nitrophenyl) sulfonyl) owyl) benzoate
The procedure is as in Example 2 starting from 2.5 g of product of Example 79 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 15 hours.

 The suspension is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 After chromatography on silica with cyclohexane / ethyl acetate eluent 5 and purification by recrystallization in 40 ml of ethyl acetate and 0.180 g of expected product (white crystals) F = 2240C.

ANALYZES
IR NUJOL (cm-1) -OH - 3462-3302 -C = O 1697 -Aromatic + NO2 1620-1607-1531 -SO2 - 1313-1190
EXAMPLE 81 Methyl 2,2-diphenyl-7 - (((2-trifluoromethoxy) phenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.49 g of chloride of 2. trifluoromethoxy benzene sulfonyl.

2.54 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHCl3 (cm-1)
Absence of OH
-O 1720
Aromatic 1622-1593-1502
EXAMPLE 82 Methyl 3 - (((2- (trifluoromethoxy) phenyl) sulfonyl) oxy) 4,5-dihydroxybenzoate
The procedure is as in Example 2 starting from 2.2 g of the product of Example 81 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 15 hours.

 The suspension is poured into 300 ml of water and the crystals are drained, washed with water and with isopropyl ether.

 After chromatography on silica with cyclohexane / ethyl acetate eluent mixture, 1.5 g of expected product (white crystals) are obtained. Mp = 138 ° C.

ANALYZES
IR NUJOL (cm ~ l)
Region OH / NH: max: 3476-3316 + general absorption
-O 1693
Aromatic 1617-1608-1593-1540
EXAMPLE 83 Methyl 3- ((((4-aminophenyl) sulfonyl) oxy-4, 5-dibidylbenzoate
The procedure is as in Example 2, starting from 0.43 g of product of Example 78 in 40 ml of tetrahydrofuran, adding 0.05 g of activated palladium on activated carbon at 18 t and hydrogen for one hour under 600 mbar of pressure. .

 After purification on silica with cyclohexane / ethyl acetate mixture and then recrystallization from 20 ml of ethyl acetate, 0.120 g of expected product (white crystals) = 1650 ° C. are obtained.

ANALYZES
IR NUJOL (cm-1)
OH / NH absorption
-O 1706
Aromatic + NH2 def 1646-1612-1598-1537-1507
EXAMPLE 84 Methyl 3- ((13-amino-phenyl) sulfonyl) oxy) -4,5-dibydrotylbenzoate
The procedure is as in Example 28, starting from 0.25 g of product of Example 80 in 30 ml of tetrahydrofuran, adding 0.05 g of 18% palladium on activated carbon and hydrogen for one hour under 600 mbar of pressure. .

 After purification on silica with a cyclohexane / ethyl acetate mixture and then recrystallization from ethyl acetate, 0.035 g of expected product (white crystals) F = 1940 ° C. are obtained.

ANALYZES
IR NUJOL (cal)
OH / NH Complex Absorptions
-O 1680-1692
Aromatic NH2 1614-1603-1537-1518
EXAMPLE 85 Methyl 4- ((((2-cyanophenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.2 g of chloride of 2. cyano benzene sulfonyl.

3 g of expected product (crystals) are thus obtained
ANALYZES
IR CHCl3 (cal)
Absence of OH function
-o 1722
Aromatic 1624-1589-1572-1502 -C3N 2240
EXAMPLE 86 Methyl 3- ((((2-cyanophenyl) sulfonyl) oxy-4,5-dibydrowylbenzoate
The procedure is as in Example 2 starting from 3 g of product of Example 85 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 20 hours.

 The solution is poured into 300 ml of water and the crystals are drained and washed with 80 ml of isopropyl ether.

 After purification by recrystallization from 50 ml of ethyl acetate and 10 ml of cyclohexane, the mixture is filtered off with suction and washed with isopropyl ether to give 1.1 g of the expected product (white crystals), mp = 1950 ° C.

ANALYZES
IR NUJOL (cm-1)
Absorptions: OH / NH 3470-3310 C = -N-2235
-O 1694
Aromatic 1618-1610-1565-1544
EXAMPLE 7 - Methyl ((((3-bromo-2-chloro-5-thienyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 1.6 ml of triethylamine and 1.7 g of chloroform. -bromo-2-chloro-thiophene-5-sulfonyl chloride.

3.39 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHCl3 (cal)
-O 1720
Conj. + Aromatic 1621-1585-1501
EXAMPLE 88 Methyl 5- ((((3-bromo-2-chloro-5-thienyl) sulfonyl) oxy) 3,4-dihydroxybenzoate
The procedure is as in Example 2 starting from 1.6 g of the product of Example 87 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 20 hours.

 The solution is poured into 300 ml of water, extracted with three times 150 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 Recrystallized from 45 ml of ethyl acetate and 0.6 g of expected product (white crystals) F = 1950C.

ANALYZES
IR NUJOL (cal)
Region OH / NH: max - 3480-3290
= 0 1701
Aromatic Heteroatom 1613-1536
EXAMPLE 89: Methyl 7 - (((2-chloro-3-nitro-5-thienyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 120 ml of methylene chloride with 1.2 ml of triethylamine and 1.5 g of chloride of 2. chloro-3-nitrothiophene-5-sulfonyl chloride.

2.35 g of expected product (crystals) are thus obtained.
ANALYZES
IR CHCl3 (cal)
Absence of OH
-O 1720
Heterocycle + Aromatic + NO2 1624-1590-1549-1516-1504
EXAMPLE 90 5 - Methyl (((2-chloro-3-nitro-5-thienyl) sulfonyl) oxy) 3,4-dihydroxybenzoate
The procedure is as in Example 2 starting from 2.1 g of product of Example 89 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 18 hours.

 The suspension is poured into 300 ml of water and the crystals are drained and washed with 80 ml of isopropyl ether.

 It is recrystallized from 45 ml of ethyl acetate and 15 ml of cyclohexane to give 0.46 g of the expected product (white crystals), mp = 22 ° C.

ANALYZES
IR NUJOL (cal)
Absorptions OH / NH 3465-3310
-O 1696
System conj + Aromatic + NO2 1618-1610-1545-1512
EXAMPLE 91 7 - Methyl (((3,5-dichloro-2-hydroxyphenyl) sulfonyl) oxy-2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 100 ml of methylene chloride with 0.27 g of sodium hydride at 50% in oil and 2.87 g of 3,5-dichloro-2-hydroxybenzene sulfonyl chloride.

This gives 1.9 g of expected product (gum)
ANALYZES
IR CHCl3 (cm-1)
-O 1722
Aromatic 1627-1619-1587-1498
EXAMPLE 92 5 - Methyl (((3,5-dichloro-2-hydroxyphenyl) sulfonyl) oxy) 3,4-dihydroxybenzoate
The procedure is as in Example 2 starting from 1.8 g of the product of Example 91 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed overnight.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 It is recrystallized from 60 ml of ethyl acetate and 10 ml of cyclohexane to give 0.45 g of expected product (white crystals) F = 1970 ° C.

ANALYZES
IR NUJOL (cm-1)
Absorptions OH / NH region
-O 1704
Aromatic 1612-1536
EXAMPLE 93 Methyl 2,2-diphenyl-7 - (((5- (3-isoxazolyl) -2-thienyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2 g of the product obtained in Step 1 of Example 1 in 120 ml of methylene chloride with 1.2 ml of triethylamine and 1.45 g of sodium chloride. - (isoxazol-3-yl) thiophene-2-sulfonyl chloride.

2 g of expected product (crystals) are thus obtained
ANALYZES
IR CHCl3 (cm-1)
Absence of OH
-O 1722
Aromatic 1624-1606-1502
EXAMPLE 94 Methyl 3,4-dihydroxy-5 - (((5- (3-isoxazolyl) -2-thienyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.9 g of product of Example 93 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 15 hours.

 The suspension is poured into 300 ml of water and the crystals are drained and washed with 80 ml of isopropyl ether.

 It is purified by recrystallization in 45 ml of ethyl acetate and 15 ml of cyclohexane and 0.55 g of expected product (white crystals) are obtained.

ANALYZES
IR NUJOL (cal)
Absorptions OH / NH: max - 3414
-O 1694
Aromatic + heterocycle 1605-1536
EXAMPLE 95 1- (2,2-Diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxol-5-yl) -1-propanone
STAGE 1: 1- (2,2-diphenyl-7 - ((benzyl) oxy) -1,3-benzodioxol-5-yl) -1-propanone
The procedure is as in Step 4 of Example 48 starting from 3.2 g of the product obtained in Step 3 of Example 48 in 50 ml of anhydrous hexamethyl phosphotriamide, 1.1 ml of tretraethyltin and then 0.032 mg of chlorine are added. (benzyl) bis (triphenylphosphine) palladium II and heat five hours at 60oc.

 1.35 g of expected product (pale yellow crystals) are thus obtained.

ANALYZES
IR CHCl3 (cal)
-O 1678
Aromatic 1627-1603-1586-1508-1497
STAGE 2: 1- (2,2-Diphenyl-7-hydroxy-1,3-benzodioxol-5-yl-1-propanone
The procedure is as in Step 5 of Example 48, starting from 1.3 g of the product obtained in Step 1 above in 60 ml of tetrahydrofuran, adding 0.1 g of 5% palladium on activated carbon and hydrogen for two hours. hours under 600 mbar pressure.

 0.8 g of expected product (white gum which crystallizes) is thus obtained.

ANALYZES
IR NUJOL (cal)
General OH / NH absorption
Region C = 0} 1640
COO e} large complex
aromatic}
STAGE 3: 1- (2,2-Diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxol-5-yl) -1-propanone
The procedure is as in Step 6 of Example 48 starting from 0.8 g of the product obtained in Step 2 above in 60 ml of methylene chloride with 0.5 ml of triethylamine and 0.48 g of tosyl chloride. in solution in 5 ml of methylene chloride.

0.9 g of expected product (oil) are thus obtained.
ANALYZES
IR CHCl3 (cal)
-O 1682
Aromatic 1617-1599-1496
S02 1379-1192-1179
EXAMPLE 96 t2,3-dibydroxy-5- (1-oxopropyl) phenyl-4-methyl-benzenesulfonate
The procedure is as in Example 2 starting from 0.8 g of product of Example 95 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 24 hours.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water and evaporated to dryness.

 After chromatography on silica with cyclohexane / ethyl acetate eluent 5 and recrystallization from 10 ml of ethyl acetate and 5 ml of cyclohexane, 0.20 g of expected product (white crystals) is obtained. F = 1780 ° C. .

ANALYZES
IR NUJOL (cal)
Absorption complex OH / NH region
-O 1670
Aromatic 1616-1602-1545-1498
EXAMPLE 97 Methyl 2,2-diphenyl-7- (benzoylamino) -1,3-benzodiozole-5-carboxylate
STAGE 1: 3,4-dihydroxy-5-nitro-benzaldehyde
10 g of nitrovaniline are introduced into 100 g of pyridine hydrochloride and heated at 1800 ° C. for 30 minutes.

 The reaction medium is poured into 500 ml of water. The aqueous phase is extracted with three times 200 ml of ethyl acetate. The organic phase is washed extensively with a 2N hydrochloric acid solution, dried and evaporated to dryness.

The crystals obtained are pasted in isopropyl ether.

 6.3 g of expected product (brown crystals) are thus obtained.

ANALYZES
IR NUJOL (cal)
Absorption complex OH / NH 1687
Aromatic lter band N02 1621-1592-1579-1545
STAGE 2: 2,2-diphenyl-7-nitro-1,3-benzodioxole-5-carboxaldehyde
1 g of the product obtained in Stage 1 above is introduced into 1.02 ml of dichlorodiphenylmethane and stirred for 3 minutes at 1800 ° C.

 Allowed to cool to room temperature and purified on silica with cyclohexane 8 / ethyl acetate 2 eluent.

 1.1 g of the expected product are thus obtained.

ANALYZES
IR CHCl3 (cal)
Absence of OH
-O 1701
Aromatic + NO2 1628-1620-1609-1586-1541-1495
STAGE 3: methyl 2,2-diphenyl-7-nitro-1,3-benzodioxole-5-carboxylate
1.1 g of the product obtained in Step 2 above is introduced into 110 ml of anhydrous methanol, 0.6 g of sodium cyanide are added and the mixture is stirred for 30 minutes at room temperature.

 0.2 ml of glacial acetic acid and 10 g of manganese dioxide are added and the mixture is stirred for 24 hours at room temperature.

 The reaction medium is filtered, the manganese oxide washed with ethyl acetate, the filtrate washed with water and the organic phase is dried and then evaporated to dryness.

 Purified on silica with cyclohexane 7 / ethyl acetate 3 eluent and 1.2 g of expected product (yellow crystals).

STAGE 4: methyl 2,2-diphenyl-7-amino-1,3-benzodioxole-5-carboxylate
1.3 g of the product obtained in Step 3 above is introduced into 60 ml of tetrahydrofuran, 0.1 g of 18% palladium on activated charcoal is added and hydrogen is added for 2 hours under 600 mbar of pressure.

 Filtered, the catalyst is washed with ethyl acetate and the filtrate evaporated.

Purified on silica with cyclohexane 7 / ethyl acetate 3 eluent and gives 1.1 g of expected product (white gum)
ANALYZES
IR CHCl3 (cl1) = C-NH2 3430-3390
-O 1713
NH2 + Aromatic 1649-1609-1586-1508
STAGE 5: methyl 2,2-diphenyl-7- (benzoylamino) -1,3-benzodioxole-5-carboxylate
0.4 g of the product obtained in Step 4 above is introduced into 15 ml of anhydrous tetrahydrofuran, 0.25 ml of pyridine and 0.15 ml of benzoyl chloride are added and the mixture is stirred overnight at room temperature.

 Poured into 100 ml of water, the aqueous phase is neutralized with a 2N hydrochloric acid solution, and is extracted with three times 50 ml of ethyl acetate. The organic phase is washed with 100 ml of water, dried and evaporated to dryness.

 Purified on silica with cyclohexane 7 / ethyl acetate 3 eluent and 0.5 g of expected product.

ANALYZES
IR CHCl3 (cm-1)
Little or no = C-NH2 - C-NH 3430
-O 1716-1685
Aromatic + amide II 1639-1619-1602-1580-1536-1496
EXAMPLE 98 Methyl 3,4-dihydroxy-5- (benzoylamino) benzoate
The procedure is as in Example 2 starting from 0.7 g of the product of Example 97 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 4 hours.

 The solution is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water, dried and evaporated to dryness.

 After chromatography on silica with cyclohexane / ethyl acetate eluent 5 and then purification by recrystallization from 10 ml of ethyl acetate and 5 ml of cyclohexane, 0.21 g of expected product (white crystals) is obtained. = 2110C.

ANALYZES
IR NUJOL (cm-1)
Absorption OH / NH - 3420 + general absorption -C = O - 1675
Aromatic + amide II 1610-1580-1550-1510-1488
EXAMPLE 99 O-methyl-2,2-diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carbothioate
4.5 g of the product of Example 23 are introduced into 45 ml of anhydrous toluene and 18 g of Lawesson's reagent are gradually added during 8 days of reflux.

 The reaction medium is poured into 150 ml of water. The aqueous phase is extracted with three times 50 ml of ethyl acetate. The organic phase is washed with water and dried.

 After purification on silica with the cyclohexane 7 / ethyl acetate 3 eluent mixture, 1.3 g of expected product (yellow crystals) are obtained.

ANALYZES
IR CHCl3 (cm-1)
System conj + Aromatic 1620-1600-1498
EXAMPLE 100 O-methyl-3,4-dihydroxy-5- (4-methylphenyl) benzenecarbothioate
The procedure is as in Example 2 starting from 1.2 g of product of Example 99 in 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed overnight.

 The suspension is poured into 300 ml of water, extracted with three times 100 ml of isopropyl ether and the organic phase is washed with water, dried and evaporated to dryness.

 After chromatography on silica with the eluent mixture clycohexane 5 / ethyl acetate 5, then recrystallization in 30 ml of ethyl acetate and 10 ml of cyclohexane, 0.33 g of expected product is obtained.

ANALYZES
IR CHCl3 (cm-1) -OH -3563
Aromatic 1619-1598-1508-1495 -S02-1192-1178
EXAMPLE 101 Methyl 4,5-dihydroxy-3 - (((4-methylphenyl) sulfonyl) oxy) -2- (phenylmethyl) benzoate
STAGE 1: Methyl 3,4-dihydroxy-5- (phenylmethoxy) -2- (phenylmethyl) benzoate
The procedure is as in Example 3 starting from 3 g of methyl gallate in 90 ml of dimethylformamide, 1.56 g of sodium hydride, 2.7 ml of triethylborate and 2.9 ml of benzoyl bromide.

 1 g of expected product is thus obtained.

STAGE 2: 3-hydroxy-4,5- (diphenylmethoxy) -2- (phenylmethyl) methyl benzoate
2 g of the product obtained in Stage 1 above are introduced into 50 ml of dimethylformamide, 0.26 g of sodium hydride are added, the mixture is stirred for one hour at room temperature, 0.65 ml of benzyl bromide in solution in ml of dimethylformamide and stirred for two hours at room temperature.

 The solution is poured into 150 ml of water. The aqueous phase is extracted with three times 50 ml of ethyl acetate. The organic phase is washed abundantly with water, dried and evaporated to dryness.

 It is purified by recrystallization from isopropyl ether and obtains 2.39 g of expected product (yellow crystals).

ANALYZES
IR CHOC13 (cl 1) -OH - 3515
-O 1718
Aromatic 1605-1576-1502-1495
STAGE 3: 3 - Methyl ((((4-methylphenyl) sulfonyl) oxy) 4,5 (diphenylmethoxy) -2- (phenylmethyl) benzoate
0.4 g of the product obtained in Stage 2 above is introduced into 40 ml of anhydrous methylene chloride, 0.15 ml of triethylamine is added, the mixture is stirred for 5 minutes at room temperature, 0.170 g of tosyl chloride dissolved in 10 ml of chloride. of methylene and stirred for two hours at room temperature.

 The solution is poured into 150 ml of water. The aqueous phase is extracted with three times 150 ml of methylene chloride. The organic phase is washed abundantly with water and then with 5 ml of a 2N hydrochloric acid solution and dried.

 It is purified by chromatography on silica with cyclohexane / ethyl acetate 3 eluent mixture and 0.6 g of expected product (white crystals) are obtained.

ANALYZES
IR CHCl3 (cal)
Absence of OH
-O 1722
Aromatic 1599-1565-1500-1495
STAGE 4: Methyl 4,5-dihydroxy-3 - (((4-methylphenyl) sulfonyl) oxy) -2- (phenylmethyl) benzoate
0.6 g of the product obtained in Step 3 above in 30 ml of tetrahydrofuran, 0.1 g of 10% dry palladium on activated charcoal and hydrogen for one hour at a pressure of 500 mbar are added.

 Filtered, the catalyst is washed with ethyl acetate and the filtrate evaporated.

 Purified on silica with cyclohexane 7 / ethyl acetate eluent and then by rescritallization in 5 ml of ethyl acetate and 3 ml of cyclohexane and 0.180 g of expected product (white crystals) F = 1690C.

ANALYZES
IR NUJOL (cm-1)
Absorption OH / NH - 3418 \ - O 1702
Aromatic 1620-1596-1518-1494
EXAMPLE 102 3,4-Dihydroxy-2- (phenylmethyl) -5- (phenylmethoxy) benzoic acid
1 g of the product obtained in Step 1 of Example 101 is introduced into 25 ml of concentrated sodium hydroxide and heated for 1 hour at 800 ° C.

 300 ml of ice + 26 ml of concentrated hydrochloric acid are added and the mixture is stirred for one hour.

 The aqueous phase is extracted with three times 100 ml of ethyl acetate. The organic phase is washed with 500 ml of water, dried and evaporated to dryness.

 Purified on silica with the eluent mixture of methylene chloride 95 / methanol and then by recrystallization in 35 ml of ethyl acetate and 10 ml of cyclohexane and 0.45 g of expected product (white crystals) F = 1770C.

ANALYZES
IR NUJOL (cm-1)
Region OH / NH: max: 3515 + general absorption
= 0 1688
Aromatic 1620-1604-1588-1510-1506-1497
EXAMPLE 103 Methyl 2,2-diphenyl-7 - (((3-methylphenylsulfonyl) oxy) -1,3-bensodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2.1 g of the product obtained in Step 1 of Example 1 in 20 ml of methylene chloride, 1 ml of triethylamine and 1.22 g of metatoluene sulfonyl chloride. in 5 ml of Baethylene chloride.

 1.9 g of expected product (crystals) are thus obtained.

ANALYZES
IR CHCl3 (cm-1)
Absence of OH
-O 1720
Aromatic 1622-1588-1502
EXAMPLE 104 Methyl 3,4-dihydroxy-5 - (((3-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.9 g of the product of Example 103, 70 ml of acetic acid and 15 ml of water.

 The mixture is heated at 120 ° C. for 12 hours and poured on a water + ice mixture.

 Three times 100 ml of ethyl acetate are extracted and evaporated to dryness.

After chromatography on silica in ethyl acetate / cyclohexane 5, is washed with isopropyl ether and 0.65 g of expected product (white crystals)
ANALYZES
IR NUJOL (cal)
Absorption region OH / NH 3460-3270
-O 1708
Aromatic 1616-1538
EXAMPLE 105 Methyl 4-hydroxy-3- (4-methylphenylsulfonyl) oxy) -5-nitro benzoate
STAGE 1: 4 hydroxy-3- (4-methylphenylsulfonyl) oxy) -5-nitro benzaldehyde
0.5 g of the product obtained in Step 1 of Example 97 is introduced into 60 ml of anhydrous dimethylformamide, 0.26 g of 50% sodium hydride in the oil are added and the mixture is stirred at ambient temperature for 1 h.

 0.51 g of tosyl chloride dissolved in 15 ml of dimethylformamide are added dropwise and the mixture is stirred for 4 hours at room temperature.

 The reaction medium is poured into 150 ml of water and 50 ml of 2N hydrochloric acid. The aqueous phase is extracted with three times 50 ml of ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness.

 It is recrystallized from ethyl acetate (12 ml) and chromatographed on silica, eluting with ethyl acetate to obtain 0.3 g of expected product (yellow crystals).

ANALYZES
IR NUJOL (cal)
OH / NH absorption
-O 1686
Aromatic + NO2 1624-1598-1548
STAGE 2: Methyl 4-hydroxy-3- (4-methylphenylsulfonyl) oxy) -5-nitro benzoate
0.36 g of the product obtained in Stage 1 above is introduced into 40 ml of anhydrous methanol, 0.16 g of sodium cyanide are added and the mixture is stirred for thirty minutes at room temperature.

 0.08 ml of glacial acetic acid and 3 g of manganese dioxide are added and the mixture is stirred for 24 hours at room temperature.

 Filtered, the manganese oxide is washed with ethyl acetate, the filtrate is evaporated to dryness, then solubilized in 50 ml of ethyl acetate and washed with water; the organic phase is evaporated to dryness.

 Recrystallized from 6 ml of ethyl acetate and 2 ml of cyclohexane to give 0.31 g of expected product (yellow crystals).

ANALYZES
IR CHCl3 (cm-1)
OH - 3598
-O 1729
Aromatic + NO2 1629-1599-1551
EXAMPLE 106 4 - (((2,3-Dibroxy-5- (methoxy-4-ylamoxy) phenyl) oxy) sulfonyl) benzoic acid
The procedure is as in Example 2 starting from 1.2 g of product of Example 37 in 100 ml of a mixture of acetic acid 80 / water and refluxing for 48 hours.

 The solution is poured into 300 ml of water. The crystals are drained and washed with 30 ml of isopropyl ether.

 After purification by recrystallization from 15 ml of methanol, 0.33 g of expected product (white crystals)> 2600 ° C. are obtained.

ANALYZES
IR NUJOL (cm-1)
Absorption region OH / NH max - 3455-3308
-O 1695
Aromatic 1615-1580-1534
EXAMPLE 107: Methyl 2,2-diphenyl-7 - (((2,4,6-trimethylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2.1 g of product obtained in Step 1 of Example 1 in 20 ml of methylene chloride, 1 ml of triethylamine and 1.44 g of 2 mesitylene sulfonyl. chloride.

 2.4 g of expected product (crystals) are thus obtained.

ANALYZES
IR CHCl3 (cm-1)
Absence of OH
-O 1720
Aromatic 1628-1618-1605-1570-1502 S02 1305-1180
EXAMPLE 108 Methyl 3,4-dihydroxy-5 - (((2,4,6-trimethylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.6 g of the product of Example 107, 50 ml of acetic acid and 5 ml of water.

 It is heated at 1200 ° C. for 15 hours and poured on a water + ice mixture. The crystals are dewatered and washed with isopropyl ether.

 After purification by chromatography on silica in ethyl acetate / cyclohexane 5, 0.52 g of expected product (crystals) is obtained.

ANALYZES
IR NUJOL (cal)
Absorption complex OH / NH region
-O 1576
Aromatic 1612-1604-1565-1536
EXAMPLE 109 Methyl 2,2-diphenyl-7 - (((5- (2-pyridinyl) -2-thienyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2.1 g of the product obtained in Step 1 of Example 1 in 20 ml of methylene chloride, 1 ml of triethylamine and 1.9 g of chloride of 2. - (pyrid-2-yl) thiophene sulfonyl.

 3 g of expected product (crystals) are thus obtained.

ANALYZES
IR CHCl3 (cm-1)
Absence of OH
-O 1720
Aromatic Heteroatom 1628-1620-1588-1570-1502 -OS02- 1304-1186
EXAMPLE 110 Methyl 3,4-dihydroxy-5- (((5- (2-pyridinyl) -2-thienylsulfonyl) olry) benzoate
The procedure is as in Example 2 starting from 1.5 g of the product of Example 109, 50 ml of acetic acid and 10 ml of water.

 It is heated at 1200 ° C. for 15 hours and poured on a water + ice mixture. Three times 100 ml of ethyl acetate are extracted and dried. The crystals are dewatered and washed with ethyl ether.

 After purification by recrystallization from ethyl acetate + hexane, 0.53 g of expected product (crystals) is obtained.

ANALYZES
IR NUJOL (cl 1)
OH / NH Complex Absorption
-O 1703-1689
Aromatic Heteroatom 1612-1588-1570-1535
EXAMPLE 111 Methyl 7 - (((4- (acetylamino) phenyl) sulfonyl) oxy) -2,2-diphenyl-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2.1 g of the product obtained in Step 1 of Example 1 in 20 ml of methylene chloride, 1 ml of triethylamine and 1.7 g of N chloride. -acétylsulfanilyle.

 2.9 g of expected product (crystals) are thus obtained.

ANALYZES
IR CHCl3 (cal)
Absence of OH = C-NH-3440
-O 1713
Aromatic + Amide II 1629-1620-1593-1513-1503
EXAMPLE 112 Methyl 3,4-dihydroxy-5- (((4- (acetylamino) phenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.5 g of product of Example 111, 50 ml of acetic acid and 10 ml of water.

 It is heated at 120 ° C. for 12 hours and poured on a water + ice mixture. The crystals are dewatered and washed with ethyl ether and dried.

 After recrystallization from ethyl acetate, 0.65 g of expected product is obtained.

ANALYZES
IR NUJOL (cal)
Absorption complex OH / NH region
-O 1720-1674
Aromatic amide II 1604-1593-1537
EXAMPLE 113 Methyl 2,2-diphenyl-7 - (((2-thienyl) sulfonyl) oxy-1,3-benzodioxole-5-carboxylate
The procedure is as in Step 2 of Example 1 starting from 2.1 g of the product of Example 1 in 20 ml of methylene chloride, 1.25 ml of triethylamine and 1.4 g of thiophene sulphonyl chloride in 5 ml of methylene chloride.

 2.1 g of expected product (crystals) are thus obtained.

ANALYZES
IR CHCl3 (cal) -C-OMe 1720
#
O
Aromatic Heteroatom 1641-1626-1620-1503 -OS02- 1303-1186
EXAMPLE 114 Methyl 3,4-dihydroxy-5 - (((2-thienyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.9 g of the product of Example 113, 70 ml of acetic acid and 15 ml of water.

 It is heated at 120 ° C. for 12 hours and poured on a water + ice mixture. The crystals are drained and washed with water and then with isopropyl ether.

After recrystallization from ethyl acetate + hexane, 0.30 g of expected product (crystals) is obtained.
ANALYZES
IR NUJOL (cal)
OH / NH region: max - 3400 + general absorption
-O 1688
Aromatic Heteroatom 1612-1540
EXAMPLE 115 Methyl 2,2-diphenyl-6 - (((4-methylphenyl) sulfonyl) owyl) -1,3-benzodioxole-5-carboxylate
STAGE 1: methyl 2,4,5-trihydroxy benzoate
0.9 g of methyl 2,5-dihydroxy-4-methoxy benzoate, 2.7 g of aluminum chloride and 50 ml of dichloroethane are introduced.

 Refluxed for 5 hours and poured on a mixture of water + HCL 2N.

 Three times 100 ml of ethyl acetate are extracted. The total ethyl acetate phase is dried. Chromatography on silica in cyclohexane 5 / ethyl acetate mixture 55 and 0.4 g of expected product.

ANALYZES
IR NUJOL (cm-1)
Absorptions OH / NH 3460-3330
Aromatic 1608-1590-1530
STAGE 2: methyl 2,2-diphenyl-6-hydroxy-1,3-benzodioxole-5-carboxylate
0.6 g of the product obtained in Step 1 above is introduced into 0.6 ml of dichlorodiphenylmethane, brought to 180 ° C. for 10 minutes and then poured into 50 ml of water.

 The mixture is extracted three times with 50 ml of ethyl acetate. The ethyl acetate phase is dried and then evaporated to dryness.

 After chromatography on silica in cyclohexane 8 / ethyl acetate 2, 1.5 g of an oil which crystallizes; the crystals are washed with hexane and then dried at 500C under vacuum.

 0.55 g of expected product (crystals) is obtained.

ANALYZES
IR CHCl3 (cal) -OH chelated from 3500 to 3000 -C = O 1666 (chelated ester) #
OMe 1440
Aromatic 1640-1625-1602-1528-1508-1483
STAGE 3: 2,2-diphenyl-6 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylic acid methyl ester
0.3 g of the product obtained in Stage 2 above is introduced into 5 ml of dimethylformamide and 0.17 ml of triethylamine and then 0.25 g of tosyl chloride and stirred for approximately 48 hours. The reaction medium is poured into water + HCl 2N. Extracted with three times 50 ml of ethyl acetate, the total ethyl acetate phase is evaporated to dryness.

 Chromatography on silica in cyclohexane 5 / ethyl acetate 5 and then in cyclohexane 7 / ethyl acetate 3 and 0.25 g of expected product (oil).

ANALYZES
IR CHCl3 (cal) -C = O complex - 1728-1710 -C = O chelated 1655-1627 + Aromatic 1599-1577-1491 OS02 1194-1178
EXAMPLE 116 Methyl 4-dihydroxy-2- (((4-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 0.25 g of the product of Example 115, 10 ml of acetic acid and 2 ml of water.

 It is heated at 120 ° C. for 12 hours and poured on a water + ice mixture. The mixture is extracted three times with 50 ml of ethyl acetate and dried.

 After chromatography on silica in ethyl acetate / cyclohexane 5 mixture, it is washed with pentane and 0.1 g of expected product (white crystals) is obtained.

ANALYZES
IR NUJOL (cl 1) -OH - 3450-3425 -C = O 1720 -Aromatic 1620-1612-1595-1530 -OS02 possible - 1295-1190-1175
EXAMPLE 117 Methyl 2,2-diphenyl-4 - (((4-methylphenyl) sulfonyl) oy) -1,3-benzodioxole-5-carboxylate
STAGE 1: 2,3,4 methyl trihydroxy benzoate
5 g of 2,3,4-trihydroxybenzoic acid are introduced into 75 ml of methanol and 6.5 ml of thionyl chloride are added.

 Refluxed for 24 hours, removal of the excess of thionyl chloride by hexane stripping, chromatography on silica in cyclohexane 5 / ethyl acetate 5 and 4 g of the expected product.

ANALYZES
IR NUJOL (cal)
Absorption complex OH / NH region
-O 1660
Aromatic 1615-1520
STAGE 2: methyl 2,2-diphenyl-4-hydroxy-1,3-benzodioxole-5-carboxylate
2 g of the product obtained in Stage 1 above are introduced into 2.2 ml of dichlorodiphenylmethane and are heated at 1600 ° C. to 1800 ° C. for 20 minutes.

 It is allowed to cool, the reaction medium is diluted with 20 ml of ethyl acetate and chromatographed on silica in a mixture of cyclohexane 9 and ethyl acetate 1.

 3.5 g of expected product (crystals) are thus obtained.

ANALYZES
IR CHCl3 (cm-1)
OH in chelated form
-O 1682
Aromatic 1630-1615-1609-1496
STAGE 3: methyl 2,2-diphenyl-4 - (((4-methylphenyl) sulfonyl) oxy) -1,3-benzodioxole-5-carboxylate
1.4 g of the product obtained in Step 2 above are introduced into 20 ml of dimethylformamide, 0.8 ml of triethylamine and 0.84 g of tosyl chloride.

 It is stirred for 4 hours at ambient temperature, the reaction medium is poured into water + 2N HCl, extracted with three times 50 ml of ethyl acetate and the total ethyl acetate phase is evaporated to dryness.

 Chromatography on silica in cyclohexane 7 / ethyl acetate mixture 3 and gives a crystallized oil; the crystals are drained and washed with pentane and dried.

 1.5 g of expected product are obtained.

ANALYZES
IR CHCl3 (cm-1)
Absence of OH -C = O 1722-1435 #
OMe
Aromatic 1626-1595-1525-1495-1484 OS02 1295-1190-1178
EXAMPLE 118 Methyl 3,4-dihydroxy-2 - (((4-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Example 2 starting from 1.2 g of the product of Example 117, 50 ml of acetic acid and 10 ml of water.

 It is heated at 120 ° C. for 24 hours and poured on a water + ice mixture. Three times 100 ml of ethyl acetate are extracted and dried.

After chromatography on silica in ethyl acetate / cyclohexane 5 mixture, the mixture is washed with pentane and 0.44 g of expected product is obtained (white crystals).
ANALYZES
IR NUJOL (cm 1) -OH - 3540-3320 -C = O 1695 -Aromatic 1620-1598-1510-1504-1495 -OS02 possible - 1300-1190-1175
EXAMPLE 119 2,2-Diphenyl-7 - ((((4-methylphenyl) sulfonyl) oxy) -4- (phenylmethyl) -1,3-benzodioxole-5-carboxylate methyl
STAGE 1: Methyl 2,2-diphenyl-7- (phenylmethoxy) -4- (phenylmethyl) -1,3-benzodioxole-5-carboxylate
2 g of the product obtained in Step 1 of Example 101 are introduced into 1.2 ml of dichlorodiphenylmethane and heated at 600 ° C. for 2.5 hours.

 The solution obtained is cooled to room temperature and purified on silica with the cyclohexane 1 / methylene chloride 9 eluent mixture. 2.6 g of expected product (white crystals) F = 1060 ° C. are obtained.

ANALYZES
IR CHCl3 (cal)
Absence OH / NH
-O 1713
Aromatic 1639-1600-1586-1495
Methyl STAGE 2: 2, 2-diphenyl-7-hydroxy-4- (phenylmethyl) -1,3-benzodioxole-5-carboxylate
1.1 g of the product obtained in Step 1 above is introduced into 60 ml of tetrahydrofuran, 0.1 g of palladium and hydrogen are added for one hour under 400 mbar of pressure.

 Filtered, the catalyst is washed with ethyl acetate and the filtrate evaporated.

0.91 g of expected product is obtained (white foam)
ANALYZES
IR CHCl3 (cal) -OH 3579
Aromatic 1648-1613-1604-1584-1495
STAGE 3: 2,2-diphenyl-7 - (((4-methylphenyl) sulfonyl) oxy) -4- (phenylmethyl) -1,3-benzodioxole-5-carboxylate methyl
The procedure is as in Step 2 of Example 1 from 1 g of the product obtained in Step 2 above in 100 ml of anhydrous methylene chloride.

 0.5 ml of triethylamine is added, the mixture is stirred for 15 minutes, 0.46 g of tosyl chloride are added and the mixture is stirred for two hours at room temperature.

 It is poured into 300 ml of water. The aqueous phase is neutralized with a 2N hydrochloric acid solution and then extracted with three times 100 ml of methylene chloride. The organic phase is washed with 300 ml of water, dried and evaporated to dryness.

It is recrystallized from 30 ml of isopropyl ether and 0.9 g of expected product (white crystals) are obtained.
ANALYZES
IR CHCl3 (cal)
Absence of OH -OS02- 1302-1180
-O 1718
Aromatic 1632-1611-1597-1495
EXAMPLE 120 Methyl 3,4-Dihydroxy-5 - (((4-methylphenyl) sulfonylMoSy) -2- (phenylmethyl) benzoate
0.8 g of the product of Example 119 are introduced into 100 ml of a mixture of acetic acid 80 / water 20.

 Refluxed for 40 hours.

 It is poured into 300 ml of ice and stirred for one hour. The crystals are dewatered and solubilized in 75 ml of ethyl acetate. The solution is evaporated to dryness.

 After chromatography on silica with cyclohexane 7 / ethyl acetate 3 eluent mixture, 0.250 g of expected product (white crystals) F = 1370 ° C. are obtained.

ANALYZES
IR NUJOL cm 1
= 0 1718-1697
Aromatic 1598-1586-1498
EXAMPLE 121 Methyl 3-amino-4-hydroxy-5 - (((4-methylphenyl) sulfonyl) oxy) benzenecarboxylate
0.3 g of the product obtained in Example 105 is introduced into 30 ml of ethyl acetate, 0.05 g of 18% palladium on activated carbon and hydrogen are added for 2 hours under a pressure of 600 mbar.

 Filtered, the catalyst is washed with ethyl acetate and the filtrate evaporated.

 After purification by recrystallization in 18 ml of ethyl acetate, 0.21 g of expected product (beige crystals) is obtained, mp = 1900 ° C.

ANALYZES
IR NUJOL (cal)
Absorptions OH / NH 3494-3480-3396
NH2 1706
Aromatic + NH2 def 1626-1598-1520
EXAMPLE 122 Methyl 4-hydroxy-3 - ((4-hydroxybutyl) amino) -5 - (((4-methylphenyl) sulfonyl) oxy) benzoate
The procedure is as in Step 4 of Example 97, starting from 0.28 g of the product obtained in Example 105 in 30 ml of tetrahydrofuran, adding 0.05 g of 18% palladium on activated charcoal and hydrogen for one hour. a pressure of 600 mbar.

 Filtered, the catalyst is washed with ethyl acetate and the filtrate is evaporated.

 Purified on silica eluting with ethyl acetate and then by recrystallization in 5 ml of ethyl acetate and 0.08 g of expected product (yellow crystals) F = 113 ° C.

ANALYZES
IR NUJOL (cm-1)
OH / NH absorption: max - 3565-3430
-O 1712
Aromatic + NH2 1608-1599-1530
EXAMPLE 123 of pharmaceutical composition.

Tablets having the following formula were prepared
Product of Example 18 ........................... 50 mg
Excipient for a tablet finished at .............. 200 mg (details of the excipient: lactose, talc, starch, magnesium stearate).

Pharmacological results
STUDY OF ACTIVITY ON ENDOTHELIN RECEPTOR A
Membrane preparation is carried out from rat heart (ventricles). The tissue is ground with POLYTRON in a 50 mM Tris buffer pH = 7.4.

 After 30 minutes at 25 ° C. (B.M.) the homogenate is centrifuged at 30,000 g for 15 minutes (2 centrifugations with intermediate recovery in Tris buffer pH 7.4).

 The pellets are resuspended in incubation buffer (25 mM Tris, 5 microg / ml pepstatin A, 3 microg / ml aprotinin, 0.1 mM PMSF, 3 mM EDTA, 1 mM EGTA pH 7.4).

 2 ml aliquots are distributed into hemolysis tubes and 1251 Endothelin (about 50000 dpm / tube) and the product to be studied are added. (The product is first tested at 3 * 10-5 M in triplicate). When the test product displaces receptor-specific radioactivity by more than 50%, it is tested again in a range of 7 concentrations to determine the concentration that inhibits receptor-specific radioactivity by 50%. The 50% inhibitory concentration is thus determined.

 Nonspecific binding is determined by addition of endothelin at 10-6 M (in triplicate). It is incubated at 25 ° C. for 60 minutes, put back on a water bath at 0 ° C. for 5 minutes, filtered under reduced pressure, rinsed with Tris buffer 7.4 and counts the radioactivity in the presence of Triton scintillant.

 The result is expressed directly in 50% inhibitory concentration (IC 50), that is to say in concentration of the studied product expressed in nM, necessary to displace 50% of the specific radioactivity fixed on the studied receptor.

Result
The IC50s found for the products of the examples are given in Table I below, in nanomoles.

Results
TABLE I

<tb> Product <SEP> of the <SEP> examples <SEP> Receptor <SEP> A <SEP> of <SEP> the endotheline <SEP>
<tb><SEP> IC50 <SEP> in <SEP> nanomoles <SEP>
<tb><SEP> 18 <SEP> 210
<tb><SEP> 109 <SEP> 580
<Tb>

Claims (16)

 in which n represents an integer of 1 to 2, or the radical

R7 represents an alkyl, alkoxy, phenyl or amino radical optionally substituted with one or two alkyl radicals, all of these alkyl, alkoxy and phenyl radicals being optionally substituted, R31 R4 and R5 are such that they are identical or different, they are chosen from among ) the hydrogen atom, b) the hydroxyl radical optionally substituted by an alkyl, aryl or A-sulphonyl radical in which the radical A represents an alkyl or aryl radical, all the alkyl and aryl radicals being optionally substituted, ) the amino radical optionally substituted with one or two radicals chosen from the alkyl, alkylcarbonyl, arylcarbonyl and A-sulphonyl radicals as defined above, or one of R3 and R5 is chosen from the values indicated above; and the two others together form the radical  wherein X represents an oxygen or sulfur atom and

 in which R1 represents - the hydrogen atom - the formyl radical - an alkyl radical optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, aryl, free carboxy, salified, esterified or amidified radicals; , carbonyl, amino, substituted amino, carbamoyl and substituted carbamoyl, - an optionally substituted aryl radical, - mercapto, alkylthio, arylthio radicals, - alkylcarbonyloxy or phenylcarbonyloxy radicals, - free or salified carboxy radical, - radical

 CLAIMS 1) As medicaments, the products of formula (I):  as defined above, said products of formula (I) being in all possible racemic isomeric, enantiomeric and diastereoisomeric forms as well as addition salts with mineral and organic acids or with pharmaceutically acceptable inorganic and organic bases said products of formula (I).

R 2 and R 61, which are identical to or different from each other and from R 5, are chosen from the values indicated above for R 5 and the nitro, carboxy free, salified, esterified or amidified radicals and the alkyl radicals optionally substituted by a hydroxyl, alkoxy or aryl radical; , it being understood that at least two of R 2, R 3, R 4, R 5 and R 6 or, identical or different, are chosen from hydroxyl and amino radicals, these hydroxyl and amino radicals being optionally substituted as indicated above. , or together form one of the radicals 2) As medicaments, the products of formula (I) as defined in claim 1, corresponding to formula (IA)

 in which R1A represents - the hydrogen atom - the formyl radical - an alkyl radical optionally substituted by a hydroxyl or alkoxy radical, - the phenyl, pyridyl, pyrimidyl, imidazole, oxazolyl or oxazolinyl radical, - the free or salified carboxy radical - a radical C-R7A #  X in which X represents an oxygen or sulfur atom and R7A represents an alkyl, alkoxy or amino radical optionally substituted by one or two alkyl radicals R3A1 R4A and R5A are such that two of them are identical and represent the hydroxyl radical, or consecutive, together form a radical

 or are chosen from hydroxyl and optionally protected amino radicals as defined below and the other of R3A, R4A and R5A is chosen from hydrogen, amino and hydroxyl optionally substituted for to form the following radicals - Q-alkyl-Aa-Q-Aa, -Q-SO2-Aa, where Q is -O- or -NR8- with R8 is a hydrogen atom or an alkyl radical and Aa is a radical alkyl or aryl optionally substituted by one or more substituents selected from halogen atoms and hydroxyl radicals; alkyl; alkoxy; cyano; nitro; carbamoyl; trifluoromethyl; trifluoromethoxy; free, salified, esterified or amidified carboxy; amino optionally substituted with one or two alkyl radicals; acylamino; arylcarbonyl; alkylcarbonyl; pyridinyl, isoxazolyl and phenyl optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy, free carboxy, salified, esterified or amidified radicals and phenyl itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy cyano, nitro, carbonyl, trifluoromethyl, trifluoromethoxy and free carboxy, salified, esterified or amidated radicals, R 2 A and R 6 A which are identical or different are chosen from hydrogen and arylalkyl and arylsulphonyloxy radicals in which the aryl radical is optionally substituted by one or more substituents chosen from halogen atoms and hydroxyl, alkyl or alkoxy radicals; cyano, nitro, trifluoromethyl, trifluoromethoxy, free, salified, esterified or amidified carboxy, phenyl and amino optionally substituted by one or two alkyl radicals, said products of formula (IA) being in all the racemic isomeric forms, enantiomers and possible diastereoisomers, the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (IA). 3) As medicaments, the products of formula (I), as defined in claim 1, in which R1, R2, R3, R4 and R5 have the meanings indicated in claim 1 and at least one of R2 and R 6 represents a hydrogen atom, said products of formula (I) being in all the possible isomeric racemic, enantiomeric and diastereoisonial forms as well as the addition salts with mineral and organic acids or with the pharmaceutically acceptable inorganic and organic bases said products of formula (I). 4) As medicaments, the products of formulas (I) and (IA) as defined in claims 1 to 3 and corresponding to formula (IB):

 in which R 1B represents - the hydrogen atom - the formyl radical - the methyl, hydroxymethyl or methoxymethyl radical, - the free carboxy radical, esterified with an alkyl radical, salified or amidated to a carbamoyl radical optionally substituted on the amino radical by a or two alkyl radicals, an alkylcarbonyl radical, the radical

 in which R7A represents an alkoxy radical, R3B and R4B are such that either R3B and R4B are identical and represent the hydroxyl radical, or R3B and R4B together form the radical

 or R3B and R4B are chosen from atony of hydrogen and amino and hydroxyl radicals optionally substituted by a radical chosen from alkyl, phenylsulfonyl and benzyl radicals, the alkyl and phenyl radicals themselves being optionally substituted by a hydroxyl radical; or alkoxy and the phenyl radical being optionally substituted by an alkyl radical, R5B represents i) the hydrogen atom, ii) the hydroxyl radical optionally substituted in the alkoxy or arylsulphonyloxy radical in which the aryl radical is chosen from - the phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and hydroxyl radicals; alkyl; alkoxy; cyano; nitro; trifluoromethyl; trifluoromethoxy; free, salified, esterified or amidified carboxy; amino optionally substituted with one or two alkyl radicals; acylamino; arylcarbonyl; alkylcarbonyl; pyridinyl isoxazolyl and phenyl-nths optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy, free carboxy, salified, esterified or amidified radicals and phenyl itself optionally substituted by the atoms of halogen and the hydroxyl, alkyl, alkoxy, cyano, nitro, carbonyl, trifluoromethyl, trifluoromethoxy and free carboxy, salified, esterified or amidified radicals - the quinolyl radical - the isoxazolyl radical optionally substituted by one or more radicals chosen from alkyl and thienyl radicals the pyrazolyl radical optionally substituted on a carbon or nitrogen atom with one or more radicals chosen from alkyl radicals and halogen atoms; the thienyl radical optionally substituted by one or more radicals chosen from halogen atoms and the nitro, pyridinyl and isoxazolyl radicals; the naphthyl iii radical; and the amino radical optionally substituted by a phenylsulfonyl or benzoyl radical in which the phenyl radical is optionally substituted by an alkyl radical, R2B is selected from hydrogen and phenylsulfonyloxy wherein the phenyl radical is optionally substituted with an alkyl radical, said products of formula (zig) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (in). 5) As medicaments, the products of formula (I), as defined in claim 1, wherein R1, R2, R5 and R6 have the meanings given in claim 1 and R3 and R4 are identical to the hydroxyl radical, said products of formula (I) being in all isomeric forms racemic, enantiomers and diastereoisomers possible as well as addition salts with inorganic and organic acids or with the mineral and organic bases pharmaceutically acceptable said products of formula (I). 6) As medicaments, the products of formula (I), as defined in claim 1, having the following formulas - 2 - (((2,3-dihydroxy-5- (methoxycarbonyl) phenyl) oxy) sulfonyl) benzoate methyl, 3,4-dihydroxy-5 - (((2- (trifluoromethyl) phenyl) sulfonyl) oxy) benzoate methyl, 3,4-dihydroxy-5 - (((2-thienyl) sulfonyl) oxy) benzoate methyl, - methyl 3-O-tosyl gallate, - propyl 3-O-tosyl gallate, - (2,3-dihydroxyphenyl) -4-methylbenzenesulfonate. 7) Products of formula (IN) corresponding to the products of formula (I) as defined in claim 1, with the exception of a) products in which R1 represents an alkoxycarbonyl radical, R2 and R6 represent an atom of hydrogen, R4 represents a hydroxyl radical optionally substituted by a methyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl and alkylphenylsulphonyl radical and R3 and R5 are identical and represent a hydroxyl radical optionally substituted by the benzyl, alkylsulfonyl, phenylsulfonyl, phenylalkylsulfonyl or alkylphenylsulphonyl or methyl radical, at least two substituents and b) products in which two of R3, R4, R5 and R6, consecutive on the ring which carries them, represent a hydroxyl radical, the other two of R3, R4, R5 and R6 are such that the one represents a hydrogen atom and the other represents a hydroxyl radical, optionally protected and R1 is selected from: - the hydrogen atom - the unsubstituted alkyl radical, - the formyl radical and - the free or esterified carboxy radical, said products of formula (IN) being in all isomeric forms racemic, enantiomers and diastereoisonières possible as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (IN). 8) Products of formula (I), as defined in claim 1 and corresponding to formula (ID):

 in which R 1 represents the hydrogen atom or the free or esterified carboxy, formyl, alkyl, hydroxyalkyl, alkoxyalkyl, carbamoyl, N alkylcarbamoyl, N, N-dialkylcarbamoyl, alkoxycarbothioate or alkylcarbonyl radical, V 1 represents an oxygen atom or the radical -NH- and V2 represents -V1H or a hydrogen atom and A has the meaning indicated in claim 1, said products of formula (ID) being in all the racemic isomeric forms, enantiomers and diastereoisomers possible as well as the addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (ID). 9) Products of formula (I), as defined in claims 1 to 5, wherein R5 represents an arylsulfonyloxy radical, optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy, cyano, amino radicals. , nitro, free or esterified carboxy, trifluoromethoxy, trifluoromethyl, phenyl, pyridinyl and isoxazolyl, said products of formula (I) being in all isomeric forms racemic, enantiomers and diastereoisomers possible as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 10) The following products - methyl 2- (((2,3-dihydroxy-5- (methoxycarbonyl) phenyl) oxy) sulfonyl) benzoate, 3,4-dihydroxy-5 - (((2- (trifluoromethyl) phenyl) sulfonyl methyl oxy) benzoate, methyl 3,4-dihydroxy-5- (((2-thienyl) sulfonyl) oxy) benzoate. 11) Process for the preparation of the products of formulas (IN) and (ID), as defined in claims 7 to 8, characterized in that either a polyphenol of formula (II) is treated

 in which R'1 has the meaning indicated in claims 7 to 9 for R1 wherein the optional reactive functions are optionally protected, Z'1 and Z'2 represent two of the radicals R2, R3, R4, R5 and R6 as defined in claims 7 to 9 in which the possible reactive functions are optionally protected and Z represents a hydroxyl radical or a hydrogen atom.

 in which alc, R'1, Z, Z'1 and Z'2 are defined as above either by the compound of formula (IV) or (IV '):

or by at least two equivalents of a base under aprotic and anhydrous conditions to give the corresponding dianion, which is treated with a trialkyl borate of formula (B) (Oalc) 3, wherein alk represents an alkyl radical containing from 1 to 6 carbon atoms, to obtain a product of formula (III):

 in which R'1, Z, Z'1, n and Z'2 have the meanings indicated above, products of formulas (III), (12) and (I2,) than when Z represents a hydroxyl radical; optionally treated in situ with a reagent capable of introducing a substituent W on the hydroxyl radical, to obtain respectively the corresponding product of formula (V), (I3) or (I3 ') ::

 Hal- (CH2) n-Hal (IV ') in which Hal represents a halogen atom and n represents 1 to 2, to obtain the product of formula (I2) or (I2,) ::  in which R'1, Z'1 and Z'2 have the meanings indicated above and S1 and S2 both represent a hydrogen atom or one a hydrogen atom and the other substituent W1 or W2 as defined above, products of formulas (I1), (I2), (I3), (I4), (in) '(16) and (I7) which may be products of formula (IN) or (ID) and that, to obtain or of other products of formula (IN) or (ID), one can undergo, if desired and if necessary, one or more of the following transformation reactions, in any order a) an esterification reaction of acid function, b) an ester function saponification reaction in acid function, c) a conversion reaction of hydroxyalkyl radical to alkyl radical, d) an ester function conversion reaction in acyl function, e) a conversion reaction of the cyano function to acid function, f) an acid function conversion reaction to an amide function, optionally, in the thioamide function, g) a reduction reaction of the carboxy function as a function of alcohol, h) a reaction for reducing the nitro radical to an amino radical, or i) an alkoxy functional conversion reaction in hydroxyl function or hydroxyl function according to the alkoxy function, j) an alcohol function oxidation reaction based on aldehyde, acid or ketone,

Z 'to obtain the products of formula (I7) ::  in which R'1, Z ', Z'1 and Z'2 have the meanings indicated above and W1 and W2 identical or different, represent substituents of the hydroxyl and amino radicals, product of formula (I4), (I5) , and (I6) that when Z 'represents a substituted hydroxyl radical, it is possible to hydrolyze on

 in which R'11 Z ', Z'1 and Z'2 have the meanings indicated above which are optionally treated in situ to introduce a substituent on the hydroxyl radical or the amino radical to obtain the corresponding products of formula ( I5) and (il) ::

 in which Z 'represents a hydrogen atom or a substituted hydroxyl radical and R'1, Z'1 and Z'2 have the meanings indicated above, with a reducing agent to obtain the product of formula (Iq)

 in which Z'11 Z'2 and R'1 have the meanings indicated above and W represents a substituent of the hydroxyl radical, or by a salifying agent for salifying one of the free hydroxyl radicals of the product of formula (II) and then treating in situ to introduce a substituent on the salified hydroxyl radical, thus obtained product or product of formula (II) which is optionally treated in situ on one or, where appropriate, more free hydroxyl radicals for introducing a substituent on one or, where appropriate, more than one free hydroxyl radical, or else treating a compound of formula (VI):

 wherein W, Z'11 Z'21 alk, n and R'1 have the meanings indicated above, which can if desired, hydrolyze to the product of formula (I1)

 q) a reaction of transformation of the ss-ketosulfoxide function in function α-keto thio ester, r) a reaction of elimination of the protective groups that can carry the protected reactive functions, s) a salification reaction by a mineral acid or organic or with a base to obtain the corresponding salt, t) a resolving reaction of the racemic forms into split products, said products of formulas (IN) and (ID) thus obtained being in all possible isomeric forms racemic, enan tiomers and diastereoisomers.

 k) a conversion reaction of the formyl radical to esterified carboxy radical 1) a reaction of conversion of the formyl radical to carbamoyl radical, m) a conversion reaction of the carbamoyl radical to nitrile radical, n) a conversion reaction of nitrile radical to tetrazolyl , o) an oxo function conversion reaction in thioxo function, p) an acid function transformation reaction in function 12) As medicaments, the products of formulas (IN) and (ID) as defined in claims 7 to 10. 13) Pharmaceutical compositions containing as active principle at least one of the medicaments as defined in any one of claims 1 to 6 and 12. 14) Use of the products of formulas (I), (IA) and (IB) as defined in claims 1 to 6, for the preparation of pharmaceutical compositions for the treatment of conditions resulting from an abnormal stimulation of the endothelin. 15) Use of the products of formulas (IN) and (ID) as defined in claims 7 to 10, for the preparation of pharmaceutical compositions for the treatment of conditions resulting from abnormal stimulation of endothelin receptors. 16) Use of the products of formulas (I), (IA), (IB), (IN) and (ID) as defined in claims 1 to 10, for the preparation of pharmaceutical compositions intended for the treatment of hypertension induced by endothelin, all vascular spasms, treatment of cerebral post-hemorrhages, renal insufficiency, myocardial infarction and the prevention of post-angioplasty restenosis.