New substituted derivatives, of biphenyl or phenylpiridine, their preparation process and the pharmaceutical compositions that contain them
Abstract
-61- ABSTRACT Novel compounds of formula (I)wherein R1 is cycloalkyl, phenyl, naphthyl, heterocyclic, alkyl or alkenyl; A represents a bond, an oxygen or sulfur atom, a group a group or a group wherein Rc isa hydrogen atom or an alkyl or cycloalkyl group, R1 being different alkyl ungroupement C1 or C2 when A represents a bond; R2 is atomed'halogène, alkyl, alkenyl, alkynyl, cycloalkyl, formyl, carboxy, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, carbamoyl, amino, formamido, cyano, amidino, hydroxyaminométhyle, amide oxime or hydrazono, ora group of formulain which R21 represents a hydrogen atom or an alkyl or cycloalkyl group, R22 represents a hydrogen atom or an alkyl, cycloalkyl or acyl, and R23représente an alkyl or cycloalkyl group; R3 represents a hydrogen atom or alkyl ungroupement, cycloalkyl or acyl, or together form the ring ; X represents an oxygen atom orfrom sulfur or a group NR "wherein R" represents a hydrogen atom or alkyl ungroupement, cycloalkyl or acyl; ring B represents a phenyl or pyridyl ring, Ra and Rb, identical or different, represent a hydrogen or halogen atom, or an alkyl-62-group, hydroxy, alkoxy, carboxy, polyhaloalkyl, cyano, nitro, alkoxycarbonyl , cycloalkyloxycarbonyl, amino, carbamoyl, sulfo, alkylsulfonyl, cycloalkylsulfonyl or aminosulfonyl. The invention also relates descomposés isomers of formula (I) and their addition salts with an acid or an acceptable basepharmaceutiquement. The compounds of the invention are inhibitors dephosphodiestérases group IV and are therefore useful as medicaments.
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Expired 2 October 2017, 9 years ago.
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35 claims: 24 independent, 11 dependent
- 1-45 Les réalisations de l'invention, au sujet desquelles un droit exclusif de propriété ou de privilège est revendiqué, sont définies comme suit:1. Compounds of formula (I):wherein: R1 represents a cycloalkyl group, C3-C7 substituted or unsubstituted, a phénylesubstitué or no group, a substituted or unsubstituted naphthyl, a saturated groupementhétérocyclique or unsaturated, substituted or unsubstituted mono or bicyclic heterocycle containing from 1 to3 heteroatoms selected from the group consisting of nitrogen, oxygen and desoufre, an alkyl group C1-C6 linear or branched substituted or unsubstituted, linear or ungroupement alkenyl or C2-C6 substituted or unsubstituted branched;a is a bond, an atom oxygen or sulfur, a group ungroupement or a group wherein Rc represents hydrogen unatome, an alkyl group C1-C6 linear or branched or a groupementcycloalkyle C3-C7, wherein R1 is other than an alkyl group C1 or C2 when A represents a bond;R2 is a hydrogen atom, halogen, alkyl group linear C1-C6 alkyl or ramifiésubstitué or not, alkenyl linear C2-C6 alkyl or substituted or unsubstituted branched alkynyl linear ENC2-C6 alkyl or substituted or unsubstituted branched cycloalkyl, substituted C3-C7 or not, formyl, carboxy alkylcarbonyl, C1-C6 linear or branched, cycloalkylcarbonyl enC3-C7 alkoxycarbonyl, C1-C6 linear or branched, cycloalkyloxycarbonyl C3-C7 -46-carbamoyl, amino, formamido, cyano, amidino, hydroxyaminométhyle, amide oxime ouhydrazono, or a group of formula:in which R21 represents a hydrogen atom, an alkyl group C1-C6linéaire or branched, or cycloalkyl C3-C7, R22 is atomed'hydrogène or an alkyl group C1-C6 linear or branched, C3 C7, or acyl C 1 -C 6 linear or branched, and R23 represents an alkyl group C1-C6linéaire or branched, or C3-C7, the carbamoyl group being optionally substituted by one or two groupementsalkyle linear C1-C6 alkyl or branched alkenyl, C3-C7, hydroxy, C1-C6linéaire or branched, cycloalkyloxy or C3-C7, or forming together with the atom azotequi carries them a 5- to 7-membered ring containing 1 to 3 heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur, the group aminoétant optionally substituted by one or two alkyl groups C1-C6 linear ouramifié acyl, C 1 -C 6 linear or branched, or cycloalkyl C3- C7, or formantensemble with the nitrogen atom carrying them, a 5- to 7-membered ring containing from 1 to 3hétéroatomes selected from the group consisting of nitrogen, oxygen and desoufre, the amidino group is optionally substituted by one or deuxgroupements alkyl C1-C6 linear or branched, or C3-C7, or formantensemble with the nitrogen atom which carries them a 5- to 7-membered ring containing from 1 to 3hétéroatomes selected from the group consisting of of nitrogen, oxygen and desoufre, the hydroxyaminométhyle group being optionally substituted independently on the nitrogen or oxygen atom, by an alkyl group C1-C6linéaire or branched alkenyl, C3-C7 acyl or linear C1-C6 or branched legroupement amide oxime optionally substituted independently on the atomed'azote or oxygen, with an alkyl group in C 1 -C 6 linear or branched oucycloalkyle C3-C7, or forming with the the nitrogen atom carrying them a ring of 5 to 7chaînons containing 1 to 3 heteroatoms selected from the group consisting of atomesd'azote, oxygen and sulfur, the group optionally being hydrazono substituépar one or two alkyl groups C 1 -C 6 linear or branched, or C3-C7--47 or forming with the nitrogen atom which carries them a 5- to 7-membered ring containing from 1 to3 heteroatoms selected from the group consisting of atoms nitrogen, oxygen and desoufre;R3 represents a hydrogen atom, an alkyl group C1-C6 linear or branched, cycloalkyl ungroupement C3-C7 acyl group or a C 1 -C 6 linear or branched, or together form the ring ;X represents an oxygen or sulfur atom or a group NR "wherein R" represents a hydrogen atom or an alkyl group C1-C6 linear or branched alkenyl, C3-C7 or acyl;linear or branched C1-C6;Ring B represents a phenyl or pyridyl ring;Ra, Rb, identical or different, represent a hydrogen or halogen atom, or ungroupement alkyl linear or branched C1-C6 alkyl, hydroxy, C1-C6 linear ouramifié, carboxy, polyhaloalkyl linear C1-C6 or branched, cyano, nitro, alkoxycarbonyl, linear C1-C6 or branched cycloalkyloxycarbonyl C3-C7, amino, carbamoyl, sulfo, alkylsulfonyl, linear C1-C6 or branched cycloalkylsulfonyl enC3-C7 or aminosulphonyl, the amino group being optionally substituted by one ortwo alkyl groups, linear C1-C6 or branched acyl, linear C1-C6 alkyl or branched or C3-C7, the carbamoyl group being optionally substituted by unou two alkyl groups, linear C1-C6 alkyl or branched alkenyl, C3-C7 or alkoxyen linear C1-C6 or branched, the aminosulfonyl group being éventuellementsubstitué by one or two alkyl groups, linear C1-C6 alkyl or branched or cycloalkyleen C3 C7;provided that: when a represents a bond or an oxygen atom, B represents a phenyl, R1représente a cycloalkyl group substituted C3-C7 or not a phénylesubstitué group or not, a substituted or unsubstituted naphthyl group, or a group-48-.alpha.,. alpha .'- dimethylbenzyl, X represents an oxygen atom or a group NR "whereinR 'represents a hydrogen atom or an alkyl group C1-C6 linear or branched andR3 represents a hydrogen atom or an alkyl group linear or branched C1-C6, then R2 is other than a carboxyl group, their isomers and their addition salts with an acid or a base pharmaceutiquementacceptable. 1. Composés de formule (I): dans laquelle: R1 représente un groupement cycloalkyle en C3-C7 substitué ou non, un groupement phényle substitué ou non, un groupement naphtyle substitué ou non, un groupement hétérocyclique saturé ou insaturé, substitué ou non, mono ou bicyclique contenant de 1 à 3 hétéroatomes choisis dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre, un groupement alkyle en C1-C6 linéaire ou ramifié substitué ou non, ou un groupement alkényle en C2-C6 linéaire ou ramifié substitué ou non;A représente une liaison, un atome d'oxygène ou de soufre, un groupement un groupement ou un groupement dans lesquels Rc représente un atome d'hydrogène, un groupement alkyle en C1-C6 linéaire ou ramifié ou un groupement cycloalkyle en C3-C7, R1 étant différent d'un groupement alkyle en C1 ou C2 lorsque A représente une liaison;R2 représente un atome d'halogène, un groupement alkyle en C1-C6 linéaire ou ramifié substitué ou non, alkényle en C2-C6 linéaire ou ramifié substitué ou non, alkynyle en C2-C6 linéaire ou ramifié substitué ou non, cycloalkyle en C3-C7 substitué ou non, formyle, carboxy, alkylcarbonyle en C1-C6 linéaire ou ramifié, cycloalkylcarbonyle en C3-C7, alkoxycarbonyle en C1-C6 linéaire ou ramifié, cycloalkyloxycarbonyle en C3-C7, -46 carbamoyle, amino, formamido, cyano, amidino, hydroxyaminométhyle, amide-oxime ou hydrazono, ou un groupement de formule: dans lesquelles R21 représente un atome d'hydrogène, un groupement alkyle en C1-C6 linéaire ou ramifié, ou un groupement cycloalkyle en C3-C7, R22 représente un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, cycloalkyle en C3-C7, ou acyle en C1-C6 linéaire ou ramifié, et R23 représente un groupement alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, le groupement carbamoyle étant éventuellement substitué par un ou deux groupements alkyle en C1-C6 linéaire ou ramifié, cycloalkyle en C3-C7, hydroxy, alkoxy en C1-C6 linéaire ou ramifié, ou cycloalkyloxy en C3-C7, ou formant ensemble avec l'atome d'azote qui les porte un cycle de 5 à 7 chaînons contenant de 1 à 3 hétéroatomes choisi dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre, le groupement amino étant éventuellement substitué par un ou deux groupements alkyle en C1-C6 linéaire ou ramifié, acyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, ou formant ensemble avec l'atome d'azote qui les porte un cycle de 5 à 7 chaînons contenant de 1 à 3 hétéroatomes choisis dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre, le groupement amidino étant éventuellement substitué par un ou deux groupements alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, ou formant ensemble avec l'atome d'azote qui les porte un cycle de 5 à 7 chaînons contenant de 1 à 3 hétéroatomes choisis dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre, le groupement hydroxyaminométhyle étant éventuellement substitué, indépendamment sur l'atome d'azote ou d'oxygène, par un groupement alkyle en C1-C6 linéaire ou ramifié, cycloalkyle en C3-C7 ou acyle en C1-C6 linéaire ou ramifié, le groupement amide-oxime étant éventuellement substitué, indépendamment sur l'atome d'azote ou d'oxygène, par un groupement alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, ou formant avec l'atome d'azote qui les porte un cycle de 5 à 7 chaînons contenant de 1 à 3 hétéroatomes choisis dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre, le groupement hydrazono étant éventuellement substitué par un ou deux groupements alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, -47ou formant avec l'atome d'azote qui les porte un cycle de 5 à 7 chaînons contenant de 1 à 3 hétéroatomes choisis dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre;R3 représente un atome d'hydrogène, un groupement alkyle en C1-C6 linéaire ou ramifié, un groupement cycloalkyle en C3-C7 ou un groupement acyle en C1-C6 linéaire ou ramifié, ou bien forment ensemble le cycle ;X représente un atome d'oxygène ou de soufre, ou un groupement NR" dans lequel R" représente un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, cycloalkyle en C3-C7 ou acyle;en C1-C6 linéaire ou ramifié;le cycle B représente un cycle phényle ou pyridyle;Ra, Rb, identiques ou différents, représentent un atome d'hydrogène ou d'halogène, ou un groupement alkyle en C1-C6 linéaire ou ramifié, hydroxy, alkoxy en C1-C6 linéaire ou ramifié, carboxy, polyhalogénoalkyle en C1-C6 linéaire ou ramifié, cyano, nitro, alkoxycarbonyle en C1-C6 linéaire ou ramifié, cycloalkyloxycarbonyle en C3-C7, amino, carbamoyle, sulfo, alkylsulfonyle en C1-C6 linéaire ou ramifié, cycloalkylsulfonyle en C3-C7 ou aminosulfonyle, le groupement amino étant éventuellement substitué par un ou deux groupements alkyle en C1-C6 linéaire ou ramifié, acyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, le groupement carbamoyle étant éventuellement substitué par un ou deux groupements alkyle en C1-C6 linéaire ou ramifié, cycloalkyle en C3-C7 ou alkoxy en C1-C6 linéaire ou ramifié, le groupement aminosulfonyle étant éventuellement substitué par un ou deux groupements alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7;sous réserve que: lorsque A représente une liaison ou un atome d'oxygène, B représente un cycle phényle, R1 représente un groupement cycloalkyle en C3-C7 substitué ou non, un groupement phényle substitué ou non, un groupement naphtyle substitué ou non, ou un groupement -48 .alpha.,.alpha.'-diméthylbenzyle, X représente un atome d'oxygène ou un groupement NR" dans lequel R" représente un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié et R3 représente un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, alors R2 est différent d'un groupement carboxy, leurs isomères ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable.
- 12The 2-hydroxy-3- (3-nitrophenyl) -5- (4-pyridylmethyl) benzaldehyde oxime and its selsd'addition with an acid or with a pharmaceutically acceptable base. 12. Le 2-hydroxy-3-(3-nitrophényl)-5-(4-pyridylméthyl)benzaldéhyde oxime et ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable.
- 13(E) -5-benzyl-2-hydroxy-3- (3-nitrophenyl) benzaldehyde oxime and its selsd'addition with a pharmaceutically acceptable base. 13. Le (E)-5-benzyl-2-hydroxy-3-(3-nitrophényl)benzaldéhyde oxime et ses sels d'addition à une base pharmaceutiquement acceptable.
- 147- (3-nitrophenyl) -5- (4-pyridylmethyl) benzo [b] furan and its addition salts with pharmaceutically acceptable unacide. 14. Le 7-(3-nitrophényl)-5-(4-pyridylméthyl)benzo[b]furane et ses sels d'addition à un acide pharmaceutiquement acceptable.
- 15Process for preparing the compounds of formula (I) as defined in larevendication 1, characterized in that it is carried out starting from a compound of formula (II):wherein R1, A and X are as defined in claim l, which is subjected to the action of boron tribromide in dichloromethane medium to yield toa compound of formula (III): - 51-wherein R1, A and X are as defined hereinbefore, which is subjected to the action of trifluoromethanesulphonic anhydride in pyridine, pourconduire to a compound of formula (IV):wherein R1, A and X are as defined hereinbefore, which is subjected to the action of a boric acid of formula (V):B1 wherein Ra and Rb are as defined in claim 1, to yield uncomposé of formula (I / a):wherein R1, A, Ra, Rb, B and X are as defined hereinbefore, which compound of formula (I / a), which is subjected, if appropriate, oxidative cleavage to yield uncomposé of formula (I / b) : -52-wherein R l, Q, Ra, Rb, B and X are as defined hereinbefore, which compound of formula (I / b) is optionally subjected: a) either to the action of a compound of formula (VI ) in a basic medium: R22O - NH2 (VI) wherein R22 represents a hydrogen atom or an alkyl group C1-C6 linéaireou branched alkenyl, C3-C7 acyl or C1-C6 linear or branched, to yield uncomposé of formula (I / c):wherein R l, Q, Ra, Rb, B, X and R22 are as defined hereinbefore, which compound of formula (I / c), which is converted, if appropriate, when R22 is other than acyl ungroupement, in an acid medium, the compound of formula (I / d):-53-Wherein R1, A, Ra, Rb, B and X are as defined above and R'22 represents unatome hydrogen or an alkyl group C1-C6 linear or branched, or cyloalkyle C3-C7, b ) either to the action, in alcoholic medium, of a hydroxylamine of formula R23NH - OH danslaquelle R23 represents an alkyl group linear or branched C1-C6 alkyl, or C3-C7, to yield a compound of formula (I / e):wherein R1, A, B, Ra, Rb, X and R23 are as defined above, c) or to the action of a phosphorus ylid of formula R'cCH2P + (C6H5) 3Br- in laquelleR'c represents hydrogen atom, an alkyl group linear or branched C1-C4 alkyl, C3-C7 alkoxy, linear or branched C1-C6 alkylthio C1-C6 linear ouramifié, is unsubstituted or substituted, substituted or unsubstituted naphthyl, heterocyclic ouinsaturé saturated substituted or unsubstituted, in the presence of n-butyllithium, to yield a compound deformule (I / f):wherein R1, A, Ra, Rb, B, X and R'c are as defined hereinbefore, which is subjected, if appropriate, a reduction to yield a compound of formula (I / g): -54-wherein R1, A, Ra, Rb, B, X and R'c are as defined above, d) an oxidizing medium reaction, to yield a compound of formula (I / h):wherein R1, A, Ra, Rb, B and X are as defined hereinbefore, which compound of formula (I / h) which is transformed function corresponding to the acid chloride acid estéventuellement converted into ester, amide or amine e) either to the action of hydroxylamine hydrochloride, to yield a compound deformule (I / i)wherein R1, A, Ra, Rb, B and X are as defined above, - which is optionally reacted in alcoholic medium with hydrochloric acid, puisavec an amine of formula Rd-NH-Re wherein Rd and Re, identical or different, represent a hydrogen atom or an alkyl group C1-C6 linear or branched, or cycloalkyl, or together with the nitrogen atom carrying them a ring of 5 to 7-55- members containing 1 to 3 heteroatoms selected from the group consisting of atomesd'azote, oxygen and sulfur, to yield a compound of formula (I / d):wherein R1, A, Ra, Rb, X, B, Rd and Re are as defined hereinbefore, - or which is optionally reacted with a compound of formula (VI) in a basic medium: RCO-NH2 (VI) wherein Rc is as defined in claim 1, to yield a deformule compound (I / k):wherein A, B, R1, Ra, Rb, Rc and X are as defined above, f) either to the action of a hydrazine of formula wherein Rd and Re are as defined above, to yield a compound of formula (I / 1):wherein A, B, R1, Ra, Rb, Rd, Re and X are as defined hereinbefore, which compound of formula (I / a), (I / b), (I / c), (I / d), (I / e), (I / f), (I / g), (I / h), (I / i) or (I / 1) which soumetéventuellement to the action of a dialkyl sulfate or a halide alkyleen linear C1-C6 or branched acyl linear or branched C1-C6 or C3-C7, to yield a compound of formula (I / m):wherein R1, A, B, Ra, Rb, R2 and X are as defined above and R'3 represents: alkyl group linear or branched C1-C6 acyl, C1-C6 linear or branched oucycloalkyle C3-C7, compounds of formulas (I / a) to (I / m) as optionally is purified, of which sépareéventuellement isomers and which is converted, where appropriate, into their acid addition salts or toa a pharmaceutically acceptable base. 15. Procédé de préparation des composés de formule (I) telle que définie dans la revendication 1, caractérisé en ce que l'on opère au départ d'un composé de formule (II): dans laquelle R1, A et X sont tels que définis dans la revendication l, que l'on soumet à l'action du tribromure de bore en milieu dichlorométhane, pour conduire à un composé de formule (III): -51 dans laquelle R1, A et X sont tels que définis précédemment, que l'on soumet à l'action de l'anhydride trifluorométhanesulfonique dans de la pyridine, pour conduire à un composé de formule (IV): dans laquelle R1, A et X sont tels que définis précédemment, que l'on soumet à l'action d'un acide borique de formule (V) : dans laquelle B1 Ra et Rb sont tels que définis dans la revendication 1, pour conduire à un composé de formule (I/a): dans laquelle R1, A, Ra, Rb, B et X sont tels que définis précédemment, composé de formule (I/a), qui subit, le cas échéant, une coupure oxydante, pour conduire à un composé de formule (I/b) : -52 dans laquelle R l, A, Ra, Rb, B et X sont tels que définis précédemment, composé de formule (I/b) que l'on soumet éventuellement: a) soit à l'action d'un composé de formule (VI) en milieu basique: R22O - NH2 (VI) dans laquelle R22 représente un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, cycloalkyle en C3-C7 ou acyle en C1-C6 linéaire ou ramifié, pour conduire à un composé de formule( I/c): dans laquelle R l, A, Ra, Rb , B, X et R22 sont tels que définis précédemment, composé de formule (I/c), que l'on transforme, le cas échéant, lorsque R22 est différent d'un groupement acyle, en milieu acide, en composé de formule (I/d): -53 dans laquelle R1, A, Ra, Rb, B et X sont tels que définis précédemment et R'22 représente un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, ou cyloalkyle en C3-C7, b) soit à l'action, en milieu alcoolique, d'une hydroxylamine de formule R23NH - OH dans laquelle R23 représente un groupement alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, pour conduire à un composé de formule (I/e) : dans laquelle R1, A, B, Ra, Rb, X et R23 sont tels que définis précédemment, c) soit à l'action d'un ylure de phosphore de formule R'cCH2P+(C6H5)3Br- dans laquelle R'c représente un atome d'hydrogène, un groupement alkyle en C1-C4 linéaire ou ramifié, cycloalkyle en C3-C7, alkoxy en C1-C6 linéaire ou ramifié, alkylthio en C1-C6 linéaire ou ramifié, phényle substitué ou non, naphtyle substitué ou non, hétérocyclique saturé ou insaturé substitué ou non, en présence de n-butyllithium, pour conduire à un composé de formule (I/f) : dans laquelle R1, A, Ra, Rb, B, X et R'c sont tels que définis précédemment, qui subit, le cas échéant, une réduction pour conduire à un composé de formule (I/g) : -54 dans laquelle R1, A, Ra, Rb, B, X et R'c sont tels que définis précédemment, d) soit à une réaction en milieu oxydant, pour conduire à un composé de formule (I/h): dans laquelle R1, A, Ra, Rb, B et X sont tels que définis précédemment, composé de formule (I/h) dont on transforme la fonction acide en chlorure d'acide correspondant qui est éventuellement transformé en ester, en amide ou en amine, e) soit à l'action du chlorhydrate d'hydroxylamine, pour conduire à un composé de formule (I/i) dans laquelle R1, A, Ra, Rb, B et X sont tels que définis précédemment, - que l'on fait éventuellement réagir en milieu alcoolique avec de l'acide chlorhydrique, puis avec une amine de formule Rd-NH-Re dans laquelle Rd et Re, identiques ou différents, représentent un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle, ou forment ensemble avec l'atome d'azote qui les porte un cycle de 5 à 7 -55chaînons contenant de 1 à 3 hétéroatomes choisis dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre, pour conduire à un composé de formule (I/j): dans laquelle R1, A, Ra, Rb, X, B, Rd et Re sont tels que définis précédemment, - ou que l'on fait éventuellement réagir avec un composé de formule (VI) en milieu basique: RcO-NH2 (VI) dans laquelle Rc est tel que défini dans la revendication 1, pour conduire à un composé de formule (I/k): dans laquelle A, B, R1, Ra, Rb, Rc, et X sont tels que définis précédemment, f) soit à l'action d'une hydrazine de formule dans laquelle Rd et Re sont tels que définis précédemment, pour conduire à un composé de formule (I/1): dans laquelle A, B, R1, Ra, Rb, Rd, Re et X sont tels que définis précédemment, composé de formule (I/a), (I/b), (I/c), (I/d), (I/e), (I/f), (I/g), (I/h), (I/i) ou (I/1) que l'on soumet éventuellement à l'action d'un dialkylsulfate ou d'un halogénure d'alkyle en C1-C6 linéaire ou ramifié, d'acyle en C1-C6 linéaire ou ramifié ou de cycloalkyle en C3-C7, pour conduire à un composé de formule (I/m): dans laquelle R1, A, B, Ra, Rb, R2 et X sont tels que définis précédemment et R'3 représente un groupement alkyle en C1-C6 linéaire ou ramifié, acyle en C1-C6 linéaire ou ramifié, ou cycloalkyle en C3-C7, composés de formules (I/a) à (I/m) que l'on purifie le cas échéant, dont on sépare éventuellement les isomères et que l'on transforme, le cas échéant, en leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable.
- 16Process for preparing the compounds of formula (I) as defined in larevendication 1, characterized in that it is carried out starting from a compound of formula (XI):- 57-wherein X, A and R1 are as defined in claim 1, which undergoes a bromination reaction to yield a compound of formula (XII)wherein X, A and R1 are as defined hereinbefore, which is subjected to the action of a boric acid of formula (V):wherein Ra, Rb and B are as defined in claim 1, to yield uncomposé of formula (XIII):wherein A, R1, Ra, Rb, B and X are as defined hereinbefore, which compound (XIII) which undergoes a halogenation reaction to yield a compound of formula (I / n):-58-Wherein A, R l, Ra, Rb, B and X are as defined above and Hal represents unhalogène, compound (I / n) which is optionally subjected: - either to the action of zinc cyanide in the presence of a palladium catalyst to yield uncomposé of formula (I / i) as defined in claim 15, - or to the action of a tin compound in the presence of a palladium catalyst, to yield uncomposé of formula (I / p):wherein A, R l, Ra, Rb, B and X are as defined above and R21 is as quedéfini in claim 1, with the exception of a hydrogen atom, compound (I / p) that the is optionally reacted: - either with a compound of formula (VI): R22O-NH2 (VI) wherein R22 represents a hydrogen atom or an alkyl group C1-C6 linéaireou branched alkenyl, C3-C7 acyl or linear or branched C1-C6 to yield uncomposé of formula (I / Q): - 59-wherein A, B, R1, Ra, Rb, R21, R22 and X are as defined hereinbefore;or with a hydrazine of formula wherein Rd and Re, which are identical oudifférents, represent a hydrogen atom or a group alkyl, linear C1-C6 ouramifié, or cycloalkyl, or together with the nitrogen atom carrying them a ring of 5to 7-membered ring containing 1 to 3 heteroatoms selected from the group consisting of atomesd'azote, oxygen and sulfur, to yield a compound of formula (I / s):wherein A, B, R1, Ra, Rb, Rd, Re, R21, and X are as defined hereinbefore, which compounds of formulas (I / n), (I / p), (I / q) and (I / s) is optionally subjected to the action of undialkylsulfate or a linear alkyl halide or C 1 -C 6 branched acyl C1-C6linéaire or branched, or C3-C7, for yield a compound of formula (I / m) as defined in claim 15, wherein R1, a, B, Ra, Rb, R2 and X have same meaning as previously, and R3 represents an alkyl group C1-C6linéaire or branched acyl, linear C1-C6 alkyl or C3-C7 compounds of formulas (I / n) to (I / s) which, if appropriate, purified, which is sépareéventuellement isomers and which is converted , where appropriate, into their addition salts toa acid or a pharmaceutically-60- base acceptable. 16. Procédé de préparation des composés de formule (I) telle que définie dans la revendication 1, caractérisé en ce que l'on opère au départ d'un composé de formule (XI): -57 dans laquelle X, A et R1 sont tels que définis dans la revendication 1, qui subit une réaction de bromation pour conduire à un composé de formule (XII) dans laquelle X, A et R1 sont tels que définis précédemment, qui est soumis à l'action d'un acide borique de formule (V): dans laquelle Ra, Rb, et B sont tels que définis dans la revendication 1, pour conduire à un composé de formule (XIII): dans laquelle A, R1, Ra, Rb, B et X sont tels que définis précédemment, composé (XIII) qui subit une réaction d'halogénation pour conduire à un composé de formule (I/n): -58 dans laquelle A, R l, Ra, Rb, B et X sont tels que définis précédemment et Hal représente un halogène, composé (I/n) qui est éventuellement soumis: - soit à l'action du cyanure de zinc en présence d'un catalyseur palladié, pour conduire à un composé de formule (I/i) telle que définie dans la revendication 15, - soit à l'action d'un dérivé de l'étain en présence d'un catalyseur palladié, pour conduire à un composé de formule (I/p): dans laquelle A, R l, Ra, Rb, B et X sont tels que définis précédemment et R21 est tel que défini dans la revendication 1, à l'exception d'un atome d'hydrogène, composé (I/p) que l'on fait éventuellement réagir: - soit avec un composé de formule (VI): R22O-NH2 (VI) dans laquelle R22 représente un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, cycloalkyle en C3-C7 ou acyle en C1-C6 linéaire ou ramifié, pour conduire à un composé de formule (I/q): -59 dans laquelle A, B, R1, Ra, Rb, R21, R22 et X sont tels que définis précédemment;soit avec une hydrazine de formule dans laquelle Rd et Re, identiques ou différents, représentent un atome d'hydrogène ou un groupement alkyle en C1-C6 linéaire ou ramifié, ou cycloalkyle, ou forment ensemble avec l'atome d'azote qui les porte un cycle de 5 à 7 chaînons contenant de 1 à 3 hétéroatomes choisis dans le groupe constitué par les atomes d'azote, d'oxygène et de soufre, pour conduire à un composé de formule (I/s): dans laquelle A, B, R1, Ra, Rb, Rd, Re, R21, et X sont tels que définis précédemment, composés de formules (I/n), (I/p), (I/q) et (I/s) que l'on soumet éventuellement à l'action d'un dialkylsulfate ou d'un halogénure d'alkyle en C1-C6 linéaire ou ramifié, d'acyle en C1-C6 linéaire ou ramifié, ou de cycloalkyle en C3-C7, pour conduire à un composé de formule (I/m) telle que définie dans la revendication 15, dans laquelle R1, A, B, Ra, Rb, R2 et X ont la même signification que précédemment, et R3 représente un groupement alkyle en C1-C6 linéaire ou ramifié, acyle en C1-C6 linéaire ou cycloalkyle en C3-C7, composés de formules (I/n) à (I/s) que l'on purifie le cas échéant, dont on sépare éventuellement les isomères et que l'on transforme, le cas échéant, en leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable. -6017. Composition pharmaceutique contenant comme principe actif au moins un composé selon l'une quelconque des revendications 1 à 14, en association avec au moins un excipient ou véhicule inerte, non toxique et pharmaceutiquement acceptable.
- 17Pharmaceutical composition containing as active ingredient at least one composéselon to any one of claims 1 to 14, in combination with at least one excipientou inert, non-toxic and pharmaceutically acceptable. 18. Composition pharmaceutique selon la revendication 17, caractérisée en ce qu'elle est utile comme inhibiteur de phosphodiestérases du groupe IV.
Independent claims7
3 paragraphs, as filed
CA 02217455 1997-10-02- -1-The present invention relates to novel substituted biphenyl or dephénylpyridine, process for their preparation and pharmaceutical compositions lescontiennent. These compounds are phosphodiesterase inhibitors of group IV and cefait have therapeutic applications particularly intéressantes.Les functions of most organic tissues are modulated by endogenous substances (hormones, neurotransmitters, autacoids) or exogenous. For some of these substances, the biological effect is relayed intracellularly by enzymatic effectors such what adenylate cyclase or guanylate cyclase. Stimulation of these lasynthèse of enzymes responsible for cyclic nucleotides such as adenosine 3 ', 5'-cyclic monophosphate (cAMP) and guanosine 3', 5'-cyclic monophosphate (cGMP) resulting in a rise of these tauxintracellulaire second messengers involved in the regulation of many fonctionsbiologiques (EW Sutherland, and TW RALL, Pharmacol. Rev., Vol. 12, p. 265, 1960) .The degradation of cyclic nucleotides is provided by a family of enzymes, appeléesphosphodiestérases (BDP) , currently classified in 7 groups. Recognition of isoformesdifférentes within each group, and the tissue- or cell-specific distribution of certain isoforms, has stimulated the search for inhibitors becoming plusspécifiques of a particular type of isoenzyme (JA Beavo, Physiological Rev., Vol 75, No. 4, pp 725-749, 1995). Of the various PDE families, PDE IV has been identified in many tissues or cells Detrés as the brain, heart, vascular endothelium, vascular smooth muscle and le2o tracheobronchial, hematopoietic cells. The desphosphodiestérases inhibition slows the hydrolysis of cyclic nucleotides and causes augmentationde cAMP content and / or GMPc.Les PDE IV inhibitors, responsible for an increase in cAMP levels, desactivités possess anti-inflammatory and relaxing effects on tracheobronchial smooth muscle of olour therapeutic value in the field of respiratory pathology or pathologiesassociées with an inflammatory process. (MN Palfreyman, Drugs of the Future, Vol.20, No. 8, pp 793-804, 1995; JP BARNES, Eur Respir J., Vol 8, pp 457-462, 1995;... And TJ SBCHRISTENSEN Torphy, Annual Reports in Medicinal Chemistry, Vol. 29, pp 185-194, 1994, Academic Press) .3o These compounds which are phosphodiesterase IV inhibitors serontparticulièrement interesting group in therapeutic applications for inflammation CA 02217455 1997-10-02 - -2-and bronchial relaxation and specifically in asthma and bronchial chroniquesobstructives (AJ and JB DUPLANTIER CHENG, Annu Rep Med Chem, Vol 29, pp 73-81, 1994......) (CD NICHOLSON and M. SHAHID, Pulmonary Pharmacol., Vol. 7, p. 1-17.1994), (TJ Torphy, GP and SB LIVI CHRISTENSEN, Drug News Perspect., Vol. 6, pp. 03-214, 1993) (JA and JB LOWE CHENG, Drugs Future, Vol. 17, pp. 799-807, 1992) but also in all conditions such as rhinitis (I. RADERER, E. HAEN, C. Schudt and B. Przybilla , Wien. Med. Wochenschr., Vol. 145, pp. 456-8, 1995), lesyndrome of acute respiratory distress (ARDS) (CR TURNER, KM ESSER andE. B. WHEELDON, Circulatory Shock, Vol. 39, p. 237-45, 1993), allergies and dermatitis les1o (HANIFIIN JM and SC Chan, J. Invest. Dermatol., Vol. 105, p. 84S-88S, 1995) (Hanifin JM, J. Dermatol. Sci., Vol. 1, pp. 1-6, 1990), psoriasis (E. TOUITOU, N. Shaco-EZRA N. Dayan, Mr. JUSHYNSKI, R. and R. RAFAELOFF AZOURY, J. Pharm. Sci., Vol . 81, p. 131-4, 1992) (F. LEVI-SCHAFFER and E. TOUTTOU, Skin Pharmacol., Vol. 4, pp. 286-90, 1991), rheumatoid arthritis (JM ANAYA andL. R . ESPINOZA, J. Rheumatol., Vol. 22, p. 595-9, 1995), autoimmune diseases (CP GENAIN et al. Proc. Natl. Acad. Sci., Vol. 92, pp. 3601-5, 1995), multiple sclerosis (N. SOMMER et al., Nat. Med., Vol. 1, p. 244-8, 1995), dyskinesia (T. KTTATANI, S. and T. HAYASHI SAKAGUCHI, Nippon. Yakurigaku . Zasshi, Vol. 86, pp. 353-8, 1985), lesglomérulonéphrites (Mr. HECHT, M. Muller, ML-LOHMANN MATTHES Et.sub.2O EMMENDORFFER A., J. Leukoc. Biol., Vol. 57, pp. 242- 9, 1995), osteoarthritis and chocseptique (AM BADGER, DL and KM OLIVERA ESSER Circ Shock, Vol 44, p 188 to 95.1994;... SEKUT L. et al., Clin. Exp. Immunol., Vol. 100, p. 126-32, 1995), AIDS (TF GRETEN, ENDRES S. et al., Aids, Vol. 9 p.1 137-44, 1995), depression (NA SACCOMANO et al., J. Med. Chem. , Vol. 34, p. 291-8, 1991), and any maladieneurodégénérative being accompanied by inflammatory phenomena such as maladiesd Alzheimer, Parkinson, Huntington, Down and amyotrophic lateral sclerosis (GZ Feuerstein et al., Ann . NY Acad. Sci., Vol. 765, pp. 62-71, 1995) .These therapeutic indications are not limiting inasmuch as the laconcentration decrease cellular cAMP whatsoever in their cause or tissue localization , aboutit3o to cell dysfunction, pathological phenomena source, and can be a major ciblethérapeutique the described products. CA 02217455 2001-06-08-3-The state of the closest art is particularly represented by the compounds described in the brevetWO 96/03396 which describes dihydrobenzofuran derivatives as agents specifically anti-inflammatoires.Plus the present invention relates to compounds of formula (I) R - a ~ R2W ~ _ (I) X-R3 Rb Radans laquelleRl represents a cycloalkyl group (C3-C ~) substituted or unsubstituted, a phénylesubstitué group or not, a group substituted or unsubstituted naphthyl, a groupementhétérocyclique, saturated or unsaturated, substituted or unsubstituted mono or bicyclic heterocycle containing from 1 AL0 3 heteroatoms selected from nitrogen, oxygen or sulfur, an alkyl group (C1-C6) linear or branched substituted or unsubstituted, or a alkenyl group (C2-C6) -straight ouramifié substituted or not, a represents a bond (provided that in this case R is other than groupementalkyle C or CZ), oxygen, sulfur, a group - ë - Oou a group -CH- (in which Rc represents a atomei N ~ ORc ORcd'hydrogène, alkyl (C1-C6) -straight or branched alkyl or a groupementcycloalkyle (C3-C ~)), R2 is halogen, alkyl (C1-C6) -straight or substituted ramifié2o or not, alkenyl (CZ-C6) -straight or branched substituted or unsubstituted alkynyl, (CZ-C6) -straight or branched substituted or unsubstituted cycloalkyl (C3- C ~) subsitué or not, formyl, carboxy, alkylcarbonyl (Ci-C6) -straight or branched cycloalkylcarbonyl (C3-C ~), alkoxycarbonyl (C1-C6) -straight or branched cycloalkyloxycarbonyl (C3-C ~), carbamoyl (optionally substituted by one or two alkyl (CI-C6) -straight or branched CA 02217455 1997-10-02- -4-cycloalkyl (C3-C ~) alkyl, hydroxy, alkoxy (C1-C6) linear or branched, cycloalkyloxy (C3 -C ~) or together with the nitrogen atom carrying them a ring of 5 to 7 chaînonscontenant of 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) amino (optionally substituted by one or two alkyl groups (C ~ C6) -straight or branched, acyl (C1-C6) -straight or branched alkenyl, (C3-C7) or forming together with the atomed'azote carrying them, a 5- to 7-membered ring containing 1 to 3 heteroatoms choisisparmi nitrogen, oxygen and sulfur), formamido, cyano, amidino (optionally substituépar one or two alkyl groups (C ~ -C6) -straight or branched alkenyl, (C3-C ~), ouformant together with the nitrogen atom carrying them, a 5- to 7-membered containingfrom 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur), hydroxyaminométhyle (optionally substituted, independently on the nitrogen or oxygen atom, alkyl ungroupement (C ~ -C6) -straight or branched alkenyl, (C3-C7) acyl or (C1-C6) -straight or branched), amide-oxime (optionally substituted independently on the atomed'azote or oxygen with an alkyl group (C1-C6) -straight or branched alkenyl, (C3-C7) or forming with the nitrogen atom carrying them a ring of 5 to 7 chaînonscontenant of 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) hydrazono (optionally substituted by one or two alkyl groups (C ~ -C6) ouramifiés linear, cycloalkyl (C3-C7) or forming with the nitrogen atom which carries them a 5to 7-membered ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) , ou2o a group selected parmi- ~ - CN and-Rz2 - i - N (C) R23 R21 ~ R21dans which Rz represents a hydrogen atom, an alkyl group (C1-C6) linéaireou branched, or a cycloalkyl group (C3 C7), R22 represents a hydrogen atom or an alkyl group (C1-C6) -straight or branched alkenyl, (C3-C7) acyl or (C ~ -C6) -straight or branched, R23 represents an alkyl group (ICs C6) -straight or branched, or cycloalkyl (C3-C7) R3 represents a hydrogen atom, an alkyl group (C ~ -C6) -straight or branched ungroupement cycloalkyl (C3-C7) acyl group or a (C1- C6) -straight or branched Rzou good ~ together form the ring X XR ~ CA 02217455 2001-06-08-5-X represents an oxygen, sulfur or NR '(wherein R "represents an atom of group hydrogen, alkyl (Cl-C6) -straight or branched alkenyl, (C3-C ~) or acyl (C1-C6) -straight or branched), ring B represents a phenyl or pyridyl ring, Ra, Rb, identical or different, represent a hydrogen, halogen, alkyl ungroupement (C1-C6) -straight or branched, hydroxy, alkoxy (C1-C6) -straight ouramifié, carboxy, polyhalo (C1-C6) linear or branched, cyano, vitro , alkoxycarbonyl (C1-C6) -straight or branched cycloalkyloxycarbonyl (C3-C ~), amino (optionally substituted by one or two alkyl groups (C1-C6) -straight or branched 1o acyl (Cl-C6) -straight or branched alkyl or cycloalkyl (C3-C ~)), carbamoyl (éventuellementsubstitué by one or two alkyl groups (C1-C6) -straight or branched alkenyl, (C3-C ~) or alkoxy (CI-C6) -straight or branched), sulfo, alkylsulfonyl (Cl C6) -straight ouramifié cycloalkylsulfonyl (C3-C ~) or aminosulfonyl (optionally substituted by unou two alkyl groups (C1-C6) -straight or branched alkyl or cycloalkyl (C3-C ~), with the proviso that- when a represents a bond or an oxygen atom, B represents a phenyl, Rlreprésente cycloalkyl (C3-C ~) substituted or unsubstituted, a phénylesubstitué group or not, a substituted or unsubstituted naphthyl group, or a group a, a'-dimethylbenzyl, X represents an oxygen atom or a group NR '(wherein R "2o represents a hydrogen atom or an alkyl group (C1-C6) -straight or branched) and R3représente a hydrogen atom or an alkyl group (CI- C6) linear or branched, then R2 is different from a carboxyl group, their isomers and their addition salts with an acid or a base pharmaceutiquementacceptable.Parmi pharmaceutically acceptable acids include, without implied limitation the acideschlorhydrique, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, malefic, citric, ascorbic, oxalic, methanesulfonic, camphoric, etc ... CA 02217455 2001-06-08-6Parmi the pharmaceutically acceptable bases there may be mentioned, no sodium limitatifl'hydroxyde, potassium hydroxide, triethylamine, tert-butylamine, etc ... Among the preferred compounds of the present invention include compounds such as X represents a oxygen atom, those in which B represents a phenyl ring or those suchas Rl represents uri phenyl ring substituted or unsubstituted pyridyl or substituted or non.Parmi saturated heterocyclic groups or unsaturated, mono or bicyclic containingfrom 1 to 3 heteroatoms selected from nitrogen , oxygen or sulfur may be mentioned as preferred furyl, thienyl, pyridyl or imidazolyle.Par substituted alkyl, substituted alkenyl, substituted alkynyl or cycloalkyle1o substituted means substituted by one or more halogen atoms or alkoxy groups (C C6) -straight or branched alkylthio (C1-C6) -straight or branched alkenyl, (C3-C ~), phénylesubstitué or not, substituted or unsubstituted naphthyl or saturated or unsaturated heterocyclic, substituted orunsubstituted, mono or bicyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur (such as pyridyl). A preferred alkyl group is saturated or insaturésubstitué benzyl group substituted or non.Par substituted phenyl, substituted naphthyl or substituted heterocyclic or benzylesubstitué means substituted by one or more halogen atoms or alkyl (C1-C6) -straight or branched alkoxy (C1-C6) -straight or branched or trihalogénométhyle.La present invention also covers the process for preparing the compounds of formule2o (I), characterized in that there is used as starting material a compound of formula ( II) R1 A (II) wherein X OCH3dans Rr, A and X have the same meaning as in formula (I) which is subjected to the action of boron tribromide in dichloromethane medium to yield aucomposé of formula ( III) CA 02217455 1997-10-02 R1 A (~ x OHwherein R ,, A and X have the same meaning as in formula (I) which is subjected to the action of trifluoromethanesulphonic anhydride in pyridine, pourconduire the compound of formula (IV) R _ a (~) 'X OS02CF3dans wherein R1, a and X have the same meaning as in formula (I), which undergoes the action of a boric acid of formula (V) Ra BB (OH) 2 (V) Rbdans wherein B, Ra and Rb are as defined in formula (I) 1o to yield a compound of formula (I / a), a particular case of the compounds of formula ( I) R1 AX (I / a) D Ra ~ Rbdans wherein R ~, a, Ra, Rb, B and X have the same meaning as in formula (I), compound of formula (I / a), which undergoes, if desired, an oxidative cleavage to yield aucomposé of formula (I / b), a particular case of compounds of formula (I) CA 02217455 1997-10-02_g_ R1 - a, CHO__ (~) R ~ B Rbdans which R , A, Ra, Rb, B and X have the same meaning as in formula (I), compound of formula (I / b), which can either undergo the action of the compound of formula (VI) in basique8220 medium - NH2 ( VI) wherein R22 represents a hydrogen atom or an alkyl group (C1-C6) linéaireou branched alkenyl, (C3-C ~) or acyl (C1-C6) linear or branched, to yield the compound of formula (I / c), a particular case of compounds of formula (I) -A Ii N.OR22 R ~ XH (I / c) D Ra Rbdans wherein R ~, A, Ra, Rb, B, X and R22 are as defined above, compound of formula (I / c), which is optionally converted, when R22 is other than acyl ungroupement, in an acid medium, the compound of formula (I / d), a particular case of composésde formula (I) R ~ - a 122 (1 / d) tCA CA 02217455 2001-06-08-9dans wherein R1, a, Ra, Rb, B and X have the same meaning as above and R'22différent of an acyl group to the same definition as R22, b is the action, in alcoholic medium, of a hydroxylamine of formula R23NH - OH laquelleR23 represents an alkyl group (C1-C6) -straight or branched alkyl, or cycloalkyl (C3-C ~), to yield a compound of formula (I / e), a particular case of the compounds of formula (I) ~ 3 ~ N ~ 0 Rl-A Ii I XH (I / e) B Ra Rbdans which R1, A, B, Ra, Rb, X and R23 have the same meaning as above, c is the action of a phosphorus ylid of formula R'cCH2P + (C6H5) 3Br (wherein R'creprésente a hydrogen atom, an alkyl group (C1-C4) -straight or branched l0 cycloalkyl (C3-C ~) alkoxy (C1-C6) -straight or branched alkylthio (C1-C6) -straight or branched, is unsubstituted or substituted, substituted or unsubstituted naphthyl, saturated heterocyclic or insaturésubstitué or not), in the presence of n-butyllithium, to yield the compound of formula (I / f), a particular case of the compounds of formula (I) 'c R -Ai NMR B I Ra ~ -' '~ Rbdans which R, A, Ra, Rb, B, X and R'c have the same meaning as above, CA 02217455 1997-10-02- 1 ~ -who suffers, if desired, reduced to yield the compound of formula (I / g), the casparticulier compounds of formula (I) R1 - A, (CH2) 2 - R'c NMR (vg) d Ra Rbdans wherein R1, A, Ra, Rb, B, X and R'c have the same meaning as above, d is an oxidizing medium in reaction to yield the compound of formula (I / h) R1 - a '~ / C02H ~ xu (~) R ~ B Rbdans wherein R1, a, Ra, Rb, B and X have the same meaning as in formula (I), compound of formula (I / h) of which the acid function is converted into acidecorrespondant chloride, which can then be converted into ester, amide or amine correspondantsselon conventional reactions of organic chemistry, e is, action in appropriate medium hydroxylamine hydrochloride, to yield the compound of formula (I / i), a particular case of compounds of formula (I) R ~ - A, cnxH (I / i) Ra B Rbdans wherein R1, a, Ra, Rb, B and X have the same meaning as above, CA 02217455 1997-10-02-11-- that is reacted in alcoholic medium with hydrochloric acid, then with a amineRd -NH-Re (wherein Rd, Re, identical or different, represent a atomed'hydrogène or an alkyl group (C ~ -C6) -straight or branched, or cycloalkyl ouformant together with the nitrogen atom carrying them a ring of 5 to 7 members containingfrom 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur), to yield the compound of formula (I / d), a particular case of the compounds of formula (I) Rd, Re Ni R '- A, C ~ NH ~ NMR (vJ) D Ra Rbdans wherein R1, a, Ra, Rb, X, B, Rd and Re are as defined above, 1o - or is reacted with a compound of formula (VI) in basic medium RC0-NH2 (VI) wherein Rc is as defined in formula (I), to yield the compound of formula (I / k), a particular case of compounds of formula (I) ORc Nii R1 A, C ~ NHz NMR D Ra Rbdans wherein a, B, R1, Ra, Rb, Rc and X are as defined above, CA 02217455 2001-06-08-12-f or, finally, with a hydrazine h Rd 'are Re' N - NH (Rd and Re étant'tels hereinbefore defined) to yield the compound of formula (I / 1), a particular case of the compounds of formula (I) Re .rd N iN R - A, CH-NMR (I / 1 ) D Ra Rbdans wherein a, B, R1, Ra, Rb, Rd, Re and X are as defined hereinbefore, which compound of formula (I / a), (I / b), (I / c), (I / d), (I / e), (I / f), (I / g), (I / h), (I / i), (I / 1) or their dérivés- that is optionally subjected to action of a dialkyl sulfate or an alkyl halide (Cl-C6) -straight or branched alkyl or acyl (C1-C6) -straight or branched alkyl or cycloalkyl (C3-C ~), to yield the compound of formula (I / m), a particular case of the compounds of formula (I) Rl - A ~ X R2 - R'3 (I / m) D Ra Rbdans wherein R1, A, B, Ra, Rb, R2 and X have the same meaning as above, and R'31o represents an alkyl group (C1-C6) -straight or branched acyl (CI-C6) -straight or ramifiéou cycloalkyl (C3-C ~), compound of formula (I / a) to (I / m) or their dérivés- which may be, if necessary, purified according to a conventional technique of purification- are separated, where appropriate, the isomers according to a conventional separation technique, 15 - which is converted, if desired, into its addition salts with an acid or an acceptable basepharmaceutiquement. CA 02217455 1997-10-02-13-The compounds of formula (II) are generally prepared from an aldehyde of formula (VII) Br ~ CHO (V ~~ OCH3dans XH wherein X has the same meaning as in formula (I), which is reacted with 2-bromo-1,1-dimethoxyethane in the appropriate medium, for conduireau compound of formula (VIII) Br ~ OCH3 CHO (VIII X-CH 2 CHI OCH3 OCH3dans which X has the same meaning as in formula (I), the acid medium is cyclized to yield the compound of formula (IX) Br \ ~ (~) o Xt OCH3dans wherein X has the same meaning as in formula (I) , compound of formula (IX), which is subit-, the action of an organozinc compound of formula R - CH2 - ZnBr (wherein R has the mêmesignification as in formula (I), - or, after prior reaction with the hexabutyldiétain, the action of an acid chloride deformule R ~ - CO - Cl (wherein R ~ has the same meaning as in formula (I) enprésence of a palladium catalyst, provided that the function carbonyl may possibly be reduced by hydroxyl lesréducteurs conventionally used in organic chemistry, where compatible with les2o substituents on the molecule, CA 02217455 1997-10-02- 14-- or after prior reaction of an ethylene derivative of formula R1 - ~ R ~ I = CH2 (wherein R has the same meaning as in formula (1) and R'1 represents a atomed'hydrogène or alkyl (C1-C6) straight or branched alkenyl, (C3-C ~)) with LE9-borabicyclo [3.3.1] nonane, followed by reaction in the presence of a palladium catalyst, or - in the presence of a palladium catalyst, the action of a compound of formula (X) Rl-YH (X) wherein R ~ has the same meaning as in formula (I) and Y represents a desoufre or oxygen atom, to yield the compound of formula (II) .to Certain compounds of formula (I) may advantageously be obtained by using the starting commeproduit, when available, a compound of formula (XI) R ~ - a (XI) XHdans wherein X, a and R, have the same meaning as in formula (I), which undergoes bromination reaction to yield a compound of formula (XII) R ~ - a (XII) Brdans XH15 wherein X, a and R1 have the same meaning as above, which is subjected to the action of a boric acid of formula (V ) BB (OH) 2 (V) Ra Rbdans wherein Ra, Rb and B are as defined in formula (I) CA 02217455 1997-10-02-15-to yield a compound of formula (XIII) R 1 aw NMR (X ~ D Ra Rbdans wherein a, RI, Ra, Rb, B and X are as defined hereinbefore, which compound (XIII) which undergoes a halogenation reaction to yield a compound of formula (I / n), where particularly compounds of formula (I) RAH ~ Y NMR (1 / n) B Ra ~ Rbdans wherein A, RI, Ra, Rb, B and X are as defined above and Hal represents unhalogène, compound (I / n) can be soumisto - either to the action of zinc cyanide in the presence of a palladium catalyst to yield uncomposé of formula (I / i) as defined above, - either to the action of a derivative of the tin in the presence of a palladium catalyst to yield uncomposé of formula (I / p), a particular case of compounds of formula (I) R1 a ~ _ R21 NMR (UP) Ra B v Rbdans wherein a, R1, Ra, Rb, B and X are as defined in formula (I) and R21, différentd'un hydrogen atom has the same definition as in formula (I) CA 02217455 1997-10-02- 16-compound (I / w) that is made réagir- or with a compound of formula (VI) R220-NH2dans wherein R22 is as defined above, to yield the compound of formula (I / q), a particular case of the compounds of formula (I ) N, OR22 R -A Ii R21 NMR (U9) D Ra ~ Rbdans wherein a, B, R1, Ra, Rb, R21, R22 and X are as defined above, - or with a hydrazine Re ~ _ NH2 N ( Rd and Re are as defined above), to yield the compound of formula (I / s), a particular case of the compounds of formula (I) R d N ~ N ~ Re R '- A R21xH (vs> B Ra ~ Rb1o in wherein A, B, R ,, Ra, Rb, Rd, Re, R21, and X are as defined hereinbefore, which compounds (1 / n), (I / p), (I / q), (I / s) or derivatives thereof that is optionally subjected to the action of undiallkylsulfate or an alkyl halide (C1-C6) -straight or branched acyl or (CI-C6) -straight or branched alkyl, or cycloalkyl ( C3-C ~), to yield the compound of formula (I / m) as defined above, ... CA 02217455 2001-06-12composés (I / n) to (I / s) or their derivatives-17-- which may be, if necessary, purified according to a conventional technique of purifiaction, - which is optionally separated into isomers according to a conventional separation technique, - which is converted, if desired, into their addition salts with an acid or a basepharmaceutiquement acceptable.La present invention also relates to pharmaceutical compositions renfermantcomme active ingredient at least one compound of formula (I) in combination with one or plusieursexcipients or inert, non-toxic and pharmaceutically acceptables.Parmi pharmaceutical compositions according to the invention, there may be mentioned plus1o particularly those suitable for oral, parenteral, nasal, or simple lescomprimés dragees, sublingual tablets, capsules, tablets, lessuppositoires, creams, ointments, skin gels, aerosols, etc ... the dosage varies with the age and weight of the patient, nature and severity of the 'affectionainsi that the route of administration. The latter may be oral, nasal, rectal or parentérale.D'une Generally, the unit dosage ranges between 10 and 5000 mg for doStuff in 1 to 3 doses per 24 hours.The following examples illustrate the invention and limit it in any façon.Les starting materials used are known products or products prepared according to modesopératoires connus.2o the structures of the compounds described in the examples were determined according to customary spectrophotometric lestechniques (infrared, NMR, mass spectrometry ...) . EXAMPLE 1 5-Benzyl-7- (3-nitrophenyl) benzo [b] furan Step A: 5-Bromo-2- (2,2-dimethoxyethoxy) -3-méthoxybenzaldéhydeUne heterogeneous solution of 31 g (0.134 mol) of 5 bromo-2-hydroxy-3-methoxybenzaldehyde 28 g (0.166 mol) of 2-bromo-1,1-dimethoxyethane and 49 g (0.150 mol) of CA 02217455 1997-10-02- carbonate 18-cesium in 150 ml of dimethylformamide is heated to 160 ° C for 3 hours. After retourà room temperature, the mixture was filtered. The filtrate is then evaporated under pressionréduite. The solid thus obtained is taken up in 250 ml of dichloromethane and filtered again. homogeneous Lasolution is then washed with twice 200 ml of 0.1N hydrochloric then par200 ml of saturated sodium chloride solution acid. The organic phase is then séchéesur sodium sulfate then evaporated under reduced pressure to yield the expected product. Step B: 5-Bromo-7-métboxybenzo [b] furaneLe product obtained in the preceding stage is dissolved in 1000 ml of sulfuric 20 ° Io etporté to acid reflux for 3 hours. After cooling to room temperature, the solution estneutralisée with potassium carbonate and then extracted with twice 300 ml of organic phases éthyle.Les acetate are then combined, dried over sodium sulfate, filtered puisconcentrées pressurized réduite.Le residue is purified by chromatography on a silica column using as eluent unmélange dichloromethane / heptane (1/1) and yields the expected product in the form of huileincolore which crystallizes in the cold. Step C: 5-Benzyl-7-methoxybenzo [b] furane12,3 g (0.188 g-at) of powdered zinc are covered with 15 ml of tetrahydrofuran auxquelson few drops of dibromoethane and the whole is placed under argon . Onchauffe quickly and the solution poured several drops of a solution of 29.4 g (0.171 mol) of benzyl bromide in 135 ml of tetrahydrofuran. When the reaction is initiated, lemélange reaction is cooled to + 4 ° C, and the addition of benzyl bromide remaining ensolution s' operates at this temperature (time of addition about 1 hour). Estensuite the mixture stirred at + 4 ° C for 2 to 3 heures.Cette solution is then added dropwise to a mixture of 19.5 g (0.086 mol) ducomposé obtained in the preceding stage and 5.18 g (4,47.10 -3 mol) of tetrakistriphenyl phosphinePalladium (O) in 150 ml of tetrahydrofuran under argon. The mélangeréactionnel is brought to reflux for 15 hours. After returning to ambient temperature, lemilieu reaction is diluted with 300 ml of ethyl acetate and then washed successively with 200 mld'eau and 200 ml of a saturated solution of sodium chloride. The usual treatment la3o organic phase delivers oil which is purified by chromatography on silica column CA 02217455 1997-10-02--19 using as eluent a dichloromethane / heptane (1/1) and leads to the form of produitattendu 'oil. Stage D: 5-Benzyl-7-hydroxybenzo [b] furaneUne solution of 18 g (0.0755 mol) of the compound obtained in the preceding stage and 150 ml dedichlorométhane is added, under argon, to a solution of 155 ml boron detribromure 1M in dichloromethane at -78 ° C. The reaction mixture estgraduellement moved up to a temperature of -5 ° C (approximately 15 hours). A cettetempérature, 150 ml of water are poured and the organic phase is separated. The aqueous phase estsaturée with sodium chloride and re-extracted using 100 ml of dichloromethane. Ballast o organic phases are then combined, dried over sodium sulfate, filtered and concentréessous reduced pressure. The residue is purified by chromatography on a silica column enutilisant dichloromethane as eluant to yield the expected product as an oil. Step E: 5-Benzyl-7-trifluorométhanesulfonyloxybenzo [b] furaneSous inert atmosphere and at 0 ° C, 18.3 g (0.0649 mol) of anhydride trifluorométhanesulfoniquesont poured dropwise to a solution of 9.1 g (0 , 04057 mol) of the compound obtained in stadeprécédent in 60 ml of pyridine. After 2 hours, the solution is concentrated under pressionréduite. The residue is taken up with 100 ml of dichloromethane and washed successively par150 ml of a hydrochloric acid solution 2 N, 150 ml of a desodium saturated bicarbonate solution and finally 150 ml of a solution of saturated sodium. The usual traitement2o of the organic phase yields the expected product as a semi-solid. Step F: 5-Benzyl-7- (3-nitrophenyl) benzo [b] furaneSous inert atmosphere, a mixture of 11.1 g (0.08 mol) of potassium carbonate, 13 g (0.0364 mol) of the compound described in step a above, 8.6 g (0.05 mol) of acide3-nitrophénylborique and 1.49 g (1,82.10-3 mole) bis (diphenylphosphino) ferrocene palladium (II) in 250 ml of dimethylformamide A80 is worn for 18 hours. After concentration under reduced pressure of the solvent, the residue estrepris with 200 ml of ethyl acetate and havé with 200 ml of water and then 200 ml of a sodium chloride solutionsaturée. A usual treatment of the organic phase followed by a CA 02217455 1997-10-02-20-purification by chromatography on silica (eluent: toluene - heptane 6/4 then 8/1) afforded 10.11 g (0.0307 mol) of a pale yellow oil. Elemental microanalysis C% H% N% calculated 77, 07 4, 82 4,13trouvé 76.58 4.59 4.25 Example 2: 5- (4-fluorobenzyl) -7- (3-nitrophenyl) benzo [b] furan steps A and B are identical to stages A and B of example 1. Step C: 5- (4-fluorobenzyl) -7-methoxybenzo [b] Furan1 o the expected product is obtained according to the method described in example 1, replacing austade C benzyl bromide by 4-fluorobenzyl bromide. Point, scattering: 76-78 ° C The Steps D, E and F are identical to Stages D, E and F of Example 1. Stage D: 5- (4-fluorobenzyl) -7-hydroxybenzo [b] furan Step E: 5- (4-fluorobenzyl) -7-triftuorométhanesulfonyloxybenzo [b] furan stage F: 5- (4-fluorobenzyl) -7- (3-nitro-phenyl) benzo [b] furan elemental microanalysis C% H% N% calculated 72, 62 4, 06 4, 032o found 72 47 4.14 4.11 Example 3 5- (2,6-Dichloro-4-pyridylmethyl) -7- (3-nitrophenyl) benzo [b] furaneLe expected product is obtained according to the method described in example 1, replacing in step C benzyl bromide bromide for 2,6-dichloro-4-pyridylmethyl. CA 02217455 2001-06-08-21- EXAMPLE 4 5- (2-furoyl) -7- (3-nitrophenyl) benzo [b] furan Step A: 5-tributylstannyl-7-methoxybenzo [b] furaneUne solution of 10 g (0.044 mol) of 5-bromo-7-methoxybenzo [b] furan described in step B del'exemple 1, 51.10 g (0.088 mol) of hexabutyldiétain and 2.55 g (0.0022 mol) detétrakistriphénylphosphine palladium (O) in 200 ml of toluene is heated to 100 ° C, sousatmosphère argon for 4 hours. After returning to ambient temperature, the solution was stirred all lanuit with a solution of 80 ml of methanolic potassium fluoride. The mélangehétérogéne is then filtered through Celite *. The methanol is then evaporated and the remaining solutiontoluénique is washed with 100 ml of water and then 100 ml of saturated sodium chlorurel0 solution. The usual treatment of the organic phase which delivers oil estpurifiée by chromatography on silica column, eluent mélangetoluène / heptane (4/6) and yields the expected product as an oil. Step B: 5- (2-Furoyl) -7-methoxybenzo [b] furaneUne solution of 5 g (0.0114 mol) of tin compound described in the preceding stage, 1.49 g (0.0114 mol) 2-furoyl chloride and 0.12 g (0.000134 mol) Detris (dibenzylideneacetone) dipalladium (O) in 50 ml of toluene is heated at 75-80 ° Cpendant lheure 30. After returning to ambient temperature, the solution is filtered CÉLITEpuis washed with 50 ml of water then 50 ml of a saturated solution of sodium chloride. Letraitement usual of the organic phase delivers a oil which was purified by chromatographiesur column of silica using dichloromethane as eluant. Mp 121-123 ° C Step C: 5- (2-Furoyl) -7-hydroxybenzo [b] furaneLe expected product is obtained according to the process described in Stage D of Example 1 from ducomposé of Step . Point, scattering: 140-142 ° C. Stage D: 5- (2-Furoyl) -7-trifluorométhanesulfonyloxybenzo [b] furan Trademark CA 02217455 1997-10-02-22-The product is obtained according to the process described in step E of example 1 from composéobtenu the previous stage. Step E: 5- (2-Furoyl) -7- (3-nitro-phenyl) benzo [b] furaneLe expected product is obtained according to the procedure described in Step F of Example 1 from ducomposé of Step. Melting point: 148-150 ° C Elemental microanalysis C% H% N% calculated 68.47 3.33 4.201 o 68 found 42 3 56 4 48 EXAMPLE 5 7- (3-Nitrophenyl) -5-pentylbenzo [b] furan Step a: 7-Methoxy-5-pentylbenzo [b] furaneSous inert atmosphere and at 0 ° C a solution of 58.2 ml of 9-BBN 0.5 molar estadditionnée dropwise to a solution of 2 04 g (0.029 mol) of pent in 12 mlt 5 tetrahydrofuran. The end of the addition, the ice bath was removed and the solution was stirred pendant3 hours. This solution is then poured dropwise to a solution of 6 g (0.0264 mol) of 5-bromo-7-methoxybenzo [b] furan, 0.65 g (0.000796 mol) palladiumdécrit complex in Step F of example 1, 24 ml of 3 N sodium hydroxide in 84 ml of tetrahydrofuran. Lemélange reaction is heated at 65 ° C for 15 hours. After returning to ambient température20, the solution is diluted with 150 ml of ethyl acetate and washed with water and then with 150 mld'une solution of 0.1 N hydrochloric acid and finally 100 ml of a chloride solution desodium saturated. The usual treatment of the organic phase gives an oil which is purifiéepar chromatography on a silica column using as the eluent toluene / cyclohexane (4/6) .25 Step B: 7-Hydroxy-5-pentylbenzo [b] furan CA 02217455 1997-10-02-23-the expected product is obtained according to the process described in stage D of example 1 from ducomposé of step. Stage C: 5-Pentyl-7-trifluorométhanesulfonyloxybenzo (b] furaneLe product is obtained according to the process described in Step E of Example 1 from the previous stage composéobtenu stage. D: 7- (3-Nitrophenyl) -5 pentylbenzo [b] furaneLe expected product is obtained according to the procedure described in step F of example 1 from ducomposé of step. elemental microanalysis C% H% N calculated% 73 77 6.19 4 74.43 53trouvé 6.28 4.65 EXAMPLES 6 and 7 Example 6: 5-Allyl-7- (3-nitrophenyl) benzo [b] furanets EXAMPLE 7 (E) -7- (3-nitrophenyl) -5- (prop-1 -enyl) benzo [b] furan Step A: 5-Allyl-7-methoxybenzo [b] furaneUne solution of 10 g (0.044 mol) of 5-bromo-7-methoxybenzo [b] furan, 17.5 g (0.053 mol ) of allyltributyltin and 1.02 g (0.00088 mol) of tetrakistriphenylphosphine palladium (O) in 80 ml of dimethylformamide is heated at 90 ° C for 15 hours under an inert atmosphère2o. After returning to ambient temperature, the dimethylformamide was evaporated vacuo. Lamasse reaction is taken up in 200 ml of diethyl ether and washed successively with 100ml of water and 100 ml of saturated sodium chloride solution. The usual treatment of organic laphase gives an oil which is purified by chromatography on a silica column enutilisant as eluent a dichloromethane / heptane (6/4). CA 02217455 1997-10-02-24-Stage B: Mixture of 5-Allyl-7-trifluorométhanesulfonyloxybenzo [b] furan (B1) and (R, S) -5- (2-bromoprop-1-yl) -7 -trifluorométhanesulfonyloxybenzo [b] furan (B2) The mixture of these two compounds is obtenu by successively carrying décritsaux stages processes D and E of Example 1 from the compound described in the preceding stage. The composésB, and B2 are separated by chromatography on a silica column using as eluent unmélange toluene / heptane (2/8) .5-Allyl-7- (3-nitrophenyl) benzo [b] furaneLe expected product is obtained according to the process described in step F of example 1 from ducomposé B ~ obtained in the preceding stage. Elemental microanalysis C% H% N% calculated 72.11 4.69 5,01trouvé 72, 60 4, 93 5, 07 (E) -7- (3-nitrophenyl) -5- (prop-1-enyl) benzo [ b) furaneLe expected product is obtained according to the procedure described in step F of example 1 from ducomposé B2 obtained in the preceding stage. Melting point: 103-105 ° C Elemental microanalysis C% H% N% calculated 72.11 4, 69 5, 72 01trouvé 31 4, 95 4, 99 Example 8: 5-Benzyl-2-hydroxy-3- ( 3-nitrophenyl) benzaldéhydeUn ozone bubbling is performed in a solution of 3.4 g (0.01 mol) of the compound described dansl'exemple 1 in 150 ml of dichloromethane stained with "Sudan Red" at -78 ° C. Ladécoloration (3 hours) means the end of reaction. then added 4.65 g (0.075 mol) dediméthylsulfure and the solution was stirred overnight at room temperature. Estensuite the solution washed with 50 ml of water then 50 ml of saturated sodium chloride solution. CA 02217455 1997-10-02-25 usual processing of the organic phase followed by purification by surcolonne chromatography silica, eluent dichloromethane / heptane (8/2) gave the expected product as an oil colorless. Elemental microanalysis C% H% N% calculated 72.06 4.54 71.17 4.71 4.28 4,20trouvé EXAMPLE 9 5- (4-fluorobenzyl) -2-hydroxy-3- (3-nitrophenyl) benzaldéhydeLe expected product is obtained according to the method described in example 8 from the composédécrit 2.EXEMPLE in example 10: 5- (2,6-Dichloro-4-pyridylmethyl) -2-hydroxy-3- (3-nitrophenyl ) benzaldéhydeLe expected product is obtained according to the process described in example 8 from composédécrit in example 3. example 11 5-benzyl-7- (4-pyridyl) benzo [b) furaneLe expected product is obtained according to the process described in example 1 with the replacement of F 3-nitrophénylborique acid by 4-acid pyridylborique. EXAMPLE 12: 2-Hydroxy-3- (3-nitrophenyl) -5-pentylbenzaldéhydeLe expected product is obtained according to the method described in Example 8 from the composédécrit in Example 5.2o EXAMPLE 13 5-benzyl-7- (3-nitrophenyl) indoleLe expected product is obtained according to the method described in example 1, replacing in step A 5-bromo-2-hydroxy-3-methoxybenzaldehyde with 2-amino-5-bromo-3-methoxybenzaldehyde . Mp I55-157 ° C CA 02217455 1997-10-02-26- Elemental microanalysis C% H% N% calculated 76.81 4.91 8,53trouvé 76, 97 4, 86 8, 38 EXAMPLE 14: 2 -amino-5-benzyl-3- (3-nitrophenyl) benzaldéhydeLe expected product is obtained according to the method described in example 8 from the composédécrit in example 13. eXAMPLE 15: (E) -5-benzyl-2 -hydroxy-3- (3-nitrophenyl) benzaldehyde oximeUne solution of 0.9 g (0.0027 mol) of the compound described in example 8 and 0.2 g (0.0028 mol) of hydroxylamine hydrochloride in 8 ml of pyridine is heated at refluxpendant lheure 30. the solvent is evaporated and the solid is taken up in 30 ml of dichlorométhane.La solution is then washed with 10 ml of a hydrochloric acid solution 0.5 N and 10 bin ' saturated sodium chloride solution. The usual treatment of stage organiquedonne the expected product in solid form. Point, scattering: 143-145 ° C (petroleum ether) .Example 16: (E) -5- (4-fluorobenzyl) -2-hydroxy-3- (3-nitrophenyl) benzaldehyde oximeLe expected product is obtained according to the process described in example 15 from composédécrit in example 9. Point, scattering: 157-159 ° C. (toluene) elemental microanalysis C% H% N calculated% 65 57 4.13 7 65trouvé 65, 35 4.43 7.63 example 17 (E) -2- ~ Iydroxy-3- (3-nitrophenyl) -5-pentylbenzaldéhyde oximeLe expected product is obtained according to the method described in example 15 from composédécrit in example 12. CA 02217455 1997-10-02-27- Point, mp: 106-108 ° C (ethanol-water) example 18 3-Benzyl-6-methoxy-5- (3-nitrophenyl) benzaldéhydeUne solution 0.2 g (0.0006 mol) of the compound described in example 8, 0.26 g (0.0008 mol) cesium carbonate and 0.113 g (0.0009 mol) of dimethyl sulfate in 5 ml of estchauffée acetone at reflux for 1 hour. After returning to room temperature, the solution is evaporated under vacuum filtréeet. The solid is taken up in 10 ml of ethyl ether and the solution is lavéeà water. A usual treatment of the organic phase followed by purification parchromatographie silica column using as eluent mélangedichlorométhane / heptane (7/3) gave the expected product as an oil. Microanalysis élémentaireC% H% N% calculated 72, 61 4, 93 4, 73 03trouvé, 36 S, 56 3, 68 EXAMPLE 19 5-Benzyl-2-hydroxy-3- (3-nitrophenyl) benzaldehyde méthyloximeLe expected product is obtained according to the method described in example 15 by replacing hydroxylamine hydrochloride by lechlorhydrate O-methylhydroxylamine. elemental microanalysis C% H% N calculated% 69 60 5 01 7 73trouvé 70 00 5.12 7 73 EXAMPLE 20 5-benzyl-2-methoxy-3- (3-nitrophenyl) benzaldehyde méthyloximeLe expected product is obtained by the method described in example 19 from composédécrit in example 18. elemental microanalysis C% H% N% calculated 70.20 5.36 70.30 5.51 7.34 7,44trouvé CA 02217455 1997 -10-02-28- EXAMPLE 21 5-Benzyl-2-hydroxy-3- (3-nitrophenyl) benzonitrileUne solution of 0.133 ml (0.00145 mol) of phosphorus oxychloride was added àgoutte wise to a 0 solution of , 5 g (0.00143 mol) of the compound described in example 15 in 0.3 mlde dimethylacetamide and 0.9 ml of acetonitrile. The internal temperature of the reaction medium nedevant in no case exceed 30 ° C during the addition. After half an hour of stirring, lasolution is neutralized with a saturated solution of saturated sodium bicarbonate and diethyl ether extraiteà. The usual treatment of the organic phase followed by unechromatographie on a silica column using as eluent a dichloromethane / ethyl acetate (98/2) gave the expected product as a solid blanc.1o Melting point: 148- 149 ° C (petroleum ether) elemental microanalysis C% H% N% calculated 72.72 4.27 72.41 4.37 8.31 8,48trouvé ~ 5 EXAMPLE 22 5-Benzyl-2-methoxy-3- (3-nitrophenyl) benzonitrileLe expected product is obtained according to the method described in example 18 from composéobtenu in example 21. eXAMPLE 23 N-oxide of [5- (4-fluorobenzyl) -2-hydroxy-3 - (3-nitrophenyl) benzylidene) -methylamine, chlorhydrate2o a hot solution of 3 ml of ethanol containing 0.1 g (0.000284 mol) of the compound décritdans example 9 and a few grains of molecular sieves, is added in once 0.024 g (0.000284 mol) of N-methylhydroxylamine. The solution is then brought àreflux for 5 hours. After removing the solvent under reduced pressure, the crude mélangeréactionnel is deposited on a silica column using as eluent a mélange25 dichloromethane / ethyl acetate (9/1) and yields the expected product in the base form thata converted into the corresponding hydrochloride . Point, union: 92-95 ° C (ethyl ether) CA 02217455 1997-10-02-29-Example 24: 5- (4-fluorobenzyl) -3- (3-nitrophenyl) -2-hydroxybenzoate Stage A : 5- (4-tluorobenzyl) -3- (3-nitrophenyl) -2-hydroxybenzoïqueA a solution of 0.2 g (0.00057 mol) of the compound described in example 9 in 6.5 ml is added dedioxane 0.267 g (0.00222 mol) of sodium hydrogen phosphate and 0.082 g (0.000837 mol) of sulfamic acid dissolved in 2.2 ml of water. The reaction mixture estrefroidi at 10 ° C, then a solution of 0.067 g (0.00074 mol) of sodium chlorite dissolved dans0,3 ml of water is added dropwise over 20 minutes. The solution was kept to 10 ° C for 1 hour then slowly warmed to room temperature. After 2 hours, 0.0848 g (0.00067 mol) of sodium sulfite is added at once ett ol stirring is continued for 15 minutes. Of 1N hydrochloric acid is added until àobtention pH = 2. The dioxane is then evaporated under reduced pressure and the solutionaqueuse is left in the refrigerator for 15 hours. The solid, filtered and dried under vacuum, yielding the expected product. Melting point: 210-212 ° C (toluene) Step B: 5- (4-fluorobenzyl) -3- (3-nitrophenyl) -2-hydroxybenzoate méthyleA a solution of 0.0005 mol of compound described in the preceding stage in a mixture of 1 mlde methanol and 4 ml of benzene is added dropwise 0.00081 mol detriméthylsilyldiazométhane. After stirring for 30 minutes the solvents were evaporated pourconduire the expected compound. Microana elementary ~ C% H% N% calculated 66.14 4, 23 3, 67 67trouvé 03 4, 35 3, 88 EXAMPLE 25: 2-furanylcarbonyl [7- (3-nitrophenyl) benzo [b] furan 5-yl] methanone-oximeLe expected product is obtained according to the process described in example 15 from composédécrit in example 4. Point Zion 223-225 ° C CA 02217455 1997-10-02-30- Microanalysis elemental C% H% N% calculated 65, 52 3, 47 8, 04trouvé 65,19 3 66 7 94 Example 26: 7- (3-acetylaminophenyl) -5- (4-fluoro-benzyl) -benzo [b] furaneLe product expected is obtained according to the method described in example 2, replacing in step F 3-nitrophénylborique acid with 3-acétylaminophénylborique acid eXAMPLE 27 5- (4-fluorobenzyl) -7- (3-trifluoromethyl-phenyl) -benzo [ b] furaneLe expected product is obtained according to the method described in example 2 by replacing the stade1 o F 3-nitrophénylborique acid with 3-trifluorométhylphénylborique acid. EXAMPLE 28 5- (4-fluorobenzyl) -7- (3,5-ditrifluorométhylphényl) benzo [b] furaneLe expected product is obtained according to the method described in Example 2 by replacing the 3-stadeF nitrophénylborique acid by '3,5-di (trifluoromethyl) phenylboronic. EXAMPLE 29 7- (3-nitrophenyl) -5- (2-thenoyl) -benzo [b] Furan1 S The expected product is obtained according to the method described in Example 4, replacing in Step B the 2-furoyl chloride by chloride, 2-thenoyl. EXAMPLE 30 5-Benzyl-1-methyl-7- (3-nitrophenyl) indoleLe expected product is obtained according to the method described in Example 18 from composédécrit in Example 13.20 Elemental microanalysis C% H% N% calculated 77.17 5 77.21 5.47 7.97 30 8,18trouvé CA 02217455 1997-10-02-31-Example 31. 3- (3,5-Ditrifluorométhylphényl) -5- (4-fluorobenzyl) -2-hydroxybenzal-déhydeLe expected product is obtained according to the method described in Example 8 from the composédécrit 28.EXEMPLE in Example 32: 3 - (3,5-Ditrifluorométhylphényl) -5- (4-fluorobenzyl) -2-aldehyde-hydroxybenzal oximeLe expected product is obtained according to the method described in example 15 from composédécrit in example 31. elemental microanalysis C% H% N% calculated 57, 78 3 09 3 06trouvé 58, 76 3, 75 3, 08EXEMPLE 33: 7- (3-nitrophenyl) -5- (4-pyridylmethyl) benzo [b] furan, chlorhydrateLe expected product is obtained according to the method described in example 1, replacing in step 5 ~ C benzyl bromide per bromide 4-pyridylméthyle.Le corresponding hydrochloride is obtained by the action of a titrated solution of acidechlorhydrique in ethanol . Melting point: 74-78 ° C Microanalysis élémentaire2o C% H% Cl% N% calculated 65.49 4.12 9.67 65.06 4.63 10.03 7.40 7,64trouvé EXAMPLE 34: 2-Hydroxy -3- (3-nitrophenyl) -5- (4-pyridylmethyl) benzaldéhydeLe expected product is obtained according to the process described in example 8 from composé25 described in example 33. CA 02217455 1997-10-02-32 -Example 35: 2-Hydroxy-3- (3-nitrophenyl) -5- (4-pyridylmethyl) benzaldehyde oxime, chlorhydrateLe expected product is obtained according to the method described in example 15 from composédécrit in example 34. the corresponding hydrochloride is obtained by the action of hydrochloric acid in ethanol solutiontitrée. Melting point: 218-220 ° C Elemental Microanal ~ e C% H% N% Cl% calculated 58.05 4.16 10.69 found 57.27 4.19 10,821o 10.34 10.42 EXAMPLE 36: 2 -hydroxy-3- (3-nitrophenyl) -5- (4-pyridylmethyl) benzonitrileIx expected product is obtained according to the process described in (example 21 from composédécrit in example 35. usion Point: 225 ° C elemental Microanalysis C% H% N% calculated 68, 88 3, 95 12, 68trouvé 67.99 4.27 12.27 Example 37: 5- (4-fluorobenzyl) -2-methoxy-3- (3-nitrophenyl) benzaldehyde The oxime2o the expected product is obtained according to the process described in example 18 from composédécrit in example 16. elemental microanalysis C% H% N% calculated 66.31 4.50 7,36trouvé 65 55 4 60 7,15EXEMPLE 38: 2, N-dihydroxy-3'-nitro-5- (4-pyridylmethyl) biphenyl-3-carboxamidine CA 02217455 1997-10-02-33-to a solution of 0.0012 mol of the compound described in example 36 and 8 ml of ethanol estajoutée a solution of 0.0024 mol of hydroxylamine hydrochloride in 1.5 ml of water. Lemilieu reaction is heated at 75 ° C for 72 heures.Après cooling and concentration, the residue was purified desilice by gel chromatography using as eluent a dichloromethane / tetrahydrofuran 8/2, pourconduire the expected compound. Scattering point: 185-186 ° C Elemental microanalysis C% H% N% calculated 62.63 4.43 1o 15,38trouvé 63, 74 5, 06 I5, 73 Example 39: N-Methyl-5- (4-fluorobenzyl ) -2-hydroxy-3- (3-nitrophenyl) benzamideA a 10 mmol solution of the compound described in (example 24, step a in 30 ml dedichlorométhane are added 15 mmol of thionyl chloride at 0 ° C. After 1 hour of stirring, 25 mmol of methylamine are added, and the reaction medium estchauffé at reflux for 3 hours, cooled and concentrated. the residue is taken up in a mélangeeau / dichloromethane and the organic phase is dried and concentrated to yield aucomposé expected. Microanalysis élémentaire2o C% H% N% calculated 66.31 4.50 7,36trouvé 66 97 4 93 7.19 Example 40: 5- (4-fluorobenzyl) -2-hydroxy-3- (3-nitrophenyl) benzohydroxamiqueIx the expected product is obtained according to the process described in example 39 by replacing laméthylamine hydroxylamine. elemental microanalysis C% H% N calculated% 62 83 3 95 7 60.62 3.89 6.90 found 333o CA 02217455 1997 -10-02-34-Example 41. N- (2-chloroethyl) -5- (4-fluorobenzyl) -3- (3-nitrophenyl) -2-hydroxy-benzamideLe expected product is obtained according to the process described in (Example 39 by replacing laméthylamine by ethanolamine in the presence of thionyl chloride elemental microanalysis C% H% N% calculated 61.62 4.23% Hal 8,27trouvé 6.53 62.04 4.62 6.25 8.85 EXAMPLE 42. 5 - [(2-Chloro- 4-pyridyl) carbonyl] -7- (3-nitrophenyl) benzo [b] furaneLe expected product is obtained according to the method described in example 4 by replacing at stadeB chloride, 2-fuoryle by chloride, 2-chloroisonicotinoyle. elemental microanalysis C% H% N% Cl% calculated 63.42 2.93 7.40 63.53 2.96 7.42 9,36trouv 9,39EXEMPLE 43: 5 - [(2-Chloro-4-pyridyl) hydroxymethyl ] -7- (3-rutrophényl) benzo [b] furaneA a solution of 0.00061 mol of the compound described in example 42 in 6 ml detétrahydrofurane was added 0.0061 mol of sodium borohydride. After 15 minutes, 32o ml of 1N hydrochloric acid solution are added dropwise. the mixture estensuite diluted in ethyl ether and extracted, and the organic phase is dried and concentrated. Lerésidu obtained is purified by chromatography on silica gel using as eluent unmélange dichloromethane / ethyl acetate 95/5 to yield the expected compound. Melting point: 178-180 ° C Elemental microanalysis C% H% N% Cl% calculated 63.09 3.44 7.36 9,31trouvé 63, March 28 80 7 8 OS, 62 CA 02217455 1997-10- 02-35- example 44: 7- (3-nitrophenyl) -5 - [(2-thienyl) hydroxymethyl] benzo [b] furaneLe expected product is obtained according to the method described in example 43 from composédécrit in the example 29. Microanalysis élémentaireC% H% N% S% calculated 64, 95 3, 73 3, 99 9,13trouvé 65, 60 3, 88 3, 94 8, 84 eXAMPLE 45: 7- (3-nitrophenyl) -5- (2-thienylmethyl) benzo [b] furaneLe expected product is obtained according to the method described in example 1, replacing the stadet 0 C benzyl bromide by 2-chloromethylthiophene. elemental microanalysis C% H% N% S% calculated 68.04 3.91 4.18 68.47 4.20 4.26 9,56trouvé 9,26t5 EXAMPLE 46: 7- (3-nitrophenyl) -5- (4 -pyridylvinyl) benzo [b] furan, chlorhydrateLe expected product is obtained according to the method described in example 7 by replacing at stadeA, palladium tetrakistriphenylphosphine palladium (II) acetate, and fallytributylétainpar 4-vinylpyridine. The corresponding hydrochloride is obtained by reacting a hydrochloric acid solutiontitrée in féthanol.20 Melting point:> 250 ° C Elemental microanalysis C% H% Cl% N% calculated 66, 58 3, 99 9, 36 7, 39trouvé 66.16 4.24 8.97 7.2725 Example 47: 2-Iodo-6- (3-nitrophenyl) -4- (4-pyridylmethyl) phenol Step A: 2-Bromo-4- (4-pyridylmethyl) aniline CA 02217455 2001-06-08-36- a solution of 18.34 g (0.103 mol) of N-bromosuccinimide in 60 ml dediméthylformamide is added drop by drop, away from light, in a solution of 20g (0 , 1084 mol) of 4- (4-pyridylmethyl) aniline in 180 ml of dimethylformamide. After 1 hour, the solvent was evaporated under reduced pressure and the solid is taken up in 200 ml dedichlorométhane. The solution is then washed with 100 ml of water and 100 ml of a saturated sodium dechlorinate. After the usual treatment of the organic phase, oil estreprise with 500 ml of diethyl ether and the whole is left to réfrigéateur for 2 days. After filtration, the expected product is obtained. Mp 102-104 ° C Step B: 2- (3-Nitrophenyl) -4- (4-pyridylmethyl) anilineUne solution of 25 g (0.095 mol) of the compound described in the preceding stage, 23.8 g (0, 1426 mol) of 3-nitrophénylborique acid, 26.3 g (0.19 mol) of potassium carbonate and 3.9 g (0.00475 mol) of palladium complex in 320 ml of dimethylformamide is heated A80 ° C under an inert atmosphere for 16 hours. After returning to ambient temperature, is diluted with lasolution 200 ml of dimethylformamide is then filtered through Celite. Estévaporé the filtrate under reduced pressure and then taken up in 300 ml of ethyl acetate. A traitementhabituel of the organic layer followed by chromatographic purification desilice (eluent: dichloromethane - methanol 97/3) provides the title product. Point of. usion: 133-135 ° C2o Stage C: 2- (3-Nitrophenyl) -4- (4-pyridylmethyl) phénolUne solution of 13.7 g (0.045 mol) of the compound described in previous stage and 47 ml to acidesulfurique 35% is cooled to 0 ° C. The pyridinium sulphate is diluted with 50 ml of eauet maintained at 0 ° C. Then is added dropwise below the surface, a solution of 4,06g (0.058 mol) sodium nitrite and 50 ml of water while maintaining the temperature below + 5 ° C in the reactor. After 15 minutes of stirring at 0 ° C, the diazonium salt solution estajouttée dropwise to a boiling solution of 25 ml of 35% sulfuric acid (latempérature the reaction medium must always be above 70 ° C). When additionest completed, the boiling solution was poured into 80 ml of a solution of ammoniaqueconcentrée (28%) ice. The basic aqueous phase is extracted with dichloromethane containing5% methanol. A usual treatment of the organic phase followed by purification by CA 02217455 1997-10-02-37 chromatography on silica (eluent: dichloromethane - methanol: 95/5) permetd'obtenir the expected product. Melting point: 122-124 ° C Step D: 2-Iodo-6- (3-nitrophenyl) -4- (4-pyridylmethyl) phénolA a solution of 0.026 mol of the compound described in the preceding stage in 675 ml of a mixture
2/1 dichloromethane - methanol was added, at one time, 0.0654 mol of sodium bicarbonatede then 0.03 mol benzyltrimethylammonium dichloroiodate. After 2 hours lemélange is filtered and evaporated. The solid is taken up in 100 ml of dichloromethane and washed par2 times 50 ml of a sodium bicarbonate solution 5%. The usual treatment for phaseorganique followed by purification by chromatography on silica gel, provides leproduit title. Melting point: 168-170 ° C Elemental microanalysis C% H% N% I% calculated 50.02 3.03 6.48 29,36trouvé 49, 64 3, 32 6, 22 28, 94 Example 48: 2-Hydroxy -3- (3-nitrophenyl) -5- (4-pyridylmethyl) acetophenone, chlorhydrateUne solution of 0.0046 mol of compound described in example 47, 0.009 mol of tributyltin éthoxyvinyl2o, 0.028 mol of lithium chloride and 0, 0005 mol of tetrakistriphenylphosphine palladium (0) in 40 ml of tetrahydrofuran is heated at 65 ° C for 76 hours. Aprèsrefroidissement, the mixture is diluted with ethyl acetate. The organic phase is dried, concentrated and purified using as eluent dichloromethane / acétated'éthyle, 7/3 to yield the expected compound. The corresponding hydrochloride is obtained paraction a solution of hydrochloric acid in ethanol. Mp 219-221 ° C elemental microanalysis C% H% N% Cl% calculated 62.42 4.45 7.28 61.93 4.30 7.05 9.19 9,21trouvé CA 02217455 1997-10- 02-38-example 49: 2-Hydroxy-3- (3-nitrophenyl) -5- (4-pyridylmethyl) acetophenone oximeLe expected product is obtained according to the method described in example 15 from composédécrit in example 48 . melting point: 209-211 ° C elemental microanalysis C% H% N% calculated 66.11 4.72 66.15 11,56trouvé 5, March 10 89 EXAMPLE 50: 7- (3-Chlorophenyl) -5- (4-pyridylmethyl) benzo [b] furane1o the expected product is obtained according to the method described in example 33 with the replacement of
3-nitrophénylborique with 3-chlorophenylboronic acid. EXAMPLE 51: 3- (3-Chlorophenyl) -2-hydroxy-5- (4-pyridylmethyl) benzaldéhydeLe expected product is obtained according to the method described in Example 8 from the composédécrit 50.t in Example 5 EXAMPLE 52 : 3- (3-Chlorophenyl) -2-hydroxy-5- (4-pyridylmethyl) benzaldehyde oximeLe expected product is obtained according to the method described in example 15 from composédécrit in example 51. melting point: 124 -125 ° C élémentaire2o microanalysis C% H% Cl% N% calculated 60.81 4.30 9.45 61.39 4.60 9.67 7.36 7,47trouvé Example 53: 5-Benzyl-2-hydroxy 3- (3-nitrophenyl) benzaldehyde hydrazoneUne solution of 0.006 mol of the compound described in example 8 and 0.012 mol of hydrazine25 in 20 ml of toluene is refluxed for 30 minutes. After cooling, leproduit expected that precipitates is filtered and dried. CA 02217455 1997-10-02-39- elemental microanalysis C% H% N% calculated 69, IS 4, 93 12,10trouvé 69.45 5.16 11.64 Example 54: 7- (3-Nitrophenyl) -5 (4-pyridylthio) benzo [b] furan step A: 7-Methoxy-5- (4-pyridylthio) benzo [b] furaneUne solution of 0.044 mol of the compound described in example 1, step B, 0.046 mol of 4- mercaptopyridine, 0.088 mol of sodium tert-butoxide and 0.0017 mol detétrakistriphénylphosphine palladium (0) in 180 ml of n-butanol is heated at 105 ° C1 o for 6 hours. After cooling, the reaction mixture was concentrated, and the residue estpurifié by chromatography on silica gel using as eluent a mélangedichlorométhane / ethyl acetate, 8/2, to yield the expected compound. Defusion Point: 81-83 ° C Step B: 7-Hydroxy-5- (4-pyridylthio) benzo [b] furan ~ 5 The expected product is obtained according to the process described in Example 1, Step D, from ducomposé described in the previous stage. Melting point: 154-156 ° C Step C: 5- (4-pyridylthio) -7-trifluorométhanesulfonyloxybenzo [b] furaneLe expected product is obtained according to the method described in Example 1, Step E, starting from the compound described in du2o previous stage. Stage D: 7- (3-nitrophenyl) -5- (4-pyridylthio) benzo [b] furaneLe expected product is obtained according to the process described in Example 1, Step F, from ducomposé described in the previous stage. Melting point: 135-137 ° C CA 02217455 1997-10-02-40-elemental microanalysis C% H% N% Cl% calculated 65.51 3.47 8.04 9,20trouvé 65, 68 3, 63 7, 90 8 75 Example 55: 4-Benzyl-2- (but-1-enyl) -6- (3-nitrophenyl) phénolA a 0.014 mol solution of n-propyltriphenylphosphonium detetrahydrofurane in 25 ml is added dropwise to 4 ° C, a solution of 9 ml of n-butyllithium1,6 M in hexane. After 30 minutes at 4 ° C, then 30 minutes at 20 ° C, a compound of 0,0048mol solution described in Example 8 in 5 ml of tetrahydrofuran is added dropwise goutteto. The reaction mixture is then acidified with 15 ml of a 1N solution acidechlorhydrique, diluted with ether and extracted. The organic phase is concentrated and purifiéepar chromatography on silica gel using as eluent a dichloromethane / heptane 6/4 to yield the expected compound. Elemental microanalysis C% H% N% calculated 76.86 5.89 3,90trouvé 76, 53 6, 06 3, 91En using the method described in Example 55 and replacing the bromide npropyltriphénylphosphonium by corresponding triphenylphosphonium halide , onobtient the compounds of examples 56 and 57.EXEMPLE 56: 4-Benzyl-2- (2-méthoxyvinyl) -6- (3-nitrophenyl) phenol elemental microanalysis C% H% N% calculated 73.12 5 30 3, 88trouvé 73 31 5.14 4 40 Example 57: 4-Benzyl-2- (2-méthylthiovinyl) -6- (3-nitrophenyl) phenol CA 02217455 1997-10-02-41 - elemental microanalysis C% H% N % S% calculated 70.01 5.07 3.71 8,49trouvé 69 86 5.14 3 70 8,13En using the methods described above, the following compounds were obtained Example 58: 2- (2-Méthoxyvinyl) - 6- (3-nitrophenyl) -5- (4-pyridylmethyl) phenol Example 59: 7- (3-nitrophenyl) -5- (4-pyridylmethyl) benzo [b] thiophèneEXEMPLE 60: 2-Mercapto-3- (3- nitrophenyl) -5- (4-pyridylmethyl) benzaldehyde oximeEXEMPLE 61: 2-Methylthio-3- (3-nitrophenyl) -5- (4-pyridylmethyl) benzaldehyde oxime Example 62: 5- (1X 2-imidazolylmethyl) -7- ( 3-nitrophenyl) benzo [b] furan EXAMPLE 63: 2-Hydroxy-5- (1H 2-imidazolylmethyl) -3- (3-nitrophenyl) benzaldehyde oximeEXEMPLE 64: 5 - [(1-methyl-2-imidazolyl) methyl] -7- (3-nitrophenyl) benzo [b] furan EXAMPLE 65: 2-Hydroxy-5 - [(1-methyl-2-imidazolyl) methyl] -3- (3-t 5-nitrophenyl) benzaldehyde oximeEXEMPLE 66: 5- [(1-methyl-5-imidazolyl) methyl] -7- (3-nitrophenyl) benzo [b] furan EXAMPLE 67: 2-Hydroxy-5 - [(1-methyl-5-imidazolyl) methyl] -3- ( 3-nitrophenyl) benzaldehyde oximeEXEMPLE 68: 5 - [(1-methyl-4-imidazolyl) methyl] -7- (3-nitrophenyl) benzo [b] furane2o EXAMPLE 69: 2-Hydroxy-5 - [(1-methyl- 4-imidazolyl) methyl] -3- (3-nitrophenyl) benzaldehyde oxime CA 02217455 1997-10-02-42- EXAMPLE 70: 7- (3-nitrophenyl) -5- (IH-3-pyrazolylmethyl) benzo [b] furaneEXEMPLE 71: 2-Hydroxy-3- (3-nitrophenyl) -5- (IH-3-pyrazolylmethyl) benzaldéhydeoxime EXAMPLE 72: 5 - [(2-methyl-3-pyrazolyl) methyl] -7- (3-nitrophenyl) benzo [b] furans EXAMPLE 73: 2-Hydroxy-5 - [(2-methyl-3-pyrazolyl) methyl) -3- (3-nitrophenyl) benzaldehyde oxime EXAMPLE 74: 7- (3-nitrophenyl) -5- ( 2-quinolylmethyl) benzo [b] furaneEXEMPLE 75: 2-Hydroxy-3- (3-nitrophenyl) -5- (2-quinolylmethyl) benzaldehyde oxime EXAMPLE 76: 7- (3-nitrophenyl) -5- (3-quinolylmethyl) benzo [b] furaneEXEMPLE 77: 2-Hydroxy-3- (3-nitrophenyl) -5- (3-quinolylmethyl) benzaldehyde oxime EXAMPLE 78: 7- (3-nitrophenyl) -5- (2-pyrazinylméthyl) benzo [b] furan EXAMPLE 79: 2-Hydroxy-3- (3-nitrophenyl) -5- (2-pyrazinylméthyl) benzaldéhydeoxime EXAMPLE 80: 7- (4-Pyridyl) -5- (4-pyridylmethyl) benzo [b] furane15 EXAMPLE 81: 2-Hydroxy-3- (4-pyridyl) -5- (4-pyridylmethyl) benzaldehyde oxime EXAMPLE 82: 7- (3-pyridyl) -5- (4-pyridylmethyl) benzo [b] furan EXAMPLE 83: 2-Hydroxy -3- (3-pyridyl) -5- (4-pyridylmethyl) benzaldehyde oxime EXAMPLE 84: 7- (2-pyridyl) -5- (4-pyridylmethyl) benzo [b] furan CA 02217455 1997-10-02- 43 - Example 85: 2-Hydroxy-3- (2-pyridyl) -5- (4-pyridylmethyl) benzaldehyde oxime EXAMPLE 86: 7- (3-nitrophenyl) -5- (3-pyridylmethyl) benzo [b) furaneEXEMPLE 87: 2-Hydroxy-3- (3-nitrophenyl) -5- (3-pyridylmethyl) benzaldehyde oxime EXAMPLE 88: 7- (3-nitrophenyl) -5- (2-pyridylmethyl) benzo [b] furaneEXEMPLE 89: 2-Hydroxy- 3- (3-nitrophenyl) -5- (2-pyridylmethyl) benzaldehyde oxime EXAMPLE 90: 7- (3-nitrophenyl) -5- [2- (4-pyridyl) ethyl] benzo [b) furan EXAMPLE 91: 2- hydroxy-3- (3-nitrophenyl) -5- [2- (4-pyridyl) ethyl] benzaldéhydeoxime EXAMPLE 92: 7- (3-nitrophenyl) -5-phénoxybenzo [b] furanet o EXAMPLE 93: 2-hydroxy-3 - (3-nitrophenyl) -5-phenoxybenzaldehyde oxime EXAMPLE 94: 7- (3-nitrophenyl) -5- (4-pyridyloxy) benzo [b] furan EXAMPLE 95: 2-Hydroxy-3- (3-nitrophenyl) -5 - (4-pyridyloxy) benzaldehyde oxime EXAMPLE 96: 2-acetylamino-4-benzyl-6- (3-nitrophenyl) phenol Example 97: 4-benzyl-2-formamido-6- (3-nitrophenyl) phénolt 5 EXAMPLE 98: 2-acetylamino-4- (4-pyridylmethyl) -6- (3-nitrophenyl) phenol Example 99: 2-formamido-4- (4-pyridylmethyl) -6- (3-nitrophenyl) phenol Example 100: N-Methyl- 5-benzyl-2-hydroxy-3- (3-nitrophenyl) benzaldéhydehydrazone melting point: 154-156 ° C CA 02217455 2001-06-08-44 Study PHARMACOLOGY ~ iaue derivatives of the invention Example 101: Measurement of activity PDELes U937 cells are cultured in a culture medium (RPMI) containing 10% fetal calf sérumde. Briefly, the cells are lysed and then centrifuged (100,000 g, 60 min, 4 ° C) and the supernatant is recovered for HPLC separation PDE différentesformes (C. LUGNIER VB and Schini, Biochem. Pharmacol. Vol. 39, p. 75-84.1990). The PDE activity is measured by the appearance of [3H] 5'-AMP resulting from the hydrolysis of [3H] cyclic AMP. PDE and the [3H] cyclic AMP (1 ~ Ci / mL) were incubated 30 minutes a30 ° C. Radioactivity is measured using a scintillation counter liquide1o (* Beckman LS 1701). PDE IV is characterized par- hydrolysis of cyclic AMP, - the absence of inhibition by cyclic GMP of the hydrolysis of cyclic AMP, - inhibition by rolipram molecule compounds référence.Les are studied at two concentrations (10 and 10-'M-MS) in duplicate. The résultatssont expressed as% inhibition of phosphodiesterase activity. Best composésde said invention exhibit inhibition at 10- ~ M equal to or greater than 80%. EXAMPLE 102 Pharmaceutical Composition Preparation formula for 1000 tablets each containing 100 mg2o Example compound ............................. 15 .................................................. ............. 10 gHydroxypropylcellulose ................................... .................................................. ............ 2 of gAmidon 10 gLactose 100 of gStéarate 3 gTalc 3 g Trademark
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| HU9701605D0 | Hungary | D0 | |
| NZ328900A | New Zealand | A | |
| CA2217455A1 | Canada | A1 | |
| NO974586L | Norway | L | |
| EP0834508A1 | European Patent Office (EPO) | A1 | |
| AU3992797A | Australia | A | |
| FR2754260A1 | France | A1 | |
| PL322419A1 | Poland | A1 | |
| ZA978878B | South Africa | B | |
| JPH10114724A | Japan | A | |
| HU9701605A2 | Hungary | A2 | |
| HUP9701605A2 | Hungary | A2 | |
| HU9701605A3 | Hungary | A3 | |
| HUP9701605A3 | Hungary | A3 | |
| BR9704970A | Brazil | A | |
| FR2754260B1 | France | B1 | |
| US5877190A | United States of America | A | |
| AU728329B2 | Australia | B2 | |
| NO309377B1 | Norway | B1 | |
| EP0834508B1 | European Patent Office (EPO) | B1 | |
| AT204269T | Austria | T | |
| ATE204269T1 | Austria | T1 | |
| DE69706112D1 | Germany | D1 | |
| DK0834508T3 | Denmark | T3 | |
| PT834508E | Portugal | E | |
| ES2162668T3 | Spain | T3 | |
| GR3037042T3 | Greece | T3 | |
| DE69706112T2 | Germany | T2 | |
| CA2217455CThis record | Canada | C |
2 legal events, as the office reported them to INPADOC
Over the term
Point at a mark for the eventEvents
| Event | Code | |
|---|---|---|
| LapsedLapsedMKLA | MKLA | |
| Examination requestEEER | EEER |
Numbers
- Publication
- 2217455
- Publication, DOCDB
- 2217455
- Publication, EPODOC
- CA2217455
- Application
- 2217455
- Application, DOCDB
- 2217455
- Application, EPODOC
- CA19972217455
Titles2
- English
- NEW SUBSTITUTED DERIVATIVES, OF BIPHENYL OR PHENYLPIRIDINE, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM
- French
- NOUVEAUX DERIVES SUBSTITUES, DE BIPHENYLE OU DE PHENYLPIRIDINE, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT
Classification
- CPC, 26
- C07D307/79
- C07C45/71
- C07C47/57
- C07C47/575
- C07C205/20
- C07C205/44
- C07C205/60
- C07C235/60
- C07C251/48
- C07C251/86
- C07C255/53
- C07C259/10
- C07D209/08
- C07D213/50
- C07D405/04
- C07D405/06
- C07D405/12
- C07D409/06
- A61P11/00
- A61P11/08
- A61P25/00
- A61P27/16
- A61P29/00
- A61P37/00
- A61P37/08
- A61P43/00
- IPC, 80
- C07D405 00
- A61K31 11
- A61K31 15
- A61K31 16
- A61K31 34
- A61K31 38
- A61K31 395
- C07C45 71
- C07C47 57
- C07C47 575
- C07C205 20
- C07C205 44
- C07C205 60
- C07C233 25
- C07C235 60
- C07C251 48
- C07C251 86
- C07C255 53
- C07C259 10
- C07D209 08
- C07D213 50
- C07D213 53
- C07D213 56
- C07D215 14
- C07D231 12
- C07D233 64
- C07D241 12
- C07D307 79
- C07D333 54
- C07D405 04
- C07D405 06
- C07D405 12
- C07D407 04
- C07D409 02
- C07D409 06
- A61K31 05
- A61K31 135
- A61K31 165
- A61K31 275
- A61K31 343
- A61K31 40
- A61K31 403
- A61K31 404
- A61K31 415
- A61K31 44
- A61K31 443
- A61K31 4433
- A61K31 47
- A61K31 495
- A61P11 00
- A61P11 08
- A61P25 00
- A61P27 16
- A61P29 00
- A61P37 00
- A61P37 08
- A61P43 00
- C07C43 20
- C07C47 546
- C07C49 798
- C07C49 84
- C07C49 86
- C07C65 21
- C07C67 14
- C07C69 157
- C07C69 24
- C07C69 28
- C07C69 75
- C07C201 12
- C07C217 82
- C07C235 44
- C07C251 54
- C07C255 54
- C07C255 58
- C07C257 18
- C07C323 31
- C07D213 06
- C07D215 12
- C07D405 14
- C07D409 04