CH637112A5 - BENZYLIDENIC DERIVATIVES. - Google Patents
BENZYLIDENIC DERIVATIVES. Download PDFInfo
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- CH637112A5 CH637112A5 CH188579A CH188579A CH637112A5 CH 637112 A5 CH637112 A5 CH 637112A5 CH 188579 A CH188579 A CH 188579A CH 188579 A CH188579 A CH 188579A CH 637112 A5 CH637112 A5 CH 637112A5
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- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
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- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
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Description
25 La présente invention concerne des dérivés benzylidéniques, leur préparation et leur application en thérapeutique. The present invention relates to benzylidenic derivatives, their preparation and their therapeutic use.
Dans son brevet suisse N° 616148, la titulaire a décrit les composés répondant à la formule: In its Swiss patent N ° 616148, the licensee described the compounds corresponding to the formula:
jOH jOH
30 .. 30 ..
C = N-CH.-COR n 2n dans laquelle C = N-CH.-COR n 2n in which
Xls X2 et X3, qui sont identiques ou différents, représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène, notamment le chlore ou le fluor, ou bien un radical 40 méthyle ou méthoxyle, Xls X2 and X3, which are identical or different, each represent, independently of one another, a hydrogen or halogen atom, in particular chlorine or fluorine, or else a methyl or methoxyl radical,
n représente un nombre entier au moins égal à 1 et au plus égal à 10, et n represents an integer at least equal to 1 and at most equal to 10, and
R représente un radical hydroxyle, OM, NH2, NH(CH2)3-COOH, -NH(CH2)3-COOM (M représentant un 45 atome de métal alcalin, en particulier le sodium), NH (CH2)3—COOC2Hs, NH-cycloalkyle, NH-phényle, NH—benzyle (le radical benzyle pouvant porter un substituant choisi parmi les atomes d'halogène et le radical trifluorométhyle) NH—alkyle, N—(alkyl)2, N-(alkyl)(benzyl), les radicaux alkyles liso néaires ou ramifiés ayant de 1 à 4 atomes de carbone, les radicaux cycloalkyles ayant de 3 à 6 atomes de carbone, R represents a hydroxyl radical, OM, NH2, NH (CH2) 3-COOH, -NH (CH2) 3-COOM (M representing an atom of an alkali metal, in particular sodium), NH (CH2) 3 — COOC2Hs, NH-cycloalkyl, NH-phenyl, NH-benzyl (the benzyl radical possibly carrying a substituent chosen from halogen atoms and the trifluoromethyl radical) NH-alkyl, N— (alkyl) 2, N- (alkyl) (benzyl) , the linear or branched liso alkyl radicals having from 1 to 4 carbon atoms, the cycloalkyl radicals having from 3 to 6 carbon atoms,
à l'exception du composé pour lequel Xj = X3 = H, X2 = 5—Cl, n=l et R=OH. with the exception of the compound for which Xj = X3 = H, X2 = 5 — Cl, n = 1 and R = OH.
Les composés du présent brevet répondent à la formule: The compounds of this patent correspond to the formula:
55 55
X X
60 60
C H -CO-R n 2n C H -CO-R n 2n
(I) (I)
6. Procédé de préparation des composés de formule I selon la revendication 1, pour lesquels R' représente un alkyle en Cj-Cj, caractérisé en ce qu'on prépare par le procédé selon la revendication 4 les composés pour lesquels R' représente l'hydrogène et qu'on soumet les composés obtenus à une alkylation au moyen d'un agent capable de céder un alkyle en Q-C4. 6. Process for the preparation of the compounds of formula I according to claim 1, for which R 'represents a Cj-Cj alkyl, characterized in that the compounds for which R' represents the hydrogen and the compounds obtained are subjected to alkylation by means of an agent capable of yielding a Q-C4 alkyl.
dans laquelle in which
Xj, X2, X3 et X4 représentent chacun, indépendamment l'un de 65 l'autre, un taome d'hydrogène ou d'halogène, un radical CH3, CH30, N02j CF3, C(CH3)3 ou CH3CO NH, Xj, X2, X3 and X4 each represent, independently of one another, a taome of hydrogen or halogen, a radical CH3, CH30, N02j CF3, C (CH3) 3 or CH3CO NH,
n représente un nombre entier allant de 1 à 10, n represents an integer ranging from 1 to 10,
R est un radical OH, OM (M=métal alcalin), NH2, NH—cyclo- R is an OH, OM (M = alkali metal), NH2, NH-cyclo radical
3 3
637 112 637,112
alkyle, NH—phényle, NH —benzyle, NH—alkyle, N—(alkyl)2, N—(alkyl)(benzyl), et alkyl, NH — phenyl, NH —benzyl, NH — alkyl, N— (alkyl) 2, N— (alkyl) (benzyl), and
R' représente un atome d'hydrogène ou un alkyle, les alkyles ayant de 1 à 4 atomes de carbone, à l'exception des composés dans lesquels R' = H lorsque X,, X2 et X3 sont chacun, indépendamment 5 l'un de l'autre, H, Hai, CH3, CH30 et X4 = H et du composé pour lequel R' = H, X! = X3=X4 = H, X2 = Cl - 5, n = 1 et R = OH. R 'represents a hydrogen atom or an alkyl, the alkyls having from 1 to 4 carbon atoms, with the exception of the compounds in which R' = H when X ,, X2 and X3 are each, independently one on the other, H, Hai, CH3, CH30 and X4 = H and of the compound for which R '= H, X! = X3 = X4 = H, X2 = Cl - 5, n = 1 and R = OH.
Les composés exclus ci-dessus de la portée du brevet ont déjà été décrits précédemment. The compounds excluded above from the scope of the patent have already been described previously.
Selon l'invention, on prépare les composés par réaction entre une io cétone de formule: 0h et un composé de formule NH2 — CnH2n—CO — R (III) sous forme de base ou de chlorhydrate et, si on le désire, on alkyle ensuite les composés (I) obtenus dans lesquels R' = H. According to the invention, the compounds are prepared by reaction between a ketone of formula: 0h and a compound of formula NH2 - CnH2n — CO - R (III) in the form of the base or of hydrochloride and, if desired, alkylated then the compounds (I) obtained in which R '= H.
La réaction est effectuée dans un solvant alcoolique tel que le méthanol ou l'éthanol, à une température allant de 10° C à la température d'ébullition du solvant, en présence d'un métal alcalin ou d'un alcoolate de métal alcalin. The reaction is carried out in an alcoholic solvent such as methanol or ethanol, at a temperature ranging from 10 ° C. to the boiling point of the solvent, in the presence of an alkali metal or of an alkali metal alcoholate.
Une variante de préparation des composés I dans lesquels R'=H (II) 15 et R est NH2 consiste à faire réagir une hydroxybenzophénone de formule II avec un composé H2N (CH2)n CN,HC1 (intermédiaire obtenu lors de la préparation du composé III de formule: H2N—(CH2)n—CO—NH2 puis à effectuer une solvolyse du nitrile IV obtenu par condensation, selon le schéma réactionnel suivant: A variant of preparation of the compounds I in which R '= H (II) 15 and R is NH2 consists in reacting a hydroxybenzophenone of formula II with a compound H2N (CH2) n CN, HC1 (intermediate obtained during the preparation of the compound III of formula: H2N— (CH2) n — CO — NH2 then to carry out a solvolysis of the nitrile IV obtained by condensation, according to the following reaction scheme:
+ H2N-(CH2)n-CN, HC1- + H2N- (CH2) n-CN, HC1-
(CH,)CN 2, n (CH,) CN 2, n
(IV) (IV)
,C=iN- (CH2) ii-CO->IH2 , C = iN- (CH2) ii-CO-> IH2
KCl gaz KCl gas
Les composés de départ III et leur préparation sont déjà décrits dans la littérature. The starting compounds III and their preparation are already described in the literature.
Les cétones II de départ sont préparées 1) soit à partir des composés The starting ketones II are prepared 1) either from the compounds
.0 CH, .0 CH,
par réaction avec un composé: by reaction with a compound:
CO Cl puis on déméthyle l'intermédiaire obtenu avec du chlorure d'aluminium ou du trichlorure de bore, CO Cl then the intermediate obtained is demethylated with aluminum chloride or boron trichloride,
2) soit à partir des composés 2) either from the compounds
O-CH O-CH
que l'on fait réagir avec un composé that we react with a compound
Mg Biet on hydrolyse l'intermédiaire pour obtenir un composé Mg Biet hydrolyzes the intermediate to obtain a compound
30 Les cétones II sont nouvelles, à l'exception de celles pour lesquelles Xls X2, X3 sont, chacun indépendamment l'un de l'autre, H, Hai, CH3, CH30, C (CH3)3 lorsque X4 = H. Ketones II are new, with the exception of those for which Xls X2, X3 are, each independently of the other, H, Hai, CH3, CH30, C (CH3) 3 when X4 = H.
Les cétones II nouvelles font partie de l'invention. The new ketones II form part of the invention.
La préparation des cétones II est illustrée dans les exemples de 35 préparation des composés finals I. The preparation of ketones II is illustrated in the examples of preparation of the final compounds I.
Les exemples suivants illustrent l'invention. The following examples illustrate the invention.
Les analyses et spectres IR et RMN confirment la structure des composés. IR and NMR analyzes and spectra confirm the structure of the compounds.
Dans le présent brevet sont également exemplifiés plusieurs com-40 posés qui répondent à la formule générale du brevet précédent (composés 24 à 47). In the present patent are also exemplified several com-40 poses which correspond to the general formula of the previous patent (compounds 24 to 47).
Exemple 1 Example 1
N-[a-phénylhydroxy-2 trifluoromèthyl-5 benzylidényl]amino-4 buty-45 rate de sodium. N- [a-phenylhydroxy-2-trifluoromethyl-5 benzylidenyl] 4-amino-buty-45 sodium spleen.
[Xx — CFî—5 X2=X3=X^ = H R' = H R—ONan=3] [Xx - CFî — 5 X2 = X3 = X ^ = H R '= H R — ONan = 3]
1. Hydroxy-2 trifluoromèthyl-5 diphênylméthanone. 1. Hydroxy-2 trifluoromethyl-5 diphenylmethanone.
1.1 Dans un tricol de 250 ml, muni d'un réfrigérant ascendant 50 et d'une ampoule à brome, on introduit 1,68 g de magnésium (0,0691 mol), 25 ml d'éther anhydre et 1 cristal d'iode. On porte à reflux et introduit environ 10% d'une solution de 19,52 g de bromo-benzène (0,1243 mol) dans 30 ml d'éther anhydre. Lorsque la réaction est bien démarrée, on introduit le reste de façon à maintenir le 55 reflux. Après l'introduction, on porte à reflux jusqu'à disparition totale du magnésium. Ensuite, on introduit, de façon à maintenir le reflux, 9,5 g (0,0472 mol) de méthoxy-2 trifluoromêthyl-5 benzoni-trile dans 80 ml d'éther anhydre puis on chauffe 4 h à la température de reflux. Ensuite, on hydrolyse à froid et sous azote avec 40 ml 60 d'HCl 2N. Il se forme un précipité que l'on filtre, lave à l'éther et sèche. Il s'agit du chlorhydrate de l'imine 1.1 1.68 g of magnesium (0.0691 mol), 25 ml of anhydrous ether and 1 crystal of iodine are introduced into a 250 ml three-necked flask, fitted with an ascending condenser 50 and a dropping funnel. . The mixture is brought to reflux and approximately 10% of a solution of 19.52 g of bromo-benzene (0.1243 mol) is introduced into 30 ml of anhydrous ether. When the reaction is well started, the remainder is introduced so as to maintain the reflux. After the introduction, the mixture is brought to reflux until the magnesium has completely disappeared. Then, so as to maintain the reflux, 9.5 g (0.0472 mol) of 2-methoxy-5-trifluoromethyl-benzoni-trile are introduced into 80 ml of anhydrous ether and then the mixture is heated to reflux temperature for 4 hours. Then, it is hydrolyzed cold and under nitrogen with 40 ml 60 of 2N HCl. A precipitate is formed which is filtered, washed with ether and dried. This is imine hydrochloride
OCH, OCH,
que l'on déméthyle en composé II à l'aide de chlorure d'aluminium ou de trichlorure de bore. which is demethylated from compound II using aluminum chloride or boron trichloride.
HCl HCl
637 112 637,112
4 4
On reprend ce chlorhydrate par 50 ml de toluène et 50 ml de H2S04 à 25% et porte 8 h à la température de reflux. On décante alors la phase organique, la lave plusieurs fois à l'eau, sèche sur MgS04, filtre et évapore le toluène. On obtient la méthoxy-2 trifluorométhyl-5 diphénylméthanone. This hydrochloride is taken up in 50 ml of toluene and 50 ml of 25% H 2 SO 4 and brought to 8 h at reflux temperature. The organic phase is then decanted, washed several times with water, dried over MgSO4, filtered and the toluene evaporated. 2-methoxy-5-trifluoromethyl-diphenylmethanone is obtained.
Ebo,o7=170°C Ebo, o7 = 170 ° C
1.2 Dans un flacon à réaction de 250 ml, on introduit 2,8 g (1/100 mol) de méthoxy-2 trifluorométhyl-5 diphénylméthanone, 100 ml de chlorure de méthylène et l'on refoidit à — 60° C. On introduit alors 10 g de trichlorure de bore et agite ensuite 1 h à la température ambiante. On verse dans 1,51 d'eau glacée, ajoute 250 ml de chlorure de méthylène, agite, décante la phase organique, la lave 2 fois à l'eau, sèche sur MgS04, filtre et évapore le solvant. 1.2 2.8 g (1/100 mol) of 2-methoxy-5-trifluoromethyl-diphenylmethanone, 100 ml of methylene chloride are introduced into a 250 ml reaction flask and the mixture is cooled to -60 ° C. then 10 g of boron trichloride and then stirred for 1 h at room temperature. Poured into 1.51 of ice water, added 250 ml of methylene chloride, stirred, decanted the organic phase, washed 2 times with water, dried over MgSO4, filtered and evaporated the solvent.
On obtient des cristaux jaune clair que l'on recristallise dans de l'éther de pétrole avec traitement au charbon végétal. On obtient l'hydroxy-2 trifluorométhyl-5 diphénylméthanone qui fond à 84-85 C. Clear yellow crystals are obtained which are recrystallized from petroleum ether with treatment with vegetable charcoal. We obtain 2-hydroxy-5-trifluoromethyl diphenylmethanone which melts at 84-85 C.
2. N-[a-phénylhydroxy-2 trifluorométhyl-5 benzylidénylJamino-4 bu-tyrate de sodium. 2. N- [a-phenylhydroxy-2-trifluoromethyl-5 benzylidenylJamino-4 sodium bu-tyrate.
Dans un ballon de 1 1, on introduit 1,15 g d'acide amino-4 butyrique à 97%, 300 ml de méthanol et 0,62 g de méthylate de sodium et l'on agite 2 à 3 min. On introduit alors 2,8 g d'hydroxy-2 trifluorométhyl-5 diphénylméthanone et 300 ml d'éthanol. On évapore à la pression atmosphérique (100°C). On évapore enfin la totalité du solvant (sous vide), refroidit le résidu et le dissout dans 11 d'eau froide. On acidifie à pH=4 par de l'acide citrique, extrait au chloroforme, sèche la phase chloroformique sur MgS04, filtre et évapore le chloroforme. On obtient une huile qui cristallise dans de l'éther de pétrole. On filtre, essore, lave à l'éther de pétrole, essore et recristallise dans de l'éther avec traitement au charbon végétal. On obtient l'acide qui fond à 154-155° C. 1.15 g of 97% 4-amino butyric acid, 300 ml of methanol and 0.62 g of sodium methylate are introduced into a 1 liter flask and the mixture is stirred for 2 to 3 min. 2.8 g of 2-hydroxy-5-trifluoromethyl diphenylmethanone and 300 ml of ethanol are then introduced. Evaporated at atmospheric pressure (100 ° C). Finally, all the solvent is evaporated (under vacuum), the residue is cooled and dissolved in 11 of cold water. Acidified to pH = 4 with citric acid, extracted with chloroform, the chloroform phase is dried over MgSO4, filtered and the chloroform is evaporated. An oil is obtained which crystallizes from petroleum ether. It is filtered, drained, washed with petroleum ether, filtered and recrystallized from ether with treatment with vegetable charcoal. The acid is obtained which melts at 154-155 ° C.
On dissout 2,5 g d'acide dans 150 ml de méthanol et ajoute 2.5 g of acid are dissolved in 150 ml of methanol and added
0.38.g de méthylate de sodium. On évapore à sec et obtient le sel de sodium que l'on sèche 1 h à 80° C au dessiccateur. 0.38 g of sodium methylate. Evaporated to dryness and the sodium salt is obtained, which is dried for 1 hour at 80 ° C. in a desiccator.
F=216-217°C F = 216-217 ° C
Exemple 2 Example 2
N-[a-(dichloro-2',4' phênyl) chloro-5 hydroxy-2 benzylidényl] amino-4 butyramide. N- [a- (2 'dichloro, 4' phenyl) 5-chloro-2-hydroxy benzylidenyl] 4-amino butyramide.
[Xi = Cl-5 X2 = H X3 = Cl-2' X4 = Cl-4' R=NH2 R'=Hn=3] [Xi = Cl-5 X2 = H X3 = Cl-2 'X4 = Cl-4' R = NH2 R '= Hn = 3]
1. Hydroxy-2 trichloro-2',4',5 diphénylméthanone. 1. Hydroxy-2-trichloro-2 ', 4', 5 diphenylmethanone.
1.1 A une solution agitée et portée à la température de reflux de 25,7 g de p-chlorophénol et de 30,3 g de triéthylamine dans 1,21 d'éther, on ajoute lentement une solution éthérée de chlorure de dichloro-2,4 benzoyle. Puis on chauffe à la température de reflux, en agitant pendant 3 h, et laisse les produits en contact pendant la nuit. On filtre le précipité de Et3N,HCl et le lave à l'éther. La phase organique est lavée à l'eau, à l'eau bicarbonatée et à l'eau. On sèche sur MgS04, filtre et concentre aux 3A environ. Le dichloro-2,4 benzoate de p-chlorophényle précipite. On refroidit, filtre, essore et sèche au dessiccateur chauffant à 60° C. 1.1 To an agitated solution brought to the reflux temperature of 25.7 g of p-chlorophenol and 30.3 g of triethylamine in 1.21 of ether, an ethereal solution of 2-dichloro chloride is slowly added, 4 benzoyl. Then heated to reflux temperature, stirring for 3 h, and left the products in contact overnight. The Et3N, HCl precipitate is filtered and washed with ether. The organic phase is washed with water, bicarbonate water and water. Dried over MgS04, filtered and concentrated to about 3A. 2,4-dichloro benzoate p-chlorophenyl precipitates. Cool, filter, spin and dry in a desiccator heated to 60 ° C.
F=124-125°C F = 124-125 ° C
1.2 On chauffe 35,5 g de l'ester précédent jusqu'à fusion. On agite et ajoute 35,5 g de A1C13. Puis on chauffe jusqu'à 190° et agite pendant 15 min à cette température. Après refroidissement, on broie le résidu et l'hydrolyse. On le verse en agitant dans 800 g d'un mélange d'eau+glace+100 ml d'acide chlorhydrique concentré. 1.2 35.5 g of the above ester are heated until fusion. Stir and add 35.5 g of A1C13. Then heated to 190 ° and stirred for 15 min at this temperature. After cooling, the residue is ground and hydrolysis. It is poured with stirring into 800 g of a mixture of water + ice + 100 ml of concentrated hydrochloric acid.
Puis on extrait au chloroforme, sèche sur MgS04, filtre et évapore à sec. On recristallise dans de l'éther de pétrole, essore et sèche au dessiccateur. Le produit fond à 96-97° C. Then extracted with chloroform, dried over MgS04, filtered and evaporated to dryness. Recrystallized from petroleum ether, drained and dried in a desiccator. The product melts at 96-97 ° C.
2. N-[a-(dichloro-2',4' phényl)chloro-5 hydroxy-2 benzylidényl] -amino-4 butyramide. 2. N- [a- (2 'dichloro, 4' phenyl) 5-chloro-2-hydroxy benzylidenyl] -4-amino butyramide.
On évapore à sec une solution de 12,8 g de la cétone obtenue sous 1, 5,8 g de y-aminobutyramide sous forme de chlorhydrate et 2,4 g de MeONa dans 500 ml de méthanol. A solution of 12.8 g of the ketone obtained is evaporated to dryness under 1.5.8 g of γ-aminobutyramide in the form of the hydrochloride and 2.4 g of MeONa in 500 ml of methanol.
Ensuite, on évapore 4 fois de suite 350 ml d'alcool et on termine les deux dernières évaporations sous pression réduite. Le résidu est dissous dans CHC13. On lave à l'eau, sèche sur MgS04, filtre et évapore à sec. Le résidu cristallise dans de l'éther. On filtre sur fritte et essore. On traite ensuite au charbon dans du méthanol, filtre et évapore à sec. On recristallise dans de l'alcool, filtre, lave à l'éther, essore et sèche au dessiccateur chauffant. Then 350 ml of alcohol are evaporated 4 times in succession and the last two evaporations are completed under reduced pressure. The residue is dissolved in CHCl3. Washed with water, dried over MgS04, filtered and evaporated to dryness. The residue crystallizes from ether. Filter on frit and spin. It is then treated with charcoal in methanol, filtered and evaporated to dryness. Recrystallized from alcohol, filtered, washed with ether, wrung and dried in a heated desiccator.
F=141-142"C F = 141-142 "C
Exemple 3 Example 3
Acide N-[a-(chloro-4'phényl) tertiobutyl-5 hydroxy-2 benzylidényl]-amino-4 butyrique. N- [a- (4-chloro-phenyl) tert-butyl-5-hydroxy-2-benzylidenyl] -4-amino butyric acid.
[Xx —C(CH3)3—5 X2 = H X3 = Cl—4' X4. = Hn=3 R' = H R=OHJ [Xx —C (CH3) 3—5 X2 = H X3 = Cl — 4 'X4. = Hn = 3 R '= H R = OHJ
1. Tertiobutyl-5 chloro-4' hydroxy-2 diphénylméthanone. 1. Tertiobutyl-5 chloro-4 'hydroxy-2 diphenylmethanone.
1.1 A 120 g de p-tertiobutylanisole dans 180 ml de tétrachloroé-thane, on ajoute en agitant 128 g de chlorure de p-chlorobenzoyle et 0,25 g de ZnCl2 fraîchement fondu et broyé. Puis on chauffe à 140° C, en agitant, pendant 40 h. Ensuite, on évapore le solvant et distille sous pression réduite. Le distillât cristallise dans de l'éther de pétrole. On recristallise la t-butyl-5 chloro-4' méthoxy-2 diphénylméthanone dans de l'éther de pétrole avec traitement au charbon végétal. 1.1 To 120 g of p-tertiobutylanisole in 180 ml of tetrachloro-thane, 128 g of p-chlorobenzoyl chloride and 0.25 g of freshly ground and ground ZnCl2 are added with stirring. Then heated to 140 ° C, with stirring, for 40 h. Then the solvent is evaporated and distilled under reduced pressure. The distillate crystallizes from petroleum ether. The t-butyl-5-chloro-4 '2-methoxy-diphenylmethanone is recrystallized from petroleum ether with treatment with vegetable charcoal.
F=46-47° C M = 46-47 ° C
1.2 A 88 g du composé obtenu précédemment dans 150 ml de benzène on ajoute, en agitant, 46,3 g de A1C13 et on chauffe à 70°, pendant 12 h. Puis, après refroidissement, on hydrolyse en versant sur de la glace et de l'acide chlorhydrique concentré et en agitant. On décante, lave à l'eau, sèche sur MgS04, filtre et évapore à sec. Le résidu cristallise dans de l'éther de pétrole. On filtre sur fritté, essore et recristallise dans du méthanol avec traitement au charbon végétal. On sèche au dessiccateur. 1.2 To 88 g of the compound obtained above in 150 ml of benzene is added, with stirring, 46.3 g of A1C13 and the mixture is heated at 70 °, for 12 h. Then, after cooling, the mixture is hydrolyzed by pouring onto ice and concentrated hydrochloric acid and stirring. Decanted, washed with water, dried over MgS04, filtered and evaporated to dryness. The residue crystallizes from petroleum ether. Filtered on sintered glass, drained and recrystallized from methanol with treatment with vegetable charcoal. It is dried in a desiccator.
F=64-65° C F = 64-65 ° C
2. Acide N-[a- (chloro-4' phényl) tertiobutyl-5 hydroxy-2 benzylidényl]amino-4 butyrique. 2. N- [a- (4-chloro-phenyl) tert-butyl-5-hydroxy-2-benzylidenyl] 4-amino butyric acid.
On évapore à sec une solution de 5,4 g d'acide amino-4 butyrique, 3 g de MeONa et 15,4 g de la cétone obtenue précédemment dans 500 ml de méthanol et 300 ml d'alcool. On ajoute 600 ml d'alcool et évapore à sec, en terminant sous pression réduite. On recommence deux fois cette opération. On dissout le résidu dans de l'eau acidifiée à pH 4 avec de l'acide citrique. A solution of 5.4 g of 4-amino butyric acid, 3 g of MeONa and 15.4 g of the ketone obtained previously is evaporated to dryness in 500 ml of methanol and 300 ml of alcohol. 600 ml of alcohol are added and evaporated to dryness, finishing under reduced pressure. This operation is repeated twice. The residue is dissolved in acidified water to pH 4 with citric acid.
On extrait au chloroforme, sèche sur MgS04, filtre et évapore à sec. Le précipité obtenu est entraîné sur fritté avec de l'éther de pétrole. On recristallise dans de l'acétate d'éthyle avec traitement au charbon végétal. On sèche au dessiccateur chauffant. Extracted with chloroform, dried over MgS04, filtered and evaporated to dryness. The precipitate obtained is entrained on a frit with petroleum ether. Recrystallized from ethyl acetate with treatment with vegetable charcoal. Dry in a heated desiccator.
F=140-141°C M = 140-141 ° C
Exemple 4 Example 4
N-[a-(chloro-4' phényl)fluoro-5 méthoxy-2 benzylidényl]amino-4 butyramide. N- [a- (4-chloro-phenyl) 5-fluoro-2-methoxy-benzylidenyl] 4-amino butyramide.
[X1=F-5 X3 = Cl-4' X2=Xa.=HR=NH2 R' = CH3 n=3] [X1 = F-5 X3 = Cl-4 'X2 = Xa. = HR = NH2 R' = CH3 n = 3]
On évapore à sec une solution de 3,4 g de N-[a-(chloro-4' phényl)fluoro-5 hydroxy-2 benzylidényl]amino-4 butyramide et de 0,55 g de méthylate de sodium dans 150 ml de méthanol. Puis on sèche au dessiccateur chauffant à 120°. A solution of 3.4 g of N- [a- (4-chloro-phenyl) fluoro-5-hydroxy-2-benzylidenyl] amino-4-butyramide and of 0.55 g of sodium methylate in 150 ml of liquid is evaporated to dryness. methanol. Then it is dried in a drying oven heated to 120 °.
Après refroidissement, le résidu est dissous dans 100 ml de DMSO (diméthylsulfoxyde). After cooling, the residue is dissolved in 100 ml of DMSO (dimethyl sulfoxide).
On agite et introduit, goutte à goutte, dans la solution agitée, 3 g d'iodure de méthyle dans 25 ml de DMSO. Puis on agite à la température ambiante pendant 30 min. 3 g of methyl iodide in 25 ml of DMSO are stirred and introduced dropwise into the stirred solution. Then stirred at room temperature for 30 min.
On évapore à sec, sous pression réduite, dissout le résidu dans 200 ml de chloroforme, lave à l'eau, sèche et évapore à sec. Le résidu est entraîné sur fritté avec de l'éther. On recristallise le produit dans de l'alcool, le lave à l'acétone et à l'éther, l'essoré et le sèche au dessiccateur chauffant. F= 154 5_155 5°c Evaporated to dryness under reduced pressure, the residue is dissolved in 200 ml of chloroform, washed with water, dried and evaporated to dryness. The residue is entrained on a frit with ether. The product is recrystallized from alcohol, washed with acetone and ether, drained and dried in a heated desiccator. F = 154 5_155 5 ° c
Dans le tableau sont représentés les composés préparés à titre d'exemples illustrant la formule (I). In the table are shown the compounds prepared by way of examples illustrating formula (I).
5 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
5 5
Tableau Board
637 112 637,112
Composé Compound
Xi x2 Xi x2
x3 x3
x4 x4
n not
R R
R' R '
F (°C) F (° C)
1 1
N02-5 N02-5
H H
Cl-4' Cl-4 '
H H
3 3
OH OH
H H
240 (déc.) 240 (dec.)
2 2
CH3CO NH-5 CH3CO NH-5
H H
H H
H H
3 3
nh2 nh2
H H
240 (déc.) 240 (dec.)
3 3
CF3-5 CF3-5
H H
CF3-4' CF3-4 '
H H
3 3
ONa We have
H H
238 (déc.) 238 (dec.)
4 4
CF3-5 CF3-5
H H
CF3-3' CF3-3 '
H H
3 3
ONa We have
H H
218 (déc.) 218 (dec.)
5 5
CF3-5 CF3-5
H H
CF3-4' CF3-4 '
H H
3 3
nh2 nh2
H H
119,6 119.6
6 6
CF3-5 CF3-5
H H
CF3-3' CF3-3 '
H H
3 3
nh2 nh2
H H
98,7 98.7
7 7
CF3-5 CF3-5
H H
F-4' F-4 '
H H
3 3
OH OH
H H
173,5 173.5
ONa We have
H H
>250 > 250
8 8
N02-5 N02-5
H H
Cl-4' Cl-4 '
H H
3 3
nh2 nh2
H H
172,5 172.5
9 9
CF3-5 CF3-5
H H
F-4' F-4 '
H H
3 3
nh2 nh2
H H
120,6 120.6
10 10
F-5 F-5
H H
N02-4' N02-4 '
H H
3 3
oh Oh
H H
169-70 169-70
ONa We have
H H
180 (déc.) 180 (Dec)
11 11
F-5 F-5
H H
N02-4' N02-4 '
H H
3 3
nh2 nh2
H H
190-1 190-1
12 12
CF3-5 CF3-5
H H
H H
H H
3 3
OH OH
H H
154-5 154-5
ONa We have
H H
216 (déc.) 216 (dec.)
13 13
CF3-5 CF3-5
H H
H H
H H
3 3
nh2 nh2
H H
93-94 93-94
14 14
C(CH3)3-5 C (CH3) 3-5
H H
Cl-4' Cl-4 '
H H
3 3
OH OH
H H
140-1 140-1
15 15
C(CH3)3-5 C (CH3) 3-5
H H
Cl-4' Cl-4 '
H H
3 3
nh2 nh2
H H
121-2 121-2
16 16
N02-5 N02-5
H H
H H
H H
3 3
OH OH
H H
177-8 177-8
ONa We have
H H
227 (déc.) 227 (dec.)
17 17
N02-5 N02-5
H H
H H
H H
3 3
NH2 NH2
H H
185-6 185-6
18 18
C(CH3)3-5 C (CH3) 3-5
H H
H H
H H
3 3
nh2 nh2
H H
135-6 135-6
19 19
C(CH3)3-5 C (CH3) 3-5
H H
H H
h h
3 3
OH OH
h h
131-2 131-2
20 20
Cl-5 Cl-5
H H
Cl-4' Cl-4 '
Cl-2' Cl-2 '
3 3
nh2 nh2
h h
141-2 141-2
21 21
Cl-5 Cl-5
H H
Cl-4' Cl-4 '
Cl-2' Cl-2 '
3 3
OH OH
h h
172-4 172-4
ONa h ONa h
245 (déc.) 245 (dec.)
( OH ( OH
h h
140-1 140-1
22 22
F-5 F-5
H H
CF3-4' CF3-4 '
H H
3 3
(nh2 (nh2
H H
151-2 151-2
23 23
F-5 F-5
H H
Cl-4' Cl-4 '
H H
3 3
nh2 nh2
ch3 ch3
165 165
24 24
Cl-5 Cl-5
H H
Br-4' Br-4 '
H H
3 3
nh2 nh2
H H
169-170 169-170
25 25
Br-5 Br-5
H H
Cl-4' Cl-4 '
H H
3 3
nh2 nh2
H H
156-157 156-157
26 26
Br-5 Br-5
H H
H H
H H
3 3
nh2 nh2
H H
134-135 134-135
27 27
Br-5 Br-5
H H
Br-4' Br-4 '
H H
3 3
nh2 nh2
H H
164,5-166,5 164.5-166.5
28 28
F-5 F-5
H H
Cl-2' Cl-2 '
H H
3 3
OH OH
H H
85,5-87 85.5-87
29 29
CI-5 CI-5
H H
Cl-4' Cl-4 '
H H
3 3
nh2 nh2
H H
161-3 161-3
30 30
Br-5 Br-5
H H
H H
H H
3 3
ONa We have
H H
247-8 247-8
31 31
Br-5 Br-5
H H
Cl-4' Cl-4 '
H H
3 3
ONa We have
H H
230 230
32 32
Cl-5 Cl-5
H H
Cl-4' Cl-4 '
H H
3 3
ONa We have
H H
>250 > 250
33 33
Br-5 Br-5
H H
Br-4' Br-4 '
H H
3 3
ONa We have
H H
>250 > 250
34 34
Cl-5 Cl-5
H H
Br-4' Br-4 '
h h
3 3
ONa h ONa h
>235 > 235
35 35
F-5 F-5
H H
Cl-4' Cl-4 '
H H
2 2
ONa h ONa h
>240 > 240
36 36
F-5 F-5
H H
Cl-4' Cl-4 '
H H
2 2
nh2 nh2
H H
157-8 157-8
37 37
Cl-5 Cl-5
H H
H H
H H
3 3
nh2 nh2
h h
125-6 125-6
38 38
H H
H H
CH3O-2' CH3O-2 '
H H
3 3
nh2 nh2
H H
119-20 119-20
39 39
F-5 F-5
H H
Cl-4' Cl-4 '
H H
1 1
OH OH
H H
167-8 167-8
40 40
F-5 F-5
H H
Cl-4' Cl-4 '
H H
4 4
ONa h ONa h
>300 > 300
41 41
F-5 F-5
H H
Cl-4' Cl-4 '
H H
3 3
OH OH
h h
98-9 98-9
42 42
F-5 F-5
H H
Cl-4' Cl-4 '
H H
4 4
nh2 nh2
H H
140-1 140-1
43 43
Cl-5 Cl-5
H H
F-4' F-4 '
H H
3 3
nh2 nh2
H H
140-1 140-1
44 44
Cl-5 Cl-5
H H
F-4' F-4 '
H H
3 3
OH OH
H H
127-8 127-8
45 45
F-5 F-5
H H
CF3-4' CF3-4 '
H H
3 3
ONa We have
H H
>250 > 250
46 46
Cl-5 Cl-5
H H
Cl-2' Cl-2 '
H H
3 3
OH OH
H H
102 102
47 47
Cl-5 Cl-5
H H
Cl-2' Cl-2 '
H H
3 3
NH2 NH2
H H
104 104
48 48
Br-5 Br-5
H H
Br-2' Br-2 '
H H
■ 3 ■ 3
nh2 nh2
H H
133 133
49 49
Br-5 Br-5
H H
Br-2' Br-2 '
H H
3 3
OH OH
H H
138 138
50 50
Br-5 Br-5
H H
Cl-2' Cl-2 '
Cl-4' Cl-4 '
3 3
OH OH
H H
118-119 118-119
51 51
Br-5 Br-5
H H
Cl-2' Cl-2 '
Cl-4' Cl-4 '
3 3
nh2 nh2
H H
131-132 131-132
52 52
Br-5 Br-5
H H
Cl-2' Cl-2 '
H H
3 3
OH OH
H H
130-131 130-131
53 53
Br-5 Br-5
H H
Cl-2' Cl-2 '
H H
3 3
nh2 nh2
H H
125-126 125-126
54 54
Cl-5 Cl-5
H H
Br-2' Br-2 '
H H
3 3
nh2 nh2
H H
118-119 118-119
55 55
Cl-3 Cl-3
Cl-5 Cl-5
Cl-2' Cl-2 '
H H
3 3
nh2 nh2
H H
135-136 135-136
56 56
Cl-3 Cl-3
Cl-5 Cl-5
Cl-2' Cl-2 '
H H
3 3
oh Oh
H H
149-150 149-150
637 112 637,112
6 6
Les composés de l'invention ont été soumis à des essais pharma-cologiques montrant leur activité sur le système nerveux central. The compounds of the invention have been subjected to pharmacological tests showing their activity on the central nervous system.
La toxicité aiguë a été déterminée chez la souris par voie intrapé-ritonéale. La DL50 (dose létale 50%) induisant la mort chez 50% des animaux varie de 700 à plus de 1000 mg/kg. Acute toxicity was determined in mice intraperitoneally. The LD50 (lethal dose 50%) inducing death in 50% of the animals varies from 700 to more than 1000 mg / kg.
L'activité des composés a été montrée par l'antagonisme vis-à-vis de la mortalité induite par la bicuculline chez la souris. The activity of the compounds has been shown by the antagonism vis-à-vis the mortality induced by bicuculline in mice.
La bicuculline est un bloqueur relativement sélectif des récepteurs GABA-ergiques postsynaptiques, et ses effets convulsivants et létaux sont antagonisés par les composés élevant le taux de GABA cérébral ou possédant une activité GABA-mimétique. Bicuculline is a relatively selective blocker of postsynaptic GABA-ergic receptors, and its convulsive and lethal effects are antagonized by compounds raising the level of cerebral GABA or having GABA-mimetic activity.
On a évalué la dose active 50% (DA50), dose protégeant 50% des animaux contre l'effet de la bicuculline, des substances étudiées. The active dose 50% (DA50) was evaluated, a dose protecting 50% of the animals against the effect of bicuculline, the substances studied.
La DA50 des composés de l'invention varie de 20 à 80 mg/kg par voie intrapéritonéale. The DA50 of the compounds of the invention varies from 20 to 80 mg / kg intraperitoneally.
Les composés de l'invention sont actifs comme anti-convulsivants. Ils sont utilisables en thérapeutique humaine et vété-s rinaire pour le traitement de diverses maladies du système nerveux central, par exemple pour le traitement des psychoses et de certaines maladies neurologiques comme l'épilepsie. The compounds of the invention are active as anti-convulsants. They can be used in human and veterinary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of psychoses and certain neurological diseases such as epilepsy.
L'invention comprend, par conséquent, toutes compositions pharmaceutiques renfermant les composés I comme principes actifs, io en association avec tous excipients appropriés à leur administration, en particulier par voie orale (comprimés, dragées, gélules, capsules, cachets, solution ou suspensions buvables) ou parentérale. The invention therefore includes all pharmaceutical compositions containing the compounds I as active ingredients, in combination with any excipients suitable for their administration, in particular by oral route (tablets, dragees, capsules, capsules, cachets, solution or oral suspensions ) or parenteral.
La posologie quotidienne peut aller de 100 à 1500 mg. The daily dosage can range from 100 to 1500 mg.
r r
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7805578A FR2418222A2 (en) | 1975-08-01 | 1978-02-27 | Alpha-phenyl 2-hydroxy-benzylidene amino-alkanoic acid derivs. - and novel di:phenyl-ketone intermediates, useful as anticonvulsants for treating epilepsy |
| FR7820940A FR2430936A1 (en) | 1978-07-13 | 1978-07-13 | Alpha-phenyl 2-hydroxy-benzylidene amino-alkanoic acid derivs. - and novel di:phenyl-ketone intermediates, useful as anticonvulsants for treating epilepsy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH637112A5 true CH637112A5 (en) | 1983-07-15 |
Family
ID=26220461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH188579A CH637112A5 (en) | 1978-02-27 | 1979-02-26 | BENZYLIDENIC DERIVATIVES. |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS54125644A (en) |
| AT (1) | AT365564B (en) |
| AU (1) | AU520618B2 (en) |
| BE (1) | BE874488A (en) |
| CA (1) | CA1119613A (en) |
| CH (1) | CH637112A5 (en) |
| DE (1) | DE2907379A1 (en) |
| DK (1) | DK82079A (en) |
| ES (1) | ES478070A1 (en) |
| FI (1) | FI790656A (en) |
| GB (1) | GB2021559B (en) |
| GR (1) | GR66971B (en) |
| IE (1) | IE47930B1 (en) |
| IT (1) | IT1113010B (en) |
| LU (1) | LU80974A1 (en) |
| NL (1) | NL7901474A (en) |
| NO (1) | NO790646L (en) |
| NZ (1) | NZ189769A (en) |
| PT (1) | PT69288A (en) |
| SE (1) | SE7901706L (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5746951A (en) * | 1980-09-04 | 1982-03-17 | Toray Ind Inc | Production of 2-amino-4-cyanobutyric derivative |
| EP0047516B1 (en) * | 1980-09-04 | 1984-01-04 | Toray Industries, Inc. | Propylamine derivative and process of manufacturing the same |
| FR2536746A1 (en) * | 1982-11-29 | 1984-06-01 | Synthelabo | ALKYL BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2544308B1 (en) * | 1983-04-14 | 1985-06-14 | Synthelabo | SUBSTITUTED ETHINS, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS |
| EP0367671B1 (en) * | 1988-11-03 | 1993-07-28 | Fournier Industrie Et Sante | Novel beta-d-phenylthioxylosides, their method of preparation and their use as pharmaceuticals |
| WO1991007380A1 (en) * | 1989-11-08 | 1991-05-30 | Dunlena Pty. Ltd. | Arthropodicides |
| JP2005232103A (en) * | 2004-02-20 | 2005-09-02 | Nagase & Co Ltd | Optically active vicinaldiamine and method for producing the same |
-
1979
- 1979-02-26 NL NL7901474A patent/NL7901474A/en active Search and Examination
- 1979-02-26 SE SE7901706A patent/SE7901706L/en not_active Application Discontinuation
- 1979-02-26 ES ES478070A patent/ES478070A1/en not_active Expired
- 1979-02-26 JP JP2247179A patent/JPS54125644A/en active Pending
- 1979-02-26 IT IT20543/79A patent/IT1113010B/en active
- 1979-02-26 NZ NZ189769A patent/NZ189769A/en unknown
- 1979-02-26 AU AU44602/79A patent/AU520618B2/en not_active Ceased
- 1979-02-26 DE DE19792907379 patent/DE2907379A1/en not_active Withdrawn
- 1979-02-26 PT PT69288A patent/PT69288A/en unknown
- 1979-02-26 CH CH188579A patent/CH637112A5/en not_active IP Right Cessation
- 1979-02-26 NO NO790646A patent/NO790646L/en unknown
- 1979-02-26 DK DK82079A patent/DK82079A/en not_active Application Discontinuation
- 1979-02-27 GB GB7906963A patent/GB2021559B/en not_active Expired
- 1979-02-27 BE BE0/193728A patent/BE874488A/en not_active IP Right Cessation
- 1979-02-27 AT AT0149179A patent/AT365564B/en not_active IP Right Cessation
- 1979-02-27 CA CA000322406A patent/CA1119613A/en not_active Expired
- 1979-02-27 FI FI790656A patent/FI790656A/en not_active Application Discontinuation
- 1979-02-27 GR GR58490A patent/GR66971B/el unknown
- 1979-02-27 LU LU80974A patent/LU80974A1/en unknown
- 1979-08-08 IE IE556/79A patent/IE47930B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE874488A (en) | 1979-08-27 |
| DK82079A (en) | 1979-08-28 |
| GB2021559A (en) | 1979-12-05 |
| LU80974A1 (en) | 1980-09-24 |
| NO790646L (en) | 1979-08-28 |
| AU520618B2 (en) | 1982-02-11 |
| SE7901706L (en) | 1979-08-28 |
| PT69288A (en) | 1979-03-01 |
| AU4460279A (en) | 1979-09-06 |
| IE790556L (en) | 1979-08-27 |
| JPS54125644A (en) | 1979-09-29 |
| DE2907379A1 (en) | 1979-09-06 |
| GB2021559B (en) | 1982-07-07 |
| ES478070A1 (en) | 1979-07-01 |
| IE47930B1 (en) | 1984-07-25 |
| AT365564B (en) | 1982-01-25 |
| ATA149179A (en) | 1981-06-15 |
| GR66971B (en) | 1981-05-15 |
| NL7901474A (en) | 1979-08-29 |
| CA1119613A (en) | 1982-03-09 |
| IT7920543A0 (en) | 1979-02-26 |
| FI790656A (en) | 1979-08-28 |
| NZ189769A (en) | 1981-07-13 |
| IT1113010B (en) | 1986-01-20 |
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