FR2460298A1 - 2,6-Methano-3-benzazocine derivs. - used as analgesics and narcotic antagonists, prepd. from methano-benzoquinoline derivs. - Google Patents

Abstract

Methano-benzazocines of formula (I) and their acid addn. salts are new:- In (Ie R is methyl, pentyl, 3-methylbutyl, 2-phenylethyl 2-cyclopropylethyl, 2-cyclobutylethyl or 2-cyclopentylethyl. Prepn. of methano-benzazocines of formula (V) in which one of R2, R'2, R"2 and R'"2 is OH comprises cleaving the alkoxy gp. of a cpd. (V) in which one of R2, R'2, R'"2 is lower alkoxy. In the formula R1 is H, alkyl, alkenyl, alkynyl or haloalkenyl; cycloalkyl, cycloalkyl, alkyl; 2- or 3- furylmethyl (opt. ring substd. by 1-3 methyl or opt. ring-substd. phenyl-alkyl gps., or by 1 or 2 halogen, alkyl, alkoxy, alkanoyloxy or alkylthio, OH CF3 NH2 or alkanoylamino gps. or by one methylenedioxy gp.; one of R2, R'2, R"2, and R'"2 is OH or alkoxy and the others are H, or two adjacent gps. may be methylenedioxy; R3 is H or alkyl. R4 is H, alkyl, alkoxyalkyl, hydroxyalkyl alkylthioalkyl, alkylsulphinylalkyl, phenylthioalkyl, phenyl-sulphinylalkyl, alkenyl or haloalkyl; or R3 and R4 together are (CH2)m (n=3 or 4); R5 is alkylthioalkyl, alkoxyalkyl, lower alkoxy, cycloalkyl cycloalkyl-alkyl or Ar-(CH2)m; Ar is 2- or 3-aryl opt. substd. by 1-3 Me gps. or is phenyl opt. monosubstd. by methylenedioxy or mono- or disubstd. by halogen, alkyl, OH, alkanoyloxy, alkoxy, alkylthio, CF3, NH2 or alkanoylamino gps. m is 0, 2, 3 or 4 all alkyl etc. gps. are lower.

Description

 The invention relates to 2,6-methano-3-benzazocines.

que l'on peut appeler l-R1-3-R5CO-4aa-R3-5a-R4-6-R211-7-R2-8-R2,- 9-R2'''-1,2,3,4,4a,5,10,10-a-octahydro-2,5-méthanobenzo /9 7- quinoléine-3-carboxylates d'alkyle inférieur, dans la préparation de nouvelles 3-R1-6-(eq) -R4-7-R2,-8-R2-9-R2,-lO-R2, ''-ll(ax)-R3 ll (eq) -CH2CH2COR5-2, 6-méthano-3-benzazocines de formule

où dans les Formules IIIA et V
R1 est un atome d'hydrogene ou un groupement alkyle inférieur, alcényle inférieur, alcynyle inférieur, halo-alcényle inférieur, cycloalkyle, cycloalkyl-alkyle inférieur, 2- ou 3-furylméthyle, ou un groupement 2- ou 3-furylméthyle substitué sur les atomes de carbone non substitués du cycle par un a trois groupements méthyle, phényl-alkyle inférieur ou phényl-alkyle inférieur substitué sur le noyau phényle par un ou deux radicaux du groupe comprenant les radicaux halogène (comprenant le chlore, le brome et le fluor), alkyle inférieur, hydroxy, alcanoyloxy inférieur, alcoxy inférieur, alkylmercapto inférieur, trifluorométhyle, amino ou alcanoylamino inférieur, ou par un seul groupement méthylènedioxy fixé sur les atomes de carbone adjacents;;
R2, R2,, R2" et R2,,, sont chacun un atome d'hydrogène, ou bien trois d'entre eux sont un atome d'hydrogène et le quatrième est un atome d'halogène (qui peut être le brome, le chlore ou le fluor), ou un groupement alkyle inférieur, hydroxy, alcanoyloxy inférieur, alcoxy inférieur, alkylmercapto inférieur, trifluorométhyle, nitro, amino, alcanoylamino inférieur, alcoxycarbonylamino inférieur ou phényle, ou bien deux de tels groupements adjacents pris ensemble forment un groupement méthylènedioxy;
R3 est un atome d'hydrogène ou un groupement alkyle inférieur;;
R4 est un atome d'hydrogène ou un groupement alkyle inférieur, (alcoxy inférieur)-alkyle inférieur, hydroxyalkyle inférieur, (alkylthio inférieur)-alkyle inférieur, (alkyl inférieur)-sulfinyl-alkyle inférieur, phénylthio-alkyle inférieur, phényl-sulfinyl-alkyle inférieur, alcényle inférieur ou halo-alkyle inférieur, ou bien R3 et R4 pris ensemble forment un groupement alkylène inférieur divalent de formule -(CH2), où n est l'un des entiers 3 et 4; et
R5 est un groupement (alkyl inférieur)-thio-alkyle inférieur, (alcoxy inférieur)-alkyle inférieur, alcoxy inférieur, cycloalkyle, cycloalkyl-alkyle inférieur, 2- ou 3-furyle, 2- ou 3 furyl-(CH2)m où m est un entier de 2 a 4, ou de tels groupements 2 ou 3-furyle ou 2- ou 3-furyl-(CH2)m substitués sur les atomes de carbone du cycle non substitués par un à trois groupements méthyle
Selon la présente invention, on prépare es nouveaux composés de Formule V où l'un de R2, R2,, R2" et R2''' est un groupement hydroxy, à partir des éthers correspondants où le groupement choisi parmi R2, R2,, R2" et R,"' est un groupement alcoxy inférieur, en coupant le groupement éther soit par l'acide bromhydrique aqueux soit par le propylsulfure de sodium aqueux.French patent application NO 77 28584 generally describes the use of intermediates of formula

which can be called l-R1-3-R5CO-4aa-R3-5a-R4-6-R211-7-R2-8-R2, - 9-R2 '''- 1,2,3,4, 4a, 5,10,10-a-octahydro-2,5-methanobenzo / 9 7-quinoline-3-lower alkyl carboxylates, in the preparation of new 3-R1-6- (eq) -R4-7- R2, -8-R2-9-R2, -lO-R2, '' -ll (ax) -R3 ll (eq) -CH2CH2COR5-2, 6-methano-3-benzazocines of formula

where in Formulas IIIA and V
R1 is a hydrogen atom or a lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, 2- or 3-furylmethyl group, or a substituted 2- or 3-furylmethyl group on the carbon atoms unsubstituted in the ring by one to three methyl, phenyl-lower alkyl or phenyl-lower alkyl groups substituted on the phenyl ring by one or two radicals from the group comprising halogen radicals (including chlorine, bromine and fluorine) , lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylmercapto, trifluoromethyl, amino or lower alkanoylamino, or by a single methylenedioxy group attached to the adjacent carbon atoms;
R2, R2 ,, R2 "and R2 ,,, are each a hydrogen atom, or three of them are a hydrogen atom and the fourth is a halogen atom (which can be bromine, chlorine or fluorine), or a lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylmercapto, trifluoromethyl, nitro, amino, lower alkanoylamino, lower alkoxycarbonylamino or phenyl group, or two such adjacent groups taken together form a methylenedioxy group ;
R3 is a hydrogen atom or a lower alkyl group;
R4 is a hydrogen atom or a lower alkyl group, (lower alkoxy) -lower alkyl, lower hydroxyalkyl, (lower alkylthio) -lower alkyl, (lower alkyl) -sulfinyl-lower alkyl, phenylthio-lower alkyl, phenyl-sulfinyl -lower alkyl, lower alkenyl or halo-lower alkyl, or else R3 and R4 taken together form a divalent lower alkylene group of formula - (CH2), where n is one of the integers 3 and 4; and
R5 is a (lower alkyl) -thio-lower alkyl, (lower alkoxy) -lower alkyl, lower alkoxy, cycloalkyl, cycloalkyl-lower alkyl, 2- or 3-furyl, 2- or 3 furyl- (CH2) m group where m is an integer from 2 to 4, or such 2 or 3-furyl or 2- or 3-furyl- (CH2) m groups substituted on the ring carbon atoms unsubstituted by one to three methyl groups
According to the present invention, new compounds of Formula V are prepared in which one of R2, R2 ,, R2 "and R2 '''is a hydroxy group, starting from the corresponding ethers where the group chosen from R2, R2 ,, R2 "and R,"'is a lower alkoxy group, cutting the ether group either with aqueous hydrobromic acid or with aqueous sodium propylsulfide.

 When aqueous hydrobromic acid is used to effect the cleavage, the reaction is carried out by heating a solution of ether in aqueous hydrobromic acid under reflux and isolating the compound either directly from the reaction mixture in the form of hydrobromide or from a neutral solution in the form of the free base. When sodium propylsulfide is used to cut the ether, the reaction is carried out by refluxing a solution of the ether in an inert organic solvent, for example dimethylformamide (DMF) with a molar excess of sodium propylsulfide, it is prepared by adding propanethiol to sodium hydride.

Claims (6)

R E V E N D I- C A T I O N S 1. Process for the preparation of a compound of formula V

 in which -J. characterized in that the lower alkoxy group of a corresponding compound of Formula V is cut in which one of the groups R2, R2 ', R2 "and R2"' is a lower alkoxy group.  R5 is a (lower alkyl) -thio-lower alkyl, (lower alkoxy) -lower alkyl, lower alkoxy, cycloalkyl, cycloalkyl-lower alkyl, 2- or 3-furyl, 2- or 3 furyl- (CH2) m group where m is an integer from 2 to 4, or such 2 or 3-furyl or 2- or 3-furyl- (CH2) m groups substituted on the carbon atoms of the ring unsubstituted by one to three methyl groups, R4 is a hydrogen atom or a lower alkyl group, (lower alkoxy) -lower alkyl, lower hydroxyalkyl, (lower alkylthio) -lower alkyl, (lower alkyl) -sulfinyl-lower alkyl, phenylthio-lower alkyl, phenyl-sulfinyl -lower alkyl, lower alkenyl or halo-lower alkyl, or else R3 and R4 taken together form a divalent lower alkylene group of formula (CH2) n where n is one of the integers 3 and 4; and  .R3 is a hydrogen atom or a lower alkyl group ;; three of the groups Rnr R2 ', R2 "and R2 ,,, are a hydrogen atom - and the fourth is a hydroxy group; amino or lower alkanoylamino, or by a single methylenedioxy group attached to the adjacent carbon atoms; lower alkoxy, lower alkyl mercapto, trifluoromethyl, and fluorine), lower alkyl, hydroxy, lower alkanoyloxy, including halogen radicals (including chlorine, bromine  substituted on the phenyl ring by one or two radicals from the group  methyl, phenyl-lower alkyl or phenyl-lower alkyl  of carbon unsubstituted in the ring with one to three groups  or a 2- or 3-furylmethyl group substituted on the atoms  cycloalkyl, cycloalkyl-lower alkyl, 2- or 3-furylmethyl,  lower alkenyl, lower alkynyl, lower halo-alkenyl, R1 is a hydrogen atom or a lower alkyl group, 2. Method according to claim 1, characterized in that the cutting is carried out with hydrobromic acid. 3. Method according to claim 2, characterized in that the ether to be cut is heated to reflux in solution in aqueous hydrobromic acid. 4. Method according to claim 1, characterized in that the cleavage is carried out with sodium propylsulfide. 5. Method according to claim 4, characterized in that the ether to be cut is heated to reflux in solution in an inert organic solvent with a molar excess of sodium propylsulfide. 6. Compound of general formula V in which three of the groups R2, R2 ,, R2 "and R2" 'are a hydrogen atom and the fourth is a hydroxy group, when it is prepared by a process according to any one of claims 1 to 5.