Patent ES-352623-A1 (ES)
Title: 2,5(5) - di(tri)substituted - 10b-hydroxy-3,6 - dioxo-octahydro-oxazolo(3,2-a) pyrrolo(2,1-c)pyrazine derivatives of lysergic acid
IPC: C07D487/04
Filed: 1968-04-10
Abstract: The invention comprises the novel acid addition salts of oxazolo[3,2-a]pyrrolo[2,1-a] pyrazine derivatives of the Formula II wherein R2 is C 1-4 alkyl, R3 is C 1-4 alkyl or benzyl, or R2 and R3 together with the carbon atom to which they are attached form a 4-7 membered saturated carbocyclic ring and R4 is C 1-3 alkyl, novel compounds of Formula II wherein a hydrogen atom of the amino group is replaced by a benzyloxycarbonyl group, and novel lysergic acid derivatives of the Formula I wherein R 1 is H or CH 3 , and x y is CH 2 -CH or -CH = C and their pharmaceutically acceptable acid addition salts, which are prepared by reacting an acid addition salt of a compound of Formula II with a reactive functional derivative of lysergic or dihydrolysergic acid or the 1-methyl-derivatives thereof, or by hydrogenating the corresponding compounds of Formula I where x y is C = CH, or by methylating a compound of Formula I wherein R 1 is H. The novel compounds of Formula II in the form of these acid addition salts are prepared by the hydrogenolysis of the corresponding benzyloxy carbonylamino compounds, which are in turn made by refluxing the appropriate acid azide with a small excess of benzyl alcohol. 2 - Azidocarbonyl - 2 - R 4 - S - R 2 - 5 - R 3 - 3,6- dioxo - 10b - hydroxyoctohydro - 8H - oxazolo [3,2-a]pyrrolo[2,1-c]-pyrazines are made by reacting sodium azide with the corresponding acid chlorides, resulting from the reaction of oxalyl chloride on the alkali metal salts of the corresponding 2-carboxy derivatives or the reaction of phosphorous pentachloride on the corresponding free acids, obtained by the hydrolysis of the appropriate 2-alkoxy carbonyl derivatives, which are in turn made by spontaneously cyclizing the product obtained by splitting off the benzyloxy group by hydrogenation from the 2-([alpha]- alkoxycarbonyl - [alpha] - benzyloxy - [alpha] - R 4 -acetyl)-3-R 2 - 3 - R 3 - 1,4 - diozo - octahydropyrrolo [1,2 - a] pyrazine resulting from the treatment of the appropriate 3 - R 2 - 3 - R3 - 1,4 - diozo - octahydropyrrolo [1,2-a]-pyrazine with 2-R 4 -2- benzyloxy-malonic acid chloride monoalkyl ester. (81 a S) - 11,41 - Dioxooctahydrospiro[cyclohexane - 1,31 - pyrrolo[1,2 - a]pyrazine], (8 a S)- 3,3 - dimethyl - 1,4 - disooctahydropyrrolo[1,2 - a] pyrazine and (3S, 8aS) - 3 - benzyl - 1,4 - dioxo- 3 - methyloctahydropyrrolo[1,2- a]pyrazine are prepared by cyclizing (2S)-N-(1-methoxycarbonyl) - cyclohexyl - 2 - pyrrolidinecarboxylic acid amide, (2S) - N - 1 - methyl - 1 - ethoxycarbonyl) ethyl - 2 - pyrrolidinecarboxylic acid amide and (2S,[alpha]S) - N - ([alpha] - methyl - [alpha] - methoxycarbonyl) phenylethyl - 2 - pyrrolidine carboxylic acid amide respectively, which are in turn obtained by the hydrogenation of the corresponding 1- benzyloxycarbonyl - N - substituted - 2 - pyrrolidinecarboxylic acid amide, resulting from the reaction of (2S) - N - benzyloxycarbonylproline with 1 - aminocyclohexane - 1 - carboxylic acid methyl ester, [alpha]-methylalanine ethyl ester and ([alpha]S) - [alpha] - methylphenylalanine methyl ester respectively, which are made by esterifying the appropriate acids, the latter compounds being obtained by the hydrolysis of the nitriles resulting from the reaction of an alkali metal cyanide and an ammonium salt on cyclohexanone, acetone and benzylmethyl ketone respectively, and in the case of the racemic acid resulting from the hydrolysis of 1-phenyl-2-amino-2-cyanopropane resolving it into its optical isomers by conversion into a salt with (+)-camphor-10- sulphonic acid. S(+) - 2 - Benzyloxy - 2 - isopropylmalonic acid chloride monethyl ester and S(+)-2-benzyloxy - 2 - propylmalonic acid chloride monoethyl ester are prepared by reacting thionyl chloride with the corresponding monoethyl esters, obtained by resolving, by formation of salts with pseudoephedrine, the racemic mixtures resulting from the partial hydrolysis of the corresponding racemic diethyl esters, which are in turn obtained by reacting diethyl 2-hydroxy-2-isopropylmalonate with benzyl bromide and diethyl-2- propylmalonate with dibenzyl peroxide respectively. Pharmaceutical compositions, suitable for oral, parenteral or enteral administration contain the above novel lysergic acid derivation of Formula I above or the pharmaceutically acceptable acid addition salts as the active ingredient. The above compositions are suitable for the treatment of migraine attacks and other vascular headaches, hypotonic conditions of various organs, and the hydrogenated and 1- methylated derivatives are also suitable for the prophylactic treatment of vascular headaches.