Patent GB-1266744-A (GB)
IPC: A61K31/48
Filed: 1969-06-09
Abstract: 1,266,744. Ergoline and oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine derivatives. SANDOZ Ltd. 9 June, 1969 [25 June, 1968], No. 29077/69. Heading C2C. Novel ergoline derivatives of the Formula I wherein R 1  is hydrogen or methyl, acid addition salts thereof are prepared by condensing an acid addition salt of the compound of Formula II in a solvent which is inert under the reaction conditions and in the presence of a basic condensation agent, with a reactive functional derivative of 9,10-dihydrolysergic acid or 1-methyl-9,10- dihydrolysergic acid, or by methylating a compound of Formula I above in which R 1  is hydrogen, or by catalytically hydrogenating the corresponding compounds of Formula I in which there is a double bond in the 9,10-positions. The acid addition salts of Formula II are made by hydrogenolysing, in acid solution, (2R,5S,10aS,10bS) - 2 - benzyloxycarbonylamino- 3,6 - dioxo - 10b - hydroxy - 2 - isopropyl - 5- (propyl - 1) - octahydro - 8H - oxazolo[3,2 - a]- pyrrolo[2,1-c]pyrazine XI which is prepared from N - carbobenzoxy - L - proline (III) and L-norvaline methyl ester (IV) by the sequence: III + IV # N - carbobenzoxy - L - prolyl - L- norvaline methyl ester # L-prolyl-L-norvaline methyl ester # -L-prolyl-L-norvaline methyl ester # (3S,8aS) 1,4 - dioxo - 3 - (propyl - 1)- octahydropyrrolo[1,2 - a]pyrazine # (3S,8aS)- 1,4 - dioxo - 2 - (2 - benzyloxy - 2 - ethoxycarbonyl- 3 - methyl - 1 - oxobutyl) - 3 - (propyl - 1)octahydropyrrolo [1,2-a] pyrazine# (2R,5S,10aS,- 10bS) - 2 - ethoxycarbonyl - 3,6 - dioxo - 10bhydroxy - 2 - isopropyl - S - (propyl - 1)octahydro- 8H - oxazolo[3,2 - a]pyrrolo[2,1 - c]pyrazine # (2,R,5S,10aS,10bS) - 2 - carboxy - 3,6 - dioxo- 10b - hydroxy - 2 - isopropyl - 5 - (propyl - 1)octahydro - 8H - oxazolo[3,2 - a]pyrrolo[2,1 - c]pyrazine # (2R,5S,10aS,10bS) - 2 - chloroformyl (or bromoformyl) - 3,6 - dioxo - 10b - hydroxy - 2- isopropyl - 5 - (propyl - 1) - octahydro - 8H - oxazolo[3,2 - a]pyrrolo[2,1 - c]pyrazine # (2R,5S, 10aS,10bS) - 2 - azidocarbonyl - 3,6 - dioxo - 10bhydroxy - 2 - isopropyl - 5 - (propyl - 1) - octahydro - 8H - oxazolo[3,2 - a]pyrrolo[2,1 - c]pyrazine # XI. 2<SP>1</SP># - Isopropyl - 5<SP>1</SP>α - n - propylergopeptine and 1 - methyl - 2<SP>1</SP># - isopropyl - 5<SP>1</SP>α - n - propylergopeptine are made by reacting a reactive functional derivative of lysergic acid or 1- methyl-lysergic acid with an acid addition salt of the compound of Formula II. S(+) - 2 - Benzyloxy - 2 - isopropylmalonic acid chloride monoethyl ester is made by reacting thionyl chloride with R(+)-2-benzyloxy-2-isopropylmalonic acid monoethyl ester, obtained by resolving the salt obtained by reacting l-pseudoephedrine with 2-benzyloxy-2-isopropylmalonic acid monoethyl ester, which is prepared by hydrolysing 2-benzyloxy-2-isopropylmalonic acid diethyl ester, resulting from the reaction of diisopropyl sulphate or isopropyl iodide on diethyl 2-benzyloxymalonate or of benzyl bromide on diethyl 2-hydroxy-2-isopropylmalonate. Pharmaceutical compositions suitable for oral enteral or parenteral administration, comprise as active ingredients compounds of Formula I or pharmaceutically acceptable acid addition salts thereof in association with pharmaceutically acceptable carriers or diluents. The compositions are suitable for the treatment of circulatory illnesses, for example, cerebral or peripheral blood circulation disorders, and the prophylaxis of vascular headaches.