EP0018231A2
Expired / Lapsed
EP
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A process for the preparation of bis-indole-alkaloids and acid addition salts thereof and new bis-indole-alkaloids, pharmaceutical compositions containing them and their use as antitumour agents
Assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
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Filing: 1980-04-22
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Granted: —
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Expires: 2000-04-22
Abstract
Abstract A proces for the oxidation of vinblastine, leurosine or an acid addition salt thereof which comprises reacting the vinblastine, leurosine or acid addition salt thereof with chromic acid or an alkali metal dichromate, at a temperature of from -30 °C to 90°C in the presence of a water immiscible organic solvent in which alkaloids are readily soluble, acetic anhydride and optionally glacial acetic acid and/or up to 10% by volume of ethanol based on the volume of the water-immiscible organic solvent; thereafter adjusting the pH of the reaction mixture to from 8 to 10; and isolating the products obtained and/or subjecting the said products to further treatment. The specification also describes new bis-indole-alkaloids, pharmaceutical compositions containing them and their use as anti-tumour agents.
Inventors
- 👤 Karola Jovanovics
- 👤 Sandor Gorog
- 👤 Sandor Eckhardt
- 👤 Janos Sugar
- 👤 Zsuzsa Somfai
- 👤 Elek Farkas
- 👤 Ivan Hindy
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-06 14:03
CPC Classifications
C; C07; C07D; C07D519/00; C07D519/04; A; A61; A61P; A61P35/00
Claims Analysis
Total Claims: 11
Claim 1
Independent Claim
105 words
A process for the oxidation of vinblastine, leurosine or an acid addition salt thereof which comprises reacting the vinblastine, leurosine or acid addition salt thereof with chromic acid or an alkali metal dichromate, at a temperature of from -30°C to -90°C in the presence of a water-immiscible organic solvent in which alkaloids are readily soluble, acetic anhydride and optionally glacial acetic acid and/or up to 10% by volume of ethanol based on the volume of the water-immiscible organic solvent; thereafter adjusting the pH of the reaction mixture to from 8 to 10; and isolating the products obtained and/or subjecting the said products to further treatment.
Claim 2
Dependent Claim
105 words
A process for the oxidation of vinblastine, leurosine or an acid addition salt thereof which comprises reacting the vinblastine, leurosine or acid addition salt thereof with chromic acid or an alkali metal dichromate, at a temperature of from -30°C to -90°C in the presence of a water-immiscible organic solvent in which alkaloids are readily soluble, acetic anhydride and optionally glacial acetic acid and/or up to 10% by volume of ethanol based on the volume of the water-immiscible organic solvent; thereafter adjusting the pH of the reaction mixture to from 8 to 10; and isolating the products obtained and/or subjecting the said products to further treatment.
Claim 3
Dependent Claim
17 words
A process as claimed in claim 1 wherein the water-immiscible organic solvent is chloroform or methylene chloride.
Claim 4
Dependent Claim
37 words
A process as claimed in claim 1 or claim 2 wherein the oxidation is effected in a medium containing ethanol in an amount up to 10% by volume based on the volume of the water-immiscible organic solvent.
Claim 5
Dependent Claim
36 words
A process as claimed in claim 3 wherein the oxidation is effected in a medium containing ethanol in an amount of from 0.1 to 3.0% by volume based on the volume of the water-immiscible organic solvent.
Claim 6
Dependent Claim
23 words
A process as claimed in claim 3 or claim 4 wherein the oxidation is effected at a temperature of from -45°C to -90°C.
Claim 7
Dependent Claim
187 words
A process as claimed in any one of claims 3 to 5 wherein there are isolated from the reaction mixture after adjustment of the pH, either a) where vinblastine or an acid additon salt thereof is used as the starting material: N-desmethyl-vinblastine, vincristine and a compound denoted herein RGH-4451, the said compound RGH-4451 having a melting point of from 235°C to 238°C, a specific rotation f of [α] D 25 = +30.5 (c = l,chloroform), an infrared spectrum as illustrated in Fig. 1, a 1 H-NMR spectrum as illustrated in Fig. 2 and a 13 C-NMR spectrum as illustrated in Fig. 3, b) where leurosine or an acid additon salt thereof is used as the starting material: N-desmethyl-leurosine, N-desmethyl-N-formyl-leurosine and a compound denoted herein RGH-4478, the said compound RGH-4478 having a melting point of from 180°C to 182°C, a specific rotation of [a]D25 = +59.25° (c = 1, chloroform), an infrared spectrum as illustrated in Fig. 4, a 1 H-NMR spectrum as illustrated in Fig. 5 and a 13 C-NMR spectrum as illustrated in Fig. 6, which products are optionally subsequently converted into their acid addition salts.
Claim 8
Dependent Claim
49 words
A process as claimed in any one of claims 3 to 5 wherein the reaction mixture, after adjustment of the pH, is hydrolysed and the mixture of N-desmethyl and N-desmethyl-N-formyl derivatives obtained is either separated or subjected to formylation whereby the N-desmethyl derivative is converted to the N-desmethyl-N-formyl derivative.
Claim 9
Dependent Claim
46 words
A process as claimed in claim 1 or claim 2 wherein the oxidation is effected in the absence of ethanol and the mixture of N-desmethyl and N-desmethyl-N-formyl derivatives obtained is either separated or subjected to formylation whereby the N-desmethyl derivtive is converted to the N-desmethyl-N-formyl derivative.
Claim 10
Dependent Claim
25 words
A process as claimed in claim 7 wherein hydrolysis is effected by means of 0.5 to 5% aqueous sulphuric acid, hydrochloric acid or acetic acid.
Claim 11
Dependent Claim
27 words
A process as claimed in any one of claims 7 to 9 wherein formylation is effected by means of a mixture o formic acid and acetic anhydride.
References Cited (Backward Citations)
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