IL47522A - 6-demethyl-6-alkyl ergot peptide alkaloids their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

1499420 9,10-Dihydroergopeptine derivatives SANDOZ Ltd 16 June 1975 [21 June 1974] 25527/75 Heading C2C Novel compounds of the Formula I wherein R 1 is C 2-5 alkyl and R 2 is methyl or ethyl and acid addition salts thereof may be prepared by condensing a functional derivative of a compound II with an acid addition salt of a compound III 6 - Nor - 6 - isopropyl - 9,10 - dihydrolysergic acid is prepared by N-alkylation of 6-nor-9,10- dihydrolysergic acid methyl ester, followed by saponification of the ester. Its acid choride is formed in situ using oxalyl chloride. Pharmaceutical compositions of the compounds I with the usual excipients show vasoconstricter activity. [GB1499420A]

Description

on a The present invention relates to new peptide In accordance with the invention there are provided new compounds of formula wherein is alkyl of 2 to 5 carbon is methyl or and acid addition salts in accordance with the invention a compound of I may be obtained by a process comprising condensing a reactive functional derivative of an acid of formula 2 wherein is as defined with a compound of formula wherein is as defined above acid addition salt preferably is especially in the a position to the nitrogen atom to which it is The reaction of the invention is a condensation reaction for It may be carried out in a manner analogous to known The condensation is effected in an inert organic solvent or solvent mixture in the presence of an For the condensation may be effected using as reactive functional derivative of an acid of formula II the addition product resulting from the reaction of an acid of formula II with a chlorinating agent and an acid amide of an aliphatic carboxylic acid of 1 to 3 carbon 3 such as or Other reactive derivatives of an acid of formula which may be produced in accordance with known the acid chloride the acid azide or mixed anhydrides of an acid of formula II with sulphuric acid or trifluoroacetic may alternatively be Suitable organic solvents for methylene acetonitrile or dimethyl and suitable agents are tertiary organic pyridine or homologues Examples of chlorinating agents which may be used are thionyl phosgene or oxalyl The reaction may be effected at a temperature between and and at normal It is convenient to use to mols of an acid of formula II for every mol of a compound of formula III in salt The preferred salt form of the compounds of formula III is the The course of the reaction is independent of the sequence of addition of the The working up of the reaction mixture and isolation of the compounds of formula I may be effected in known Acid addition salt forms may be obtained in known manner from the free bases and vice A suitable acid is tartaric 4 The compounds of formula required as starting are new and may be obtained in accordance with known For a compound of formula wherein is as defined may be saponified under mild alkaline veniently by treatment with caustic soda solution in an organic solvent or solvent and may then be weakly The compounds of formula IV may be obtained by alkylation of acid methyl The compounds of formula III are In the following Examples all temperatures are indicated in degrees Centigrade and are Insofar as the production of the starting materials is not these are known or may be produced in accordance with known processes or in a manner analogous to known 5 which is named ergopeptine for the sake of simplicity EXAMPLE cc of oxalyl chloride dissolved in 20 cc of acetonitrile are added at to within 10 minutes to a solution of 300 cc of dimethyl formamide and 150 cc of and stirring is effected for a further 10 32 g of anhydrous acid then sprinkled into the solution at and stirring is effected at for 30 After cooling to 200 cc of pyridine and g of 3 hydrochloride are and stirring is effected at for 2 p effected by adding 100 cc of a buffer solution pH and distributing the reaction mixture between methylene chloride and a 2N sodium bicarbonate The organic phases are washed with dried with sodium sulphate and evaporated to dryness on a rotary After drying in a high the resulting crude base is dissolved in about 150 cc of ethanol and the solution is The title compound has an of in in 120 cc of ethanol at about and acid dissolved in about 10 cc of ethanol are After cooling to room the salt The precipitated salt is separated from the mother is washed with a small amount of ethanol and is then dried in a high vacuum at used as starting for be obtained by alkylation of acid methyl ester with isopropyl bromide and ation of the resulting lysergic acid ester rgic has an of in EXAMPLE Production in a manner analogous to that described in Example The title compound has an of in methylene 8 The compounds exhibit pharmacological In they exhibit vasoconstrictor as indicated by pressor activity indicated in standard in the pithed rat test and Br J Pharmac and in the test arterial vasotonic The compounds are therefore further indicated for use as vasoconstrictor agents possibly for the treatment of For this use an indicated daily dose is from about to about 3 convenient ly administered in divided doses 2 to 4 times a day in unit dosage form containing from about to about or in sustained release The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form The present invention also provides a pharmaceutical composition comprising a compound of formula free base form or in pharmaceutically acceptable acid addition salt in association with a pharmaceutical carrier or Such compositions may be formulated in conventional manner so as to for a solution or a In a group of compounds is isopropyl and especially is insufficientOCRQuality

Claims (10)

- 9 - 100-4192

1. A process for the production of a compound formula I, wherein is alkyl of 2 to 5 carbon atoms, and is methyl or ethyl, R2 comprising condensing a reactive functional derivative of an acid of formula II, II 47522/2 wherein is as defined above, with a compound of formula III, wherein R2 is as defined above, acid addition salt form.

2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Examples.

3. A compound of formula I, whenever produced by a process according to claim 1 or 2.

4. A compound of formula I, as defined in claim 1, and acid addition salts thereof.

5. A compound of claim 4 wherein is a Cg_5 a-branched alkyl. I

6. 6-demethyl-6-isopropyl-9 , 10-dihydro-2 ' &- methyl-5 ' a-isopropyl-ergopeptine. - 47522/2

7. 6-demet& l-6-isopropyl-9,10-dJiiydro- ^ 2*g-ethyl-5* a-isopropyl-ergopeptine.

8. A compound according to any one of claims 3 to 7 in free base form.

9. A compound according to any one of claims 3 to 7 in acid addition salt form.

10. A pharmaceutical composition comprising a compound according to any one of claims 3 to 7 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. PC:gd