GB2058746A

GB2058746A - 6,7-Secoergolines

Info

Publication number: GB2058746A
Application number: GB8015592A
Authority: GB
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1979-09-20
Filing date: 1980-05-12
Publication date: 1981-04-15

Abstract

6,7-Secoergolines of the formula <IMAGE> R1=H or CH3. R2=C1-C4 alkyl, benzyl or phenethyl. R3=CN, COR5, CONHR6 or CONR7R8; R5=OH, C1-C4 alkyl, phenyl, alkoxy, NH2; (a) R6=C1-C4 alkyl, or (b) optionally substituted phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or thiazolyl or (c) a cyclol residue of the formula <IMAGE> Z=C1-C3 alkyl W=C1-C4 alkyl or benzyl R7=lower alkyl, R8=lower alkyl or NR7R8 is a heterocyclic ring. R4=H, OH or OCH3, or together with R3 forms a gamma -lactone, which are useful as alpha -andrenergic blocking agents and hypotensives and also show central nervous system stimulant and/or depressant properties and dopaminergic activity, are prepared by cleavage of the corresponding ergoline quaternary salt, followed by hydrogenation the 7,8-didehydro 6,7- secoergoline formed.

Description

SPECIFICATION 6,7-Secoergolines The invention relates to 6,7-secoergoline derivatives, to their pharmaceutically acceptable acid addition salts, and to processes for their preparation.

The invention provides 6,7-secoergolines having the general formula I:

wherein R1 represents a hydrogen atom or a methyl group; R2 represents an alkyl group having from 1 to 4 carbon atoms or a benzyl or phenethyl group; R3 represents a cyano group or a group of the formula COR5,CONHR6,or CONR,R8 wherein R5 represents a hydroxy group, an alkyl group having from 1 to 4 carbon atoms, or a phenyl, alkoxy or amino group, R6 represents an alkyl group having from 1 to 4 carbon atoms, or a substituted or unsubstituted phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or thiazolyl group or a cyclol residue of the general formula

wherein Z represents an alkyl group having from 1 to 3 carbon atoms and W represents an alkyl group having from 1 to 4 carbon atoms or a benzyl group, R, and R8 independently represent lower alkyl groups or together with the nitrogen atom to which they are attached represent a heterocyclic ring; and R4 represents a hydrogen atom, or a hydroxy or methoxy group; or R3 and R4 together form a y-lactone.

If R, and R8 together with the nitrogen atom to which they are attached represent a heterocyclic ring, this may suitably be a pyrrolidine, morpholine, piperidine or piperazine residue.

The invention further provides a process for the preparation of 6,7-secoergolines of the general formula I as above defined, the process comprising cleaving an ergoline quaternary salt of the general formula II below under basic conditions to give a 6,7-secoergoline of the general formula Ill below (Rr, R2, R3 and R4 having the meanings ascribed to them above and A- representing an anion) and catalytically hydrogenating the secoergoline.

The elimination reaction may be carried out with bases such as sodium hydroxide, sodium or potassium or lithium amide, sodium hydride, lithium tetramethylpiperidide or potassium diisopropyl amide in a protic or aprotic solvent such as alcohol, water, liquid ammonia, tetrahydrofuran, dimethylformamide or dimethylsulphoxide at a temperature from -300C to 700C, for a period from 2 to 24 hours.

The hydrogenation process may be carried out in an alcohol at atmospheric pressure or above at ambient temperature in the presence of a suitable catalyst such as platinum or palladium deposited on a suitable support such as carbon or barium sulphate. When the reaction is complete the product may be isolated and purified according to known techniques.

The compounds according to the invention and their pharmaceutically acceptable salts display important and unexpected pharmacological properties accompanied by low toxicity. They are useful as a-adrenergic blocking agents and hypotensives, and they show central nervous system stimulant and/or depressant properties as well as dopaminergic activities. Accordingly the invention further provides a pharmaceutical composition comprising a 6,7-secoergoline derivative of the formula I or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

The following Examples illustrate the invention; Example 1 6,6-Dimethyl-8-methoxycarbonyl-1 O-methoxy-7,8-didehydro-6,7-secoergol ine 1.19 ml of methyl iodide were added at room temperature to a suspension of 3 g of 6-methyl-8 methoxycarbonyl-10cr-methoxy-ergoline in 30 ml of nitromethane. The mixture was left under stirring overnight, and then 40 ml of diethyl ether were added. The resultant solid was filtered off and 2 g of it were added to a suspension of 0.420 g of sodium hydride in 60 ml of tetrahydrofuran. The resulting reaction mixture was heated to 600C and maintained under stirring at that temperature for about 8 hours. It was then decomposed at room temperature by the addition of methanol and evaporated to dryness. The residue was extracted into chloroform and washed with water.The chloroform layer was removed by evaporation and the residue crystallized from diethyl ether to give 1 g of 6,6-dimethyl-8 methoxycarbonyl-1 0a-methoxy-7,8-didehydrn-6,7-secoergoline, m.p. 126-128 0C.

Example 2 6,6-Dimethyl-8-methoxycarbonyl-1 Onr-methoxy-6,7-secoergoline A solution of 3 g of 6,6-dimethyl-8-methoxycarbonyl-10a-methoxy-7,8-didehydro-6,7- secoergoline, prepared as described in Example 1, in 100 ml of methanol was hydrogenated in the presence of 0.5 g of 10% palladium-on-carbon. After evaporation off of the solvent the residue was chromatographed on a silica gel column, using chloroform as the eluting solvent, to give 1 g of the title compound, m.p. 230-2320C.

Example 3 6,6-Dimethyl-8-acetyl-7,8-didehydro-6,7-secoergoline Operating as described in Example 1, but employing 6-methyl-8P-acetyl-ergoline, the title compound, m.p. 154-1 560C, was obtained in 70% yield.

Example 4 6,6-Dimethyl-8-carbamoyl-1 Oa-methoxy-6,7-secoergoline Operating as described in Example 2, but employing 6,6-dimethyl-8-carbamoyl-101x-methoxy- 7,8-didehydro-6,7-secoergoline, the title compound is obtained as a foam in 60% yield.

PMR Spectrum (CDCl3): 1.17 6 and 1.23 S (2d, CH3), 2.37 S and 2.43 8 (2s, N(CH3)2).

Example 5 6,6-Dimethyl-8-cyano-7,8-didehydro-6,7-secoergoline Operating as described in Example 1, but employing 6-methyl-8p-cyano-ergoline, the title compound was obtained an an oil in 65% yield.

Example 6 6,6-Dimethyl-8-carbamoyl-6,7-secoergoline Operating as described in Example 2, but employing 6,6-dimethyi-8-carbamoyl-7,8-didehydro- 6,7-secoergoline (m.p. 160--1630C), the title compound, m.p. 140-1 600C, was obtained in 60% yield.

Example 7 6-M ethyl-9. 1 O-d i hyd ro-7.8-d idehyd ro-6.7-secoergota mine Operating as described in Example 1, but employing 9,10-dihydro-ergotamine, the title compound was obtained as an oil in 65% yield.

Example 8 6-Methyl-9,1 O-dihydro-7,8-didehydro-6,7-secoergocristine Operating as described in Example 1, but employing 9,1 0-dihydro-ergocristine, the title compound was obtained as a foam in 70% yield.

PMR Spectrum (CDCl3): 0.8 8 to 1.2 8 (m, CH(CH3)2, 2.27 8 (s, N(CH3)2, 4.63 8 (t, CH(5')), 5.36 8 and 5.83 8 (2m, CH2=).

Example 9 6-Methyl-9,1 0-dihydro-6,7-secoergotarnine Operating as described in Example 2, but employing 6-methyl-9,1 0-dihydro7,8-didehydro-6,7- secoergotamine, prepared as described in Example 7, the title compound was obtained as a foam in 45% yield.

Example 10 6-Methyl-9,10-dihydro-6,7-secoergocristine Operating as described in Example 2, but employing 6-methyl-9,1 0-dihydro7,8-didehydro-6,7- secoergocristine, prepared as described in Example 8, the title compound was obtained as an oil in 50%yield.

PMR Spectrum (DMSO-d): 0.7 S to 1.3 8 (m, CH(CH3)2, CHCH3), 2.23 8 (s, N(CH3)2, 4.25 8 (t, CH(5')).

Example 11 5-Methyl-7,8-d idehydro-6,7-secolumilysergic acid y-lactone Operating as described in Example 1, but employing lumilysergic acid y-lactone, the title compound was obtained in 65% yield.

Example 12 1 ,6-Dimethyl-7,8-didehydro-6,7-secolumilysergic acid y-lactone Operating as described in Example 1, but employing 1 -methyl-lumilysergic acid y-lactone, the title compound, m.p. 179-181 0C, was obtained in 70% yield.

Example 13 6,6-Dimethyl-8-acetyl-6,7-secoergoline Operating as described in Example 2, but employing 6,6-dimethyl-8-acetyl-7,8-didehydro-6,7secoergoline, the title compound was obtained as a foam in 55% yield.

Example 14 6,6-Dimethyl-7,8-didehydro-8-[N-(6'-methoxy-3'-pyridazinyl)-carbamoyl]-6,7-secoergoline Operating as described in Example 1, but employing 6-methyl-8/3-[N-(6'-methoxy-3'-pyridazinyl)- carbamoyl]-ergoline, the title compound was obtained in 70% yield. m.p. 182-1 84cC.

Example 15 6,6-Dimethyl-8-[N-(6'-methoxy-3'-pyridazinyl)-carbamoyl]-6,7-secoergoline Operating as described in Example 2, but employing 6,6-dimethvl-7.8-didehydro-8-[N-(6'- methoxy-3'-pyridazinyl)-carbamoyl]-6,7-secoergoljnet the title compound was obtained as a foam in 45% yield.

Example 16 6,6-Dimethyl-8-methoxycarbonyl-7,8-didehydro-6,7-secoergoline Operating as in Example 1, but employing 6-methyl-8-methoxycarbonyl-ergoline, the title compound, m.p. 130-1 320C, was obtained in 50% yield.

Claims

1. A 6,7-secoergoline having the general formula I as herein defined or a pharmaceutically acceptable salt thereof.

2. 6,6-Dimethyl-8-methoxyca rbonyl- 1 0-methoxy-6,7-secoergoline.

3. 6,6-Dimethyl-8-carbamoyl-l 10ce-methoxy-6,7-secoergoline.

4. 6,6-Dimethyl-8-carbamoyl-6,7-secoergoline.

5.6-Methyl-9,10-dihydro-6,7-secoergotamine.

6.6-Methyl-9,10-dEhydro-6,7-secoergocristine.

7. 6,6-Dimethyl-8-acetyl-6,7-secoergoline.

8. 6,6-Dimethyl-8-[N-(6 '-methoxy-3 '-pyridazinyl)-carba moyl]-6,7-secoergoline.

9. A process for the preparation of a 6,7-secoergoline having the general formula I as herein defined, the process comprising cleaving an ergoline quaternary salt of the general formula II as herein defined by the action of a base, and catalytically hydrogenating the resultant 7,8-didehydro-6,7secoergoline.

10. A process according to claim 9 in which the cleavage reaction is carried out using sodium hydroxide, sodium or potassium or lithium amide, sodium hydride, lithium tetramethylpiperidide or potassium diisopropylamide in a solvent at from -300C to 700C for 2 to 24 hours.

11. A process according to claim 9 or claim 10 in which the hydrogenation reaction is carried out in an alcohol at atmospheric pressure or above at ambient temperature in the presence of a platinum or palladium on carbon or barium sulphate catalyst.

12. A process according to claim 9 substantially as described herein with reference to Examples 1 and 2, or Examples 7 and 9, or Examples 8 and 10, or Examples 3 and 13 or Examples 14 and 1 5.

13. A pharmaceutical composition comprising a 6,7-secoergoline according to any of claims 1 to 8 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.