GB2058746A - 6,7-Secoergolines - Google Patents
6,7-Secoergolines Download PDFInfo
- Publication number
- GB2058746A GB2058746A GB8015592A GB8015592A GB2058746A GB 2058746 A GB2058746 A GB 2058746A GB 8015592 A GB8015592 A GB 8015592A GB 8015592 A GB8015592 A GB 8015592A GB 2058746 A GB2058746 A GB 2058746A
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- GB
- United Kingdom
- Prior art keywords
- secoergoline
- dimethyl
- alkyl
- examples
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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 (13)
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.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8015592A GB2058746A (en) | 1979-09-20 | 1980-05-12 | 6,7-Secoergolines |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7932589 | 1979-09-20 | ||
GB8015592A GB2058746A (en) | 1979-09-20 | 1980-05-12 | 6,7-Secoergolines |
Publications (1)
Publication Number | Publication Date |
---|---|
GB2058746A true GB2058746A (en) | 1981-04-15 |
Family
ID=26272949
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8015592A Withdrawn GB2058746A (en) | 1979-09-20 | 1980-05-12 | 6,7-Secoergolines |
Country Status (1)
Country | Link |
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GB (1) | GB2058746A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0070562A1 (en) * | 1981-07-21 | 1983-01-26 | FARMITALIA CARLO ERBA S.p.A. | Ergoline derivatives, processes for their preparation and pharmaceutical compositions containing them |
US4632990A (en) * | 1982-04-13 | 1986-12-30 | Farmitalia Carlo Erba S.P.A. | Ergoline carboxamides |
US4654345A (en) * | 1984-10-24 | 1987-03-31 | Sandoz Ltd. | Occular formulation comprising bromocriptine |
CN115894519A (en) * | 2022-10-21 | 2023-04-04 | 浙江大学 | Tripeptide alkaloid compound and preparation method and application thereof |
-
1980
- 1980-05-12 GB GB8015592A patent/GB2058746A/en not_active Withdrawn
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0070562A1 (en) * | 1981-07-21 | 1983-01-26 | FARMITALIA CARLO ERBA S.p.A. | Ergoline derivatives, processes for their preparation and pharmaceutical compositions containing them |
US4675404A (en) * | 1981-07-21 | 1987-06-23 | Farmitala Carlo Erba S.P.A. | 8-pyridazinylcarbamoyl ergolines |
US4632990A (en) * | 1982-04-13 | 1986-12-30 | Farmitalia Carlo Erba S.P.A. | Ergoline carboxamides |
US4654345A (en) * | 1984-10-24 | 1987-03-31 | Sandoz Ltd. | Occular formulation comprising bromocriptine |
CN115894519A (en) * | 2022-10-21 | 2023-04-04 | 浙江大学 | Tripeptide alkaloid compound and preparation method and application thereof |
CN115894519B (en) * | 2022-10-21 | 2024-05-17 | 浙江大学 | Tripeptide alkaloid compound and preparation method and application thereof |
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Legal Events
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WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |