GB2051049A - Secoergoline Derivatives - Google Patents
Secoergoline Derivatives Download PDFInfo
- Publication number
- GB2051049A GB2051049A GB8015588A GB8015588A GB2051049A GB 2051049 A GB2051049 A GB 2051049A GB 8015588 A GB8015588 A GB 8015588A GB 8015588 A GB8015588 A GB 8015588A GB 2051049 A GB2051049 A GB 2051049A
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- GB
- United Kingdom
- Prior art keywords
- secoergoline
- dimethyl
- didehydro
- general formula
- ergoline
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- 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
There are provided 5,6- secoergoline derivatives of formula <IMAGE> R<1>=C1-C4 alkyl, allyl or 2- phenylethyl. R2=CH2R', CH2NHR'' or COR''' where R'=H, halogen, OH, alkoxy, acyloxy, NH2CO, substituted NH2CO, esterified COOH, tosyloxy, mesyloxy, CN, CH2CN or substituted CH2CN; R''=C1-C4 alkyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl; R'''=alkoxy, NH2 or substituted NH2. R3=R4=H or together R3 and R4 form a double bond. R5=H or CH3. These compounds and their salts are useful alpha -andrenergic blocking agents, hypotensives, central nervous system depressants, antispasmodics, analgesics and antiprolactinic agents. Pharmaceutical compositions containing them and methods of making them are also claimed.
Description
SPECIFICATION
Secoergoline Derivatives
The invention relates to secoergoline derivatives, to processes for their preparation, and to pharmaceutical compositions containing them.
The invention provides 5,6-secoergoline derivatives of the general formula I:
in which R1 represents an alkyl group having from 1 to 4 carbon atoms, an allyl group or a 2phenylethyl group; R2 represents a group of the formula CH2R' or CH2NHR" or COR"'
In which R' represents a hydrogen or halogen atom or hydroxy, alkoxy, acyloxy, carbamoyl, substituted carbamoyl, carboxy ester, tosyloxy, mesyloxy, cyano, cyanomethyl or substituted cyanomethyl group,
R" represents an alkyl group having from 1 to 4 carbon atoms or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or thiazolyl group, and
R"' represents an alkoxy, amino group or substituted amino group;
R3 and R4 both represent hydrogen atoms or together form a double bond; and R5 represents a hydrogen atom or a methyl group.
An example of a substituted cyanomethyl group which R' may represent is that of the formula -CH(CN)-CONH2. Examples of substituted amino groups which R"' may represent are 3hydroxypropylamino, cycloalkylamino, piperidino, 1-pyrrolidinyl and morpholino groups, and a cyclitol amine residue of the formula
in which A represents a methyl or isopropyl group and B represents a benzyl, isopropyl, isobutyl or s-butyl group.
5,6-Secoergoline derivatives of the general formula I can be prepared by processes within the scope of the invention from 9,1 O-didehydroergoline derivatives li, 8,9-didehydro-1 0-methoxy-ergoline derivatives Ill and 1 0-methoxy-ergoline derivatives IV, wherein the Imeanings of R2 and R5 are as defined above.
These ergoline derivatives of the formulae II, 111 and iV are known compounds or can be readily prepared by established procedures, see United States Patent Specifications Nos. 3,814,765 and 3,228,943;Tetrah. 25,2401 (1969); Belgian Patent Specification No.712,054; and Czech. Chem.
Comm. 36,2200 (1971).
The processes are carried out by reacting the ergoline derivatives of the formula II, Ill and IV with an appropriate alkyl halide R,Hal wherein R, has the meaning given above and Hal represents a halogen atom to give the corresponding quaternary ammonium salt. This is then reduced, in liquid ammonia, with an alkali metal such as lithium, sodium or potassium. The reduction is carried out at a temperature of from -600C to -300C, preferably for a time of from 2 to 3 hours. When the reduction is over, the liquid ammonia is distilled off and the resultant residue may be isolated and purified by conventional procedures.
The 5,6-secoergolines of the formula I, wherein R3 and R4 together represent a double bond, may be obtained from the 9,1 0-didehydroergolines II and 8,9-didehydro-1 0-methoxy ergolines Ill in the absence of a proton source.
The 5,6-secoergolines of the formula I, wherein both R3 and R4 represent hydrogen atoms, may be obtained from 9,10-didehydroergolines 11,8,9-didehydro-10-methoxy-ergolines III and 10-methoxy ergolines IV using methanol, ethanol or t.butanol as a proton source.
The 5,6-secoergolines of the formula I are generally yellowish or white oils. Those in which R3 and R4 both represent hydrogen atoms are prepared as a mixture of 1 ova and 1 OP isomers which can eventually be separated by chromatography. Those in which R3 and R4 together represent a double bond are prepared as a mixture of stereoisomers at C8 and also, eventually, cis-trans stereoisomers.
The new 5,6-secoergoline derivatives of the formula I and their pharmaceutically acceptable salts are useful as a-adrenernic blocking agents, hypotensives, central nervous system depressants, antispasmodics, analgesics and antiprolactinic agents. Accordingly the invention further provides a pharmaceutical composition comprising a 5,6-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-hydroxymethyl-5,6-secoergoline 0.87 ml of methyl iodide were added at room temperature to a suspension of 2 g of 1 0-methoxy 6-methyl-8P-hydroxy-methyl-ergoline in 30 ml of nitromethane. After 24 hours under stirring at room temperature the suspension was filtered and the solids were washed with diethyl ether. The washed solids were dissolved in 350 ml of liquid ammonia and 0.5 ml of methanol and 0.80 g of sodium metal were added at -600C. The reaction mixture was kept at -600C for 1 hour. It was then treated with solid ammonium chloride, allowed to come to room temperature and left until all the liquid ammonia had evaporated off. The residue was treated with water and extracted with chloroform.Evaporation off of the solvent gave 1.5 g of 6,6-dimethyl-8-hydroxymethyl-5,6-secoergoline as a yellowish oil.
ajax: 225,284,293 nm (MeOH)
PMR spectrum (CDC13): 2.33 a (s, Me2N)
IR (KBr): 1025 cm-l (vC-O) MS: m/e 272 (M+) 227 (M-Me2NH), 58 CH2=NMe2)
The title compound may also be obtained by operating as above described, but employing 9,10 didehydro-6-methyl-8,8-hydroxymethyl-ergoline in place of 10-methoxy-6-methyl-8p-hydroxymethyl- ergoline.
Example 2 6,6-dimethyl-8-carbamoylmethyl-5,6-secoergol ine
Operating as in Example 1, but employing 10-methoxy-6-methyl-8p-carbamoylmethyl-ergoiine in place of 10-methoxy-6-methyl-8/3-hydroxymethyl-ergoline, the title compound was obtained in 80% yield as a yellowish-oil: Amax 225,284, 293 nm (MeOH)
PMR spectrum (CDCl3): 2.1 6 and 2.22 a (s, NMe2) IR (KBr): 1660 cm-' (vC=O)
MS: m/e 299 (M+), 254 (M-Me2NH), 58 (CH2=NMe)
Example 3 6,6-dimethyl-8-(2-carbamoyl-2-cyano-ethyl)-5,6-secoergoline Operating as in Example 1, but employing 1 O-methoxy-6-methyl-8P-(2-ca rba moyl-2-cyano- ethyl)-ergoline in place of 1 0-methoxy-6-methyI-8-hydrnxymethyl-ergoline, the title compound was obtained in 80% yield as a yellowish-oil.
Amax 225,284, 293 nm (MeOH)
PMR spectrum (CDCl3): 2.1 7 and 2.23 S (s, Me2N)
IR (KBr): 2240 cm-1 (vC=-N), 1685 cm- (vC=O) 3 MS: m/e 338 (M+), 293 (M-Me2NH), 58 CH2=N-Me2) Example 4 6,6-dimethyl-8-cyanomethyl-5,6-secoergol ine
Operating as in Example 1, but employing 10-methoxy-6-methyl-8ss-cyanomethyl-ergoline in place of 1 0-methoxy-6-methyl-8,B-hydroxymethyl-ergoline, the title compound was obtained as a white oil in 50% yield after chromatography over on silica gel.
Amax 225,284, 293 nm (MeOH)
PMR spectrum (CDCl3: 2.12 and 2.21 #(s, NMe2)
IR (CHCl3): 2240 cm-1 (#C#N) MS: m/e 281 (M+), 236 (M-Me2NH), 58 (CH2=NMe2)
Example 5 6,6-dimethyl-8-acetoxymethyl-5,6-secoergoline
Operating as in Example 1, but employing 10-methoxy-6-methyl-8ss-acetoxymethyl-ergoline in place of 10-methoxy-6-methyl-8ss-hydroxymethyl-ergoline, the title compound was obtained as a white oil in 70% yield after chromatography over silica gel
Amax 225,284, 293 nm (MeOH)
PMR spectrum (CDCl3): 2.04, 2.14 and 2.56 a (s, NMe2 and MeCO)
IR (film): 1730 cm-l (vC=O), 1240 cm-l (vC-O) Example 6 6,6-di methyl-8-benzoyloxymethyl-5,6-secoergoline
Operating as in Example 1, but employing 10-methoxy-6-methyl-8ss-benzoyloxymethyl-ergoline in place of 10-methoxy-6-methyl-8ss-hydroxymethyl-ergoline, the title compound was obtained as a white oil in 75% yield after chromatography over silica gel.
Amax 225, 284, 293 nm (MeOH)
PMR spectrum (CDCI3): 2.25 a (s, Me2N), 6.5-8.4 a (m, 9 aromatic protons)
IR(film): 1715 cm-' (vC=O), 1275 cm- (vC--O), 750 and 710 cm-' (mono-substituted phenyl group)
Example 7 6,6-dimethyl-8-(5'-bromonicotinoyloxymethyl)-5,6-secoergoline Operating as in Example 1, but employing 1 0-methoxy-6-methyl-8,B-(5'- bromonicotinoyloxymethyl)-ergoline in place of 10-methoxy-6-methyl-8ss-hydroxymethyl-ergoline, the title compound was obtained as a yellowish oil in 60% yield after chromatography over silica gel )Qmax 225, 284, 293 nm (MeOH).
PMR spectrum (CDCl3): 2.30 and 2.39 S (s, NMe2), 8.3-9.3 a (m, 3 pyridine ring protons) lFl(film): 1720 cm- (vC=O), 1270 cm-1 (vC-O) 0
MS: m/e 457 and 455 (M+), 58 (CH2=N-Me2) Example 8 6,6-di methyl-8-(3',5'-dimethyl-2'-pyrrocarbonyloxymethyl)-5,6-secoergoline Operating as in Example 1, but employing 10-methoxy-6-methyl-8ss-(3',5'-dimethyl- 2-pyrrocarbonyloxymethyl)-ergoline in place of 10-methoxy-6-methyl-8ss-hydroxymethyl-ergoline, the title compound was obtained as a white oil in 80% yield after chromatography over silica gel Amax 224,278 nm (MeOH)
PMR spectrum (CDCl3): 2.17, 2.20, 2.25 and 2.33 a (s, NMe2 and Me) IR (KBr): 1660 cm-' (vC=O), 1275 cm- (vC-O) 0
MS: m/e 393 (M+), 348 (M-Me2NH), 58 (CH2=NMe2)
Example 9 6,6-dimethyl-8-carbamoyl-5,6-secoergoline
Operating as in Example 1, but employing 10-methoxy-6-methyl-8P-carbamoyl-ergoline in place of 10-methoxy-6-methyl-8ss-hydroxymethyl-ergoline, the title compound was obtained in 70% yield as a yellowish oil.
Amax 225,284,293 nm (MeOH) PMR spectrum (CDCI3): 2.16 and 2.26 S (s, NMe2) MS: m/e 285 (M+),240 (M-Me2NH), 58 (CH2=NMe2)
The title compound may also be obtained by operating as described in Example 1, but employing lysergic acid amide in place of 10-methoxy-6-methyl-8jB-hydroxymethyl-ergoline.
The title compound may also be obtained by operating as described in Example 1, but employing 1 0-methoxy-6-methyl-8,9-didehydro-8-carbamoyl-ergoline in place of 10-methoxy-6-methyl-8p- hydroxymethyl-ergoline.
Example 10 6,6-di methyl-8-carbamoyl-9,1 0-didehydro-5,6-secoergoline
Operating as in Example 1, but employing 1 0-methoxy-6-methyl-8,9-didehydro-8-carbamoyl- ergoline in place of 10-methoxy-6-methyl-8,B-hydroxymethyl-ergoline and without addition of methanol, the title compound was obtained as a yellowish oil in 40% yield after chromatography over silica gel Amax 224,240,317 nm (MeOH).
PMR spectrum (C5D5N): 2.28 a (s, NMe2), 3.8-4.3 a (m, C(8)-H), 6.64 a (d, J=9Hz, C(9)H)
MS: m/e 283 (M+), 238 (M-Me2NH, 58 (CH2=NMe2)
The title compound may also be obtained by operating as above described, but employing lysergic acid amide in place of 1 0-methoxy-6-methyl-8,9-didehydro-8-carba moyl-ergoline.
Example 11 6,6-dimethyl-5,6-secoergotamine Operating as in Example 1, but employing 8,9-didehydro-1 0-methoxy-9,1 0-dihydroergotamine in place of 10-methoxy-6-methyl-8ss-hydroxymethyl-ergoline and without addition of methanol, the title compound was obtained as a white foam in 40% yield after chromatography over silica gel.
Amax 224, 240,315 nm (MeOH).
PMR spectrum (CsDsN): 1.80 a (s, Me), 2.28 and 2.29 a (s, NMe2), 6.48 (d, J=9 Hz, C(9)-H) Field desorption mass spectrum: m/e 597 (M+)
The title compound may also be obtained by operating as above described, but employing ergotamine in place of 8,9-didehydro-1 0-methoxy-9,1 0-dihydroergotamine.
Example 12
By methods analogous to those described in the previous Examples, the following compounds have been prepared: 6,6-dimethyl-5,6-secodihydroergotamine, 6,6-dimethyl-5,6-secodihydroergocristine, 6,6-dimethyl-5,6-secodihydroergocryptine, 6,6-dimethyl-5,6-secodihydroergocornine, 6,6-dimethyl-5,6-secoergocryptine, 6,6-dimethyl-9, 10-didehydro-5,6-secoergometrine, 6,6-dimethyl-8-diethylcarbamoyl-9,10-didehydro-5,6-secoergoline, 6,6-dimethyl-9, 10-didehydro-8-aminomethyl-5,6-secoergoline, 6,6-dimethyl-8-hydroxymethyl-9,10-didehydro-5,6-secoergoline, 6,6-dimethyl-8-(N-[1 '-pyrimidinyl]-aminomethyl)-5,6-secoergoline, 6,6-dimethyl-8-(N-[1 '-pyridinyl]-aminomethyl)-5,6-secoergoline, 6,6-dimethyl-8-(N-[1 '-pyrazinyl]-aminomethyl)-5,6-secoergoline, and 6,6-dimethyl-8-aminomethyl-5,6-secoergoline.
Claims (30)
1. A 5,6-secoergoline derivative of the general formula I as herein defined or a pharmaceutically acceptable salt thereof.
2. 6,6-dimethyl-8-hydroxymethyl-5,6-secoergoline.
3. 6,6-dimethyl-8-carbamoyl methyl-5,6-secoergoline.
4.2-cyano-3-(6',6'-dimethyl-5',6'-secoergoline-8')-propionamide.
5.6,6-dimethyl-8-cya nomethyl-5,6-secoergoline.
6. 6,6-dimethyl-8-acetoxymethyl-5,6-secoergoline.
7. 6,6-dimethyl-8-benzoyloxymethyl-5,6-secoergoline.
8. 6,6-dimethyl-8-(5'-bromonicoti noyloxymethyl)-5,6-secoergoline.
9. 6,6-dimethyl-8-(3',5'-dimethyl-2'-pyrroca rbonyloxy-methyl)-5,6-secoergoline.
10. 6,6-dimethyl-8-carba moyl-5,6-secoergoline.
11. 6,6-dimethyl-8-carbamoyl-9,10-didehydro-5,6-secoergoline.
12. 6,6-dimethyl-5,6-secoergotamine.
13. 6,6-dimethyl-5,6-secodihydroergotamine.
14. 6,6-dimethyl-5,6-secodihydroergocristi ne.
15. 6,6-dimethyl-5,6-secodihydroergocryptine.
16. 6,6-dimethyl-5,6-secodi hydroergocornine.
1 7. 6,6-dimethyl-5,6-secoergocrypine.
1 8. 6,6-dimethyl-9,1 O-didehydro-5 ,6-secoergometrine.
1 9. 6,6-dimethyl-8-diethylcarbamoyl-9, 1 0-didehydro-5,6-secoergoline.
20. 6,6-dimsthyl-9,10-didehydro-8-aminomethyl-5,6-secoergoline.
21. 6,6-dimethyl-8-hydroxymethyl-9,10-didehydro-5,6-secoergoline.
22. 6,6-dimethyl-8-(N-[1 '-pyrimidinyl]-aminomethyl)-5,6-secoergoline.
23. 6,6-dimetliyl-8-(N-[1 t-pyridinyl]-a minomethyl)-5,6-secoergoline.
24. 6,6-dimethyl-8-(N-[1 t-pyrazinyl]-aminomethyl)-5,6-secoergoline.
25. 6,6-dimetyl-8-aminomethyl-5,6-secoergoline.
26. A process for the preparation of a 5,6-secoergoline derivative of the general formula I wherein R3 and R4 together represent a double bond and Fl1, R2 and R5 are as herein defined, the process comprising reacting a 9,1 0-didehydro-ergoline of the general formula II as herein defined or an 8,9-didehydro-1 0-methoxy-ergoline of the general formula Ill as herein defined with an alkyl halide of the general formula R1Hal as herein defined in the absence of a proton source and reducing the resultant quaternary ammonium salt with an alkali metal in liquid ammonia at from -600C to -300C.
27. A process for the preparation of a 5,6-secoergoline derivative of the general formula I wherein R3 and R4 both represent hydrogen atoms and R1 R2 and Rs are as herein defined, the process comprising reacting a 9,10-didehydro-ergoline of the general formula II as herein defined, an 8,9 didehydro-10-methoxy-ergoline of the general formula Ill as herein defined or a 1 0-methoxy-ergoline of the general formula IV as herein defined with an alkyl halide of the general formula R1Hal as herein defined in the presence of methanol, ethanol or t.butanol as a proton source and reducing the resultant quaternary ammonium salt with an alkali metal in liquid ammonia at from -600C to -300C.
28. A process according to claim 26 or claim 27 in which the reduction is carried out for from 2 to 3 hours.
29. A process according to claim 26 or claim 27 substantially as described herein with reference to any of the Examples.
30. A pharmaceutical composition comprising a 5,6-secoergoline derivative according to any of claims 1 to 25 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8015588A GB2051049A (en) | 1979-05-16 | 1980-05-12 | Secoergoline Derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7917079 | 1979-05-16 | ||
| GB8015588A GB2051049A (en) | 1979-05-16 | 1980-05-12 | Secoergoline Derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2051049A true GB2051049A (en) | 1981-01-14 |
Family
ID=26271547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8015588A Withdrawn GB2051049A (en) | 1979-05-16 | 1980-05-12 | Secoergoline Derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2051049A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 GB8015588A patent/GB2051049A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |