DE3018543A1 - SECOERGOL DERIVATIVES - Google Patents

Description

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description

The invention relates to secoergoline derivatives, processes for their production and pharmaceutical preparations containing them.

The invention relates to 5 »6-Secoergoline derivatives of the general Formula I.

R ₁ denotes an alkyl group having 1 to 4 carbon atoms, an allyl group or a 2-phenylethyl group;

R ₂ denotes a group of the formula CH ₂ R ¹ or CH ₂ NHR "or COR" ¹ , in which R ^{1 represents} a hydrogen or halogen atom or a hydroxy, alkoxy, acyloxy, carbamoyl, substituted carbamoyl, carboxy ester , Tosyloxy, mesyloxy, cyano f , cyanomethyl or substituted cyanomethyl group, R "is an alkyl group having 1 to 4 carbon atoms or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or thiazolyl group and R" ^{1 is} an alkoxy -, amino or substituted amino group;

R, and R ^ both represent a hydrogen atom and together form a double bond; and

Rc represents a hydrogen atom or a methyl group ..-'.- "" -

0 300A8 / 076 6

An example of a substituted cyanomethyl group which R 'may represent is that of the formula -CH (CN) -CONH ₂ . Examples of substituted amino groups which R ″ can mean are 3-hydroxypropylamino, cycloalkylamino, piperidino, 1-pyrrolidinyl and morpholino groups and a cyclitol radical of the formula

- HN

where A denotes a methyl or isopropyl group and B denotes a benzyl, isopropyl, isobutyl or s-butyl group stands.

5,6-Secoergoline of the general formula I can after Process according to the invention from 9 »10-didehydroergoline derivatives (II.), 8,9-didehydro-10-methoxyergoline derivatives (III) and 1O-methoxyergoline derivatives (IV) produced who

den, where the substituents have meaning.

N - CH

and R, - the one given above

II

N-CH.

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CH.

IV

These ergoline derivatives of the formulas II, III and IV are known Compounds or can be easily prepared by well known methods [see FIG. U.S. Patents 3,814,765 and 3,228,943; Tetrah. 25: 2401 (1969); BE-PS 712 054; and Czech.Chem.Comm. 36, 2200 (1971)].

The processes are carried out by reacting the ergoline derivatives of the formulas II, III and IV with a suitable alkyl halide of the formula R ₁ Hai, in which R _{1 has} the meaning given above and Hai is a halogen atom, to form 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 conducted at a temperature from -60 to -30 ⁰ C, preferably for a period of 2 to 3 hours is performed. When the reduction is complete, the liquid ammonia is distilled off and the resulting residue can be isolated and purified by methods known per se.

The 5,6-secoergolines of the formula I, in which R 1 and R ^ together can mean a double bond from 9,10-didehydroergolines (II) and 8,9-didehydro-10-methoxyergolines (III) can be prepared in the absence of a proton source.

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The 5 | 6-secoergolines of the formula I, in which. R ^ and. R ^ both Can mean hydrogen atoms from 9,10-didehydroergolines (II), 8,9-didehydro-10-methoxyergolines (III) and 10-methoxyergolines (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 R- * and R ^ are both hydrogen atoms are obtained as a mixture of the 10a and 10β isomers, which can ultimately be separated by chromatography. Such compounds in which R 1 and R together represent a double bond are obtained as a mixture of the stereoisomers at C _Q and also possibly as cis-trans stereoisomers. *

The new 5,6-secoergoline derivatives of the formula I and their Pharmaceutically acceptable salts are useful oc-adrenergic blockers, antihypertensive agents Agents, central nervous system depressants, antispasmodics, analgesics, and antiprolactin agents. The invention thus further relates to a pharmaceutical preparation which contains a 5,6-secoergoline derivative of the formula I. or one of their pharmaceutically acceptable salts in admixture with a pharmaceutically acceptable diluent or contains carrier.

The following examples illustrate the invention.

example 1

6, e-Dimethyl-S-hydroxymethyl- ^ 16-secoergoline

0.87 ml of methyl iodide become one at room temperature Suspension of 2 g of 10-methoxy-e-methyl-eß-hydroxymethylergoline given in 30 ml of nitromethane. After stirring for 24 hours at room temperature, the suspension is filtered and the solids are washed with diethyl ether. The GE-

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what solids are served in 350 ml of liquid ammonia dissolved and at -60 ° C with 0.5 ml of methanol and 0.80 g of sodium metal offset. The reaction mixture is kept at -60 ° C. for 1 hour. It is then treated with solid ammonium chloride, then allowed to cool to room temperature and left to stand, until all of the liquid ammonia has evaporated. The residue is treated with water and with chloroform extracted. Evaporation of the solvent gives 1 »5 g of ejS-dimethyl-e-hydroxymethyl-Sie-secoergoline as yellowish oil.

^ _max : 225, 284, 293 nm (MeOH)
PMR spectrum (CDCIi) I S 2.33 (S, Me ₂ N) IR (KBr): 1025 cm-T (l / CO) _φ

MS: m / e 272 (M ⁺ ), 227 (M-Me ₂ NH), 58 (CH ₂ = NMe ₂

The title compound can also be obtained by one works as described above, but 9,10-didehydro-6-methyl-8ß-hydroxymethyl-ergoline instead of 10-methoxy-6-methyl-8ß-hydroxymethyl-ergoline used.

B e i s ρ i e 1 2

6, e-Dimethyl-S-carbamoylmethyl-S »6-secoergoline

The procedure is as described in Example 1, but using 10-methoxy-S-methyl-Sß-carbamoylmethyl-ergoline instead of lO-methoxy-e-methyl-eß-hydroxymethyl-ergoline. The title compound is obtained as a yellowish oil in a yield of 80%.

²² 5V 284, 293 nm (MeOH)

PMR spectrum (CDCl ₃ ): ^ 2.16 and 2.22 (S, NMe ₂ )

IR (KBr): 1660 cm " ¹ (\ 7 C = O) Θ

MS: m / e 299 (M ⁺ ), 254 (M-Me ₂ NH), 58 (CH ₂ = NMe).

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Example 3

2-cyano-3- (6 ', 6'-dimethyl-5', 6'-secoergoline-8 ') propionamide

The procedure is as described in Example 1, but using 2-cyano-3- (iO'-methoxy-6'-methyl-ergoline-8'ß) propionamide instead of 10-methoxy-S-methyl-eß-hydroxymethylergoline. The title compound is obtained as a yellowish oil in a yield of 80%.

Λ! 225, 284, 293 nm (MeOH)

PMR spectrum (CDCl ₃ ): S 2.17 and 2.23 (S, IR (KBr): 2240 (v> C = N) and 1685 cm "MS: m / e 338 (M ⁺ ), 293 (M -Me ₂ NH), 58

Example 4 6,6-dimethyl-8-cyanomethyl-5,6-secoergoline

The procedure is as described in Example 1, but used lO-methoxy-G-methyl-Sß-cyanomethyl-ergoline instead of lO-methoxy-e-methyl-eß-hydroxymethyl-ergoline. The title compound is obtained after chromatography on silica gel as a white oil in a yield of 50%. * ·. 225, 284, 293 mn (MeOH)

PMR spectrum (CDCl ₃ ): S 2.12 and 2.21 (S, NMe ₂ )

IR (CHCl ₅ ): 2240 cm " ¹ (v ^ C = N> φ

MS: m / e 281 (M ⁺ ), 236 (M-Me ₂ NH), 58 (CH ₂ = NMe ₂ ).

Example 5

6,6-dimethyl-8-acetoxy-methyl-5 »6-secoergoline

The procedure is as described in Example 1, but using 10-methoxy-δ-methyl-eß-acetoxymethyl-ergoline instead of 10-methoxy-o-methyl-ß-hydroxymethyl-ergoline. After chromatography on silica gel, the title compound is obtained as a white oil in a yield of 70%.

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s 225 »284, 293 mn (MeOH)

PMR spectrum (CDCl ₃ ): S 2.04, 2.14 and 2.56 (S, NMe _£ and

MeCO)
IR (film): 1730 cm " ¹ (\) C = O) and 1240 cm" ¹ (>? CO).

B e i s ρ i e 1 6

6 _> 6-dimethyl-8-benzoyloxymethyl-5 _> 6-secoergoline

The procedure is as described in Example 1, but used IO-methoxy-6-methyl-Sß-benzoyloxymethyl-ergoline instead of lO-methoxy-ö-methyl-eß-hydroxymethyl-ergoline. After Chromatography on silica gel gives the title compound as a white oil in a yield of 75%.

\ _m '. 225, 284, 293 nm (MeOH)

PMR spectrum (CDCl ₃ ): 6 2.25 (S, Me ₂ N), 6.5-8.4 (M, 9 aromatic protons)

IR (film): 1715 (\> C = O), 1275 (v ^ CO), 750 and 710 cm ^-1 (mono- ■ -.- substituted phenyl group).

B e 1 game I 7

6.6 "dimethyl ~ 8- (5 '-broianicotinoyloxymethyl) -5 > 6-secoergoline

The procedure is as described in Example 1, but used 10-methoxy-6-methyl-8β- (5'-bromonicotinoyloxymethyl) -ergoline instead of IO-methoxy-6-methyl-Sβ-hydroxymethylergoline. After chromatography on silica gel, the Title compound as a yellowish oil in a yield of 60% received.

²⁸⁴ ' ²⁹³

PMR spectrum (CDCl ₃ ): S 2.30 and 2.39 (S, NMe ₂ ), 8.3-9.3 (M,

3 pyridine ring protons)
IR (film): 1720 (v? C = O) and 1270 cm ~ l (\? CO) MS: m / e 457 and 455 (M ⁺ ), 58 (CH ₂ -N-Me ₂ )

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Example 8

6, ö-dimethyl-e- (3 ', 5'-dimethyl-2'-pyrrocarbonyloxymethyl) -

5,6-secoergoline ; .

Man. works as described in Example 1, but uses 10-methoxy-6-methyl-8β- (3 ', 5'-dimethyl-2 ¹ -pyrrocarbonyloxymethyl) -ergoline instead of 10-methoxy-6-methyl-8β-hydroxymethyl-ergoline. After chromatography on silica gel, the title compound is obtained as a white oil in a yield of 80%.
Λ _m : 224, 278 nm (MeOH)

PMR spectrum (CDCl ₃ ): SZ _t 17, 2.20, .2.25 and / 2.33 (S, NMe ₂ and Me)

IR (KBr): 1660 (^ C = O) and 1275 cm " ¹ (v? C-Ol MS: m / e 393 (M ⁺ ), 348 (M-Me ₂ NH), 58 (CH ₂ = NMe ₂ ).

Example 9

6, o-dimethyl-S-carbamoyl-S , 6-secoergoline

The procedure is as described in Example 1, but using 10-methoxy-δ-methyl-Sβ-carbamoyl-ergoline instead of 10-methoxy-δ-methyl-3-hydroxymethyl-ergoline. The title compound is obtained as a yellowish oil in a yield of 70%.

A- 225, 284, 293 nm (MeOH)

PMR spectrum (CDCl ₃ ): ύ 2.16 and 2.26 (S, NMe ₂ ) MS: m / e 285 (M ⁺ ), 240 (M-Me ₂ NH), 58 (CH ₂ = NMe ₂ ) .

The title compound can also be obtained by one works as in Example 1, but lysergic acid amide instead of 10-methoxy-6-methyl-8ß-hydroxymethyl-ergoline used.

The title compound can also be obtained by working according to Example 1, but 1O-methoxy-6-methyl-8,9-didehydro-8-carbamoyl-ergoline instead of 10-methoxy-6-methyl-8β-hydroxymethyl-ergoline used.

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Example 10

6, S-dimethyl-e-carbamoyl-g «10-didehydro-5,6-secoercoline

The procedure is as described in Example 1, except that 10-methoxy-6-methyl-8,9tiidehydro-8-carbainoyl-ergoline is used instead of 10-methoxy-O-methyl-S-hydroxymethyl-ergoline and no methanol is added. After chromatography on silica gel, the title compound is obtained as a yellowish oil in a yield of 40%.
Äs 224, 240, 317 nm (MeOH)
PMR spectrum (C ₅ D ₅ N): 6 2.28 (S, NMe ₂ ), 3.8-4.3 [M, C (8) -H),

6.64 [D, J = 9 Hz, C (9) H]. ^ MS: m / e 283 (M ⁺ ), 238 (M-Me ₂ NH), 58 (CH ₂ = NMe ₂ ).

The title compound can also be obtained by one works as described above, but lysergic acid amide instead of 1O-methpxy-6-methyl-8, g-didehydro-e-carbamoylergoline used.

Example 11

6,6-dimethyl-5.6-secoergotamine

The procedure is as described in Example 1, but uses e ^ -Didehydro-IO-methoxy-gtiO-dihydroergotamine instead of lO-methoxy-ö-methyl-eß-hydroxymethyl-ergoline and does not add any methanol. After chromatography on silica gel, the title compound is obtained as a white foam in a yield of -4056.
A _m -: 224, 240, 315 nm (MeOH)
PMR spectrum (C ₅ D ₅ N): S 1.80 (S, Me), 2.28 and 2.29 (S ₁ NMe ₂ ),

6.48 (D, J = 9 Hz, C (9) -H)
Field desorption mass spectrum: m / e 597 (M).

The title compound can also be obtained by one works as described above, but uses ergotamine instead of Sjg-didehydro-IO-methoxy-gtiO-dihydroergotamine.

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Example 12

According to procedures analogous to those in the previous ones As described in the examples, the following compounds are prepared.

6,6-dimethyl-5,6-secodihydroergotamine, 6,6-dimethyl-5,6-secodihydroergocristine, ejö-dimethyl-Sfö-secodihydroergocryptin, 6,6-dimethyl-5,6-secodihydroergocornine, 6,6-dimethyl-5,6-secoergocryptine,

6,6-dimethyl-9,1O-didehydro-5,6-secoergometrine, 6, ö-dimethyl-e-diethylcarbamoyl-g, 1O-didehydro-5,6-seeo-

ergolin,

6,6-dimethyl-9,1O-didehydro-S-aminomethyl- ^ je-secoergoline, 6,6-dimethyl-8-hydroxymethyl-9,1O-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, ö-dimethyl-e- [N- (I ¹ -pyrazinyl) aminomethyl] -5 »6-secoergoline,

6, δ-dimethyl-e-aminomethyl-S, 6-secoergoline.

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Claims (1)

PATENT LAWYERS DR. WALTER KRAUS DIPLOMA CHEMIST ■ DR.-ING. ANNEKÄTE WEISERT DIPL.-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 · D-8OOO MUNICH 71 ■ TELEPHONE 089 / 797077-797078 - TELEX O5-212156 kpatd TELEGRAM CRAUS PATENT 2579 AW / My FARMITALIA CARLO ERBA S.p.A. M.ilano, Italy Secoergoline derivatives Claims 1. 5 »6-secoergoline derivative of the general formula I. (D • ^R 5 wherein R ₁ denotes an alkyl group having 1 to 4 carbon atoms, an allyl group or a 2-phenylethyl group; R ₂ denotes a group of the formula CH ₂ R ¹ or CH ₂ NHR "or COR" ¹ , in which R ^{1 represents} a hydrogen atom or a halogen atom or a hydroxy, alkoxy, acyloxy, carbamoyl, substituted carbamoyl, carboxy ester , Tosyloxy, 0300A8 / 0766 -z- Mesyloxy, cyano, cyanomethyl or substituted cyanomethyl group, R "is an alkyl group with 1 to 4 carbon atoms or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or thiazolyl group, and R" ^{1 is} an alkoxy , Amino or substituted amino group; R ^ and R ^ both mean hydrogen atoms or together form a double bond; and Rc denotes a hydrogen atom or a methyl group,
or one of its pharmaceutically acceptable salts. 2. 6,6-dimethyl-8-hydroxymethyl-5,6-secoergoline. 3. 6,6-Dimethyl-8-carbamoylmethyl-5,6-secoergoline. 4. 2-Cyano-3- (6 ·, e'-dimethyl-S ¹ , ö'-secoergoline-e ¹ ) -propionamide. 5. 6, δ-dimethyl-S-cyanomethyl-S, 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'-bromonicotinoyloxymethyl) -5 _f 6-secoergoline. 9. 6, δ-dimethyl-e- (3 ', 5'-dimethyl-2 · -pyrrocarbonyloxymethyl) -5,6-secoergoline. 10. 6,6-Dimethyl-8-carbamoyl-5,6-secoergoline. 11. 6, o-Dimethyl-e-carbamoyl-S, 10-didehydro-5 > 6-secoergoline. 0300A8 / 0766 12. 6,6 ~ dimethyl-5,6-secoergotamine. 13 · 6,6-dimethyl-5,6-secodihydroergotamine. -Ϊ5 · e ^ ö-Dimetliyl-Siö-secodihydroergocryptin. 16. 6,6-Dimethyl-5 »6-secodihydroergocornine. 17. ■ - ■ "" "" "'.- öj-ö-D.iniethyl- ^ i.e-secoergocryptin. 18. öjee 19. ejo 20. 6,6-Dimethyl-9,10-didehydro ~ 8-aminomethyl-5,6- secoergoline. secoergoline. 22. 6,6 ^ dimethyl-8-] M- (1 ^f -pyrimidinyl) aminomethyl] -5 * 6-secpergoline. 23. 6,6-Dimethyl-8- [N- (1 '-pyridinylJ-aminomethyll-S ^ - 24. 6,6-Dimethyl-8- [N- (1'-pyrazinyl) aminomethyl] -5,6- secoergqlin. , _v . ..'..- i -. - =. --... .-. ■ .- ■ .... ^ mQ : Γ ~ i6. _r 6-pimethyl-Q-? am ^: inpme.thyl-5,6-secoergplin. 3O0A8 / O766 -A- 26. A process for the preparation of a 5,6-secoergoline derivative of the general formula I according to claim 1, wherein R, and Rr together form a double bond and R ₁ , Rp and Rc have the definitions given above, characterized in that a 9> 10 -Didehydro-ergoline of the general formula II - R, II in which the substituents have the meanings given above, or an 8,9-didehydro-IO-methoxy-ergoline of the general type Formula III ^CH 3 ° N-CH. wherein the substituents have the meanings given above, with an alkyl halide of the general formula R ₁ HaI 0300A8 / 0766 wherein R ₁ is as defined in claim 1 and Hal represents a halogen atom, is reacted in the absence of a proton source, and the resulting quaternary ammonium salt is reduced with an alkali metal in liquid ammonia at -60 ° to -30 ⁰ C. 27. Process for the preparation of a 5 »6 secoergoline derivative of the general formula I according to claim 1, wherein R, and R ^ are both hydrogen atoms and R ,,, Rp and Rc have the meanings given in claim 1, thereby characterized in that a 9,10-didehydro-ergoline of the general formula II • R, N - CH. II an 8,9-didehydro-IO-methoxy-ergoline of the general formula R, CH-O N-CH. III 0300A8 / 0766 or a 1O-methoxyergoline of the general formula IV N -CH. in which the substituents have the meaning given above, with an alkyl halide of the general formula R ₁ HaI wherein R ₁ has the meaning given above and Hal represents a Hälogenatom, in the presence of methanol, ethanol or t-butanol as a proton source are reacted and the resulting quaternary ammonium salt is reduced with an alkali metal in liquid ammonia at -60 to -30 ⁰ C. 28. The method according to claim 26 or 27, characterized in that the reduction is carried out for 2 to 3 hours will. 29. Pharmaceutical preparation, characterized in that it is a 5,6-secoergoline derivative according to one of the claims 1 to 25 or one of their pharmaceutically acceptable salts in admixture with a pharmaceutically acceptable diluent or contains carrier. 0300A8 / 0766