DE3018477A1 - SECOERGOL DERIVATIVES - Google Patents

Description

- 6 description

The invention relates to secoergoline derivatives and processes for their preparation.

The invention relates to 6,7-secoergolines of the general formula I.

^R 4

R ₁ 'denotes an alkyl group with 1 to 4 carbon atoms or a benzyl or phenethyl group;

R _{2 is} a hydroxy, acyloxy, alkoxy, amino, cyano or carbamoyl group or a substituted or unsubstituted heterocyclic group whose ring is through

5 or 6 atoms is formed, of which at least one is a nitrogen atom and carries the bond to the methylene group, no more than 3 atoms are nitrogen and / or oxygen and / or sulfur atoms and the remainder is carbon atoms, or a group of general formula SR ₅ , NHR ₅ , SC- (O) _n -R ₆ , NH-C- (O) _n -R ₆ or CHR ₇ R ₈

XX

indicates where R _{u is} a substituted or unsubstituted

P.
te heterocyclic group whose ring is replaced by 5 or

6 atoms are formed, at least one of which is a nitrogen atom is, no more than 3 atoms are nitrogen and / or oxygen and / or sulfur atoms and the remainder are carbon

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represents material atoms, X for an oxygen or sulfur atom is, η is 0 or 1, Rg is an aliphatic Group with 1 to 4 carbon atoms, a benzyl group or a substituted or unsubstituted amino group, Ry stands for a hydrogen atom or a cyano group and Rq represents a hydrogen atom or an alkoxycarbonyl or carbamoyl group;

R ₇ denotes a hydrogen atom or a methoxy group; and

R / represents a hydrogen atom or a methyl group.

According to the invention, the compounds of the general formula I can be prepared by reacting a compound of the general formula III, in which R ₂ > R ^ and R ^ have the meanings given above, with a halide of the general formula

R ₁ Y

wherein R _{1 has} the meaning given above and Y is a halogen atom, and hydrogenation of the resulting quaternary ammonium salt of the general formula IV in an anhydrous or aqueous aliphatic alcohol or in an inert solvent in the presence of a suitable catalyst.

CH ₂ R ₂

CH.

III

IV

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The catalyst can be any known hydrogenation catalyst such as platinum, palladium, their salts or oxides, either as such or deposited on a suitable carrier such as carbon, barium sulfate or calcium carbonate.

Hydrogenation-hydrogenolysis is preferred at or above Atmospheric pressure at ambient temperature for a period of 2 to 6 hours. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo » wcbeimai receives the crude product, which is then isolated and can be cleaned.

The compounds of general formula III can by Condensation of a compound of the general formula II

II

where R ^ and Rr have the meanings given above, with a compound of the general formula

R ₂ H

wherein Rp has the meaning given above will.

The Secoergolxnderivate according to invention are yellowish or white or colorless oils or white or colorless, crystalline Solids. They are presented as mixtures of their 8R and

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ORIGINAL INSPECTED

8S diastereoisomers obtained. The mixtures can be separated by chromatography or crystallization.

The secoergoline derivatives according to the invention and their pharmaceuticals acceptable salts are useful α-adrenergic Blocking agents, antihypertensive agents, central nervous system calming agents, Antispasmodics, analgesics, and antiprolactin agents. The invention further relates to pharmaceutical preparations, which is a 6,7-secoergoline derivative of the formula I or one of them pharmaceutically acceptable salts in admixture with a pharmaceutical diluent or carrier.

The following examples illustrate the invention.

example 1

e-methyl-S-chloromethyl-e, 9-didehydro-1O-methoxy-ergoline (II: Η, = OCH ,; R ₄ = H)

A stirred mixture of 1 g of 6-methyl-8-hydroxymethyl-8,9-didehydro-10-methoxy-ergoline, 0.147 g of lithium chloride and 0.509 ml of s-collidine in 5 ml of dimethylformamide is added dropwise after cooling to 0 ° C. with 0.301 ml of methanesulfonyl chloride treated. The mixture is stirred for a further hour at 0 ^° C. The reaction mixture is then poured over ice-cold water and extracted with cold chloroform. Evaporation of the solvent in vacuo gives a residue which is crystallized from diethyl ether. 0.7 g of the title compound is obtained, melting point 148 to 150 ^° C.

Example 2

6-methyl-8- (S-ethoxycarbonyl-Z-cyanoethyl) -8,9-didehydro-

10-methoxy-ergoline ___;

[III: R ₂ = C ₂ H ₅ OOCCH (CN); R ₃ = OCH ₃ ; R ₄ = H) A mixture of 0.446 g of sodium ethyl cyanoacetate and 1 g of 6-methyl-8-chloromethyl-8,9-didehydro-10-methoxy-ergoline,

prepared according to Example 1, in 10 ml of dimethyl sulfoxide Stirred for 2 h at room temperature. The solution is in cold Yfesser poured * the precipitate is filtered off and on chromatographed on an alumina column using acetone as the eluent. 0.6 g of the is obtained Title compound in the form of a foam.

Example 3

6-methyl-8- (dimethylcarbamoyl-aminoethyl) -8,9-didehydro- 10-methoxy-ergoline -

[III: R _z = (CH ₄ ) 2 N-CONH; R ₃ = OCH ₃ ; R ₄ = H] 0.8 g of 6-methyl-8-aminomethyl-8,9-didehydro-10-methoxy-cooled to -1O ⁰ C and reacted with 0.3 ml ^ dimethylcarbamoyl chloride in 10 ml of pyridine. The reaction mixture is kept at this temperature for 10 minutes and then at room temperature for 10 minutes. It is then diluted with chloroform and methanol and washed with aqueous sodium carbonate. The chloroform is evaporated from the chloroform layer and the residue is chromatographed on a silica gel column using chloroform and then 1% methanol in chloroform as the eluent. Evaporation of the solvent gives the title compound as an oil in a yield of 35%.

Example 4

6, e-Dimethyl-S-hydroxymethyl-iO-methoxy-6,7-secoergoline 1.6 ml of methyl iodide are added at room temperature to a suspension of 4 g of δ-10-methoxy-ergoline in 40 ml of nitromethane. The mixture is left to stand overnight with stirring and then 80 ml of diethyl ether are added. The solid obtained is filtered off, dissolved in 250 ml of methanol and hydrogenated for 6 h at room temperature and atmospheric pressure in the presence of 3 g of platinum dioxide catalyst. After filtering off the catalyst and evaporation of the solvent, the

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Dissolve residue in water, make basic by adding sodium bicarbonate and then extract with chloroform. Evaporation of the chloroform gives 3 g of 6,6-dimethyl-8-hydroxymethyl-IO-methoxy-6-secoergoline in the form of a foam.

PMR spectrum (CDCl ₃ ): - S 0.9-1.23 (M, Me), 2.43 and 2.49

(2S, Me ₂ N), 2.87 and 2.96 (2S, MeO) IR (KBr): 1075 and 1035 cm ^-1 (v> C = O) MS: m / e 302 (M ⁺ ), 287 (M-Me).

Example 5

6, ö-dimethyl-S- (3,5-dimethyl-pyrrbl-2-carboxymethyl) -10-

methoxy-6,7-secoergoline

The procedure is as described in Example 4, but 6-methyl-8- (3,5-dimethyl-pyrrole-2-carboxymethyl) -8,9-didehydro-10-methoxyergoline is used. The title compound is obtained as a foam in a yield of 45%. >

Example 6

1,6, S-trimethyl-S- (5-bromonicotino.yloxymethyl) -10-methoxy- 6,7-seaoergoline

The procedure is as described in Example 4, but used 1, e-Dimethyl-S-iS-bromnicotinoyloxymethyli-Sjg-didehydro-10-methoxy-ergoline. The title compound is obtained in a yield of 359 ^.

FMR spectrum (CDCl ₃ ): S 0.95 and i, 08 (2D, CHCH ₅ ), 2.42 and 2.48 [2S, -NCCH ₃ ) _2. ], 2.95 (S, OCH ₃ ) .

Example 7

6, ö-dimethyl-S- (2-ethoxy-carbonyl-2-cyanoethyl) -10-methoxy-

6,7-secoergoline

The procedure is as described in Example 4, but used the compound of Example 2. The title compound is all ^ s foam in a yield of 60? ί> obtain.

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Example 8

6,6-dimethyl-8- (Z-carbamoyl-Z-cyanoethyl) -1O-methoxy-6,7-

s eco ergolin. ~

The procedure is as described in Example 4 ″, but used 6-methyl-8- (2-carbamoyr-2-cyanoethyl) -8,9-didehydro-10-methoxy-ergoline. The title compound is obtained as an oil in a yield of 65%.

Example 9

6,6-dimethyl-8 ~ (2-carbamoyl-2-cyanoethyl) -6,7-secoergoline

The procedure is as described in Example 4, but 6-methyl-8- (2-carbamoyl-2-cyanoethyl) -8,9-didehydroergoline is used. The title compound is obtained as an oil in a yield of 55%.

Example 10

6 ₁ 6-Dimethyl-8-morpholinomethyl-10-methoxy-6,7-secoergoline

The procedure is as described in Example 4, but e-methyl-S-morpholinomethyl-e, 9-didehydro-10-methoxyergoline is used, which in turn has been obtained by reacting the product of Example 1 with morpholine. The title compound is obtained as an oil in a yield of 70%.

Example 11

6,6-dimethyl-8 - [(2-pyrimidinylamino) methyl] -10-methoxy-

6,7-secoergoline - _:.

The procedure is as described in Example 4, but 6-methyl-8 - [(2-pyrimidinylamino) methyl] -8,9-didehydro-10-methoxyergoline is used, which in turn was obtained by reacting the product of Example 1 with 2-aminopyrimidine has been. The title compound is obtained as an oil in a yield of 50%.

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For example ρ i el 12

6, S-dimethyl-e - [(2-pyridyl) thiomethyl] -10-methoxy-6,7-

secoergoline ; - '

The procedure is as described in Example 4, but using 6-methyl-8 - [(2-pyridyl) thiomethyl] -8,9-didehydro-10-methoxy-ergoline, in turn, through the implementation of the product of Example 1 with 2-mercaptopyridine. The title compound is found as an oil in a yield received by 45%.

For example I 13

6, e-Dimethyl-e-f (2-pyrimidinyl) ^ thiomethylj-6,7-secoergoline

The procedure is as described in Example 4, but used 6-methyl-8- [(2-pyrimidyl) -thiomethyl] -8,9-didehydroiergoline. The title compound is obtained as an oil in a yield of 55%.

Example I 14

6,6-dimethyl-8 - [(1-methyl-2-imidazoIyI) -thiomethyl] -10-meth-

oxy-6,7-secoergoline

The procedure is as described in Example 4, but used 6-methyl-8 - [(1-methyl-2-imidazoIyI) -thiomethyl] -8,9-didehydro-10-methoxyergoline, in turn by reacting the product from Example 1 with i-methyl-2-mercapto-imidazole has been made. The title compound is saved as a Oil in one? 45% yield obtained.

Example 15

6,6-dimethyl-8- (dimethylcarbamoyl-aminomethyl) -10-methoxy-

6,7-secoergoline

The procedure is as described in Example 4, but used the compound of Example 3. The title compound is obtained as an oil in a yield of 55%.

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Example 16

6,6-dimethyl-8- (benzoyloxycarbonyl-aminomethyl) -10-methoxy-

6,7-secoergoline - ·. -

One works as described in Example 4, but uses cn 8- (Benzyloxycarbonyl-aminomethyl) -6-methyl-8,9-didehydro-10-methoxy-ergoline. The title compound is obtained as a foam in a yield of 4596.

Example 17

6,6-dimethyl-8- (ethoxycarbonyl-aminomethyl) -1O-methoxy-

6,7 secoergoline

The procedure is as described in Example 4, but used 6-methyl-8- (ethoxycarbonyl-aminomethyl) -8,9-didehydro-10-methoxy-ergoline. The title compound is obtained as an oil in a yield of 70%.

Example 18

6,6-dimethyl-S- (benzyloxycarbonyl-aminomethyl) -6,7-seco-

ergolin -

The procedure is as described in Example 4, but used 6-methyl-8- (benzyloxycarbonyl-aminomethyl) -8,9-didehydroergoline. The title compound is obtained as a foam in a yield of 35%.

PMR spectrum (CDCl ₃ ): <T0.96 and 1.03 (.2D, CHCH ^), 2.24

[S, N (CH ₃ ) ₂ ].

Example 19

6,6-dimethyl-8- (dimethylcarbamoyl-aminomethyl) -6,7-seco-

ergolin ' -. - - ~ - - ■■.,. '

The procedure is as described in Example 4, but 6-methyl-8- (dimethylcarbamoyl-aminomethyl) -8,9-didehydroergoline is used. The title compound is obtained as a foam in a yield of 60%.

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PMR spectrum (CDCl ₅ ) y £ 0.53 to 1.17 (M, CHCH,), 2.22 [S, N (CH ₃ ) ₂ ].

Example 20

6, e-dimethyl-S- (dimethylthiocarbamoyl-aminomethyl) -6,7-

secoergoline ----- -

The procedure is as described in Example 4, but used 6-methyl-8- (dimethylthio carbamoyl-aminomethyl) -8,9-didehydroergoline. The title compound is obtained as an oil in a yield of 70%.

PMR Spectrum (CDCl ₃ ): S 0.93 to 1.37 [M, CHCH ₃ , CH (CH ₃ ) ₂ ], 2.30 [S, N (CH ₃ ) ₂ ].

B e i s ρ ie I 21

6,6-dimethyl ~ 8- (5-bromonicotinoyloxymethyl) -IO-methoxy-6,7-

s eco ergolin \ ^;

The procedure is as described in Example 4, but 6-methyl-8- ( 5- bromnicotinoyloxymethyl) -8,9-didehydro-10-methoxyergoline is used. The title compound is obtained as a foam in a yield of 40%.

PMR spectrum (CDCl ₃ ): 0.96 and 1.08 (2D, CHCH ₃ ), 2.42 and 2.47 [2S, N (CH ₃ ) ₂ ], 2.98 (S, OCH ₃ ).

Example 22 6, S-dimethyl-S-benzoyloxymethyl-IO-methoxy-e, 7-secoergoline

The procedure is as described in Example 4, but used G-methyl-S-benzoyloxymethyl-S, 9-didehydro-10-methoxyergoline. The title compound is obtained as a foam in a yield of 6096.

PMR spectrum (CDCl ₃ ): 6 1.00 and 1.10 (2D, CHCH ₃ ), 2.42 [S, N (CH ₃ ) ₂ ].

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Summary .

The invention relates to 6,7-secoergolines of the formula

CH 3

R ₁ = C _{1 -Zj} -alkyl, benzyl, phenethyl;

R ₂ = OH, acyloxy, alkoxy, NH ₂ , CN, NH ₂ CO, substituted. Or unsubstituted heterocyclic group, the ring of which is formed by 5 or 6 [atoms, of which at least one is an N atom and the bond to carries the methylene group ,. no more than 3 atoms are N and / or 0 and / or S atoms and the remainder represents C atoms, or SR ₅ , NHR ₅ , SC- (O) _n -R ₆ , NH-C- (O ) _n -R ₆

X X.

or CHRyRg, where R ^ = a substituted or unsubstituted heterocyclic group formed by 5 or 6 atoms, of which at least one is an N atom, no more than 3 atoms are N and / or 0 and / or S atoms and the remainder represents carbon atoms, X = O or S, η = 0 or 1, R ₆ = C _1- ^ aliphatic group, benzyl, NH ₂ or substituted NH ₂ , R ₇ = H or CN, Rg = H or Alkoxycarbonyl or NH ₂ CO;

H or CH ₅ O; and
H or CH ,.

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These compounds are useful α-adrenergic blocking agents, antihypertensive agents, central nervous system sedatives, antispasmodics, Analgesics and anti-prolactin agents. The invention also relates to pharmaceutical preparations, these compounds included, and process for their preparation.

End of description.

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Claims (1)

KRAUS & WEiSERT PATENT LAWYERS DR. WAUTER KRAUS DIPLOMA CHEMIST ■ DR.-ING. ANNEKÄJE WEISERT DIPL.-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 D-8OOO MÜNCHEN 71 -TELEPHONE 089 / 797077-797078 TELEX O5-212156 kpatd TELEGRAM CRAUS PATENT 2578 AW / My FARMITALIA CARLO ERBA S.p.A. Milano, Italy Secoergoline derivatives Patent a η s ρ r ü c h e 1. 6,7-secoergoline of the general formula I. (I) in which. R ₁ denotes an alkyl group with 1 to 4 carbon atoms or a benzyl or phenethyl group; Rp is a hydroxy, acyloxy, alkoxy, amino, Cyano or carbamoyl group or a substituted or unsubstituted heterocyclic group means whose Ring is formed by 5 or 6 atoms, at least one of which is a nitrogen atom, and which is bonded to 7624 ORIGINAL INSPECTED -Z- carries the methylene group and does not contain more than 3 nitrogen and / or oxygen and / or sulfur atoms, where the remaining atoms are carbon atoms, or a group of the general formula SR ^, NHR, -, SC- (O) -R ^ -, NH-C- (O) -Kf- or CHRr ₇ R ₀ means, where R ^ "'n 6'"'n 6 7 8 5 X X for a substituted or unsubstituted heterocyclic Group whose ring is formed from 5 or 6 atoms, of which at least one is a nitrogen atom, no more as three nitrogen and / or oxygen and / or sulfur atoms and the remainder is carbon atoms, X is an oxygen or sulfur atom, η is 0 or 1 Rg represents an aliphatic group having 1 to 4 carbon atoms, represents a benzyl group or a substituted or unsubstituted amino group, R ^ represents a hydrogen atom or represents a cyano group and Rg represents a hydrogen atom or an alkoxycarbonyl or carbamoyl group; R represents a hydrogen atom or a methoxy group; and Rr denotes a hydrogen atom or a methyl group,
or one of its pharmaceutically acceptable salts. Line 6, δ-dimethyl-S-hydroxymethyl-IO-methoxy-e, 7-secoergoline. 3. 6,6-Dimethyl-8- (3 »5-dimethyl-pyrrole-2-carboxymethyl) -IO-methoxy-6,7-secoergoline. 4. 1,6,6-trimethyl-8- (5-bromonicotinoyloxymethyl) -10-methoxy-6,7-secoergoline. 5.. öje methoxy-6,7-secoergoline. 1300 09/0668 ■ - 3 - 6. 6,6-Dimethyl18- (2-carbamoyl-2-cyanoethyl) -10-methoxy-6,7-secoergoline. 7. 6,6-Dimethyl-8- (2-carbamoyl-2-cyanoethyl) -6,7-secoergoline. 8. 6,6-Diinethyl-8-morpholinomethyl-10-methoxy-6,7-secoergoline. 9. 6,6-Dimethyl-8 - [(2-pyrimidinylamino) methyl] -10- methoxy-6,7-secoergoline. 10. 6,6-Dimethyl-8 - [(2-pyridyl) thiomethyl] -10-methoxy-6,7-secoefgoline. 11. 6,6-Dimethyl-8 - [(2-pyrimidinyl) thiomethyl] -6,7-secoergoline. 12. 6 _i 6-Dimethyl-8 - [(i-methyl-2-imidazolyl) -thio- -10-methoxy-6,7-secoergoline. 13. ejö-Dimethyl-S-Cdimethylcarbamoyl-aminomethylJ-IO- ' methoxy-6,7-se co ergoline. 14. 6,6-Dimethyl-8- (benzyloxycarbonyl-aminomethyl) -10-methoxy-6,7-secoergoline. 15 x 6, G-Dimethyl-S-i-ethoxycarbonyl-aminomethyl) -10-methoxy-6,7-SeCOe rgolin-, 16. öjG-Dimethyl-S-Cbenzyloxycarbonyl-aminomethyl) -6,7-secoergoline. 17. 6,6-dimethyl-8- ^; (dimethylcarbamoyl-aminomethyl) 6,7-secoergoline. 130009 / 066-8 18477 18. 6,6-Dimethyl-8- (dimethylthiocarbamoyl-aminomethyl) 6,7-secoergoline. 19. 6,6-Dimethyl-8- (5-bromonxcotinoyloxymethyl) -1O-methoxy-6,7-secoergoline. 20. 6, e-Dimethyl-S-r -benzoyloxymethyl-10-methoxy-6,7-secoergoline. 21. Process for the production of 6,7-secoergoline der general formula I as in claim. 1 defined by it characterized in that a compound of the general formula III CH. III wherein Rp, R, and R ^ have the meanings given in claim 1 possess, with a halide of the general formula R ₁ Y wherein R _{1 has} the meaning given in claim 1 and Y is a halogen atom, and the quaternary ammonium salt formed is hydrogenated in an anhydrous or aqueous aliphatic alcohol or in an inert solvent in the presence of a suitable catalyst. 130009/066 8 22. The method according to claim 21, characterized in that that the catalyst for the hydrogenation is platinum, palladium or a salt or an oxide of platinum or palladium, if appropriate on charcoal, barium sulfate or calcium carbonate as a carrier. 23. The method according to claim 21 or 22, characterized in that the hydrogenation at or above atmospheric pressure is carried out at ambient temperature for a period of 2 to 6 hours. 24. Pharmaceutical preparation, characterized in that that it is a 6,7-secoergoline derivative according to one of the claims 1 to 20 or one of its pharmaceutically acceptable salts in admixture with a pharmaceutically acceptable diluent or contains carrier. 130009/0668