CS271626B1 - Method of ergopeptines' derivatives production - Google Patents

Abstract

The method for the production of derivates of ergopeptines of the general formula I, where R<1> stands for n-propyl, allyl, propargyl, ethoxycarbonylmethyl, benzyl, acetyl, methyl sulfonyl or benzyloxycarbonyl, and R<2> stands for methyl or isopropyl and their salts and pharmaceutically acceptable acids, where R<1> stands for n-propyl, allyl, propargyl, ethoxycarbonylmethyl, or benzyl, by which the derivates of ergopeptines are made available in such a way that the whole molecule of 9,10-dihydroderivate of peptide ergot alkaloid has a three-stage sequence of reactions. These pharmacodynamically effective derivates of ergopeptines were hitherto hardly accessible by the reaction of the activated derivates 6-nor-6-alkyl-9,10-dihydrolysergic acids with totally synthetically prepared aminocyclols representing the peptide part of the molecule of ergot alkaloid, while this production method requires more than twenty synthetic degrees.<IMAGE>

Description

The invention relates to a novel process for the preparation of ergopeptin derivatives of the general formula I (see Annex) in which R ¹ denotes n-propyl, allyl, propargyl, ethoxycarbonylmethyl, benzyl, o-acetyl, methylsulfonyl or benzyloxycarbonyl and R denotes methyl or isopropyl; acceptable acids when R 1 is n-propyl, allyl, propargyl, ethoxycarbonylmethyl or benzyl and R is as defined above, characterized in that the ergopeptin of formula II (see Annex), wherein R is as defined above, is converted by reaction with cyanogen bromide in an inert solvent to an ergopeptin of formula III (see Annex) in which R is as defined above and is hydrogenated to an ergopeptin of formula IV (see Annex) in which R is as defined above and the ergopeptin thus obtained is converted to the ergopeptins of formula I by reaction with the corresponding alkylating or acylating agents (cf. ha) wherein R ¹ is n-propyl, allyl, propargyl, ethoxycarbonylmethyl, benzyl, acetyl, methylsulfonyl or benzyloxycarbonyl; and

R is methyl or isopropyl and the compounds thus prepared are optionally converted into salts with pharmaceutically acceptable acids when R 1 is n-propyl, allyl, propargyl, ethoxycarbonylmethyl or benzyl.

Derivatives of ergopeptins of the formula I are understood to be derivatives of the natural peptic ergot alkaloids in the 9,10 position dihydrogenated. The preparation of similar ergopeptin derivatives is described in the German patents 2,544,619 and 2,557,792 synthetically by reaction of the corresponding reactive 6-nor-6-alkyl-9,10-dihydrolysergic acid substitution derivatives with synthetic aminocyclols, i.e. cyclic peptides representing the peptide portion of ergopeptin derivatives of general The reactive substitution derivatives of 6-nor-6-alkyl-9,10-dihydrolysergic acids are prepared partially synthetically from natural D-lysergic acid in several synthetic stages, aminocyclols ie (2R, 5S, 10aS, 10bS) -2- amino-5β-benzyl-2H-methyl-3,6-dioxo-10b-hydroxyoctahydro-8H-oxazolo (3,2-a) pyrrolo (2,1c) pyrazine and (2R, 5S, 10aS, 10bS) - 2-amino-5'-benzyl-2H-isopropyl-3,6-dioxo-10b-hydroxyoctahydro-8H-oxazolo (3,2-a) pyrrolo (2,1c) pyrazine is prepared totally synthetically up to twenty stages (for example, Hofmann A. et al., Helv.Chem.Acta 46-2306 (1963)). According to our production method, these ergopeptins of formula I are obtained in three stages by partially synthetic variations carried out with the entire molecule of the 9,10-dihydroderivative of the natural peptide ergot alkaloid. Thus, our process for producing the ergopeptin derivatives of formula I represents a significant improvement and shortening of the production of these ergopeptin derivatives.

For the N-demethylation of ergopeptins, we used the classical Braun demethylation of tertiary amines with cyanogen bromide, which he described for lysergic acid derivatives Fehr sp. (Helv. Chem. Acta 53, 2197 (1970)). We have found that the cleavage of the cyano group from our 6-nor-6-cyander derivatives of ergopeptins is best accomplished by hydrogenation with Raney nickel in aqueous dioxane. Fehr se sp. they cleave the cyano group from the 6-nor-6-cyander derivatives of 9,10-dihydrolysergic acid by hydrogenation with Raney nickel in dimethylformamide. Cleavage of the cyano group with zinc in acetic acid, also according to Fehr et al. (cited above) is accompanied by considerable losses due to their decomposition. By suitably adjusting the N-demethylation conditions with respect to the characteristic properties of the peptide portion of the ergopeptin molecule, we have been able to prepare the corresponding 6-nor-derivatives of the ergopeptins of formula III, which we have 6-alkylated and 6-acylated under gentle conditions using conventional methods.

Said ergopeptin derivatives of the formula I have interesting pharmacodynamic properties and can serve as medicaments in human or veterinary medicine themselves or as intermediates for their preparation.

Further details of the preparation of the ergopeptin derivatives of the formula I according to our invention are given in the following examples.

The preparation was carried out under an inert gas, argon or nitrogen atmosphere and protected from daylight. Melting points (decomposition) are given in degrees Celsius.

CS 271 626 Bl

Example 1

6-nor-6-cyanodihydroergotamine

A solution of cyanogen bromide (5 g; 47 mmol) in 20 mL of chloroform was added with stirring to a solution of dihydroergotamine (17.15 g; 29 mol) in 1500 mL of chloroform. After stirring at 20 ° C for 96 h, the reaction mixture was filtered, evaporated under reduced pressure and the residue purified by silica gel column chromatography in chloroform using ethanol as eluent. Crystallization of the residue of the fraction containing 6-nor-6-cyano-dihydroergotamine from methanol gave 14.21 g of 6-nor-6-cyano-dihydroergotamine, mp 223-225.37 ° (c = 0.76, piridine).

Analogously was prepared from dihydroergocristine 6-nor-6-cyano-dihydroergocristine mp 194-195 ° θ ^{0 +} 1.73 (c = 0.5, pyridine). ·

Example 2

6-nor-dihydroergotamine

6-NO-6-cyano-dihydroergotamine (4.50 g; 7.7 mmol) dissolved in 70 mL dioxane containing 10% water by volume was hydrogenated in the presence of Raney nickel for 3 hours at 40 ° C under normal pressure. After separation of the catalyst, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography in chloroform with 10% by volume of ethanol. Crystallization from acetone gave 3.49 g of 6-nor-dihydroergotamine mp 182-186 ⁰ -39.44 ° (c = 0.5, pyridine).

In an analogous manner, 6-nor-dihydroergocristine was prepared from 6-nor-6-cyano-dihydroergocristine. The benzene crystallizate melts at 182-184 -33.71 ° (c = 0.2, pyridine).

Example 3. 6-nor-6-propyl-dihydroergotamine

To a solution of 6-nor-dihydroergotamine (2.26 g; 4 mmol) in a mixture of 40 mL of methanol and 12 mL of chloroform was added propionaldehyde (0.51 g; 8.8 mmol) and sodium cyanoborohydride (0.504 g; V mml) and the mixture was adjusted to 5.2 with acetic acid. After 4 stirring at 20 ° C, the reaction mixture was diluted with chloroform, shaken with dilute aqueous ammonia solution and water. The organic phase after drying over sodium sulfate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using chloroformacetone (3: 2). Crystallization from benzene gave 1.72 g of 6-nor-6-n-propyl-dihydroergotamine, m.p. 178 DEG-180 DEG C. [.alpha.] D @ 20 = -64.2 DEG (c = 0.5, pyridine).

The 6-nor-6-n-propyl-dihydroergotamine base was dissolved in ethanol and tartaric acid was added to the hot solution in an amount sufficient to prepare the hydrogen tartrate. 6-nor-6-n-propyldihydroergotamine hydrogen tartrate, mp 197-198 ° C; δ ° C ⁰ -6.09 ° (»0.2, 504 ethanol) was precipitated after addition of excess diethyl ether. Analogously to the 6-nor-6-n-dihydroergotamine were prepared: 6-nor-6-n-propyl-dihydroergocristine mp 210-215 ° C (methanol) (^ 7 ^ ⁰ -47.09 ° (c = 0.2 pyridine), 6-nor-6-benzyl-dihydroergotamine mp 232-233 ° C (acetone;

[.Alpha.] D @ 20 = ^-91 DEG (25 DEG = 0.2, pyridine),

6-nor-6-benzyl-dihydroergocristine m.p. 205-207 ° C (acetone); [.alpha.] D @ 20 -72.55 DEG (c = 0.2, pyridine). .

Example 4

6-nor-6-allyl-dihydroergotamine • A mixture of a solution of 6-nor-dihydroergotamine (1.14 g; 2 mmol) in 40 ml of dioxane, allyl bromide (0.48 g; 4 mmol) and sodium bicarbonate (0.67 g; 8 mmol) was heated with stirring

13.5 h at 50 ° C. The residue of the reaction mixture was shaken with honey. chloroform and water. The organic phase was dried over sodium sulfate and the residue was purified by silica gel column chromatography on silica gel

CS 271 626 B1 chloroform using ethanol as eluent, crystallization from acetone gave

0.350 g of 6-nor-6-allyl-dihydroergotamine m.p. 178-182 -68.09 ° (c = 0.2, pyridine) Analogously were prepared:

6-nor-6-allyl-dihydroergocristine m.p. 192-195 ° C (methanol);

-61.16 ° (c = 0.2, pyridine), i

6-nor 6-propargyl-dihydroergotamine m.p. 236-237 ° C (ethanol);

[.Alpha.] D @ 20 -66.81 DEG (c = 0.25, pyridine),

6-nor-6-propargyl-dihydroergocristine m.p. 214-218 ° C (ethanol);

/ ° 5Όθ ^{'56' 64} ° ^(c = ° · ² pyridine),

6-nor-6-ethoxycarbonylmethyl-dihydroergotamine m.p. 171 DEG-172 DEG C. (acetone); -45.44 ° (c = 0.5, pyridine) a

6-nor-6-ethoxycarbonylmethyl-dihydroergocristine mp 158-161 ° C (diethyl ether); (X 10 ° - ³⁹ > ³⁸ ° < ^c = °> ⁵ · pyridine).

Example 5

6-nor-6-acetyl-dihydroergotamine

To a solution of 6-nor-dihydroergotamine (0.57 g; 1 mmol) in 10 mL of pyridine was added dropwise acetic anhydride (0.81 g; 8 mmol) and the mixture was stirred at 20 ° C for 1 h. The mixture was then diluted with water under external cooling. The precipitate was aspirated and dried. Crystallization from ethanol gave 0.51 g of 6-nor-6-acetyl-dihydroergotemin, m.p. Mp 198-200 ° C;

C ^ Jo ° - ¹⁰³ · ⁹⁵ ° ^(C ° · ⁵ · pyridine).

Analogously, 6-nor-6-acetyl-dihydroergocristine was prepared. 191-192 ° C (ethanol); [Α] 20 D -96.1 ° (c = 0.5, pyridine).

Example 6

6-nor-6-methylsulfonyl-dihydroergocristine

A mixture of a solution of 6-nor-dihydroergocristine (1.19 g; 2 mmol) in 40 mL of dioxane, triethylamine (0.22 g; 2.2 mmol) and methyleulfochloride (0.25 g; 2.2 mmol) was stirred for 7 h at 20 ° C and then evaporated to dryness under reduced pressure. The residue was partitioned between chloroform and water. The chloroform phase residue was purified by silica gel column chromatography in chloroform using ethanol as eluent. Crystallization from acetone gave 0.53 g of 6-nor-6-methylsulfonyldihydroergocristine m.p. 210-212-223.99 (c = 0.2, pyridine).

The following were prepared analogously:

6-nor-6-methylsulfonyl-dihydroergotamine m.p. 231-233 ° C (acetone) -33.23 ° (c = 0.2, pyridine),

6-nor-6-benzyloxycarbonyl-dihydroergotamine mp 232-233 ° C (acetone) -45.31 ° (c = 0.2, pyridine) and

6-nor-6-benzyloxycarbonyl-dihydroergokrÍ8tin mp 155-160 ° C (acetone-water) ZZI D ° - ^{37 '94} ° (c = 0.2, pyridine).

Claims (3)

A process for the preparation of ergopeptin derivatives of the general formula I in which R is n-propyl, allyl, propargyl, ethoxycarbonylmethyl, benzyl, acetyl, 2 methylsulfonyl or benzyloxycarbonyl and R is methyl or isopropyl and their salts with pharmaceutically acceptable acids when R * is n-propyl, allyl, propargyl, 2 is ethoxycarbonylmethyl or benzyl; and R is as defined above, characterized in that ergo- (2) in which R is as defined above, is converted by reaction with cyanogen bromide in an inert solvent to the ergopeptin of formula III, Wherein R is as defined above and is converted by hydrogenation to the ergopeptin of formula IV, H. COMH · " CS 271 626 B1 in which R is as defined above and the ergopeptin thus obtained is reacted with corresponding alkylating or acylating agents to give ergopeptins of the general formula I in which R * denotes n-propyl, allyl, propargyl, ethoxycarbonylmethyl, benzyl, acetyl, methylsulfonyl 2 or benzyloxycarbonyl and R is as defined above, and the compounds thus prepared are optionally converted to salts with pharmaceutically acceptable acids when R 1 is n-propyl, allyl, propargyl, ethoxycarbonylmethyl or benzyl. 2. A process according to claim 1, wherein the reaction of cyanogen bromide with ergopeptin of formula (II) in which R is as defined above is carried out in chloroform or dichloromethane at 20 to 40 ° C. 3. A process according to claim 1, wherein the hydrogenation of the ergopeptins of the general formula III, in which R is as defined above, is carried out in dioxane containing from 5 to 10%. 30% by volume of water at 30 to 50 ° C under normal pressure and in the presence of Raney nickel catalyst.