CS221926B2 - Method of making the ergopeptine derivatives - Google Patents

Description

The present invention provides a process for the preparation of compounds of formula I

in which

R ₁ represents an alkyl group having 1 to 4 carbon atoms,

R ₂ represents an alkyl group having 1 to 6 carbon atoms or benzyl,

R (b) and R (4) independently of one another are hydrogen or (C1-C4) -alkyl,

R 1 represents a hydrogen atom, and when Ry represents a hydrogen atom, it may also represent a bromine atom, and

R g and R y together form a single bond or each of R g and R y represents a hydrogen atom, or R g represents a methoxy group and R y represents a hydrogen atom, and their acid addition salts.

In formula I R ₁ for example methyl or isopropyl, R ₂ is for example a benzyl group or preferably a branched alkyl group having 3 or 4 carbon atoms, R₁ is for example n-propyl or isopropyl, es preferably methyl. and R 6 are preferably hydrogen, and R 8 and R 7 are conveniently a bond.

The compounds of formula I may exist in the form of two isomers, in the form of compounds having the 8R configuration and compounds having the 8S configuration. Compounds of formula I having the 8R configuration are preferred.

Swiss Patent Specification No. 588485 already describes the preparation of a wide product group including, but not limited to, the compounds of formula I of the present invention in the 8R configuration, wherein R 1 is methyl and R 8, R 8 and Ry are each hydrogen. However, neither peptide ergot alkaloid substituted in position 2 is specifically mentioned in this patent. Furthermore, no therapeutic use is reported for this class of compounds.

According to the invention, the compounds of the formula I and their acid addition salts are produced by bringing into the mixture 2 the compounds of the formula II

in which

R1 to Ry are as defined above, introducing a methyl group, and optionally converting the obtained compounds to their acid addition salts.

The introduction of the methyl group according to the invention can be carried out in a manner known per se. The 9,1O-dihydroderivatives of the peptidic ergot alkaloids are obtained, for example, by 2-aminomethyl-alkali followed by hydrogenolysis of the corresponding unsubstituted compounds.

Preferably, the introduction of the methyl group is carried out in two steps, the first step being the introduction of the sulfur-containing group and the second step the reduction of the group.

The compounds of the invention can be isolated from the reaction mixture and purified in a manner known per se.

When the compounds described are unsaturated at the 9,10 position, they are obtained in the form of mixtures of 8R and 8S isomers which can be separated in a manner known per se, for example by chromatography. The 8R- and 8S-isomers can be epimerized in a manner known per se, for example by treatment with acids.

The free bases can be converted into acid addition salts and vice versa. Acids suitable for the preparation of salts are, for example, hydrochloric acid, sulfuric acid, maleic acid, fumaric acid and tartaric acid.

If the preparation of the starting materials is not described, they are either known or can be prepared by methods known per se or by processes analogous to those described herein.

The compounds produced by the process of the invention have not been previously described in the literature. These substances exhibit interesting pharmacological properties in animal experiments and can therefore be used as medicaments.

In particular, the compounds produced by the process of the invention show a stimulating effect on dopamine receptors.

Due to their dopaminergic properties, the novel compounds can be used to treat parkinsonism.

Furthermore, the compounds produced by the process of the invention exhibit a prolactin secretion inhibiting effect and can therefore be used to treat acromegaly.

The disclosed compounds further increase alertness and exhibit psychostimulatory effects. They can therefore be used in cerebral vascular damage, cerebral sclerosis, cerebral insufficiency or in clear consciousness disorders due to cranial trauma.

In addition, the compounds produced by the process of the present invention exhibit antidepressant activity and can therefore be used as antidepressant agents.

Finally, these substances have vascular toning effects and affect both peripheral and central circulation. The compounds according to the invention can therefore be used for the treatment of migraine and orthostatic disorders or for the prophylaxis of thrombosis.

The compounds produced by the process of the invention may be mixed with conventional pharmaceutically acceptable diluents or carriers and optionally other excipients and administered, for example, orally or parenterally.

The compounds may be orally administered in the form of tablets, dispersible powder, granules, capsules, syrups, suspensions, solutions and elixirs, and parenterally in the form of solutions or suspensions, for example, sterile injectable aqueous solutions. To achieve good appearance and good organoleptic properties, the oral compositions may contain one or more ingredients such as sweetening, flavoring, coloring and preservative agents.

Tablets may be obtained by mixing the active ingredient with customary, pharmaceutically acceptable excipients such as inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents such as starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate, stearic acid and talc. Tablets may be coated by known methods to slow their disintegration and absorption in the gastrointestinal tract and prolong the duration of action.

In suspensions, syrups and elixirs, the active ingredient may also be present in admixture with excipients usually used in the preparation of such compositions, such as suspending agents such as methylcellulose, tragacanth and sodium alginate, wetting agents such as lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate, and preservatives. agents such as ethyl p-hydroxybenzoate. The capsules may contain as active ingredient a cell of the active ingredient according to the invention itself or a mixture thereof with a solid diluent such as calcium carbonate, calcium phosphate or kaolin.

Injectables are also prepared in conventional manner.

The pharmaceutical preparations contain up to about 90% of the active ingredient, the remainder being the carrier and / or additives. Because of their preparation and administration, solid dosage forms such as tablets or capsules are preferred.

The following is a composition of pharmaceutical compositions which are manufactured in a manner known per se.

Tablets component weight compound of formula I, for example 2-methyl-9,10-

-dihydroe.rgo tamin-melamine 1,025 mg tartaric acid 0.1 mg laktóaa 84,975 mg cornstarch 8 mg gelatine 0.3 mg magnesium stearate 0.5 mg stearic acid 1.1 mg talc 4 &

Capsule ingredient weight compound of formula I, for example 2-methyl-9,10-dihydroergotamine 1 mg diluent (starch, etc.) 299 mg

Liquid formulations weight (mg) component sterile injectable suspension for oral administration compound of formula I

for example 2-methyl-9,10-dihydroergotamine 0.5 0.5 sodium carboxymethylcellulose USP 1,25 12.5 methylcellulose 0.4 - polyvinylpyrrolidone 5 - lecithin 3 - benzyl alcohol 0.01 - magnesium aluminum silicate - 47.5 flavoring - as required dye - as required methylparaben, USP - 4,5 propylparaben, USP - 1.0 polysorbate 80 (e.g., Tween 80), USP 5 70% sorbitol solution, USP - 2 500 a buffer to regulate the pH value to stabilization as required as required water make up to 1 ml make up to 5 ml

For the above applications, the dosage employed will, of course, vary depending upon the agent to be administered, the mode of administration and the treatment desired. In general, however, favorable results are obtained at doses of about 0.01 to 10 mg / kg body weight. The appropriate dose may be administered once daily or in several divided doses. For larger mammals, the daily dose ranges from about 0.5 to 100 mg of active ingredient. Suitable dosage forms for oral administration contain, in addition to solid or liquid carriers, generally about 0.1 to 50 mg of active ingredient.

The invention is illustrated by the following non-limiting examples. In these cases, temperature data are given in degrees Celsius and are corrected.

Example!

2-methyl-alpha-ergocryptine

a) 2- (1,3-Dithlan-2-yl) -alpha-ergocryptine

To a vigorously stirred solution of about 1.2 equivalents of 2-chloro-1,3-dithiane in absolute chloroform, cooled to -15 °, was quickly added dropwise a solution of 11.9 g (20 mmol) of alpha-ergocryptine in chloroform. The reaction mixture was warmed to about 5-10 ° with immediate precipitation of a black colored granulated precipitate, stirred at the same temperature for 10 minutes and then worked up.

For work-up, the reaction mixture was basified with 2N sodium carbonate solution and extracted with methylene chloride / methanol (9: 1). The organic phase is washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated after filtration. 16.7 g of an orange-brown foamy product are obtained which can be used directly for the subsequent desulfurization or which can be purified by chromatography on 50 times silica gel using 2% methanol in methylene chloride as the eluent and crystallize from ethyl acetate after addition of an equivalent amount of maleic acid. ether such as hydrogen maleate.

The product melts with decomposition at 163-165 ° and has an optical rotation = + 111 ° (c = 0.55 in dimethylformamide).

b) 2-methyl-alpha-ergocryptine

An aqueous suspension of 105 ml of Raney-Nickel (W-6) is repeatedly suspended in 100 ml of a mixture of acetone and dimethylformamide (8: 2) under a nitrogen atmosphere until the supernatant solution virtually becomes cloudy after the addition of methylene chloride (about three to four times). ).

7.5 g of the crude product obtained in a) in 150 ml of acetone containing 20% dimethylformamide are quickly added to a suspension of 105 ml of the previously treated Raney-nickel in 100 ml of the same solvent mixture. After stirring for 15 minutes at room temperature (not more than 30 ° C), the catalyst is filtered off, washed several times with about 300 ml of the solvent mixture described above, then the solvents are evaporated off under vacuum. A brownish foamy residue is obtained, from which, after addition of 1 equivalent of fumaric acid, the desired product crystallizes as the hydrogen fumarate melting at 181 DEG -184 DEG C. with an optical rotation of [.alpha.] D @ 20 = + 25.1 DEG (c = 0.2 in ethanol). ).

Analogous to Example 1, 2-methyl-.alpha.-ergocryptinine can also be prepared, melting after crystallization from a mixture of dichloromethane and ether with decomposition at 225 DEG-227 DEG C., as well as the compounds of Examples 2-17.

Example 2

2-methylergotaminin

The title compound melts after crystallization from methylene chloride / ether with decomposition at 219-221 °.

Example 3

2-methylergotamine

The above compound melts after crystallization from a mixture of methylene chloride and benzene with decomposition at 169-171 ° and has an optical rotation of [α] g ° = -100 ° (c - 1.0 in chloroform).

Example 4

1,2-dimethylergotamine

The above compound crystallizes as the hydrogen tartrate from absolute ethanol. The product has a melting point of 178-179 ° and an optical rotation of [α] ρθ ⁼ * 44 ° (c = 1.0 in dimethylformamide).

Example 5

2-methyl-6-nor-6-isopropyl-9,10-dihydroergotamine

The above compound melts after crystallization from methanol with decomposition at 172 ° and has an optical rotation [α] _D = -60.2 ° (c = 1.3 in methylene chloride).

Example 6

2-methyl-9,10-dihydro- N-ergocryptine

The above compound melts after crystallization from methylene chloride / ether with decomposition at 187-190 ° and has an optical rotation of [α] D = -3.8 ° (c = 0.4 in chloroform). Example 7

2-methyl-9,10-dihydroergotamine

The above compound melts after crystallization from methylene chloride / ethyl acetate with decomposition at 185-186 ° and has an optical rotation of? -77.5 ° (c = 1.0 in pyridine). Example 8

2-methyl-9,10-dihydroergocristine

The above compound crystallizes as hydrogen fumarate from a mixture of methylene chloride and ethyl acetate. The product melted at 191 °, 92 ° and has an optical rotation ^[a] D = -13.9 ° (c = 0.6 in methanol).

Example 9

2-methyl-9,10-dihydroergonine

The product melts after recrystallization from methylene chloride and benzene with decomposition at 174-176 ° and having the optical rotation ^[a] D = -57 ° (c = 1.0 in pyridine).

Example 10

2-methyl-9,1O-dihydrogrgocornine

The product melts after crystallization from methylene chloride / benzene with decomposition at 172-174 ° and has an optical rotation of [α] D = -58 ° (c = 1.0 in pyridine).

Example 11

2-methyl-9,1O-dihydro-alpha-ergocryptine

The product melts after crystallization from methylene chloride / ether with decomposition at 179-182 ° and has an optical rotation of [α] = -2.4 ° (c = 0.55 in chloroform).

Example 12

2-methyl-2 'beta-isopropyl-5'-alpha-n-butylergopeptin

The product melts as the hydrogen fumarate after crystallization from a mixture of ethyl acetate and acetone with decomposition at 157-160 ° C and has an optical rotation of [α] = + 54.0 ° (c = 0.55 in dimethylformamide).

Example 13

2-methylergocristine

The product melts after crystallization from mixtures of methylene chloride and isopropyl ether with decomposition at 165-168 ° and has an optical rotation = + 40.9 ° (c = 0.45 in dlmethylformamide).

Example 14

2-methyl-beta-ergocryptine

The product melts after crystallization from a mixture of methylene chloride and isopropyl ether with decomposition at 177-180 ° and has an optical rotation of [?] + 30.0 ° (c = 0.53 in dlmethylformamide).

Example 15

2-methylergokorni n

The above compound crystallizes as hydrogen fumarate from a mixture of ethyl acetate and ethanol. The product melts with decomposition at 186-189 ° and has an optical rotation of [ ^α ] g ° = + 40.7 ° (c = 0.59 in dlmethylformamide).

Example 16

2-Methyl-6-demethyl-2 'beta-isopropyl-5'alpha-isobutylergopeptin

The above compound melts after crystallization from methylene chloride / ether with decomposition at 172-175 ° and has an optical rotation of [α] ^D = + 60.0 ° (c = 0.21 in dimethylformamide).

Example 17

2-Methyl-6-demethyl-6-ethyl-2 'beta-isopropyl-5'-alpha-isobutylergopeptin

The above compound crystallizes as hydrogen sulfate from ethyl acetate / ether. The product melts with decomposition at 142-147 ° and has an optical rotation of + 43.2 ° (c = 0.45 in dimethylformamide).

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of ergopeptin derivatives of the general formula I in which: R | represents an alkyl group having 1 to 4 carbon atoms, R 8 represents a C 1 -C 6 alkyl group or a benzyl group, R @ 1 and R @ 4 each independently represent a hydrogen atom or a C1 -C4 alkyl group; is hydrogen, may also be bromine, and Rg and R? together form a single bond or each of Rg and R? is hydrogen, or R is methoxy and R is a hydrogen atom, and their addition salts with acids, characterized in that the position 2 of a compound of the general formula II ^R 1 OH CO — NH (II) in which Rj to R? as defined above, introduces a methyl group, and the resulting compounds are optionally converted into their acid addition salts.