CS221924B2 - Method of making the ergopeptine derivatives - Google Patents

Abstract

The invention provides a process for the preparation of compounds of formula I (AND) in which R 1 is C 1 -C 4 alkyl, R 8 is C 1 -C 6 alkyl or benzyl; R1, R4 independently of one another are hydrogen or alkyl having 1 to 4 atoms carbon, R 1 represents a hydrogen atom and, when R a represents a hydrogen atom, it may be equal to or equal to than bromine, and Rg and Ry together form a single bond or each of Rg and Ry is a hydrogen atom or R 8 is methoxy and R y is hydrogen, and their acid addition salts.

Description

(54) A method for producing ergopeptin derivatives

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

(I) in which

R ₁ 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, R 2, independently of one another, are hydrogen or C 1 -C 4 alkyl,

R 6 represents a hydrogen atom, and when R y represents a hydrogen atom, it may be equal to a bromine atom, and

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

In formula (I), R @ _{1 is,} for example, methyl or isopropyl, R @ ₂ is, for example, benzyl or preferably branched alkyl having 3 or 4 carbon atoms, R @ 1 is, for example, n-propyl or isopropyl, and preferably methyl. R @ 1 and R @ 2 are each preferably hydrogen, and R @ 8 and R @ 7 form a bond.

Compounds of formula X 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 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 6, R 8 and B 8 are each hydrogen. However, no 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 prepared by the acid addition salt of a compound of the formula II

in which

R ₁ and R 8 are as defined above, condensed with a reactive acid derivative of the formula III

in which

R @ 1, R @ 1, R @ 1, R @ 8 and R @ 8 are as defined above, and the compounds obtained are optionally converted into their acid addition salts.

The reaction according to the invention can be carried out in a manner analogous to known methods of condensation, by which analogous peptide ergot alkaloids are prepared.

A suitable acid addition salt of aminocyclol is hydrochloride.

As reactive functional derivatives of 2-methyllysergic acid, for example, the acid chloride, the acid azide or a mixed anhydride thereof with sulfuric or trifluoroacetic acid can be used.

However, it is also possible to use an addition product of a 2-methyllysergic acid derivative with dimethyl formamide or acetamide and thionyl chloride, with phosgene or scalic acid chloride.

The reaction is preferably carried out in the presence of triethylamine or pyridine. Suitable solvents are, for example, chloroform, methylene chloride, dimethylformamide or acetonitrile.

The reaction may be carried out at a temperature between -30 ° C and +20 ° C.

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

In particular, the compounds 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 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 of the invention have antidepressant activity and can therefore be used as antidepressants.

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 ortho-static disorders or for the prophylaxis of thrombosis.

The compounds 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 in the form of 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. The tablets may be coated by known methods to slow disintegration and resorption in the gastrointestinal tract and to 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 the active ingredient either the active ingredient according to the invention alone 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 ingredient weight

a compound of formula I, Example 2-methyl-9,10-dihydroergota- min-mesylate 1,025 mg tartaric acid 0.1 mg lactose 84,975 mg cornstarch 8 mg gelatine 0.3 mg magnesium stearate 0.5 mg stearic acid 1.1 mg talc 4 mg

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

299 mg mg

Liquid formulations

Component

Weight (mg)

Sterile Liquid suspension suspension ^for oral administration

a 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 -

221934 continued

Weight (mg)

Sterile injectable susDenze Liquid suspension for oral administration 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 buffer for pH control for stabilization according to needs as required water add 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 desired treatment. In general, however, favorable results are obtained at dosages of about 0.01 to 10 mg / kg body weight. The appropriate dose may be administered once daily or optionally 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 from about 0.1 to 50 mg of active ingredient.

The invention is illustrated by the following non-limiting examples. In these examples, the temperature data is given in degrees Celsius and is not corrected.

He did

2-methyl-alpha-ergocryptinin and 2-methyl-alpha-ergocryptin (procedure a)

2.82 g (10 mmol) of anhydrous 2-methyllysergic acid was dissolved in 25 ml of absolute dimethylformamide by adding 2.28 g (20 mmol) of trifluoroacetic acid and the solution was cooled to -10 ° C with stirring. At this temperature, a solution of 2.52 g (12 mmol) of trifluoroacetic anhydride in 12 ml of absolute acetonitrile was added dropwise to the solution over 5 minutes, the resulting clear solution was stirred for a further 10 minutes. 81 g (5 mmol) of (2R, 5S, 10aS, 10bS) -2-amino-5-isobutyl-10b-hydroxy-2-isopropyl-octahydro-3,6-dioxo-8H-oxazolo [3,2-a] pyrrolo [ The reaction mixture was stirred at -10 ° C to 0 ° C for 1 h.

For working-up, the reaction mixture was diluted with 200 ml of methylene chloride and thoroughly shaken with 100 ml of 2N sodium carbonate solution. The aqueous phase is extracted three more times with 100 ml of methylene chloride each time. The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on a 50-fold amount of silica gel, eluting with 2% methanol in methylene chloride to afford pure 2-methyl-alpha-ergocryptinine, which is crystallized from a mixture of methylene chloride and ether. The product melts at 225-227 ° C with decomposition.

3% methanol in methylene chloride was eluted first with the mixed fractions and then with pure 2-methyl-alpha-ergocryptine, which upon addition of 1 equivalent of fumaric acid crystallized from absolute ethanol as the hydrogen fumarate melting at 181-184 ° C with optical rotation = +25 0 ° (c = 0.2 in ethanol).

The following compounds corresponding to formula I can be obtained in an analogous manner to Example 1:

Example 2

The above compound melts after 219 DEG-221 DEG C. after crystallization from a mixture of methylene chloride and ether.

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 = -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] D = + 44 ° (c = 1.0 in dimethylformamide). Example 5

2-methyl-6-nor-6-isopropyl-9,10-dihydroergotamine, m.p.

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

Example 6

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

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

2-methyl-9,10-dihydroergotamine

The above compound melts after crystallization with a mixture of methylene chloride and ethyl acetate with decomposition at 185-186 ° and has an optical rotation of [α] D = -77.5 ° (c = 1.0 in pyridine). Example

2-methyl-9,10-dihydroergocristine

The above compound crystallizes as hydrogen fumarate from a mixture of methylene chloride and ethyl acetate. The product melts at 191-192 ° and has an optical rotation = -3.9 ° (c = 0.6 in methanol).

22,924

Example 9

2-methyl-9,1O-dihydroergonine

The product melts after crystallization from methylene chloride / benzene with decomposition at 74 DEG-176 DEG and has an optical rotation of Μρθ = -57 ° (c = 1.0 in pyridine).

He did

2-methyl-9,1O-dihydroergocornine

The product melts after crystallization from a mixture of methylene chloride and benzene with decomposition at 172-174 ° and has an optical rotation Μρθ = -58 ° (c = 1.0 in pyridine).

Example 11

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

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

Example 1 a d 12

2-Methyl-2'-beta-isopropyl-5'-alpha-n-butylenegopeptin

The product melts as the hydrogen fumarate after crystallization from a mixture of ethyl acetate and acetone with decomposition at 157-160 ° and has an optical rotation of [α] ^D = + 54.0 ° (c = 0.55 in dimethylformamide). Example 13

2-methylergocristine

The product melts after crystallization from a mixture of methylene chloride and isopropyl ether with decomposition at 165-168 ° and has an optical rotation of [α] p = + 40.9 ° (c = 0.45 in dimethylformamide). Example 14

2-methyl-beta-ergocryptine

The product melts after crystallization from a mixture of methylene chloride and isopropyl ether with decomposition at 177 to 80 ° and has an optical rotation = + 30.0 ° (c = 0.53 in dimethylformamide).

Example 15

2-methylergocornine

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] D = + 40.7 ° (c = 0.59 in dimethylformamide).

Example

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

The above compound melts after crystallization from a mixture of methylene chloride and ether with decomposition at 172-175 ° and my optical rotation [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 the hydrogen sulfate from a mixture of ethyl acetate and ether. The product melts with decomposition at 142-147 ° and has an optical rotation of + 43.2 ° (c = 0.45 in dimethylformamide). «.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of ergopeptin derivatives of the general formula X (I) in which R | represents an alkyl group having 1 to 4 carbon atoms, R ₂ represents an alkyl group and 1 to 6 carbon atoms or benzyl, R ^ and R ^ are each independently hydrogen or C až-C alky alkyl, R 8 represents a hydrogen atom and when R 8 represents a hydrogen atom; is hydrogen, may also be bromine, and R 8 and R 8 together form a single bond or each of R 8 and R 8; R @ 2 is hydrogen or R @ 8 is methoxy and R @ 8 is hydrogen; represents a hydrogen atom, and acid addition salts thereof, characterized in that the acid addition salt of the compound of formula (II): R ₁ and R 8 are as defined above, condensed with a reactive acid derivative of the formula III 221 (III) where R 1, R 2, R 8, R 8 and R 8 are as defined above, and the compounds obtained are optionally converted into their acid addition salts. 2. The process of claim 1, wherein 3e is a compound of formula (II) wherein R1 is as defined in (1) and R8 is C1 -C4 alkyl or benzyl. , and a compound of the above formula (III), wherein R 1 is as defined in point 1, with the meaning of R 1, R 8 and R 7 are each hydrogen, not R 6 is methyl. 3. A process according to claim 1, wherein the compounds of formula (II) in which R @ 1 is as defined in (1) and R @ 8 is alkyl, and compounds of formula (III) above, are used as starting materials. wherein R 1 is a methyl group, R 1 is as in point 1, and each of R 1, R g and R y is each a hydrogen atom.