CS221925B2 - 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 8 represents a C 1 -C 6 alkyl group or a benzyl group,

R ^ and R ^ are each independently hydrogen or C až-C alky alkyl,

R 6 represents a hydrogen atom, and when R 6 represents a hydrogen atom, it may also represent a bromine atom, and

R 8 and R 8 together form a single bond or each of R 8 and R 8 represents a hydrogen atom or R 8 represents a methoxy group and R 6 represents a hydrogen atom, and their acid addition salts.

In formula (I), R 1 is, for example, methyl or isopropyl, R 8 is, for example, benzyl or preferably branched C 3 or C 4 alkyl, R 1 is, for example, n-propyl or isopropyl, and preferably methyl, R 6 and Preferably, R ^ is each hydrogen, and Rg and R? Are each hydrogen. expediently form a bond.

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 1 with configuration 88 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 R 8 are R 8. each represents a hydrogen atom. However, no peptide ergot alkaloid substituted in the 2-position is specifically mentioned in this patent. In addition, no therapeutic use is reported for this class of compounds.

. In accordance with the invention, the compounds of formula I and their acid addition salts are prepared by reducing the compound of formula II

in which

Rj to R? are as defined above and

R 8 represents a residue reducible to a methyl group corresponding to formula III

-CHR 3 -S-Rg (III) wherein

R 8 represents a lower alkyl group or a benzyl group and

Rjq represents a hydrogen atom or a group -S-Rjj wherein Rjj represents a lower alkyl group, a benzyl group or together with Rg forms a - (CH ₂ ) _n - group in which n is 2 or 3, -CHg-S-CHg or the compounds obtained are optionally converted into their acid addition salts.

The reduction according to the invention can be carried out in a manner known per se, for example catalytically, with Raney-nickel of medium activity being particularly suitable as the catalyst. The reaction may be carried out in an inert solvent under the reaction conditions, preferably in a mixture of acetone and dimethylformamide.

The reduction is preferably carried out at room temperature, which is made possible by the pretreatment of Raney nickel as a catalyst.

Under these mild conditions, the potentially present double bond at position 9, 10 of the lysergic acid residue will practically not be attacked.

The pretreatment of Raney-nickel as a catalyst is carried out, for example, by partially replacing the aqueous catalyst slurry with a mixture of acetone and dimethylformamide.

However, the reduction can also be carried out with suitable reducing agents such as sodium borohydride, lithium aluminum hydride and the like hydrides in the presence of metal salts such as copper, zinc, titanium and nickel salts and the like in protic or aprotic solvents. In situ prepared nickel boride in ethylene glycol has proven to be particularly suitable.

Preferred radicals for Rg are 1,3-dithian-2-yl and 2- (1,3) -dithiolane.

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.

The starting materials of formula (II) may be prepared by treating an acid addition salt of a compound of formula (IV)

in which

R 1 and R 8, as defined above, are condensed in a manner known per se with a reactive acid derivative of the general formula V

in which

R ₃ to R g are as defined above.

The compounds of uvcds ^'5!.' Ce of formula VI, V p obtained by reacting compounds of the Formulas

(VI) in which:

R p R 6, R j, R g and γ are as defined above, with a compound of formula VII

LR ₈ (VII) wherein

Rg is as defined above and

L represents, with or without the action of Lewis acids, a readily removable group, such as chlorine, a lower alkoxy group or a radical of formula VIII

(VIII) wherein n is as defined above.

This reaction is carried out, for example, in an inert solvent under reaction conditions, such as chloroform or methylene chloride. The reaction may optionally be carried out in the presence of a Lewis acid such as titanium tetrachloride. The reaction temperature is preferably from -10 to +40 ° C.

The compounds of general formula VII used are, for example, 2-methoxy-1,3-dithiolane, 2-chloro-1,3-dithiane or 1,2-thio (1,3-dithiolan-2-ylthio) ethane . The two first-mentioned compounds are preferably prepared by sieving. Use of in situ prepared 2-chloro-1,3-dithiane [see J, Org. Chem. 44. 1847 U979)] allows the introduction of a 1,3-dithianyl function under mild conditions and without the use of a Lewis acid.

If no lion is used; The compounds of formula (II) may also be obtained by treating a lysergic acid derivative (a compound of formula (V) in which Rg is a refractive index) with an aminocyclol of formula (II). IV introduces a radical Rg, for example as described in Example 1.

If the preparation is not described in any of these, these are either known or can be prepared by methods. and optionally the processes described herein.

The compounds of the invention have not been described in the literature. These substances exhibit interesting pharmacological properties in animal experiments and can therefore be administered. j ⁽ⁱⁿ the drug.

In particular, the compounds prepared according to the invention exhibit 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. The compounds can therefore be used in cerebral vascular damage, cerebral sclerosis, cerebral insufficiency or in disorders of clear consciousness due to cranial trauma.

In addition, the compounds produced by the process 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 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 powders, 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 disintegration and resorption 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 commonly 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 such as ethyl p-hydroxybenzoate. The capsules may contain as the active ingredient either the active ingredient itself according to the invention, 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 Mass a compound of formula I, for example 2-methyl-9,10-dihydroergotamine mesylate 1,025 mg tartaric acid 0.1 mg lactose 84,975 mg corn starch 8 mg gelatine 0.3 mg magnesium stearate 0.5 mg stearic acid 1.1 mg talc 4 mg Capsule Component Mass a compound of formula I, for example 2-methyl-9,1O-dihydroergotamine 1 mg thinner (starch, etc.) 299 mg

Liquid formulations Component Sterile suspension for injection Liquid suspension for oral administration a compound of formula I, for example 2-methyl-9,10-dihydroergotamine 0.5 0.5 sodium carboxymethylcellulose USF 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 methylparben, USF - 4,5 propylparben - 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 make up to 1 ml add to 5 ml

For the above-mentioned 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 from about 0.01 to 10 mg / kg body weight. The appropriate dose may be administered once daily or. optionally in several portions.

For larger mammals, the daily dosage is in the range of about 0.5 to 100 mg of active ingredient. Suitable dosage forms, for example, for oral administration generally contain, in addition to solid or liquid carriers, 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.

Example 1

2-methyl-alpha-ergocryptine

a) 2- (1,3-dithian-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 11.5 g (20 mmol) of alpha-ergocryptine in chloroform. The reaction mixture was warmed to about 5-10 ° with immediate precipitation of a black, oily 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 a mixture of methylene chloride and methanol (9: 1). The organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated after filtration. 16.7 g of an orange-brown foam are obtained which can be used directly for the subsequent desulfurization or can be purified by chromatography on 50 times silica gel using 2% methanol in methylene chloride as the eluent and crystallizing 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 of +111 (c = 0.55 in dimethylformamide).

b) 2-methyl-alpha-ergocryptine

Aqueous suspension of Raney Nickel (W-6) (105 ml) was repeatedly suspended in 100 ml of acetone / dimethylformamide (8: 2) under nitrogen until the supernatant solution became practically 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 rapidly 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 [deg.]), 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. To yield a brownish foamy residue, which, after addition of one equivalent of fumaric acid the product crystallizes as the hydrogen fumarate melting at 181 to 184 °, with an optical rotation of ⁼ 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 1 compound 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] D 10 = 10 ° (e = 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-9,1O-dihydroergotamine

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

Example 6

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

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

Example 7

2-methyl-9,1O-dihydroergotamine

The above compound melts after crystallization from a mixture of methylene chloride and ethyl acetate with decomposition at 185-186 ° and has an optical rotation of [α] = -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 melts at 191-192 ° and has an optical rotation of -13.9 ° (c = 0.6 in methanol).

Example 9

2-methyl-9,1O-dihydroergonine

The product melts after crystallization from methylene chloride / benzene with decomposition at 174-176 ° and has an optical rotation of [α] = -57 ° (c = 1.0 in pyridine).

Example 10

2-methyl-9,10-dihydroergocornine

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

Example, 1

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 -2.4 ° (c = 0.55 in chloroform).

Example 12

2-methyl-2 'methyl-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 ° and my optical rotation λ '= + 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 E "1d °" ⁺ 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 177-180 ° and has an optical rotation = + 30.0 ° (c = 0.53 in dimethylformamide).

Example 15

2-methylergocornine a

The above compound crystallizes as hydrogen fumarate from a mixture of ethyl acetate and ethanol. The product melted with decomposition at 186-189 ° and had an optical rotation [delta] ^ ⁰ = + 40.7 ° (c = 0.59, dimethylformamide).

Example 16

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

The title compound melts after crystallization from methylene chloride and ether to decomposition at 172-175 ° and having the optical rotation E «j ^ ^C = + 60.0 ° (c = 0.21, dimethylformamide). Example 17

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

The above compound crystallizes as hydrogen sulfate from a mixture of ethyl acetate and ether. The product melts with decomposition at 142-147 ° and has an optical rotation of [α] D ^{= +} 43.2 ° (c = 0.45 in dimethylformamide).

Example

2-methyl-6-nor-6-isopropyl-9,1O-dihydroergotamine

To a solution of 3.58 g (5 mmol) of 2- [2- (1,3) -dithiolano] -6-nor-6-isopropyl-9,1O-dihydroergotamine and 11.9 g of nickel chloride hexahydrate in 120 ml of ethylene glycol is slowly added. 3.8 g of sodium borohydride in 50 ml of water are added dropwise and the mixture is then heated at 90 DEG for 2 hours. The resulting black suspension was filtered off with suction and the filtrate was extracted with methylene chloride. After washing with water, drying and evaporation of the solvent, an off-white panic product is obtained which is chromatographed on a 50-fold amount of silica gel. The title compound was eluted with 3% methanol in methylene chloride and crystallized from methanol.

The product melted with decomposition at 172 °, and has an optical rotation of [delta] P ⁰ = -60.2 ° (c = 1.3 in methyl enchloridu).

The starting material can be prepared as follows.

ml of absolute dimethylformamide was cooled to -20 DEG while stirring, and a solution of 2.7 g of oxalic acid chloride in 8.5 ml of acetonitrile was added dropwise. 7.1 g (17.7 mmol) of dry 2- [2- (1,3) -dithiolano] -6-nor-6-isopropyl-9,10-dihydrolysergic acid are then added to the mixture, starting from the transient A dark brown precipitate precipitates. After stirring for 30 minutes at 0 °, the mixture was diluted with vigorous cooling with 18 ml of absolute pyridine and treated with 3.24 g (8.8 mmol) of (2R, 5S, 10aS, 10bS) -2-amino-5-benzyl- 10b-Hydroxy-2-methyl-octahydro-3,6-dioxo-8H-oxazolo [3,2-a] pyrrolo [1,1-c] pyridazine hydrochloride. The reaction mixture was stirred vigorously for 2 hours, allowed to rise from -10 ° to 0 °, then diluted with 36 mL of citrate buffer pH 4 and basified with 2N sodium carbonate solution. The resulting mixture was extracted with methylene chloride, the extract was dried, evaporated and the residue chromatographed on a 20-fold amount of silica gel. 2- [2- (1,3) -dithiolano] -6-nor-6-isopropyl-9,1O-dihydroergotamine is obtained as a yellow foam. This product can be used for further desulfurization without further purification.

The compounds of Examples 2 to 4 and 6 to 17 can also be prepared in an analogous manner to Example 18.

Claims (3)

A process for the preparation of ergopeptin derivatives of the general formula I in which R1 is C1-C4alkyl, R ₂ represents an alkyl group having 1 to 6 carbon atoms or benzyl, R ₃ and R ₄ are each independently hydrogen or C 1 -C 4 alkyl; R _? represents a hydrogen atom and when R? 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 represents a hydrogen atom, or R 8 represents a methoxy group and R 8 represents a hydrogen atom, and their acid addition salts, characterized in that a compound of formula II in which R1 to Ry are as defined above and R 8 represents a residue reducible to a methyl group corresponding to formula III -chr ₁₀ -sr ₉ (III), where R 8 represents a lower alkyl group or a benzyl group and R ₁₀ represents hydrogen or -SR _1, wherein R ₁₁ represents lower alkyl, benzyl, or together with R forms a group - (CH _{2) n} - in which n is 2 or 3, a group -Chg- The S-CH 3 - or the compounds obtained are optionally converted into their acid addition salts. 2. The process of claim 1 wherein Rg is C1-C4alkyl or benzyl; Rg is a 2- (1,3) -dithiolane radical. and the remaining general symbols have the meanings given in 1, except that -11Rj, Rg and Ry are each hydrogen, Rj is not a methyl group. 3. A process according to claim 1 wherein Rg is C1-C4alkyl or benzyl; R6 is methyl, each of Rg, Rg. and Ry represents a hydrogen atom, Rg represents a 2- (1,3) -dithiolane radical and the remaining general symbols have the meanings given in 1.