CS255876B2 - Process for preparing new 10 alpha-methoxy-6-methyl-ergolines - Google Patents

Abstract

A process for the preparation 10???-methoxy-6-methyl-ergoline derivatives of formula (I> <IMAGE> wherein R is hydrogen or methyl, X is hydrogen, chlorine, bromine oriodine, R' is hydrogen or a 5-bromo-nicotinoyl group, and physiologically acceptable acid addition salts thereof, comprises photochemical methoxylations of a 2-halo-lysergol, optionally followed by modification of the groups at R, X and R<1>. The partly new compounds of formula (I) are valuable intermediates in the preparation of nicergoline, a potent peripheral vasodilator. Moreover, the compounds of formula (I) in which R is Hormethyl, R' is H and X is chlorine, bromine or iodine claimed per se, show D2-receptor blocking activity.

Description

The present invention relates to a novel process for the preparation of partially novel 10α-methoxy-6-methyl-ergoline derivatives of formula (I)

in which it represents a hydrogen atom or a methyl group, it represents a hydrogen, chlorine, bromine or iodine atom and

represents a hydrogen atom or a 5-bromo-nicotinoyl group, and their physiologically acceptable acid addition salts.

According to this method, 2-halo-lysergol (2-halo-6-methyl-8-hydroxymethyl-ergol-9-en) of formula II

wherein X is a chlorine, bromine or iodine atom, converts to the new 2-halo-lumilysergol of formula I wherein R and R 'both are hydrogen, X is a chlorine, bromine or iodine by photochemical methoxylation, if desired, The 2-halogenlumilysergol is methylated and, if desired, removed from the new 1-methyl-2-halo-lumilysergol of formula I wherein R is methyl, X and R 'are as described above from position 2 of the ergoline backbone a chlorine, bromine or iodine atom and, if desired, obtained

1-methyl-lumilysergol of formula I wherein R is as described above, R * is hydrogen and X is hydrogen is converted to nicergoline of formula I wherein R is methyl, X is hydrogen and R ' means 5-bromo-nicotinoyl (10o-methoxy-1,6-dimethylergoline-8'-methanol, 5-bromo-nicotinate). The .alpha.-methoxy-6-methyl-ergoline derivatives obtained at any stage of the synthesis may be converted to the corresponding physiologically acceptable acid addition salts.

The partially novel compounds of formula I are valuable intermediates in the preparation of nicergoline, a salt peripheral vasodilator. In addition, the new 2-halo-lumilysergols (in the general formula Ϊ R and R 'are both hydrogen and X is chlorine, bromine or iodine) and the new 1-methyl-2-halo-lumilysergols (in the general formula IR is methyl (R 'represents a hydrogen atom and X represents a bromine, chlorine or iodine atom) are pharmaceutically active as such, in particular exhibit D 2 -receptor blocking activity. Also, these novel compounds and pharmaceutical compositions containing them as an active ingredient are within the scope of the invention.

There are several methods for preparing nicergoline known to those skilled in the art.

Esterified derivatives of 10-methoxy-1,6-dimethyl-crgoline-8-methanol including nicergoline were first disclosed in U.S. Pat. No. 3,228,944 and in U.S. Pat. No. 2,112,273 (Farmitalia Milano). According to the US patent, a β-carboxy group of lumilysergic acid or a carboxylic acid

The 1-methyl-lumilysergic compound is reduced to the corresponding alcohol by the action of lithium hydride and lithium ether in ether. Subsequent esterification is performed by treatment with the corresponding carboxylic acid anhydride or chloride in the presence of a tertiary amine. When starting with lumilysergic acid, methylation is performed with methyl halide in liquid ammonia in the presence of potassium metal.

When starting lumines are prepared, the desired liquid is dissolved in dilute mineral acid and irradiated with ultraviolet light. According to German Patent 2,112,273, lumilysergol is used as the starting material, which is esterified and subsequently methylated.

According to German Patent Specification 2,752,533 (LEK, Yugoslavia), nicergoline is prepared from 1-methyl-lumilysergol. The resulting compound was esterified with 5-bromo-nicotinic acid. The esterification is carried out in the presence of an imidazole-triphenylphosphite complex in hexamethylene phosphotriamide.

According to European Patent 4,664 (Mora, Italy), lysergol is used as the starting material for the preparation of nicergoline. Lysergol is converted to lumilysergol by methoxylation in the presence of methanol by irradiation with ultraviolet light. Indole-N-methylation is carried out with methyl iodide in dimethylsulfoxide in the presence of potassium hydroxide. The obtained 1-methyl-lumilysergol is esterified with 5-bromo-nicotinic acid in tetrahydrofuran in the presence of dicyclohexylcarbodidimide as condensing agent (DCC). Nicergoline is obtained.

Experiments show that the introduction of the methoxy group on the carbon atom of the ergoline backbone can only be carried out photochemically. Attempts to replace the photochemical reaction with another treatment (U.S. Pat. No. 3,814,765) were not successful because the end product could not be purified from the ergolene by-products formed.

Chemical Abstracts 95, 43 434y describes an improved photochemical reaction in which, in the case of lysergic acid, the conditions under which the reaction was carried out were optimized.

In addition to the indole-N-methylation process described above, methylation according to European Patent Specification 0 533 may also be carried out in the presence of a phase transfer catalyst.

In summary, the above-described methods can be said to be a known method of preparing nicergoline by the photochemical step, which is accompanied by side reactions. This leads to undesirable by-products which contaminate the end product. The consequence is that the product can be isolated and separated from the structural isomers and from the undesired color compounds only by complex chromatographic purification.

Surprisingly, it has been found that when 10-methoxyergoline derivatives are prepared from 2-halo-ergoline derivatives, the amount of by-products and structural isomers formed in the photochemical reaction is substantially lower than in reactions using lysergol or lysergic acid as the starting material. Desired 2-halo-lumino compounds may be isolated instead of chromatographic purification by simple crystallization or other conventional methods. The yields are greatly increased.

The presence of the activating group (halogen atom) on the C 2 - carbon atom of the ergoline backbone also carries with it another unexpected advantage. In the known methylation processes, in addition to the desired N-methyl compound, a substantial amount of the corresponding O-methyl derivative is also formed, from which the desired product must be separated. Our experiments have shown that using halogenated ergoline derivatives as starting material results in N-methylation in a shorter time and more selectively than in the prior art processes.

This results in a significant increase in yields. Another advantage is that the N-methyl-2-halo-lumino compounds are considerably less soluble than the corresponding non-halogenated compounds. Thus, their isolation is simpler (e.g., no chloroform extraction is required) and can be performed in higher yields.

The 2-halo-lysergols used as starting compounds in the process of the invention are prepared as illustrated in Examples 1, 2 and 3 of this application either by halogenating lysergol or by isomerizing 2-halo-elymoclavin.

According to the invention, the 2-halo-lysergol of the formula II is converted to the 2-halo-lumilysergol in the first step by a photochemical reaction. The photochemical reaction is carried out in a methanolic medium containing sulfuric acid. The reaction mixture is irradiated with ultraviolet radiation. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was poured into water. The pH of the solution is adjusted to 6 by addition of ammonium hydroxide. The mixture is extracted with a water-immiscible solvent such as chloroform, dichloromethane, benzene, carbon tetrachloride and toluene, preferably chloroform.

The chloroform phase is then dried and evaporated. The residue which contains 2-halo-lum-lysergol is dissolved in a mixture of an aprotic solvent such as acetone, ethyl acetate, benzene and acetonitrile, preferably acetonitrile. The 2-halo-lumilysergol is dissolved in a dipolar aprotic solvent, preferably in a mixture of dry dimethyl sulfoxide and potassium hydroxide at 15-20 ° C. Methyl iodide was added with stirring of the reaction mixture for 30 to 35 minutes. The reaction mixture was then poured into ice-water. The precipitated 1-methyl-2-halo-lumilysergol is filtered off, dried in vacuo and isolated by crystallization as described in connection with a photochemical reaction, preferably from acetone or, if desired, a halogen atom from 1-methyl-2-chloro -lumilysergol eliminates by dehalogenation.

Dehalogenation is carried out by dissolving 1-methyl-2-halo-lumilysergol in a protic or aprotic solvent such as ethanol, methanol, ether, ethyl acetate, acetonitrile, tetrahydrofuran, benzene and toluene, preferably ethanol. The solution obtained is added to pre-moistened palladium carbon. 10% palladium on carbon is used based on the amount of compound to be reduced. The reduction is carried out by passing hydrogen gas through the solution. The progress of the reaction was monitored by thin layer chromatography.

After the reduction is complete, the catalyst is filtered off, the filtrate is evaporated under reduced pressure and the product is crystallized from an aprotic solvent, preferably acetone. Nicergoline is prepared from 1-methyl-lumilysergol by esterification. The esterification is carried out in two stages. In the first step, the active ester is prepared. In the second step, the esterification is then carried out with the active ester from step 1.

The active ester is prepared by dissolving N-hydroxysuccinimide in an aprotic solvent such as tetrahydrofuran and ethyl acetate, preferably ethyl acetate. The solution was added

5-bromo-nicotinic acid and then Ν, Ν-dicyclohexylcarbodiimide. An equimolar amount of dicyclohexylcarbodiimide relative to N-hydroxysuccinimide is used. The mixture was stirred at room temperature. The precipitate was filtered off. The mother liquors were evaporated under reduced pressure. The active ester is obtained as a white amorphous precipitate which, if desired, is recrystallized from ethanol.

In the second step, esterification with the active ester obtained is carried out at temperatures of from 20 to 60 ° C, preferably at room temperature, in an aprotic solvent such as tetrahydrofuran, benzene and acetonitrile, preferably in tetrahydrofuran, in the presence of an organic base such as triethylamine and pyridine, preferably pyridine. When esterified, the organic base can also serve as a solvent. The 1-methyllumilysergol is dissolved in the selected solvent or in a pure organic base, and the active ester prepared as described above is added to the solution. The progress of the reaction was monitored by thin layer chromatography. After the esterification was complete, the solvent was removed in vacuo. The product was separated from the organic base by extraction, dried, evaporated in vacuo and crystallized from diethyl ether. If desired, the product can be further purified by silica gel column chromatography.

The D-receptor blocking activity of the novel compounds of this invention ^{out of} 3 is tested by the Seeman method (P. Seeman: Dopamine receptor measurement with (H) -ligands, Methods in Biogenic Amine Research, ed. S. Parvez, T. Nagatsu, I. Nagatsu and H. Parvez, 1983, 591-622, Elsevier.). The assays are performed on the rat striatum membrane using ( ³ H) -spiroperidol as ligand.

The 10β-methoxy-6-methyl-ergoline derivatives of the invention are isolated as bases. If desired, they are purified by recrystallization and / or converted into a physiologically acceptable acid addition salt. The recrystallization is carried out from a suitable protic or aprotic solvent, preferably from acetone or ether.

The compounds of formula (I) may be converted into acid addition salts by reaction with suitable pharmaceutically acceptable acids. The salt is prepared, for example, in an inert organic solvent such as a C 1 -C 6 aliphatic alcohol by dissolving the compound of formula I in a solvent and adding the selected acid or a solution thereof to the solution until the reaction of the original solution does not become acidic. The acid addition salt is then separated, e.g. by filtration, from the reaction mixture.

The novel 2-halo-lumilysergol or 1-methyl-2-halo-lilysergol active compounds of formula I can be formulated for therapeutic purposes. The invention also relates to pharmaceutical compositions which contain as active ingredient at least one compound of the formula I together with pharmaceutical carriers and / or excipients. Carriers which are conventionally used for this purpose and which are suitable for parenteral or enteral administration as well as other additives (additives) may be used. As carriers, solid or liquid compounds, for example water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, etc. can be used.

These compounds may be formulated as conventional pharmaceutical compositions, for example, in solid form (globular or angular tablets, dragees, capsules, e.g. hard gelatin capsules) or in liquid form (injectable oily or aqueous solutions or suspensions). The amount of solid carrier may be varied within wide limits, but preferably between 25 mg and 1 g.

The compositions may also contain, if desired, conventional pharmaceutical additives such as preservatives, wetting agents, salts for adjusting the osmotic pressure, buffers, dyes, and fragrance delivery agents. The pharmaceutical compositions may be prepared by conventional techniques including sieving, mixing, granulating and compression. The compositions can then be processed, for example, by sterilization.

The invention is illustrated in detail by the following examples, which are not intended to limit the scope of the invention in any way.

Example 1

2-Chloro-lysergol g Lysergol is dissolved in 400 ml of dry dimethylsulfoxide. The solution is saturated with dry hydrogen chloride gas, taking care not to exceed 30 ° C. The progress of the reaction was monitored by thin layer chromatography. When all the starting material is consumed, the dimethylsulfoxide solution containing hydrochloric acid is poured into 200 ml of ice water. The pH of the solution is adjusted to 1 by the addition of ammonium hydroxide. The precipitate is filtered off, dried under vacuum and, if desired, further purified by column chromatography. Kieselgel 60, eluting with a 80:20 mixture of chloroform and methanol. Yield: 1 g of product (60%). 207 ° C.

Example2

2-Chloro-lysergol A gram of 2-chloro-elymoclavine and 10 g of alumina (activity I according to Brockman) was suspended in 70 ml of toluene. The reaction mixture was boiled for 15 minutes, cooled to room temperature and the alumina was filtered off. The catalyst was mixed with three 50 ml portions of methanol at 40-50 ° C and filtered. The combined organic phase was evaporated in vacuo. The title compound is obtained. Yield: 0.8 g (80%). 207 ° C.

Example '3

2-Chloro-lysergol phosphate

One gram of 2-chloro-elymoclavin is isomerized as described in Example 2. The product is isolated without crystallization. After evaporation of the solvent, the obtained residue (0.8 g) was dissolved in 70 ml of a 4% phosphoric acid solution at 80-90 ° C. 2-Chloro-lysergol phosphate is recrystallized from phosphoric acid solution by cooling to 0-5 ° C. The product was filtered off. Yield: 0.8 g (75%). M.p .: 248 ° C. Eutectic melting point with dicyandiamide: 189 ° C.

Example 4

2-Chloro-lysergol phosphate

0.5 g of 2-chloro-elymoclavin is isomerized as described in Example 2. After cooling, aluminum oxide is isolated by filtration. The catalyst was stirred with three 50 ml portions of a 4% phosphoric acid solution at 80-90 ° C for 15 minutes. The phosphoric acid solution is filtered while hot. The title compound is obtained in crystalline form (cooling the filtrate to 0-5 ° C). Yield: 0.4 g (60%). M.p .: 248 ° C.

Example 5

2-bromo-lysergol

Three grams of anhydrous lysergol is dissolved in 500 ml of dry dioxane at 60 ° C. 2.5 g of N-bromosuccinimide in dioxane are added dropwise to the obtained solution. The reaction mixture was stirred at 60 ° C for 30 minutes. The pH was adjusted to 8 with triethylamine and the mixture was evaporated under reduced pressure. Kieselgel 60 column chromatography, eluting with a mixture of chloroform and methanol (80:20), then isolates 2-bromo-lysergol, which is recrystallized from acetonitrile. Yield:

2.2 g (55%). 193 ° C.

Example 6

2-iodo-lysergol)

Three grams of anhydrous lysergol is dissolved in 600 ml of dry dioxane at 60 ° C. ·

The mixture was reacted with 3.0 g of N-iodosuccinimide according to the procedure described in the example.

5. The following steps were also carried out according to the procedure of Example 5. Yield: 2.15 g (48%). 1 H NMR Spectrum (CDCl 3 + DMSO d 6): 2.46 (broad signal, N-CH 3), 3.97 (broad signal, 2H, CH ₂ -OH) 6.29 (broad signal, 1H, olefinic proton) ) and 6.96 (multiplet, 3H, aromatic protons). Ultraviolet spectrum: Д _тах л ³ 12 nm.

Example 7

2-chloro-lumilysergol,

Two grams (0.0007 mol) of 2-chloro-lysergol were dissolved in 200 ml of methanol / sulfuric acid (40:75). The reaction mixture is maintained at 25-30 ° C and irradiated with a 250 W lamp (HgO, Tungsram). The progress of the reaction was monitored by thin layer chromatography (Kieselgel 60 F ₂ 54 ' ^eluting with a 80:20 mixture of chloroform and methanol). When the reaction is complete, the methanolic sulfuric acid solution is mixed with 0.2 g of activated carbon, filtered and poured into 300 ml of ice water. The pH of the solution was adjusted to 8 by the addition of ammonium hydroxide. This solution was extracted with three 70 ml portions of chloroform. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The solvent was evaporated and the residue was recrystallized from acetone. Yield: 2.0 g (90%).

Melting point: 227 ° C. ¹ H NMR spectrum (CDCl ₃ + DMSOdg) ppm: 2.50 (broad signal, 3H, N-CH ₃ ), 2.85 (broad sognal, 3H, -O-CH.p, 3.55 (multiplet, 2H) , -СН ₂ -ОН) and 7.13 to 7.24 (multiplet, 3H, aromatic hydrogens) Infrared Spectrum (KBr): 2910 (-OCH.J and 780 (aro-1 ^J math)) cm.

r

Example 8

2-Chloro-lumilysergol maleinate

0.8 g (2.46 mmol) of 2-chloro-lumilysergol is dissolved in a mixture of 40 ml of methanol and 30 ml of dichloromethane. To this solution was added 0.3 g (2.58 mmol) of maleic acid. After the solution is completely dissolved, the solvent is removed from the mixture under reduced pressure. The solid residue is triturated with 50 ml of diethyl ether. The precipitated product is filtered off, washed with ether and dried. Yield of product: 0.92 g (85.9%).

Example 9

1-Methyl-2-chloro-lumilysergol

Powdered potassium hydroxide (1.54 g) was added to dimethyl sulfoxide (12.7 ml). The mixture was stirred at room temperature for 10 minutes. 2 grams are added to the reaction mixture at 15-20 ° C

2-chloro-lumilysergol and stirred for an additional 25 minutes then allowed to warm to room temperature.

0.6 g of methyl iodide is then added to the reaction mixture, the mixture is stirred for 10 minutes, poured into 400 ml of ice-water and the precipitate is filtered off. Evaporation in vacuo and crystallization gave the product in a yield of 1.77 g (85%). Melting point: 252 ° C. 1 H NMR Spectrum (DMSOd 6 + TFA) ppm: 2.50 ^L (broad signal, 3H, N-CH ₃ ), 2.85 (broad signal, ZN, -O-Si, 3.55 (broad signal, 2H, -CH ₂ OH), 3.73 (broad signal, 3H, indole-N-CH 2) and 7.13 to 7.44 (multiplet, 3H, aromatic protons). Infrared (KBr): 2910 (OCH 2) and 2,820 (indole-CH-J cm -1 780 (aromatic-1 J 3 halogen)) cm.

Example 10

1-Methyl-2-chloro-lumilysergol hydrochloride.

0.3 g (0.89 mmol) of 1-methyl-2-chloro-lumilysergol is dissolved in 40 ml of absolute ethanol. An equimolar amount of a 10% solution of hydrochloric acid in ethanol is added to the solution (the acid content is determined by titration with sodium hydroxide). The solution was evaporated to a volume of 10 ml and allowed to stand overnight at 0 ° C. The precipitated crystals are filtered off and washed with cold ethanol. Yield: 0.28 g (83.8%).

Example 11.

2-bromo-lumilysergol

The procedure of Example 8 was followed except that 2.0 g (0.005 98 mol) of 2-bromo-lysergol was used as the starting material. Yield: 1.86 g (85%). Eutectic melting point with dicyandiamide: 206 ° C. NMR (CDC1 ₃₎ ppm: 2.47 (br, 3H, N-CH _3), 2.87 (br, 3H, OCH _3), 3.47 (m, 2H, _2-ОН СН ) and 7.07 (multiplet, 3H, aromatic protons). Infrared (KBr): 3400 (OH), 2910 (-OCH ₃ ), and 3 '150 (indole-NH) cm

Example 12

1-methyl-2-bromo-lumilysergol

Using the procedure of Example 9, but starting from 1.0 g (0.0027 mol) of 2-bromo-lumilysergol, which was prepared according to the procedure of Example 11, 0.78 g (75%) of 1 was obtained. -methyl-2-bromo-lumilysergol. Melting point: 244-242 ° C. NMR (DMSO-d ^): 2.49 (br, 3H, NCH ^), 2.9 (br, 3H, OCH ^), 3.55 (m, 2H, _CH2 OH);

3.75 (br, 3H, indole-N-CH _q) and 7.17 to 7.51 (m, 3H, aromatic hydrogens).

^J -1 IR (KBr): 2910 (= CH ₂ ), 2920 (indole-N-CH 2) cm

Example 13 1-methyl-lumilysergol

0.1 g of 10% palladium on carbon is moistened with 3 ml of ethyl alcohol. 1.0 g of 1-methyl-2-chloro-lumilysergol in tetrahydrofuran was then added to the catalyst. The reaction is carried out by passing hydrogen through the solution gradually. The progress of the reaction was monitored by thin layer chromatography. When the hydrogenation is complete, the catalyst is filtered off, washed with two 4 ml aliquots of ethanol and the combined organic phase is evaporated in vacuo. The oily product is recrystallized from acetone. Yield 0.85 g (95%). Melting point: 213-215 ° C.

Example 14

N-hydroxy-succinimide 5-bromo-nicotinate active ester

1 g of N-hydroxy-succinimide a is dissolved in 100 ml of absolute ethyl acetate at 50 ° C

5.2 g of 5-bromo-nicotinic acid. To this solution was added 1.77 g of N, N-dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature for four hours, cooled to 5 ° C and the precipitated white crystals were filtered off. The filtrate was evaporated. The residue is recrystallized from ethanol.

Example 15

Nicergoline

One gram of 1-methyl-lumilysergol is dissolved in 100 ml of dry pyridine. To this solution was added 0.96 g of the active ester prepared according to Example 14. The reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by thin layer chromatography. When the reaction is complete, the reaction mixture is evaporated under reduced pressure, poured into 200 ml of 100% sodium carbonate solution and the product is extracted with three 30 ml portions of chloroform. The chloroform phase is washed with water, the combined organic phases are dried over magnesium sulphate, filtered, evaporated under reduced pressure and the residue is recrystallized from ether. If desired, the product is further purified by chromatography. Yield: 1.5 g (93%). 135 ° C.

Claims (2)

A process for the preparation of partially novel 104? -Methoxy-6-methyl-ergoline derivatives of the general formula I ch ₂ or wherein R represents a hydrogen atom or a methyl group, X represents a hydrogen, chlorine, bromine or iodine atom; R * represents a hydrogen atom or a 5-bromo-nicotinoyl group, and their physiologically acceptable acid addition salts, characterized in that the 2-halo-lysergol of the formula II is methoxylated N-CH3 X CH ₂ OH (II), in which X represents a chlorine, bromine or iodine atom, by photochemical reaction, if desired, isolating 2-halo-lumilysergol in which both R and R 'are hydrogen atoms and X is as defined above or, if desired, the above compound is methylated and, if desired, isolates 1-methyl-2-halo-lumilysergol of formula I wherein R is methyl, X and R 'are as described above, if desired, dehalogenated, and, if desired, esterifying the obtained 1-methyl-lumilysergol of formula I wherein R is as defined above, R 'is hydrogen and X is hydrogen, and, if desired, the resulting 10? The methoxy-6-methyl-ergoline derivative of the Formula I at any stage of the synthesis to a physiologically acceptable acid addition salt. 2. The process according to claim 1, wherein the esterification is carried out with an active ester.