LU86486A1 - METHOD FOR THE PRODUCTION OF 10-METHOXY-6-METHYLERGOLINE DERIVATIVES AND THEIR ACID ADDITION SALTS - Google Patents

Description

* <1

Process for the preparation of lCa-methoxy-ô-methylergoline derivatives and their acid addition salts

The invention relates to a new process for the preparation of partially known 10üc-methoxy-6-methylergoline derivatives and their acid addition salts. The compounds to be prepared correspond to the general formula (I) CH2OR 'ch3 ° * (| / 0 * k ^ N-CH3 (i)

R-N - ^ \ Y

where Λ R is hydrogen or methyl group, X is hydrogen, chlorine, bromine or iodine and R * is hydrogen or 5-bromo-nicotinoyl group.

A 3815-67 MR / tO

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The compounds and their pharmacologically acceptable acid addition salts are prepared by using 2-Haiogen-lysergο1e (2-halo-6-methyl-8-hydro: xyraethyl-ergol-9-ene) of the general formula (II)

CH2OH

, HN-L

Xx in which X is chlorine, bromine or iodine, converted by a photochemical reaction to 2-halogen-lumilysergols of the general formula (I) in which R and R * are hydrogen and the meaning of X is chlorine, bromine or iodine, if desired, the 2-halogen-lumilysergols obtained are methylated, if desired from the obtained 1-methyl-2-halogen-lumilysergols of the general formula (I) in which R represents a methyl group, while the meaning of X and R * is the same as above, the chlorine, bromine or iodine atom in the 2-position of the ergoline skeleton is removed by reduction, if necessary 1-methyl-lumilysergole of the general formula (I), in which R * represents hydrogen, by esterification to that under the Formula (I) falling hicergoline (1 Qx-Hethoi-l, 6-dimethyl-ergoline-8ß-methanol-5-bromnico tina t), in which X is hydrogen, R * is 5-bromo-nicotinoyl group and R is liethyl group , implemented, in each step of the synthesis the 10ä> methoxy-6-methyl-er if desired, goline derivatives can be converted to their physiologically tolerable acid addition salts.

Some of the compounds that can be produced according to the invention are valuable intermediaries for the manufacturers: * - 3 - J *

Position of the nioer-goline known as peripheral vasodilator; on the other hand, the new 2-halogen-lumily-sergols containing R and R 'are hydrogen, as * X chlorine, bromine or iodine, and those are R methyl group, R' is hydrogen and as X chlorine, bromine or iodine-containing new l-methyl-2-halogen-lumilysergole itself pharmacologically active # therefore, the invention extends to the pharmaceutical compositions containing the new compounds of general formula (I) and their preparation.

Several processes are known from the literature for producing nicergoline. The preparation of esterified derivatives of IQ-methoxy-1,5-dimethyl-ergoline-8-methanol, including nicergoline, are described for the first time in Df-PS 2 112 273 and US Pat. No. 3,228,943 (Parmitalia Milano ).

According to the cited US patent, lumilysergic acid or 1-methyl-lumilysergic acid is used as the starting point, and the oarboxyl group ff is reduced in the 8-position with lithium aluminum hydride in an ether to the OH group. This is then esterified with the anhydride or the chloride of the corresponding alcohol in the presence of a tertiary amine. When using lumysergic acid as the starting material, the methylation is carried out with a methyl halide, in liquid ammonia and in the presence of metallic potassium. To produce the corresponding Lurai compounds, the respective acids are dissolved in a dilute mineral acid and irradiated with UV light. According to DT-PS 2 112 273, Lumilysergol is assumed and methylated after the esterification.

According to DT-PS 2 752 533 (LEK, Yugoslavia) the nicergoline is obtained by esterifying 1-methyl-lumilysergol with 5-brota-nicotinic acid. The esterification is carried out with an imidazole triphenylphosphite complex in the presence of hexamethylene phosphorus triamide.

The method described in European Patent No. 4,664 (Mora, Italy) starts from lysergol to produce the nicergoline. * The lysergol is methoxylated with UV light in the presence of methanol to lumilysergol. The a l - 4 - N-indole methylation then takes place in dimethyl sulfoxide, in the presence of potassium hydroxide with methyl iodide. The 1-methyl-lumilysergol obtained is then esterified in tetrahydrofuran, in the presence of dicyclohexyl-carbodiimide as a condensing agent, with 5-bromo-nicotinic acid to give nicergoline.

As can be seen from the literature, the connection of the methoxy group to the carbon atom in the 10-position of the ergoline structure has so far only been possible by photochemical means. The attempts to circumvent the photochemical reaction (US Pat. No. 3,814,765) were unsuccessful because ergolene derivatives were formed, from which the desired starting compounds could not be produced.

LEK has optimized the reaction for introducing the methoxy group in the presence of UV light for the pall of lysergic acid (C.A. ££ 434 34y).

In addition to the methods described in the three above-mentioned patents from European patent 0 533, a methylation process carried out as a phase transfer reaction is known for carrying out the indole-N-methylation.

The processes described above for the production of nicergoline have the common disadvantage that significant amounts of by-products are formed in the photochemical step, with the result that complicated chromatographic procedures are required to obtain the product and to separate the structural isomers and undesirable dyes formed during the reaction Procedures are required.

It has now surprisingly been found that in the preparation of the 10-methoxy-ergoline derivatives from derivatives halogenated in the 2-position of the ergolene structure, considerably fewer by-products and structural isomers are formed in the photochemical reaction than is the case with those of Lysergol. 5 - or outgoing lysergic acid photochemical reactions the Pall is. Therefore, the resulting 2-halogen-lurai compounds do not need to be purified chromatographically, but a simple crystallization is sufficient for their purification, and the yield is higher than that previously achieved with the known processes.

Introducing an activating group into center C-2 has other unexpected advantages. In the known methylation processes, in addition to the desired a-methyl compound, there is always a significant proportion of O-methyl derivative, from which the desired product must then be separated. It has now been found that the H-methylation carried out with halogenated ergoline derivatives takes less time and is more selective than the known processes, and this leads to significantly higher yields.

It is also advantageous that the N-methyl 1-2-halogen-lumiverbundungen are much less soluble than the corresponding compounds not containing the halogen atom. This makes it easier to isolate them - for example without extraction with chloroform - which also leads to a higher yield. .

The 2-halogen-lysergols of the general formula (II) which serve as starting materials for the process according to the invention can be prepared in accordance with Examples 1-3. According to these examples, Lysergol is halogenated or 2-halogen-elimoclavines are isomerized *

In the first step of the process according to the invention, the 2-halogen-lysergols of the general formula (II) are converted into 2-halogen-lumilysergols in a photo-chemical reaction.

The photochemical reaction is carried out in sulfuric acid methanol by irradiation with a UV light source. The reaction is followed by thin-layer chromatography. After the photoohemic reaction, the reaction mixture is poured onto ice water, the mixture is adjusted to pH 6 with ammonium hydroxide and extracted with a water-immiscible solvent, such as chloroform, dichloromethane, benzene, carbon tetrachloride or toluene, but preferably with chloroform. The extract is dried and evaporated. The evaporation residue containing the 2-halogen-lumilysergol is made from an aprotic solvent, to the 91st

Example, acetone, ethyl acetate, benzene or acetonitrile, crystallized. For methylation, the 2-halo-lumilysergol is dissolved in a dipolar aprotic solvent, preferably in a 15-20 ° C. warm mixture of anhydrous dimethyl sulfoxide and potassium hydroxide. After stirring the mixture for 30-35 minutes, the methyl iodide is added. Then the reaction mixture is poured onto ice water and the precipitated l-methyl-2-halogen-lumilysergol is filtered off and dried in vacuo. The product is recrystallized from one of the solvents mentioned in the photochemical reaction, preferably from acetone, or, if desired, the halogen atom is removed from the 1-methyl-2-halo-lumilysergol by dehalogenation. For dehalogenation, the l-methyl-2-halogen-lumilysergol is in a protic or aprotic solvent, for example in

tt tf | Y

Ethanol, methanol, ether, ethyl acetate, acetonitrile, tetrahydrofuran, benzene or toluene, but preferably dissolved in ethanol. This solution is added to previously moistened palladium activated carbon, the amount of which should be 10 # based on the amount of the substance. The reduction is carried out with hydrogen gas flowing through and followed by thin layer chromatography.

After the reduction has ended, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The evaporation residue is crystallized from an aprotic solvent, for example acetone. The nicergoline is produced from the resulting -7-l-methyl-lumilysergol by esterification. This is done in two stages. An active ester is prepared in the first stage and used in the second stage for esterification.

To prepare the active ester, N-hydroxysuccinimide is dissolved in an aprotic solvent, for example tetrahydrofuran or ethyl acetate (preferably in the latter) and the solution first with an excess of 5-bromo-nicotinic acid, then with based on the N-hydroxysuccinimide molar equivalent amount of Ν, Ν-dicyclohexyl-carbodiimide added. The mixture is stirred at room temperature, the precipitate which has separated out is filtered off and the filtrate is reduced

Druok evaporated. The active ester obtained in the form of a white amorphous substance can, if necessary, be crystallized from ethanol.

In the second step, the esterification is carried out with the active ester at 20-60 ° C., preferably at room temperature, in an aprotic solvent, for example tetrahydrofuran, benzene or acetonitrile, but preferably in tetrahydrofuran, in the presence of an organic base such as triethylamine t | or pyridine (preferably pyridine). The organic base can simultaneously act as a solvent.

! The 1-liethyl-lumilysergol is dissolved in a suitable solvent or in excess of the organic base and the active ester is added to the solution. The reaction is getting thin- $! followed by layer chromatography «When the esterification has ended: the solvent is removed in vacuo

The end product is separated from the organic base by extraction and crystallized from diethyl ether after drying and evaporating the extract in vacuo. If necessary, the product can be purified by column chromatography.

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Of the compounds of the general formula (I) prepared by the process according to the invention, those are new which contain hydrogen as R and B 'and contains X, chlorine, bromine or iodine (2-halogen-lumilysergols), and those which are methyl groups as R 'is hydrogen and as I is chlorine,

Contain bromine or iodine (l-methyl-2-halogen-lumilysergole).

These compounds also have valuable pharmacological effects per se, in particular they have a blocking action on the D ^ receptors.

The studies on the blocking of the Dg receptors were carried out according to the method of Seeman (P. Seeman: Dopamin reoeptor measurment with -ligands, Methods in Biogenic Amine Research, Ed. By S. Parvez, T »Hagatsu, 1, flagatsu and H. Parvez , p. 591-622 / 1983 /, Elsevier). Striatum membranes from rats and the ligand DjjJ-Spiroperidol were used for the investigations.

The lûa-methoxy-6-methyl-ergoline derivatives of the general formula (I) prepared by the process according to the invention are isolated as a base, if necessary purified by recrystallization or, if desired, converted to a physiologically tolerable acid addition salt.

An aprotic or protic solvent, preferably acetone or ether, can be used for recrystallization.

To prepare the acid addition salts, the compound is dissolved in an inert solvent, for example an aliphatic alcohol with 1-6 xcarbon atoms, and the solution is mixed with the corresponding acid or the solution of this acid prepared with the same solvent until the mixture is acidic . The precipitated acid addition salt is then separated from the reaction mixture in a suitable manner, for example by filtration.

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The new 2-halogen-lumilysergols or 1-methyl-2-halogen-lurailysergols of the general formula (I) can be mixed with the non-toxic inert solid or liquid carriers, extenders, which are common in the pharmaceutical industry and are suitable for parenteral or enteral administration. and / or auxiliaries are mixed and formulated into pharmaceutical preparations. Suitable carriers are, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils (for example peanut oil and olive oil). The active substances can be formulated in the form of the usual pharmaceutical preparations, for example in solid form (rounded or angular tablets, coated tablets, capsules such as gelatin capsules, pills, suppositories). The amount of solid carrier can vary within a wide range and is generally 25 mg to 1 g for a dosing unit. The preparations can optionally contain the usual auxiliaries, for example preservatives, stabilizers, wetting and emulsifying agents, etc. The preparations are produced in a manner known per se, for example - in the case of solid preparations - by sieving, mixing, granulating and pressing the components. The preparations can be subjected to further operations customary in pharmaceutical production, for example sterilized.

The invention is explained in more detail using the following exemplary embodiments, but is not restricted to these examples.

Example 1 2-chloro-lysergol 1 g of Itfsergol is dissolved in 400 ml of anhydrous dimethyl sulfoxide and the solution is saturated with dry hydrochloric acid gas, with the result that the temperature of the reaction mixture does not rise above 30 ° C. The progress of the reaction is monitored by thin layer chromatography. If no more starting substance can be detected, the mixture is poured onto 200 ml of ice water and its pH is adjusted to 7 with ammonium hydroxide. The precipitate is filtered off and dried in vacuo. If necessary, the compound can be further purified on a column filled with silica gel with an 80:20 mixture of chloroform and methanol as eluent. One obtains 1g (60 #) of the title compound, which melts at 207 ° C.

Example 2 2-chloro-lysergol 1 g of 2-chloro-elimoclavine is suspended together with 10 g of aluminum oxide of activity Brockman I in 70 ml of toluene. The reaction mixture is boiled for 15 minutes, then cooled to room temperature and the alumina is filtered off. The filtered catalyst is slurried three times with 50 ml of methanol at a temperature of 40-50 ° G and filtered off. The combined organic phases are evaporated in vacuo.

Han receives 0.8 g (80 jb) of the title compound, which melts at 207 ° C.

Example 3 2-chloro-lyosergol-phosphate contains 1 g of 2-chloro-elimoclavine isomerized in the manner described in Example 2 and the product isolated without crystallization. After evaporation, the solvent-free evaporation residue (0.8 g) is dissolved in 70 ml of 4 # phosphoric acid at 80-90 ° C. The solution is cooled to 0-5 ° C., during which the title compound crystallizes out. Kan receives 0.8 g (75%) of the substance, which melts at 248 ° C.

Eutectic melting point in dicyandiamide: 189 ° C.

Example 4 2-chlorosergol phosphate 0.5 g of 2-chloro-elimoclavine is isomerized in the manner described in Example 2. The aluminum oxide is filtered off from the cooled reaction mixture. The filtered - 11 -

The catalyst is slurried three times at 80-90 ° C. with 15 ml of 4% phosphoric acid each, stirred for 15 minutes each and the solution is then filtered hot. The filtrate is cooled to 0-5 ° C, the title compound crystallizing. 0.4 g (60%) of the phosphate is obtained, which melts at 248 ° C.

Example 5 2-bromo-lysergol 3 g of anhydrous lysergol are dissolved in 500 ml of anhydrous dioxane at 60 ° C. The solution of 2.3 g of K-bromosuccinimide prepared with dioxane is added dropwise to the solution with constant stirring. The reaction mixture is stirred at 60 ° C for 30 minutes, then adjusted to pH 8 with triethylamine and evaporated under reduced pressure. The product is chromatographed on a column filled with silica gel 60 with a semis prepared in a ratio of 80:20 from chloroform and methanol and then recrystallized from acetonitrile. 2.2 g (55%) of the titanium compound are obtained, which melts at 193 ° C.

Example 6 2-iodine-lysergol 3 g of anhydrous lysergol are dissolved in 600 ml of anhydrous dioxane at 60 ° C. and reacted with 3.0 g of H-iodosuccinimide in the manner described in Example 5. The mixture is worked up in the manner described in Example 5. 2.15 g (48%) of the title compound are obtained.

^ H NMR (CDC13 + DMSOdg): 2.46 (b., 3H, H-CH3), 3.97 (b., 2H, CH2-0E), 6.29 (b., 1H, olefinic), 6.96 (m, 3H, aromatic hydrogen).

UV: λ = 312 nm max

Example 7 2-chloro-lumily ergol 2.0 g (0.007 mol) of 2-chloro-lysergol are dissolved in 200 ml of a 40:75 mixture of methanol and sulfuric acid. At 25 ~ 30 ° C the mixture is irradiated with a TTJHGSRAM mercury vapor lamp with the power of 250 W.

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The reaction is followed by thin-layer chromatography (silica gel 60 F ^, Cilloroform 1111 (1 methanol in a ratio of 80; 20). After the reaction has ended, the mixture is clarified with 0.2 g of activated carbon, poured into 300 ml of white water and filtered with ammonium hydroxide pH 8. The mixture is extracted three times with 70 ml of chloroform each time, the combined organic phases are dried over sodium sulfate, filtered and evaporated in vacuo, the residue from the binder vapor is crystallized from acetone to give 2.0 g (90%) of Title compound that melts at 227 ° C.

(DMSOd'k + CDCl ^) ppm; 2.50 (b., 3H, N-CH ^), 2.85 (b., 3H, -Q-CH3), 3.55 Cm, 2H, -CH2-0H), 7.13-7.24 (m, 3H, aroma H) IR (in KBr) cm ”1: 2910 (-OCH ^), 780 (aroma halogen).

Example 8 2-chloro-lumilysergol maleate 0.8 g (2.46 ml) of 2-chloro-lumilysergol are dissolved in a mixture of 40 ml of methanol and 30 ml of dichloromethane and 0.3 g (2.58 mmol) to the solution ) Given maleic acid. After everything has dissolved, the solvent is removed under reduced pressure. The dry residue is triturated with 50 ml of diethyl ether, filtered, washed with ether and then dried. Yield; 0.92 g (84.9, ¾).

Example 9 l-methyl-2-chloro-lumilysergol * 1.54 g of finely powdered potassium hydroxide become 12.7 ml

Given dimethyl sulfoxide. The mixture is stirred at room temperature for 10 minutes, then heated to 15-20 ° C. and mixed with 2.0 g of 2-ghlorumylysergol. The mixture is stirred for 35 minutes, then warmed to room temperature, mixed with 0.6 g of methyl iodide and, after stirring for a further 10 minutes, poured onto 400 ml of water. The precipitate is filtered off. The filtrate is concentrated in a vacuum, * - 13 -; evaporates and the .Resalt crystallized from acetone. 1.77 g (85 #) of the title compound are obtained, which melts at 252 ° C.

^ H-BMR (DMSOdg + TPA) ppm: 2.50 (b., 3H, li-CH ^), 2.85 (b., 3H, -0-CH3), 3.55 (o, 2ÏÏ, - CH20H), 3.73 (b., 3H, indole-IF-CH3), 7.13-7.44 (m, 3H, aromatic H).

IR (in KBr) cm “1! 2910 (OCB ^), 2820 (indole-C ^), 780 (aroma CI) Example 10 1- methyl-2-chloro-lumilysergol-hydrochloride 0.3 g (0.89 mmol) l-methyl-2-chlorine -lumilysergol are dissolved in 40 ml of absolute ethanol. 10% tl of hydrochloric acid ethanol is added to the solution in a molar equivalent amount. (The exact acidity of the hydrochloric acid ethanol is determined beforehand by titration with hatron lye.) The solution obtained is evaporated to a volume of 10 ml and left to stand at 0 ° C. over night. The precipitated crystals are filtered off and washed with cold ethanol. Yield: 0.28 g (83.8 #).

Example 11 2-Bromo-lumilysergol

The procedure is as described in Example 8, but 2.0 g (5.98 mmol) of 2-bromo-lysergol are used as the starting material. Yield: 1.86 g (85%)

Eutectic melting point with dicyandiamide: 206 ° C.

1H-NMR (CDC13) ppm: 2.47 (b., 3H, H-CH ^, 2.87 (b., 3H, 0-CH ^, 3.47 (m, 2H, CHg-OH), 7 , 07 (m, 3H, aromatic H) IR (in KBr) cm "1: 3400 (OH), 2910 (-0CH3), 3150 (indole-HH).

Example 12 l-methyl-2-bromo-lumilys ergol

1.0 g (2.7 mmol) of the 2-bromo-lumilysergol prepared according to Example 11 serves as the starting material. The procedure is as described in Example 9. 0.78 g (75%) of the title compound is obtained, which melts at 240-242 ° C.

- 14 - 1H-HMR (DMSOdg) 2.49 (b., 3H, N-CH ^, 2.9 (b., 3H, OCH ^, 3.55 (m, 2H, CH ^ OH), 3, 75 (b., 3H, indole-), 7.17-7.31 (æ, 3H, aromatic H).

IE (in KBr) cm “1: 2910 (OC ^), 2920 (Indol-N-CH. ^),

Example 13 l-methyl-lumilysergol. «0.1 g 10% palladium activated carbon is moistened with 3 ml ethanol. The solution of 1.0 g of l-methyl-2-chloro-lumilysergol prepared with tetrahydrofuran is added. Hydrogen is allowed to flow through the mixture and the course of the reduction is followed by thin layer chromatography. After the hydrogenation has ended, the catalyst is filtered off and washed twice with 4 ml of ethanol each time. The combined organic phases are evaporated in vacuo. The oily residue is crystallized from acetone. Han receives 0.85 g (95%) of the title compound, which melts at 213-215 ° C.

Example 14 ïi-Hydroxy-succinimide-5-bromo-nicotinate (active ester) 1 g of N-hydroxy-succinimide and 5.2 g of 5-bromo-nicotinic acid "0 are dissolved in 100 ml of anhydrous ethanol at 50 ° and become the solution 1.77 g of Ι, ϊΓ-dicyclohexyl-carbodiimide are added and the reaction mixture is stirred at room temperature for 4 hours, then cooled to 5 ° C. and the precipitated white crystalline substance is filtered off, the filtrate is evaporated in vacuo and the evaporation residue is recrystallized from ethanol ·

Example 15 Nicergoline 1 g of 1-ethyl-lumilysergol is dissolved in 100 ml of anhydrous pyridine. 0.96 g of the active ester prepared according to Example 14 is added to the solution. The reaction mixture is stirred at room temperature for 4 hours. The progress of the reaction is followed by thin-layer chromatography. After the esterification, the reaction mixture is evaporated under reduced pressure. The residue is poured into 200 ml of 10% sodium carbonate solution and extracted three times with 30 ml of chloroform. The combined organic phases are washed with water, dried over magnesium sulfate and after filtering under reduced tt

Druok evaporated. The residue is crystallized from ether * and, if necessary, purified by chromatography. He holds 1.5 g (93%) of the title compound, which melts at 135 ° C.

Claims (4)

4. Process for the preparation of 10oc-methoxy-6-methyl-ergoline derivatives of the general formula (I) ch2or 'i CH3 ° * (| οι N "CH3 R-nJCx t 4 i - 17 - $ A wherein" R for Is hydrogen or methyl group, X is hydrogen, chlorine, bromine or iodine and R 'is hydrogen or 5-bromo-nicotinoyl groups and their acid addition salts, characterized in that 2-halogen-lysergols (2-halogen-6-methyl- 8-hydroxyraethyl-ergol-9-ene) of the general formula (II) CH2OH (oÇT • HN_JS in which X is chlorine, bromine or iodine, by a photo-chemical reaction to give 2-halo falling under the general formula (I) lumilysergols, in which R and R * stand for hydrogen and X is chlorine, bromine or iodine, if desired, methylates these 2-halogenurylysergols, if desired the l-methyl-2-halogenulumyserols obtained, in which R represents methyl group and X represents chlorine, bromine or iodine, dehalogenated, if desired l-methyl-lumilyser-gole of the general Formula (I), in which R * stands for hydrogen, is esterified, and the IQx-methoxy-6-methyl-ergoline derivatives can be converted into their physiologically tolerable acid addition salts in each step of the synthesis. 5. The method according to .Anspruch 4, characterized in that l-methyl-lumilysergol with an active ester, preferably with the active ester prepared from li-hydroxy-suocinimide and 5-brora-niootinic acid, to 10 »-Methoxy-l, 6-diraethyl-ergoline-8ß-methanol-5-bromnicotinate (nicergoline) esterified. »- 13 - 6. Medicinal products, characterized by a content of 10G-methoxy-6-methyl-ergoline derivatives of the general! my formula (I) according to claim 1 or its acid addition salts 1. 7. A process for the preparation of pharmaceutical preparations, characterized in that lObc-methoxy-6-methyl-ergoline derivatives of the general formula (I) according to Claim 1 or the acid addition salts of these compounds with the carriers, extenders and customary in the pharmaceutical industry / or formulated excipients for pharmaceutical preparations. ! i i \ \) i i 5 i! δ t t! »> T» i