GB2177090A - 10???-methoxy-6-methyl-ergoline derivatives - 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

SPECIFICATION 10a-methoxy-6-methyl-ergoline derivatives The present invention relates to a new process for the preparation of 10e-methoxy-6-methyl-ergoline derivatives of formula (I)

wherein R is hydrogen or methyl, X is hydrogen, chlorine, bromine or iodine, R' is hydrogen or a 5-bromo-nicotinoyl group, and physiologically acceptable acid addition salts thereof.

The esterified derivatives of 10-methoxy-1,6--dimethyl-ergoline-8-methanol, including nicergoline, (10a methoxy-1,6-dimethylergoline-8ss-methanol 5-bromonicotinate) were first described in United States Patent Specification 3,228,943 and in German Patent Specification 2,112,273 (Farmitalia Milano). According to the U.S. patent the 8-carboxyl group of lumilysergic acid or 1-methyl-lumilysergic acid was reduced into the corresponding alcohol with lithium aluminium hydride, in the presence of an ether. The subsequent esterification was performed with the corresponding carboxylic acid anhydride or chloride, in the presence of a tertiary amine. When starting from lumilysergic acid, the methylation was carried out with a methyl halide, in liquid ammonia, in the presence of potassium metal.When preparing the starting lumi-compounds, the desired acid was dissolved in a dilute mineral acid and illuminated with u.v. light.

According to German Patent Specification 2,112,273 lumilysergol is used as a starting material which is esterified and subsequently methylated.

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

According to European Patent Specification 4,664 (Mora, Italy) nicergoline is prepared starting from lysergol. Lysergol is converted into lumilysergol by methoxylation in the presence of methanol, under illumination with u.v. light, whereupon the indole-N--methylation is carried out with methyl iodide, in dimethyl sulfoxide, in the presence of potassium hydroxide. The 1-methyl-lumilysergol obtained is esterified with 5-bromo-nicotinic acid in tetrahydrofuran, in the presence of dicyclohexyl carbodiimide as a condensing agent, to yield nicergoline.

Experiments show that the introduction of the methoxy group to the 10-carbon atom of the ergoline skeleton can be carried out only via a photochemical route. The attempts to replace the photochemical reaction by other treatments (United States Patent Specification 3,814,765) were unsuccessful, since the end product could not be purified from the ergolene by-products formed.

An improved photochemical reaction is reported in C.A. 95 43434y, in which the conditions of the reaction carried out under u.v. illumination were optimized in the case of lysergic acid.

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

A common drawback of the above-described, known processes for the preparation of nicergoline is that the photochemical step is accompanied by side-reactions resulting in undesired by-products, which contaminate the end product. As a result, the product can be isolated and separated from the structural isomers and undesired colouring substances only by a complicated chromatographic purification.

We have surprisingly found that if the 10-methoxy-ergoline derivatives are prepared starting from 2halo-ergoline derivatives, the amount of by-products and structural isomers formed in the photochemical reaction is substantially lower than in the case of the reactions starting from lysergoi or lysergic acid.

Therefore, the desired 2-halo-lumi-compounds may be isolated by simple crystallization or other conventional technique instead of chromatographic purification and the yields are considerably increased.

According to one aspect of the invention, we provide a process for the preparation of a compound of formula (I) as defined above in which a 2-halo-lysergol (2-halo-6-methyl-8-hydroxymethyl-ergol-9-ene) of formula (II)

wherein X is chlorine, bromine or iodine, is converted into a new 2-halo-lumilysergol of formula 81), in which R and R' are both hydrogen, X represents chlorine, bromine or iodine, by photochemical methoxylation, if desired, the 2-halo-lumilysergol obtained is methylated, and if desired, from the new 1-methyl-2halo-lumilysergol of formula (I) obtained in which R is methyl and X and R' are as defined above, the chlorine, bromine or iodine atom in the 2-position of the ergoline skeleton is removed.If desired, the 1methyl-lumilysergol of formula (I) obtained, in which R is as defined above, R' is hydrogen and X is hydrogen, may be converted into nicergoline of formula (I), in which R is methyl, X is hydrogen, R' is a 5bromo-nicotinoyl group (10(x-methoxy-1,6-dimethyl-ergoline-8ss-methanol 5-bromo--nicotinate) by esterification.

The 10a-methoxy-6-methyl-ergoline derivatives obtained in any step of the synthesis may be converted into the corresponding, physiologically acceptable acid addition salts.

Many of the compounds of formula (I) are new and are vaiuable intermediates in the preparation of nicergoline, a potent peripheral vasodilator. Moreover, the new 2--halo-lumilysergols (in formula (I) R and R' are both hydrogen, X is chlorine, bromine or iodine) and the new 1-methyl-2-halo-lumilysergols (in formula (I) R is methyl, R' is hydrogen, X is chlorine, bromine or iodine) are pharmaceutically active per se, in particular show D2-receptor blocking activity. These new compounds and the pharmaceutical compositions containing them as active ingredients are also within the scope of the invention.

The presence of a halogen atom as a foam of activating group on the 2-carbon atom of the ergolene skeleton brings about a further unexpected advantage. In the known processes for methylation 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 proved that when starting from halogenated ergoline derivatives, the N-methylation took place in a shorter time and more selectively than in the case of the hitherto known processes. This results in a significant increase in yields. A further advantage is that the N-methyl-2--halo-lumi-compounds are considerably less soluble than the respective non-halogenated compounds. Therefore their isolation is simpler - e.g. without extraction with chloroform - and can be accomplished with higher yields.

The 2-halo-lysergols used as starting compounds in the process according to the invention are prepared as illustrated in Examples 1, 2 and 3 of the instant application, either by halogenation of lysergol or by isomerization of 2-halo-elymoclavine.

In the process of the invention a 2-halo-lysergol of formula (II) is first converted into 2-halo-lumilysergol by a photochemical reaction.

The photochemical reaction is most desirably carried out in a methanolic medium containing a mineral acid e.g. sulfuric acid and the reaction mixture is illuminated by u.v. light. The progress of the reaction may be monitored by thin layer chromatography. When the reaction is complete, the reaction mixture is generally poured onto water, the pH adjusted to 6 with ammonium hydroxide, and the mixture may be extracted with a water-immiscible solvent, e.g. chloroform, dichloromethane, benzene, carbon tetrachloride, or toluene, and preferably chloroform. The chloroform phase may then be dried, evaporated and the evaporation residue containing the 2-halo-lumilysergol dissolved in a mixture of an aprotic solvent, such as acetone, ethyl acetate, benzene, or acetonitrile, preferably acetonitrile.If it is desired to methylate the 2-halo-lumilysergol, this may then be dissolved in a dipolar aprotic solvent, preferably in a mixture of dry dimethyl sulfoxide and potassium hydroxide at 15"C to 20"C. Methyl iodide is generally added after stirring the reaction mixture for 30 to 35 minutes. The reaction mixture is then poured onto ice water, and the precipitated 1-methyl-2-halo-lumily-sergol is isolated e.g. by filtration, dried in vacuo and then crystallised as described above in connection with the photochemical reaction, preferably from acetone.

If desired, the 1-methyl-2-chloro-lumilysergol may be dehalogenated. Dehalogenation is preferably carried out by dissolving the 1-methyl-2-halo-lumily-sergol in a protic or aprotic solvent, such as ethanol, methanol, ether, ethyl acetate, aceto-nitrile, tetrahydrofuran, benzene, toluene, preferably ethanol. The solution obtained is added to pre-wetted palladium-on-charcoal used in an amount of 10 % related to the amount of the substance to be reduced. The reduction is carried out by passing hydrogen gas through the solution. The progress of the reaction is monitored by thin layer chromatography.

When the reduction is complete, the catalyst may be removed e.g. by filtration, the filtrate evaporated under reduced pressure and the product crystallized from an aprotic solvent, preferably acetone. From the 1-methyl-lumily-sergol obtained nicergoline is prepared by esterification. Esterification may be carried out in two steps. In the first step the active ester is prepared, while in the second step the esterification is carried out by means of the active ester obtained in the first step.

The active ester is preferably prepared by dissolving N--hydroxy-succinimide in an aprotic solvent, such as tetrahydrofuran or ethyl acetate, preferably ethyl acetate, and adding 5-bromo-nicotinic acid and subsequently N,N-dicyclohexyl carbodiimide to the solution, the latter compound in an equimolar amount related to the N-hydroxy-succinimide. After stirring at room temperature the precipitate is filtered and the mother liquor is evaporated under reduced pressure. If desired, the active ester obtained as a white amorphous substance is crystallized from ethyl alcohol.

In a second step, the esterification with the obtained active ester is carried out at 20 to 60 OC, preferably at room temperature, in an aprotic solvent, such as tetrahydrofuran, benzene, or acetonitrile, preferably tetrahydrofuran in the presence of an organic base, such as triethyl amine, or pyridine, preferably pyridine. During the esterification the organic base may serve as a solvent as well. 1-methyl-lumilysergol is dissolved in the selected solvent or pure organic base and the active ester prepared as described above is added to the solution. The progress of the reaction may be monitored by thin layer chromatography.

When the esterification is complete, the solvent is removed in vacuo, the product is separated from the organic base by extraction, dried, evaporated in vacuo and crystallized from diethyl ether. If desired, the product may be further purified by column chromatography.

The D2-receptor blocking activity of the new compounds according to the invention was tested by Seeman's method [P. Seeman: Dopamin receptor measurement with [3jligands, Methods in Biogenic Amine Research, Ed. by S. Parvez, T. Nagatsu, I. Nagatsu and H. Parvez, p. 591-622 (1983), Elsevier]. The tests were carried out with rat striatum membrane, using [3,1-spiroperidol as a ligand.

The 10a-methoxy-6-methyl-ergoline derivatives according to the invention are generally isolated as bases and, if desired, may be purified by recrystallization and/or converted into a physiologically acceptable acid addition salt with a suitable acid.

The recrystallization may be carried out from a protic or aprotic solvent, preferably acetone, ether.

Compounds of formula (I) can be converted into their acid addition salts by reaction with suitable pharmaceutically acceptable acids.

Salt formation can be carried out, for example, in an inert organic solvent such as a C,~6-aliphatic alcohol in such a way that the compound of formula (I) is dissolved in the solvent and the selected acid or a solution thereof formed with the same solvent is added to the first solution until it becomes slightly acidic. Thereafter the acid addition salt separates and can be removed from the reaction mixture e.g. by filtration.

The new 2-halo-lumilysergol or 1-methyl-2-halo--lumilysergol active compounds of formula (I) may be formulated for therapeutic purposes. The invention therefore further extends to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), in association with pharmaceutical carriers and/or excipients. Conventional carriers for this purpose and suitable for parenteral or enteral administration as well as other additives may be used. As carriers solid or liquid compounds, for example water, gelatine, lactose, starch, pectin, magnesium stearage, stearic acid, talc, vegetable oils, such as peanut oil, olive oil, etc. can be used.The compounds can be formulated as conventional pharmaceutical formulations, for example in a solid (globular and angular pills, drawees, capsules, e.g. hard gelatine capsules) or liquid (injectable oily or aqueous solutions or suspensions) form. The quantity of the solid carrier can be varied within wide ranges, but preferably is between 25 mg. and 1 g. The compositions optionally contain also conventional pharmaceutical additives, such as preserving agents, wetting agents, salts for adjusting the osmotic pressure, buffers, flavouring and odouring substances. The pharmaceutical compositions may be prepared by conventional techniques including sieving, mixing, granulation and pressing. The formulations obtained may then be subjected to additional conventional treatments, such as sterilization.

Various aspects of the invention are illustrated in more detail by the following Examples, which are not intended to limit the scope of the invention in any way.

Example 1 2-Chloro-lysergol 1 g. of lysergol is dissolved in 400 ml. of dry dimethyl sulfoxide, the solution is saturated with dry hydrochloric acid gas, taking care that the temperature of the reaction mixture should not exceed 30 "C.

The progress of the reaction is monitored by thin layer chromatography. When the total amount of the starting material is used up, the dimethyl sulfoxide solution containing hydrochloric acid is poured onto 200 ml. of ice water and the pH is adjusted to 7 with ammonium hydroxide. The precipitate is filtered off, dried in vacuo and, if desired, is further purified by chromatography on a Kieselgel 60 column, using a 80 : 20 mixute of chloroform and methanol as an eluant.

Yield: 1 g. (60 %) Melting point: 207 "C.

Example 2 2-Chloro-lysergol 1 g. of 2-chloro-elymoclavine and 10 g. of alumina (Brockman I activity) are suspended in 70 ml. of toluene. The reaction mixture is boiled for 15 minutes, cooled to room temperature and the alumina is filtered off. The catalyst is admixed with three 50-ml. portions of methyl alcohol at 40 to 50 OC and is then filtered off. The combined organic phase is evaporated in vacuo to yield the title compound.

Yield: 0.8 g. (80 %) Melting point: 207 "C.

Example 3 2-Chloro-lysergol phosphate 1 g. of 2-chloro-elymoclavine is isomerized as described in Example 2 and the product is isolated without crystallization. After evaporation the solvent--free residue (0.8 g.) is dissolved in 70 ml. of a 4 % phosphoric acid solution, at 80 to 90 "C. 2-Chloro--lysergol phosphate is crystallized from the phosphoric acid solution by cooling to 0 to 5 "C, and is then filtered off.

Yield: 0.8 g. (75 %) Melting point: 248 "C Eutectic melting point with dicyane diamide: 189 "C Example 4 2-Chloro-lysergol phosphate 0.5 g. of 2-chloro-elymoclavine are isomerized as described in Example 2. From the reaction mixture alumina is filtered off after cooling, and the catalyst is stirred with three 50 ml. portions of a 4 % phosphoric acid solution at 80 to 90 OC, for 15 minutes. The phosphoric acid solution is filtered while hot; title compound is obtained in a crystalline form upon cooling the filtrate to 0 to 5 OC.

Yield: 0.4 g. (60 /O) Melting point: 248 "C Example 5 2-Bromo-lysergol 3 g. of anhydrous lysergol are dissolved in 500 ml. of dry dioxane at 60 "C, and to the solution obtained a solution of 2.5 g. of N-bromo-succinimide in dioxane is added dropwise, under continuous stirring. The reaction mixture is stirred at 60 "C for 30 minutes, the pH is adjusted to 8 with triethyl amine, and the mixture is evaporated under reduced pressure. The 2-bromo-lysergol is then isolated by chromatography on a Kieselgel 60 column, using a 80 : 20 mixture of chloroform and methanol as an eluant, and is crystallized from aceto-nitrile.

Yield: 2.2 g. (55 %) Melting point: 193 "C Example 6 2-lodo-lysergol 3 g. of an hydros lysergol are dissolved in 600 ml. of dry dioxane at 60 "C, and the mixture is reacted with 3.0 g. of N-iodo-succinimide, following the procedure described in Example 5. The subsequent steps are also performed as described in Example 5.

Yield: 2.15 g. (48 %) 1H-NMR spectrum (CDCl2 + DMSOd6): 2.46 (br, 3H, N-CH3) 3.97 (br, 2H, CHz-OH) 6.29 (br, 1H, olefin) 6.96 (m, 3H, aromatic hydrogens) u.v. spectrum cm,,: 312 nm.

Example 7 2-Chloro-lumilysergol 2.0 g. (0.007 moles) of 2-chloro-lysergol are dissolved in 200 ml. of a 40 : 75 mixture of methanol and sulfuric acid. The reaction mixture is kept at 25 to 30 "C and is illuminated with a HgO 250 W lamp (Tungsram). The reaction is monitored by thin layer chromatography (Kieselgel 60 F254, a 80 : 20 mixture of chloroform and methanol). When the reaction is complete, the methanolic solution containing sulfuric acid is admixed with 0.2 g. of activated carbon, filtered, poured onto 300 ml. of ice water and its pH is adjusted to 8 with ammonium hydroxide. It is then extracted with three 70 ml. portions of chloroform, the combined organic phase is dried over an hydros sodium sulfate, filtered and evaporated in vacuo.

The evaporation residue is crystallized from acetone.

Yield: 2.0 g (90 %) Melting point: 227 "C 'H-NMR spectrum (DMSOd, + CDCI3) ppm: 2.50 (br, 3H, N-CH3) 2.85 (br, 3H, -0-CH3) 3.55 (m, 2H, -CH2-OH) 7.13-7.24 (m, 3H, aromatic hydrogens) IR spectrum (KBr cm-'): 2910 (-OCHs), 780 (aromatic halogen) Example 8 2-Chloro-lumilysergol maleinate 0.8 g. (2.46 mmoles) 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 mmoles) of maleic acid are added to the solution. When the dissolution is complete, 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, washed with ether and dried.

Yield: 0.92 g. (84.9 %) Example 9 1-Methyl-2-chloro-lumilysergol 1.54 g. of powdered potassium hydroxide are added to 12.7 ml. of dimethyl sulfoxide, and the mixture is stirred at room temperature for 10 minutes. To the reaction mixture of 15 to 20 "C, 2.0 g. of 2-chlorolumilysergol are added, the mixture is stirred for 35 minutes and then heated up to room temperature.

Thereafter 0.6 g. of methyl iodide are added to the reaction mixture, which is stirred for 10 minutes, poured to 400 ml. of ice water and the precipitate obtained is filtered off, evaporated in vacuo and crystallized from acetone.

Yield: 1.77 g. (85%) Melting point: 252 "C IH-NMR spectrum (DMSOd6 + TFA) ppm: 2.50 (br, 3H, N-CH3) 2.85 (br, 3H, -O-CH3) 3.55 (br, 2H, -CH2OH) 3.73 (br, 3H, indole-N-CH3) 7.13-7.44 (m, 3H, aromatic hydrogens) IR spectrum (KBr cm-'):: 2910 (OCH3), 2820 (indole CHs) 780 aromatic halogen Example 10 1-Methyl-2-chloro-iumilysergol hydrochloride 0.3 g. (0.89 mmoles) of 1-methyl-2-chloro-lumilysergol are dissolved in 40 ml. of absolute ethanol, whereupon a 10 % solution of hydrochloric acid in ethanol is added (the acid content is determined by titration with sodium hydroxide) in an equimolar amount.The solution obtained is evaporated to 10 ml., and allowed to stand at 0 "C overnight. The precipitated crystals are filtered off and washed with cold ethanol. Yield: 0.28 g. (83.8%) Example ii 2-Bromo-lumilysergol The procedure described in Example 8 is followed, except that 2.0 g. (0.00598 moles) of 2-bromo-lysergol are used as starting material.Yield: 1.86 g. (85 %) Eutectic melting point with dicyane diamide: 206 "C aH-NMR spectrum (CDCl3) ppm: 2.47 (br, 3H, N-CH3) 2.87 (br, 3H, O-CH3) 3.47 (m, 2H, CH2-OH) 7.07 (m, 3H, aromatic hydrogens) IR spectrum (KBr) cm-1: 3400 (OH), 2910 (-OCH3).

3150 (indole NH) Example 12 1-Methyl-2-bromo-lumilysergol Following the procedure described in Example 9 but starting from 1.0 g. (0.0027 moles) of 2-bromo-lumilysergol prepared as described in Example 11, 0.78 g. (75 %) of 1-methyl-2-bromo-lumilysergol are obtained.

Melting point: 240 to 242 "C 1H-NMR spectrum (DMSOd6): 2.49 (br, 3H, NCH3) 2.9 (br, 3H, OCH3) 3.55 (m, 2H, CH2OH) 3.75 (br, 3H, indole N-CH3) 7.17-7.51 (m, 3H, aromatic hydrogens) IR spectrum (KBr) cm-': 2910 (=CH3), 2920 (indole NCH3) Example 13 1 -Methyl-lumilysergol 0.1 g. of 10 % palladium-on-charcoal are wetted with 3 ml. of ethyl alcohol. A solution of 1.0 g. of 1methyl-2-chloro-lumilysergol in tetrahydrofuran is then added to the catalyst, and the reduction is carried out by passing hydrogen through the solution. The progress of the reaction is monitored by thin layer chromatography. When the hydrogenation is complete, the catalyst is filtered off, washed with two 4 ml.

portions of ethanol, and the combined organic phase is evaporated in vacuo. The oily product obtained is crystallized from acetone. Yield: 0.85 g. (95 %) Melting point: 213 to 215 "C Example 14 N-Hydroxy-succinimide 5-bromo-nicotinate active ester 1 g. of N-hydroxy-succinimide and 5.2 g. of 5--bromo-nicotinic acid are dissolved in 100 ml. of absolute ethyl acetate at 50 "C and 1.77 g. of N,N--dicyclohexyl-carbodiimide are added to the solution. The reaction mixture is stirred at room temperature for 4 hours, cooled to 5 "C and the precipitated white crystals are filtered off. The filtrate is evaporated and the evaporation residue is recrystallized from ethanol.

Example 15 Nicergoline 1 g. of 1-methyl-lumilysergol are dissolved in 100 ml. of dry pyridine and 0.96 g. of the active ester prepared according to Example 14 are added to the solution. The reaction mixture is stirred at room temperature for 4 hours. The progress of the reaction is monitored by thin layer chromatography. When the esterification is complete, the reaction mixture is evaporated under reduced pressure, poured onto 200 ml. of a 100 % sodium carbonate solution and extracted with three 30 ml. portions of chloroform.

The chloroform phase is washed with water, the combined organic phase is dried over magnesium sulfate, filtered, evaporated under reduced pressure and the residue is crystallized from ether. If desired, the product is further purified by chromatography.

Yield: 1.5 g. (93 %) Melting point: 135 "C

Claims (12)

1. A process for the preparation of 10 < x-methoxy-6-methyl ergoline derivatives of formula (I)

wherein R is hydrogen or methyl, X is hydrogen, chlorine, bromine or iodine, R' is hydrogen or 5-bromo-nicotinoyl, and physiologically acceptable acid addition salts thereof, which comprises methoxylating a 2-halo-lysergol of formula (II) wherein

X is chiorine, bromine or iodine, by a photochemical reaction, in order to obtain a 2-halo-lumilysergol, in which R and R' are both hydrogen, and X is as defined above, followed, if it is desired to obtain a compound of formula (I) in which R is methyl, by methylating said compound in order to obtain a 1-methyl-2-halo-lumilysergol of formula (I) obtained, in which R is methyl, and X and R' are as defined above, followed, if it is desired to obtain a compound of formula (I) in which X is hydrogen by dehalogenating the 1-methyl-2-halo lumilysergol and, followed, if desired, by esterifying the 1-methyl lumilysergol of formula (I) obtained, in which R is as defined above, R' is hydrogen and X is hydrogen to form the corresponding compound in which R' is a 5-bromo-nicotinoyl group, and, if desired, followed by conversion of a 10 -methoxy-6-methyl-ergoline derivative of formula (I) obtained in any of the above steps into a physiologically acceptable acid addition salt thereof.

2. A process as claimed in claim 1 wherein the photochemical methoxylation is effected by subjecting the compound of formula (II) as defined in claim 1 to U.V. light in a methanolic medium containing sulphuric acid.

3. A process as claimed in claim 1 or claim 2 wherein any methylation reaction is carried out using methyl iodide in a dipolar aprotic medium.

4. A process as claimed in any one of claims 1 to 3 wherein any dehalogenation is carried out using hydrogen and a palladium-on-charcoal catalyst.

5. A process as claimed in any of claims 1 to 4 in which the esterification is carried out with an active ester.

6. A process as claimed in claim 5, in which the active ester is prepared by reacting N-hydroxy-succinimide with 5-bromo-nicotinic acid.

7. A process as claimed in claim 1 substantially as hereinbefore described.

8. A process for the preparation of a 10(x-methoxy-6-methyl ergolene derivative substantially as hereinbefore described and with reference to any of Example 7-15.

9. Compounds of formula (I) as defined in claim 1, in which R is hydrogen or methyl, R' is hydrogen, X is chlorine, bromine or iodine and physiologically acceptable acid addition salts thereof.

10. A 2-halo-6-methyl-8-hydroxymethyl-10-methoxy--ergoline and physiologically acceptable acid addition salts thereof.

11. A 1-methyl-2-halo-6-methyl-8-hydroxymethyl-10a--methoxy-ergoline and physiologically acceptable acid addition salts thereof.

12. A pharmaceutical composition which comprises at least one compound of formula (I), as shown in claim 1 and in which R is hydrogen or methyl, R' is hydrogen, X is chlorine, bromine or iodine or a physiologically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier and/or excipient.