HU187600B - Process for preparing 2-methyl-9,10-didehydro-ergolines - Google Patents

Description

The present invention relates to novel 2-methyl-9,10-didehydro-ergolines in free base or acid addition salt form and to pharmaceutical compositions containing them.

The present invention relates to compounds of formula (I): wherein

X is oxygen or sulfur,

R _{t is} hydrogen, (C 1 -C 4) -alkyl or phenyl;

R _{2 is C} 1-3 alkyl and

R _{3 represents a C} 1-4 alkyl group or a phenyl or pyridyl group optionally substituted with C 1-4 alkyl group in the form of its free base or an acid addition salt thereof.

When the compounds of formula (I) contain alkyl groups as defined above, they preferably have one or two carbon atoms and are preferably methyl.

In the compounds of the formula I, preferably X is sulfur and Rj is preferably hydrogen. R _{3 is,} for example, an unsubstituted 2-pyridyl group.

In a preferred group of compounds of formula I, X is sulfur, R _{3 is} hydrogen and R _{3 is} 2-pyridyl.

According to the invention, the compounds of the formula I and their salts are prepared by reacting a compound of the formula II - R 1 and R _{2 have} the meaning given above and Y is an interchangeable group - with a compound of the formula III - X and R ₃ and M is hydrogen or alkali metal to give the compound of formula (I) as a base or acid addition salt.

The reaction of the present invention may be carried out analogously to known methods for preparing similar compounds.

Exchangeable group Y is, for example, a halogen atom such as chlorine or bromine, or a group -O-SO ₂ -R-R lower alkyl or optionally substituted phenyl.

The reaction of the compounds of formula (II) and (IV) is conveniently carried out in the presence of a solvent. Particularly suitable under reaction conditions are inert, aprotic polar solvents such as amides of organic carboxylic acids such as dimethylformamide, but also hexamethylphosphoric triamide or acetonitrile, optionally mixed with a small amount of water.

Preferably, higher temperatures, for example about 50 to 100 ° C, are employed.

The reaction is conveniently carried out with the exclusion of oxygen, for example under nitrogen.

Preferably, the compound of formula (III) is used in excess, for example, 2 to 10 mol of compound (III) is used per mole of compound (II).

Preferably the appropriate mesylate or tosylate is used as the compound of formula (II).

In the compound of formula (III), M is preferably an alkali metal.

Work-up of the reaction mixture obtained by the above process and purification of the compounds of formula (I) thus obtained can be carried out according to known methods.

The compounds of formula (I) may be in free form or in the form of their addition salts with acids. Acid addition salts can be prepared from the free bases in a known manner and vice versa.

For example, starting compounds of formula (II) may be prepared by _reducing compounds of formula (IV) - R ₁₅ R ₂ and Y in a manner known per se.

Compounds of formula IV may be prepared from compounds of formula V: R _1; R ₂ and Y are as defined above - by methods well known for reacting 1,3-ditiánnal.

Compounds of formula (II) wherein R1 is hydrogen may also be prepared by protecting the 1-position of the 6-alkylergoline-8β-carboxylic acid alkyl ester in a known manner, for example by benzyloxycarbonyl. the methyl group and the protecting group are removed to give 6-alkyl-2-methylergoline-8β-carboxylic acid which is converted to the desired compound of formula II.

The starting compounds, the preparation of which is not described, are known or can be prepared in a known manner or in an analogous manner to the methods described or known herein.

The compounds of the invention, in free form or in the form of their addition salts with physiologically tolerated acids, have shown valuable pharmacodynamic properties in animal experiments and are thus useful as medicaments.

In an observational study, the compounds of the invention are administered at doses of 3 mg / kg orally (mice) or 30 mg / kg i.p. p. dosing (rats) prolonged wakefulness and increased responsiveness to external stimulation.

In addition, electrically induced acetylcholine release (serotonin antagonist activity) from rat hippocampal sections was increased at 0.1 mg / ml in vitro.

Based on these effects, the compounds of the present invention are useful in the treatment of senile dementia.

Further, the compounds were 3-30 mg / kg p.o. She. doses inhibited paradoxical sleep without subsequent rebound effect.

Based on the latter effect, the compounds are useful as antidepressants.

The compounds of the present invention antagonize the apomorphine effect in vitro at a dose of 1 mg / liter in rats to selectively stimulate acetylcholine on striatum section. Markstein Method, J. Neural Transmission 51, 39-59 (1981)].

In the striatum, 10 mg / kg p. She. in doses of 3,4-dihydroxyphenylacetic acid and homovanilic acid (DOPAC and HVA) induce a strong increase in dopamine metabolites [quantification of parameters F. Karoum et al., Europ. J. Pharmacol. 44, 311-318 (1977) and H.R. Bürki et al., Psychopharmacology 57, 227-237 (1978). The same dose concurrently increases the female-21, 187,600.

tyrosine hydroxylase activity (A. Carlson et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 163-168). (These properties suggest a dopamine antagonizing effect.) Based on the latter effects, the compounds of the present invention are useful as neuroleptics, particularly for the treatment of schizophrenia.

The compounds further increase the uptake of ⁴ C-deoxyglucose (0.01-0.1 mg / kg iv or 10 mg / kg po) in certain areas of the brain, particularly the lateral habenular nuclei (L. Sokoloff method; Journal of Cerebral. Blood Flow and Metabolism 1981, 7, 7-36; E. Savaki et al., Brain Research 1982, 233, 347 and J. McCulloch et al., Journal of Cerebral Blood Flow and Metabolism 1981, 7, 133-136).

Based on the latter effects, the compounds can be recommended for the treatment of cerebral insufficiency.

The compounds also have vasoconstrictor activity, which can be detected in vitro at 10 nM in spinal fibers of the carotid artery externa of dogs [E. Müller-Schweinitzer: NaunynSchmiedeberg's Arch. Pharmacol., 292, 113-118 (1976)].

Based on the latter effect, the compounds of the invention are useful in the treatment of migraine.

Of course, the dosage to be used in these fields of application will depend upon the particular compound, the mode of treatment and the effect desired. Generally, satisfactory results are obtained with a dose of about 0.1 to about 10 mg / kg body weight; treatment may be given as a single daily dose or as several divided doses as needed. For larger mammals, the daily dose is about 1-100 mg of active ingredient; Suitable dosage forms, for example for oral administration, generally contain from 0.3 to 50 mg of the active ingredient in a solid or liquid carrier or diluent.

The invention also relates to pharmaceutical compositions containing the compounds of the invention. Excipients and carriers customary in the art of pharmacy may be used.

In the following examples, which illustrate the invention in more detail, the temperature data is given in degrees Celsius and is not corrected.

Example 7

2,6-Dimethyl-$ - (2-pyridylthiomethyl) -9,10-didehydro-ergoline hydrochloride

a) 2- (1,3-Dithian-2-yl) lysergol mesylate

To a solution of dithian (4.2 g, 33.9 mmol) in chloroform (100 mL) was added dropwise sulfuryl chloride (2.9 mL, 35.6 mmol) in chloroform (15 mL) over 30 min at -30 °. After warming to 20 ° C, stir at this temperature for 30 minutes. 7.5 g (22.6 mmol) of lysergol mesylate in 100 ml of chloroform are then added at -10 °. After the reaction mixture has warmed to 20 ° C, it is stirred at this temperature for 30 minutes. For work-up, ice water was added, neutralized with 2N sodium carbonate solution and extracted with methylene chloride containing 10% isopropanol. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. 11 g of crude product are obtained which is chromatographed on silica gel with 2% methanol in methylene chloride to give 2.7 g of lysergol mesylate and 4.3 g of the title compound.

b) 2-Methyl-lysergol mesylate

The aqueous Raney nickel suspension (100 mL) was washed 4 times with 100 mL of a 1: 4 mixture of dimethylformamide and acetone. To the washed Raney nickel was added 115 mL of a 1: 4 mixture of dimethylformamide and acetone under argon. To the stirred suspension at room temperature was added a solution of 4.3 g (9.6 mmol) of 2- (1,3-dithian-2-yl) -isergol mesylate in 80 ml of a 1: 4 mixture of dimethylformamide and acetone and 2 for 1 hour at room temperature. It was then filtered and the filtrate washed twice with 115 ml of a 1: 2 mixture of dimethylformamide and acetone. After evaporation of the filtrate and drying under high vacuum, 2 g of crude title compound are obtained, which is eluted on 90 g of silica gel with 2% methanol in methylene chloride. 1.3 g of the title compound are obtained in the form of a beige foam.

c) 2,6-Dimethyl-8β - (2-pyridylthiomethyl) -9,10-didehydro-ergoline

To a solution of 2-methyl-lysergol mesylate (1.3 g, 3.75 mmol) and 2-mercaptopyridine (1 g, 9 mmol) in dimethylformamide (20 mL) was added 2N sodium hydroxide solution (4.5 mL) and stirred at room temperature for 18 hours. Water was added and the mixture was extracted with 10% isopropanol in methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and dried under high vacuum. The crude product was chromatographed on 120 g of silica gel with chloroform containing 2% methanol and 0.1% concentrated ammonia. 1.3 g of the free compound are obtained. The title free compound is dissolved in ethanol and an equivalent of hydrochloric acid is added at room temperature. The hydrochloride crystallizes on evaporation. M.p. 253 °;

[.alpha.] D @ 20 = + 58 DEG (c = 0.370 in 1: 1 ethanol / water).

In analogy to the procedure described in Example 1, the following compounds can be prepared.

Example 2

2-Methyl-6-ethyl-8 $ - (2-pyridyl) thiomethyl-ergoline -9,10didehidro

M.p. 21O '; (α) θ = + 45 ° (c = 0.435 in 1: 1 ethanol-water).

187,600

Example 3

1,2-Dimethyl-6-ethyl-8,8- (2-pyridylthiomethyl) -9,10didehydro-ergoline hydrochloride

M.p. 185 °; [.alpha.] D @ 20 = + 28 DEG (c = 0.33, 1; 1 in ethanol / water).

Example 4

2.6- Dimethyl-1-phenyl-8β- (2-pyridylthiomethyl) -9,10didehydro-ergoline hydrochloride

191-192 ° (dec.); [.alpha.] D @ 20 = + 294 DEG (c = 0.85.1: 1 in ethanol / water).

Example 5

2.6- Dimethyl-8β - (p-methyl) phenylthiomethyl-9,10didehydroergolirt

M.p. 206-208 ° (dec.); [α] D = + 22 ° (c = 0.54, in pyridine).

Example 6

2.6- Dimethyl-8,8-phenyl-thiomethyl-9,10-didehydro-ergoline

178-180 ° (dec.); [α] D = + 33 ° (c = 0.76, in pyridine).

Example 7

2.6- Dimethyl-8β- (p-methyl-phenoxymethyl) -9-10-didehydro-ergoline

173-175 ° C; (Dec); [α] D = + 39 ° (C = 0.65, in pyridine). It is prepared by reacting 2-methyl-lysergol mesylate with 4-methylphenol sodium salt.

Example 8

2,6-Dimethyl-8-thiomethyl $ -methyl-9,10-didehidroergolin hydrochloride

288-289 °; [α] D = +92 '(c = 0.5 in a 1: 1 mixture of ethanol and water).

Example 9

2-Methyl-6-propyl-8,8-methyl-thiomethyl-9,10didehydro-ergoline hydrochloride

Melting point 252-253 ° with decomposition.

Example 10

1,2,6-Trimethyl-$ 8 - (2-pyridylthiomethyl) -9,10didehydro-ergoline hydrochloride

188-189 ° (dec.); [α] D = + 49 ° (c = 0.59, 1: 1 in ethanol-water).

Claims (5)

Patent claims A process for the preparation of 2-methyl-9,10-didehydro-ergolines of the formula I and their acid addition salts thereof X is oxygen or sulfur, R 1 is hydrogen, C 1-4 alkyl, or phenyl, R ₂ is C 1 -C 3 alkyl and R ₃ is C 1 -C 4 alkyl or phenyl or pyridyl optionally substituted with C 1 -C 4 alkyl, wherein R ₂ and R _{2 are} as defined above. and Y is an interchangeable group, preferably a halogen atom or a group -O-SO ₂ -R wherein R is a lower alkyl group or an optionally substituted phenyl group with a compound of formula III - X and R _{3 are} as defined above and M is hydrogen or alkali metal. and reacting to obtain the compound of formula (I) as the free base or an acid addition salt thereof. (Priority: 08.08.1983) Process for the preparation of a compound of formula (I) according to claim 1, wherein X is sulfur, R 1, R ₂ and R _{3 are} as defined in claim 1, characterized in that it is reacted with a compound of formula (III): X is sulfur, R ₃ and M are as defined in claim 1. (Priority: 08.08.1983) A process for the preparation of a compound of formula (I) according to claim 1 wherein R, hydrogen, R _{2 are} as defined in claim 1, R ₃ 2 -pyridine is substituted and X is sulfur; compound of the formula wherein R is hydrogen, R ₂ and Y are as defined in claim 1, is reacted with a compound of formula (III) wherein R ₃ 2-pyridyl, X and M are as defined in claim 1. (Priority: 08.08.1982) A process for the preparation of 2,6-dimethyl-8β- (2-pyridylthiomethyl) -9,10-didehydro-ergoline according to claim 1, characterized in that a compound of formula II wherein R 1 is hydrogen, R ₂ methyl and Y are as defined in claim I, is reacted with a compound of formula (III) wherein X is sulfur, R ₃ 2-pyridyl and M are as defined in claim 1. (Priority: 08.08.1983) 5. A compound which is (i) 2-methyl-9,10-didehydro-ergoline of the formula - the meaning of R "R _2, R ₃ and X in claim 1. - pharmaceutical compositions containing the free base or acid addition salt form thereof, wherein 1-4. The active ingredient produced by the process of any one of claims 1 to 6 is formulated with a common carrier, diluent and / or other excipients of the pharmaceutical compositions to form a pharmaceutical composition. (Priority: 08.08.1983)