CS236786B2 - Processing of ergoline derivative aryled in position 1 - Google Patents

Abstract

1-aryl ergot alkaloids and their acid addition salts thereof are indicated for use as an anti-parkinson agent, anti-depressant, neuroleptic, vigilance increasing agent or for the treatment of senile dementia. Aryl includes heteroaryl and may be substituted.

Description

(54) A method for producing ergoline derivatives arylized at the 1-position

The present invention relates to a process for the preparation of ergoline derivatives of the 1-position aryl having valuable therapeutic properties.

The present invention provides a process for the preparation of ergoline derivatives which are substituted in the 1-position by an aryl group of the formula I

in which

Ar represents a phenyl group which is optionally monosubstituted or disubstituted with chlorine or fluorine, or which is optionally monosubstituted with hydroxy, methyl, methoxy or trifluoromethyl,

R, R 1 and R 2 are each hydrogen or

R is hydrogen and R 1 and R 2 together form a single bond or

R 1 and R 1 together form a single bond and R 2 is hydrogen,

R 5 is hydrogen, methoxycarbonyl or CH 2 -X in which X is hydrogen, hydroxy, cyano, carboxy, pyridylthio, C 2 -C 5 alkylcarbonyloxy or nicotinoyloxy, and

R 4 represents a C 1 -C 3 alkyl group, in the form of the free bases or their acid addition salts.

When R is hydrogen, the R 3 substituent may have the α- or З-configuration. The configuration is preferred.

Compounds of formula I include, for example, those in which:

Ar represents a phenyl group,

R is hydrogen,

R 1 and R 2 together form a single bond or

R1 and R2 are each hydrogen,

R3 represents a group -CH 2 R 3 ¹ in which

R3 * is hydrogen, hydroxy, cyano or carboxy;

R4 represents a methyl group.

Ar is preferably unsubstituted phenyl.

Suitably R1 and R2 form a single bond.

Preferably R3 is represented by CH2-X. X is, for example, hydroxy, cyano or carboxy, especially hydroxy.

Preferably R4 is methyl.

Of particular interest is the compound described in Example 1 below.

According to the present invention, the compounds of formula I and their salts are obtained by treating the compounds of formula III

in which

R, R 1, R 2, R 3 and R 4, as defined above, act by compounds of formula II

Ar — Xi (II) in which

Ar has the above. meaning a

X 1 is chlorine, bromine or iodine.

The process according to the invention can be carried out in a manner known per se under the conditions of the Ullmann reaction.

The catalyst is preferably. using . powdered copper.

The reaction can either be carried out without a solvent or using, for example, pyridine, quinoline, toluene, nitrobenzene, dimethylsulfoxide or dimethylformamide.

When. use of solvents,. For example, potassium carbonate may be added which does not bind the acid.

Reaction temperatures generally range between 80 ° C and 200 ° C.

The reaction is preferably carried out under an atmosphere of an inert gas such as nitrogen or argon.

The free bases can be converted into acid addition salts and vice versa. Acids suitable for salt formation are, for example, hydrochloric acid, sulfuric acid, maleic acid, fumaric acid and tartaric acid.

The starting compounds of formulas II and III are known or can be prepared by methods known per se.

The compounds of formula I and their acid addition salts have not been previously described in the literature. These. compounds. have interesting pharmacological properties in animal experiments and can therefore be used as medicaments.

In particular, these substances affect the biogenic metabolism. amines, such as serotonin, dopamine and noradrenaline, in various regions of the rat brain.

Both in the cortex and in the hippocampus, the new substances cause a decrease in 5-hydroxyindole acetic acid (5-HIAA) when applied at 10 mg / kg s. C.

In the striatum, these compounds cause an increase in both dopamine metabolites, i.e. 3,4-dihydroxyphenylacetic acid and homovanilic acid (DOPAC and HVA) when administered subcutaneously at 50 mg / kg.

In the hypothalamus and pons / medulla region, the noradrenaline metabolite, i.e., 4-hydroxy-3-methoxyphenylethylene glycol (MHPG-SO-), increases considerably with 50 mg / kg subcutaneously.

[For quantitative determination of the above biochemical parameters, see F. Karoum et al., Europ. J. Pharmacol. 44, 311-318 (1977); Β. H. C. Westrink et al., Europ. J. Pharmacol. 42, 179-190 (1977) and H. R. BURKI et al., Psychopharmacology 57, 227-237 (19713)].

In addition, the novel substances in the cat's sleep-wake cycle. At - oral - administration of 3-10 mg / kg reduce paradoxical sleep time without affecting classical sleep and prolong waking time.

In addition, these new compounds cause rotation in the Ungerstedt rat (U. Umgerstedt method, Acta physiol. Scand. Suppl. 387, 69-93 (1971)) to the opposite side, relative to the side on which it is located in the nigrostriatal region in doses - 1 to 3 mg / / kg ip

In the above experiments, 8 H -hydroxymethyl-6-methyl-1-phenyl-9,10-didehydroergoline has a particularly interesting effect profile. In the sleep-wake cycle. in a cat, for example, this compound reduces paradoxical sleep time by about 30% after oral administration of 3 mg / kg.

Based on in vivo biochemical experiments on a rat with serotinin and noradrenaline metabolism and on the results of the Ungerstedt model, these may be. - use new substances as antidepressants especially - in older people.

Based on biochemical experiments in vivona in rats with serotonin, dopamine and noradrenaline metabolism and results in the Ungerstedt model and in the cat sleep-wake cycle, these novel compounds are useful for the treatment of senile dementia, especially at an early stage.

Based on the results of the cat's sleep-wake cycle, these substances can also be used to increase vigilance.

In addition, on the basis of in vivo biochemical experiments in a rat with dopamine metabolism, these substances are also useful as neuroleptics.

The present invention also relates to pharmaceutical compositions comprising the compounds produced by the process of the invention. Auxiliaries and excipients used in pharmacy can be used in their manufacture.

Furthermore, the present invention relates to the use of the novel compounds as pharmaceuticals, for example in therapeutic treatment, for example in the treatment of senile dementia at an early stage or as antidepressants or vigilance agents.

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

Example 1

8'-Hydroxymethyl-6-methyl-1-phenyl-9,10-didehydroergoline (1-phenyllysergol)

5.7 g of copper powder and 3.3 g of potassium carbonate are introduced into a sulphonation flask and then a solution of 5.1 g of lysergol in 60 ml of dimethylformamide and 4.5 ml of iodobenzene is added. The brown copper slurry was stirred at 170 ° C for 5 hours under a nitrogen atmosphere. After cooling, the brown mixture was diluted with methylene chloride and filtered through celite. The filtrate was extracted three times with 2N sodium carbonate solution. The combined organic phases were washed with water, clarified with activated carbon, dried over sodium sulphate and evaporated. 5.5 g of crude product are obtained, which crystallizes from a mixture of ether and petroleum ether. Recrystallization from methylene chloride / hexane twice gave white crystals, m.p. 133-136 ° C.

[Α] D - + 19.1 ° (c = 0.74, chloroform).

Hydrogen maleate:

mp 199-201 ° C (decomposition) [α] D ²⁰ =. - + 88.0 ° (c = 0.7 in dimethylformamide).

The following compounds can be prepared in an analogous manner to that described in Example 1.

Example 2

8β-hydroxymethyl-6-methyl-1-phenylergoline (1-phenyl-9,10-dihydrolysergol)

Melting point: 200-202 ° C.

[ «Id ²⁰ = -93.5 ⁰ (c - 0.73, chloroform).

Example 1 a d 3

8 / S-Hydroxymethyl-6-methyl-1-phenylergoline (1-phenyl-9,10-dihydrolysergol)

Melting point: 164-167 ° C.

[α] D ²⁰ = + 41.7 ° (c = 0.63, chloroform).

Example 1-phenyl-6-methyl-9,10-didehydroergoline-8/3-acetic acid (1-phenyl-homo-lysergic acid)

270 DEG C. (decomposition).

Example 1 a d 5

8-Hydroxymethyl-6-methyl-1-phenyl-8,9-didehydroergoline (1-phenyl-elymoclavin)

Melting point: 140-143 ° C.

= -118.0 ° (c = 0.58 in chloroform). Example

9.10-Didehydro-8H-hydroxymethyl-6-methyl-1- (4-chlorophenyl) ergoline

201 DEG-202 DEG C. (decomposition).

[.Alpha.] D @ ²⁰ = + 12.8 DEG (c = 0.5 in chloroform).

Example 7

9.10-Didehydro-8β-hydroxymethyl-6-methyl-1- (3,4-dichlorophenyl) ergoline

Melting point: 107 ° C (decomposition).

Ыо ²⁰ = -10.3 DEG (c = 0.5 in dimethylformamide) Example

9.10-Didehydro-8 (3-hydroxymethyl-6-

methyl-1- (4-methoxyphenyl) ergoline

Melting point: 160 to 161 ° C (decomposition).

^Ыо й = + 41.5 ° (c = 0.7 in chloroform).

Example 9

9.10-Didehydro-8/3-hydroxymethyl-6-methyl-1- (4-fluorophenyl) ergoline

23678В

Melting point: 200 to 201 ° C (decomposition).

[.alpha.] D @ ²⁰ = -5.5 DEG (c = 0.5 in dimethylformamide).

Example 10

9.10-Didehydro-8H-hydroxymethyl-6-methyl-1- (2-methoxyphenyl)

155 DEG-157 DEG C. (decomposition).

[.Alpha.] D @ ²⁰ = - + 18.2 DEG (c = 0.5 in dimethylformamide).

Example 11

9.10-Didehydro-8 H -hydroxymethyl-6-methyl-1- (2-fluorophenyl) ergoline

M.p .: 141-144 ° C (dec.).

[.Alpha.] D @ ²⁰ = + 13 DEG (c = 0.5 in dimethylformamide).

Example 12

9.10-didehydro-8R-hydroxymethyl-6-

methyl-1- (4-methylphenyl) ergoline

M.p .: 202-203 ° C (dec.).

[Α] _D ²⁰ - -1.2 ° (c = 0.5 in dimethylformamide).

Example 13

O, 10-Didehydro-N, 4-Hydroxyinethyl-e-methyl-1- (4-trifluoromethylphenyl) ergoline

151-152 ° C (dec.).

Ыо ²⁰ = -7.3 DEG (c = 0.5 in dimethylformamide).

Example 14

9.10-didehydro-8H-hydroxymethyl-6-

methyl-1- (3-chlorophenyl) Jergoline

Melting point: 170-172 ° C.

[.Alpha.] D = -6.0 DEG (c = 0.45 in dimethylformamide).

Example 15

9.10-Didehydro-8/3-hydroxymethyl-6-

methyl-1- (3-methoxyphenyl) ergoline

Melting point: 160-162 ° C.

[Α] D = = - 2.8 ° (c = 0.5 in dimethylformamide).

Example 16

8H-Acetoxymethyl-9,10-didehydro-6-methyl-1-phenylergoline hydrogen fumarate

190 DEG-194 DEG C. (decomposition).

[.alpha.] D ^{@ 20} = + 9.0 DEG (c = 0.5 in dimethylformamide).

Example 17

9.10-didehydro-6-methyl-8S-nicotinoyloxymethyl-1-phenylergoline

135 DEG-138 DEG C. (decomposition).

[.alpha.] D @ ²⁰ = + 20.0 DEG (c = 0.5 in dimethylformamide).

Example 18

9.10-dihydro-6-methyl-1-phenyl-8H-trimethylacetoxymethylergoline

Melting point: 130-133 ° C.

= + 14.0 ° (c = 0.7 in dimethylformamide).

Example 19

9,10-didehydro-6,8, 5-dimethyl-1-phenylergoline hydrochloride

Melting point: 282-285 ° C (decomposition).

[.alpha.] D ^{@ 20} = + 109 DEG (c = 0.5 in dimethylformamide).

Example 20

O.10-didehydro-η 4 -hydroxymethyl-e-propyl-1-phenylergoline hydrochloride

Melting point: 270 to 273 ° C (decomposition).

[α] ²⁰ - + 68 ° (c = 1.0 in dimethylformamide).

Example 21

9,10-Dihydro-1-phenyllysergic acid methyl ester

M.p .: 155-157 ° C.

[.alpha.] D @ ²⁰ = -91.8 DEG (c = 0.55 in chloroform).

Example 22 1-phenyl-6-methylergoline

Melting point: 242-243 ° C.

[.alpha.] D @ ²⁰ = -46.8 DEG (c = 0.77, in DMF).

Example 23

9.10-Didehydro-6-methyl-1-phenyl-8 ₍ 6-

- (2-pyridylthiomethyl) ergoline

Melting point: 107-109 ° C.

[.alpha.] D @ ²⁰ = -20.0 DEG (c ~ 0.4 in chloroform).

Example 24

9.10-Didehydro-8'-hydroxymethyl-6-methyl-1- (3-hydroxyphenyl) ergoline

Melting point: 201-203 ° C (decomposition).

[.alpha.] D @ ²⁰ = -4-1.0 DEG (c = 0.5 in dimethylformamide).

Example 25

9,10-Didehydro-8 H -dimethylhydroxy-6-

methyl-1- (4-hydroxyphenyl) ergoline

Melting point: 186-190 ° C.

[^] ²⁰ =

4-5.0 ° (c = 0.55 in dimethylformamide).

Example 26

8α-Cyanomethyl-6-methyl-1-phenylergoline

Melting point: 147-149 ° C.

[С *] ²⁰ =

- 99.0 ° (c = 0.94 in chloroform).

Claims (2)

OBJECT OF THE INVENTION CLAIMS 1. A process for the preparation of ergoline derivatives of arylated in position 1 of the formula I, which comprises: Ar represents a phenyl group which is optionally monosubstituted or disubstituted with chlorine or fluorine, or which is optionally monosubstituted with hydroxy, methyl, methoxy or trifluoromethyl, R, R 1 and R 2 are each hydrogen or R represents a hydrogen atom; together represent a single bond; or R 1 and R 1 together form a single bond and R 2 represents a hydrogen atom, R3 represents a hydrogen atom, a methoxycarbonyl group or a N-X group in which X represents a hydrogen atom, a hydroxy group, a cyano group, a carboxy group, a pyridylthio group. (C 2 -C 5) alkylcarbonyloxy or nicotinoyloxy group; and R 4 represents a C 1 -C 3 alkyl group, and pharmaceutically acceptable salts thereof; R, R 1, R 2, R 3 and R 1 are as defined above, with compounds of formula II Ar — Xi (И) in which Ar is as defined above and X 1 is chlorine, bromine or iodine and the resulting compounds are optionally converted into their pharmaceutically acceptable salts. 2. Process according to claim 1, characterized in that the compounds of the general formula (III) are used as starting materials Ar represents a phenyl group which is optionally monosubstituted or disubstituted with chlorine or fluorine, or which is optionally monosubstituted with hydroxy, methyl, methoxy or trifluoromethyl, R, R 1 and R 2 are each hydrogen or R is hydrogen and R 1 and R 2 together form a single bond, R 3 is CH 2 -X in which X is hydrogen, hydroxy, cyano, carboxy or C 2 -C 5 alkylcarbonyloxy, and R4 represents a methyl group.