FI73679B - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA ERGOLINDERIVAT OCH MELLANPRODUKT FOER ANVAENDNING VID FOERFARANDET. - Google Patents

Description

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The invention relates to a process for the preparation of novel therapeutically useful ergoline derivatives of the formula I and their acid addition salts, CH-X-R-

10 | J

II)

X. N-R I

Wherein X is an oxygen or sulfur atom, R 1 is hydrogen, C 1-4 alkyl or phenyl, R 2 is C 1-3 alkyl and R 2 is C 1-4 alkyl, or a phenyl or pyridyl group which may be mono-, di- or trisubstituted by halogen having an atomic number of 9 to 35, by C3-4 alkyl or by C1-4 alkoxy.

Alkyl and alkoxy groups are preferably those having 1 or 2 carbon atoms, in particular methyl or methoxy.

The symbol X is preferably broken. R 1 is preferably hydrogen. denotes, for example, an unsubstituted 2-pyridyl group. When R 1 represents halogen, it is preferably chlorine or bromine.

Preferred compounds of formula I are those wherein X is sulfur, R 1 is hydrogen and R 3 is a 2-pyridyl group.

The compounds of formula I can exist as two groups of isomers, namely as compounds having the 8R configuration and as compounds having the 8S configuration. Compounds of formula 35 I having the 8R configuration are preferred.

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Ergoline derivatives of formula I and their acid addition salts can be prepared by Y in a compound of formula

5 CH2-Y

R 1 -N 2 -CH 3 wherein and R 2 are as defined above and Y is a halo-15 gene or -O-SC 2 -R 4 where R is lower alkyl or phenyl which may be substituted, replaced by a group

-X-R3 III

wherein X and R 2 are as defined above, and if desired, the compound of formula I obtained is converted into an acid addition salt.

The group of formula III is preferably attached by reacting a compound of formula II with a compound of formula

MX-R3 IV

25 wherein X and R3 are as defined above and M is hydrogen or an early metal.

The reaction can be carried out in a manner known per se.

The reaction between the compounds of formulas II and IV is conveniently carried out in a solvent. Particularly suitable for the purpose under the reaction conditions are inert, aprotic, polar solvents, e.g. amides of organic carboxylic acids, such as dimethylformamide or also hexamethylphosphoric acid triamide or acetonitrile, optionally in admixture with a small amount of water.

The reaction is preferably carried out at an elevated temperature, for example at about 50-100 ° C.

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The reaction is conveniently carried out without oxygen, for example under a nitrogen atmosphere.

Preferably, an excess of a compound of formula III is used, e.g. about 2-10 moles of a compound of formula III per mole of compound of formula II.

The corresponding mesylate or tosylate is preferably used as the compound of formula II.

Usually M in the compounds of formula IV is preferably an alkali metal.

The work-up of the reaction mixtures obtained as described above and the purification of the compounds of the formula I thus obtained can be carried out according to methods known per se.

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

The starting materials of the formula II can be prepared according to methods known per se.

The compounds of the formula I in free form or as addition salts with physiologically acceptable acids have been found to have interesting pharmacodynamic properties in animal experiments and can be used as medicaments.

The compounds of formula I cause an increase in wakefulness and an increase in reactivity to external stimuli at an oral dose of at least 3 mg / kg (in mice) or at an intraperitoneal dose of 30 mg / kg (in rats).

In addition, at a dose of 0.1 mg / ml in vitro, they potentiate the electrically induced release of acetylcholine from rat edematous sections (serotonin agonist effect).

Based on this activity, the compounds of formula I can be used in the treatment of boredom in old age.

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Furthermore, in an EEG study performed on rats for 48 consecutive hours (H. Kleinlogel et al., Waking and Sleeping 1980, 4, pp. 77-85), at oral doses of 3-30 mg / kg, paradoxical 5 sleep inhibition was obtained without associated sleep increase (rebound effect).

Based on this effect, the compounds can be used as antidepressants.

The compounds of the formula antagonize the effect of this additional 10 mg / l in vitro dose of apomorphine on the electrically stimulated release of acetylcholine from rat striated sections / Methode nach R. Markstein, J. Neural Transmission 51, 39-59 (19 81) _7 -

In the brainstem, the compounds induce, at an oral dose of 10 mg / kg, an increase in both dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanilic acid (DOPAC and HVA) / To quantify the parameters, see F. Karoum et al. ., Europ.

J. Pharamcol. 44, 311-318 (1977) and HRBurki et al., 20 Psychopharamacology 57, 227-237 (1978/7). Concomitant administration of the same dosage increases the in vivo tyrosine hydroxylase activity (Methode nach A. Carlson et al., Naunyn- Schmiedeberg's Arch. Pharmacol. 275, 163-168) (These properties speak in favor of dopamine antagonistic activity.) Based on this activity, the compounds of the invention can be used as neuroleptics, i.e. stress-relieving agents, especially in the treatment of schizophrenia.

They further enhance the uptake of intravenous dosing at 0.01-0.1 mg / kg or oral dosing at 10 mg / kg β-deoxyglucose in certain areas of the brain, especially in the outer Habenula nuclei (Methode nach L.Sokoloff, Journal of Cerebral Blood Flow and Metabolism 1981, 1, 7-36, HE Savaki et al., Brain Research 1982, 233, 347 and J. McCulloch et al., Journal of Cerebral Blood Flow and Metabolism 1981, 1, 133-136).

II

5,73679 Based on this activity, the compounds can be used in the treatment of brain dysfunction.

In addition, the compounds have vasoconstrictive activity, which can be demonstrated in vitro in Muller-Schweinitzer spinal strips of the canine outer carotid artery,

Naunyn-Schmiedeberg's Arch. Pharmacol., 292, 11-118 (1976), with a dosage starting from 10 nmol / liter.

Based on this effect, the compounds of the invention can be used in the treatment of migraine.

10 The dosage used for the above-mentioned uses will, of course, vary with the particular agent employed, the mode of administration and the treatment desired. In general, however, satisfactory results are obtained at doses of about 0.1 to Ι mg / kg; dosing may be daily with 15 single doses or, if necessary, several sub-doses.

In larger mammals, the daily dose is about 1-100 mg of substance, suitable dosage forms, e.g. for oral use, generally containing about 0.3-50 mg of active ingredient in addition to solid or liquid carriers or diluents.

The following is a comparison of a compound of formula I (Compound A) prepared in Example 1 from Pharmacology 16 (suppl. 1); 156-173 (1978) to 9,10-didehydro-6-methyl-8β- (2-pyridylthiomethyl) ergoline (Compound B).

H-, ^ // Λ ^: sAw iQfj Xch3 '' XcH3 hX— \ H-l_l 35 "° Η3 <Λ) (B)" 73679

Compound A in the form of hydrochloride and Compound B in the form of tartrate were used for comparison.

Both compounds A and B were found to react with dopamine and serotonin recognition sites, but differ substantially in that compound A has antagonistic activity at D-2 and serotonin receptors, whereas compound B has agonistic activity at these receptors. . This surprising profile indicates that Compound A is useful as a neuroleptic agent, especially in the treatment of schizophrenia. In contrast to Compound B, Compound A has dualistic activity, which is manifested in that, in addition to the D-2 antagonist, it has (like Compound B) D-1 agonist properties, suggesting that it does not cause extra-pyrimidatic side effects. Based on this, Compound A is a neuroleptic agent that is unlikely to cause extrapyrimidal side effects, while Compound B can best be used in combination with a neuroleptic agent that has the effect of reducing extrapyrimidal side effects. The ability of Compound A to act on various nonoaminergic systems in a partially dualistic manner further demonstrates that the compound is useful in the treatment of aging boredom.

The difference in the activity profiles of compounds A and B with respect to dopamine 25 and serotonin receptors has been demonstrated by various standard in vitro and in vivo biochemical experiments.

In Compound Adenylate Cyclone, both Compound A and Compound B have agonist activity at D 1 receptors, but in the acetylcholine release assay, Compound A, but not Compound B, has the ability to exhibit conventional neuroleptic agents. inhibit D2 ~ receptors. This appears to be the predominant, central effect of the compound, which was completely unexpected.

The dualistic effect of Compound A on dopamine receptors also occurs in vivo, with Compound A having 7,73679 a) significant antagonistic properties in that (i) it increases the rate of conversion of dopamine metabolites, (ii) it increases tyrosine hydroxylase activity, (iii) it inhibits apomorphine treated rats from the rodent and (IV) increases prolactor secretion after intravenous administration; b) weak agonist properties (compared to compound B) in that (i) compared to compound B it causes poor lateral rotation behavior in rats treated with 6 6 -HDA and (ii) in reserpine-pretreated rats only compound B causes deoxy-glucose utilization from post-synaptic, dopaminergic stimulation.

The above indicates that compound Λ (not compound 15 B) is a neuroleptic, especially an antiscizofrenino agent. Unlike Compound B, it is not an anti-Parkinson's agent. The results of the deoxyglucose binding assay also indicate that it can be used to treat brain dysfunction.

In addition, in assays examining acetylcholine release, adenylate cyclase, and isolated vasculature, Compound A had an antagonistic effect on serotomin receptors, whereas Compound B had an agonistic effect. This difference was demonstrated in vivo, with 25 (i) Compound B, but not Compound A, having serotonin-mimetic properties expressed as a reduction in PGO peaks in the PGO vibration test in cats, (ii) in sleep / wake cycles, Compound A differs from classical serotonin mimetic drugs in that it prolongs the duration of classical sleep.

The above indicates that Compound A (not Compound B) can be used in the treatment of senile boredom. In addition, the results of the sleep / wake cycle indicate that Compound A is an antidepressant.

35 Compound A also affects noradrenergic neurotransmission, as demonstrated, for example, by a standard study in which isolated strips of the rabbit outer carotid artery were examined. Compound A can thus be used as an anti-migraine agent and in the treatment of headache. Such a property has never been reported for compound B.

The following examples illustrate the invention. All temperature values are in degrees Celsius and are uncorrected. Example 1: 2,6-Dimethyl-8β- (2-pyridylthiomethyl) -9,10-didehydroergoline a) 2- (1,3-Dithian-2-yl) -lysergol mesylate To a solution of 4.2 g (33.9 mmol) of dithian in 100 ml of chloroform are added dropwise over 30 min. at -30 ° C 2.9 ml (35.6 mmol) of sulfuryl chloride in 15 ml of chloroform. After the temperature has risen to 20 °, stir for 30 min. time at 20 °. At -10 °, 7.5 g (22.6 mmol) of lysergol mesylate in 100 ml of chloroform are added. After the temperature of the reaction mixture has risen to 20 °, stir for 30 min. time at this temperature. For further work-up, ice / water is added, neutralized with 2N sodium hydroxide solution and extracted with methylene chloride containing 10 .mu.l of iso-20 propanol. The combined organic phases are dried over sodium sulfate, filtered and evaporated. 11 g of crude product are obtained, which is chromatographed on silica gel using methylene chloride containing 2% methanol, eluting with 4.3 g of the title compound and 2.7 g of lysergol mesylate.

b) 2-methyl-lysegol mesylate 100 ml of a suspension of Raney nickel in water are washed 4 times with 100 ml of dimethylformamide / acetone (1: 4) each time. 115 ml of dimethylformamide / acetone (1: 4) are added to the washed Raney nickel under an argon atmosphere. A solution of 4.3 g (9.6 mmol) of 2- (1,3-dithian-2-yl) -ergergol mesylate in 80 ml of dimethylformamide / acetone (1: 4) is poured into the stirred suspension at room temperature and stirred at 21 / ml. For 4 hours at room temperature-35 sa. Finally, filter and wash the filter residue two times with 9 ml-each of 115 ml of dimethylformamide / acetone (1: 2). After evaporation of the filtrate and drying under high vacuum, 2 g of crude ozicon compound are obtained, which is chromatographed on 90 g of silica gel using methylene chloride containing 2% methanol.

1.3 g of the title compound are eluted as a beige foam.

c) 2,6-Dimethyl-8β- (2-pyridylthiomethyl) -9,10-didehydroergoline To a solution of 1.3 g (3.75 mmol) of 2-methyl-isergol mesylate and 1 g (9 mmol) of 2-mercapto-pyridine in 20 ml of dimethylformamide are added 4.5 ml of 2N sodium hydroxide solution and stirred for 18 hours at room temperature. Water is added to the mixture and extracted with methylene chloride containing 10% isopropanol. The combined organic phases are dried over sodium sulfate, filtered, evaporated and dried under high vacuum. The crude product is chromatographed on 120 g of silica gel using chloroform containing 2 ", methanol 20 and 0.1% conc. NH ^: a. 1.3 g of the title compound are obtained. The hydrochloride of the title compound crystallizes on evaporation from ethanol. M.p .: decomposing from 253 °; 7yj ^ = + 58 ° ζο = 0,. '70 ethanol / water (1: 1) ^ 7.

Similarly, as in the method described in Example 1, the following compounds can also be prepared:

Example 2: 2-methyl-6-ethyl-8- (2-pyridyl-thiomethyl) -9,10-didehydroergoline M.p .: dec. From 210 °; = + 45 ° ζο. - 0.435 ethanol / water (1: 1) ^ 7.

Example 3: 1,2-Dimethyl-6-ethyl-8β- (2-pyridylthiomethyl) -9,10-didehydroergoline Melting point of hydrochloride: decomposition from 185 °; ~ + 28 ° (c = 0.33 ethanol in water (1: 1)).

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Example 4: 2,6-Dimethyl-1-phenyl-8β- (2-pyridyl-thiomethyl) -9,10-didehydroerao.LLini_ o

Hydrochloride melting point: 191-192 (dec.); ~ + 294 ° Qz - 0.85 ethanol in water (1: 1).

Example 5: 2,6-Dimethyl-8A- (p-methylphenyl-thiomethyl) -9,10-didehydroergoline M.p .: 206-208 ° (dec.); = + 22 ° (c = 0.54 in pyridine).

Example 6: 2,6-Dimethyl-8,3-phenylthiomethyl-9.10-10 d idehydroergoline

M.p .: 178-180 ° (dec.); = + 33 ° (c = 0.76 in pyridine).

Example 7: 2 ± 6-dimethyl-8H - (p-methylphenoxymethyl) -9,10-didehydroergoline mp: 173-175 ° (dec.); = + 39 ° (c = 0.65 in pyridine).

Example 8: 2,6-Dimethyl-8β-methylthiomethyl-9,10-didehydroergoline

Hydrochloride mp: 288-289 °; ~ + 92 ° 20 ζο = 0.5 ethanol / water (1: 1) J.

Example 9: 2-methyl-6-propyl-8H-methylthiomethyl-.9,10-didehydroergoline Hydrochloride melting point: 252-253 ° (dec.). Example 10: 1,2,3-Trimethyl-Sγ- (2-pyridyl-thiome-25-style) -9,10-didehydro-ergoline

Melting point of the hydrochloride: 188-189 ° (dec.), O n -Q = + 49 ° (c = 0.59 ethanol / water (1: 1)).

Claims (6)

11 73679 A process for the preparation of new therapeutically useful organoline derivatives of the formula I and their acid-5 addition salts, ch2-x-r3 Λ ίο! | R 1 is R 1 -N-1-CH 3 wherein X is an oxygen or sulfur atom, R 1 is hydrogen, C 3-4 alkyl or phenyl, R 2 is C 1-4 alkyl and R 3 is alkyl or a phenyl or pyridyl group which may be mono-, di- or trisubstituted by halogen having an atomic number of 9 to 35, C 1-4 alkyl or C 1-4 alkoxy, characterized in that Y in the compound of formula ch 2 -Y 25. I 'N- R_ ιΓΥ> · Vy RN - * - CH3 30 wherein R1 and R2 are as defined above and Y is halogen or -O-SO2 "R, wherein R is lower alkyl or phenyl which may be substituted, is replaced by 35 -X-R 3 111 73679 wherein X and R 1 are as defined above, and if desired, the compound of formula I obtained is converted into an acid addition salt. Process according to Claim 1, characterized in that the compound of the formula II is reacted with a compound of the formula mx-r 3 IV in which X and R 1 have the same meaning as above and M is hydrogen or an alkali metal. Intermediate for use in the process according to claim 1, characterized in that it has the formula ch2-y 15 ιΛ iT VN-L CH 3 wherein R 1 is hydrogen, C 1-4 alkyl or phenyl, R 2 is C 1-3 alkyl and Y is halogen or -O-SO 2 -R with lower alkyl or phenyl which may be substituted . 13 73679