GB2125041A

GB2125041A - Ergot alkaloids

Info

Publication number: GB2125041A
Application number: GB08321222A
Authority: GB
Inventors: Peter Gull
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1982-08-09
Filing date: 1983-08-05
Publication date: 1984-02-29
Also published as: DE3327705A1; DK361983D0; HU187600B; FI832789A; JPS5948480A; GB2125041B; GB8321222D0; FI832789A0; ATA286383A; IT8322490A0; ES524815A0; IL69450A; FR2531433B1; AU1767283A; AT383125B; PT77168B; CA1215972A; AU563736B2; SE8304315D0; BE897473A

Abstract

2-methyl-lysergyl ethers and thioethers are useful neuroleptics, anti-migraine agents, cerebral insufficiency agents, agents for senile dementia and anti-depressants. Preferably compounds of formula <IMAGE> where X is O or S, R1 is H, C1-4 alkyl or phenyl, R2 is C1-3 alkyl and R3 is phenyl or pyridyl, which may be substituted, or alkyl are used.

Description

SPECIFICATION Ergot alkaloids This invention relates to ergot alkaloids.

The present invention provides 2-methyl-lyserg-8-yl ethers and thioethers and acid addition salts hereinafter referred to as compounds of the invention.

The compounds of the invention are substituted in the 2 and 8 positions of the ergoline nucleus and may be substituted in any other position. The compounds may be exist in isomeric form, e.g. as 8R and 8S isomers.

The invention particularly provides compounds of formula I

wherein X is --OO- or --SS-, R1 is hydrogen, (C,~4) alkyl or phenyl, R2 is (C1~3) alkyl and R3 is phenyl or pyridyl, unsubstituted or monosubstituted or independently di- or tri- substituted by halogen of atomic number from 9 to 35 (cm~4) alkyl or (cm~4) alkoxy or (C14alkyl and acid addition salts thereof.

A compound of the invention may be produced by a process which includes the step of replacing the group Y in a corresponding 8-CH2-Y derivative wherein Y is a leaving group with an ether or a thioether radical and recovering the compound as such or as an acid addition salt thereof.

In particular a compound of formula I or an acid addition salt may be produced by a process which includes the step of replacing the group Yin a compound of formula II

wherein R1 and R2 are as defined above, and Y is a leaving group, by a group of formula Ill -XR3 Ill wherein R3 and X are as defined above and recovering the compound of formula I as such or as an acid addition salt thereof.

The above process may be effected in conventional manner. Y may be for example halogen, e.g.

chlorine or bromine, or a group of formula -0-S02-R wherein R is lower alkyl or optionally substituted phenyl, containing e.g. up to 10 carbon atoms. Preferably Y is mesyloxy or tosyloxy.

Conveniently the reaction is effected in a solvent, e.g. an inert aprotic polar solvent such as an organic carboxylic acid amide such as dimethyl formamide or hexamethylphosphoric tri-amide or acetonitrile. If desired water, preferably in small quantities, may be present.

Suitable reaction temperatures may be elevated temperatures, e.g. from about 50 to about 1000C.

Conveniently the reaction is effected in an inert gas atmosphere, e.g. under nitrogen.

Preferably the radical of formula Ill is introduced by using a compound of formula IV MXR3 IV wherein X and R3 are as defined above and M is hydrogen or preferably an alkali metal.

Conveniently an excess of a compound of formula III is used. For example from 2 to 10 Mol compound of formula III per mole of compound of formula II may be used.

The side chain in the 8 position in the compound of formula I may have the a or,3 configuration.

Any alkyl or alkoxy radical has preferably 2 carbon atoms and especially 1 carbon atom. Halogen is preferably chlorine or bromine. X is preferably S.

R, is preferably hydrogen. R3 is conveniently unsubstituted pyridyl, preferably 2-pyridyl.

In one group of compounds X is -S-, R, is hydrogen and R3 is 2-pyridyl.

The compounds of the invention may be isolated and purified in conventional manner.

The compounds of the invention may be converted into acid addition salts in conventional manner and vice versa. A suitable acid for salt formation includes hydrochloric acid.

The starting materials may be produced in conventional manner. For example compounds of formula II may be produced by reducing a compound of formula V

Compounds of formula V may be produced by reaction of a compound of formula VI

with 1,3-dithiane as described in the examples.

Compounds of formula II may alternatively be produced from the known lysergic acid or 6homologue thereof, reducing it to the alcohol and then replacing the hydroxyl group by the radical Y.

Insofar the preparation of any particular starting material is not particularly described this is known or may be produced in conventional manner.

In the following Examples all temperatures are in degrees Centigrade and are uncorrected.

Optical rotations are at 200 and at the D line with the substance in ethanol/water 1:1 unless otherwise stated.

Abbreviations: 1=optical rotation in pyridine 2=Decomposition 3=Hydrochloride Nomenclature: lysergyl=9,1 O-didehydro-6-methylergolin-8P-yl-methyl Example 1 9,1 O-didehydro-2,6-dimeThyl-8p-(2-pyridylthiomethyl)ergoline a) 2-(1 ,3-dithian-2-yl)-lysergyl mesylate 2.9 ml sulfuryl chloride in 1 5 ml chloroform are added dropwise to a solution of 4.2 g 1,3dithiane in 100 ml chloroform at --300 within 30 minutes. After the temperature has risen to 200, the mixture is stirred for 30 minutes at 200. 7.5 g lysergyl mesylate in 100 ml chloroform are added at 100. After the temperature has risen to 200, the mixture is stirred for a further 30 minutes at 200.To work up the mixture is treated with ice/water, neutralised with 2N sodium carbonate and extracted with methylene chloride containing 109/0 isopropanol. The extracts are dried with sodium sulphate, filtered and concentrated. The resultant product is chromatographed on silicagel using methylene chloride containing 2% methanol as eluant to give the heading compound.

b) 2-methyl-lysergyl mesylate 100 ml of a suspension of Raney-Nickel in water is washed four times each with 100 ml dimethylformamide/acetone 1:4. The washed Raney-Nickel is treated under argon with 11 5 ml dimethylformamide/acetone (1:4), and the stirred suspension is treated at room temperature with a solution of 4.3 g 2-(1,3-di-thian-2-yl)lysergyl mesylate in 80 ml dimethylformamide/acetone (1 :4). The mixture is stirred for 2 1/2 hours at room temperature, filtered and the filter residue washed twice each time with 11 5 ml dimethylformamide/acetone (1:2). The filtrate is concentrated and dried up in a high vacuum to give the crude product which is chromatographed on 90 g silicagel with methylene chloride containing 2% methanol as eluant to give the heading compound as a beige foam.

c) 9,1 0-didehydrn-2,6-dimethyl-8-(2-pyridylthiomethyl)-ergoline A solution of 1.3 g 2-methyl-lysergyl mesylate and 2-mercaptopyridine in 20 ml dimethylformamide is treated with 4.5 ml 2N sodium hydroxide and stirred at room temperature. The mixture is stirred with water and extracted with methylene chloride containing 10% isopropanol. The extracts are dried with sodium sulphate, filtered, concentrated and dried in a high vacuum. The crude product is chromatographed on 120 g silicagel with chloroform containing 2% methanol and 0.1% concentrated ammonia to give the heading compound. M.pt. decomp. from 2530, [a]=+580 (c=0.37).

The foilowing compounds of formula I having an 8p side chain are produced in analogous manner: [a] Example R1 R2 R3 X M.pt. (c) 2102 +450 (0.435) 2 H C2H5 2-pyridyl S 2102 +450(0.435) 3 CH3 C2H 2-pyridyl S 18523 +280(0.33) 4 Phenyl CH3 2-pyridyl S 191223 +2940 (0.85) 5 H CH3 p-methylphenyl S 20682 +220 (0.54)1 6 H CH3 phenyl S 178-802 +330(0.76)1 7 H CH3 p-methylphenyl 0 173~52 +390(0.65)1 8 H CH3 CH3 S 28893 +920 (0.5) 9 H nC3H7 CH3 S 252-323 10 Methyl Methyl 2-pyridyl S 188~923 +490 (0.59) The compounds of the invention are pharmacologically active and are therefore indicated for use as pharmaceuticals.

The compounds of the invention exhibit antagonistic effects on dopamine receptors as indicated in standard animal tests, e.g. using the rat brain. Thus, the compounds lead on administration p.o. of about 10 mg/kg to an increase of concentration of the dopamine metabolites, 3,4-dihydroxyphenyl- acetic acid (DOPAC) and homovallinic acid (HVA) in the striatum.

The biochemical parameters may be measured according to the principles of F. Karoum et al., Europ. J. Pharmacol. 44, 311-318, (1977) and H. R. Biirki et al., Psychopharmacology 57, 227-237 (1978).

At the same doses the activity of tyrosine hydroxylase in vivo is increased according to the method of A. Carlson et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 1 63-1 68.

The compounds furthermore antagonise in vitro at about 8.10-9 mole/L the apomorphine effect on electrically-stimulated acetylcholine release in striatum slices of the rat in accordance with the method of R. Markstein, J. Neural. Transmission 51,39-59(1981).

The compounds are therefore indicated for use as neuroleptics, especially for the treatment of schizophrenia.

The compounds of the invention also exhibit serotonin agonist activity as indicated in standard animal tests.

For example, the compounds also increase at from about 3.10-9 mole/L the electrically induced acetyl choline release in the Hippocampus in the rat.

This is confirmed in the observation test over 6 hours on administration i.p. at from about 30 to about 50 mg/kg in rats or p.o. at from about 3 to about 10 mg/kg body weight in mice wherein the compounds induce a prolongation of the wake phase and an increased reaction to external stimuli, in accordance with the principles described in J. M. Vigouret et al., Pharmacology, 16, (Suppl. 1), 1, 156-173(1978).

The compounds are therefore indicated for use in dementia, especially senile dementia.

The compounds of the invention also exhibit anti-depressant activity as indicated in standard animal tests. For example in the 48 hour chronically implanted rat test effected according to H.

Kleinlogel et al., Waking and Sleeping, 1 980,4, 77-85, the compounds in p.o. administration of from about 3 to about 30 mg/kg, lead to a reduction of the paradoxical sleep phase without a significant rebound.

The compounds are therefore additionally indicated for use as anti-depressants, especially for geriatrics.

The compounds also have a vasoconstricting activity as indicated by a noradrenaline potentiation in the method of E. Müller-Schweinitzer, Naunyn-Schmiedeberg's Arch. Pharmacol., 292, 113-118 (1976) in vitro on isolated strips of canine Arteria carotis externa at doses of from about 10-10 to 10-8 M/litre.

The compounds are therefore of use as anti-migraine agents and for the treatment of tension headache.

Moreover, the compounds increase the local cerebral glucose utilisation in the sensomotor cortex, e.g. lateral Nucleus habenula, as indicated by the carbon-14-2-deoxyglucose autoradiographic technique with the rat brain on administration i.v. of from about 0.01 to about 0.1 mg/kg or p.o. 10 mg/kg of the compounds [for method see e.g. L. Solokoff, Journal of Cerebral Blood Flow and Metabolism,1981, (1), 7-36; H. E. Savaki et al., Brain Research 1982, 233, 347-358, and J.

McCulloch petal., Journal of Cerebral Blood Flow and Metabolism 1981,1,133-136.

The compounds of the invention are thus additionally indicated for use in the treatment of cerebral insufficiency.

For all the above indications an indicated daily dose is from about 1 to about 100 mg conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing about 0.3 to about 50 mg, or in sustained release form.

The present invention provides also a compound of the invention in pharmaceutically acceptable form for use as an antidepressant, neuroleptic, for the treatment of dementia, cerebral insufficiency or migraine.

The preferred indication is senile dementia. The preferred compound is the compound of Example 1.

The compounds of the invention may be administered as such or as the pharmaceutically acceptable acid addition salt thereof. Such acid addition salts exhibit the same order of activity as the free bases. The present invention provides accordingly a pharmaceutical composition which comprises a compound of the invention in a pharmaceutically acceptable form in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be for example tablets or solutions.

Claims

1. A process for the production of a 2-methyl-lyserg-8-yl ether or thioether or an acid addition salt thereof which includes the step of replacing the group Y in a corresponding 8-CH2Y derivative wherein Y is a leaving group with an ether or a thioether radical and recovering the compound as such or as an acid addition salt thereof.

2. A process for the preparation of a compound of formula I

wherein X is --OO- or -S- R, is hydrogen, (C1~4)alkyl or phenyl R2 is (C1~3)alkyl and R3 is phenyl or pyridyl, unsubstituted monosubstituted or independently di- or tri- substituted by halogen of atomic number from 9 to 35, (C14)alkyI or (C14)alkoxy, or (C1~4)alkyl or an acid addition salt thereof, which includes the step of replacing the group Y in a compound of formula II

3. A process for the preparation of a 2-methyl-lyserg-8-yl ether or thioether or an acid addition salt thereof substantially as hereinbefore described with reference to any one of the Examples.

4. A 2-methyl-lyserg-8-yl ether or thioether or an acid addition salt thereof.

5. A compound of formula I as defined in claim 2 or an acid addition salt thereof.

6. A compound of claim 5 wherein X is sulphur or an acid addition salt thereof

7. A compound of claim 6 wherein R1 is hydrogen, and R3 is 2-pyridyl or an acid addition salt thereof.

8. A compound of claim 5 wherein R3 is phenyl, unsubstituted ar substituted by (C,~4)alkyl, pyridyl or (C1~4)alkyl and the 8 side chain has the beta configuration or an acid addition salt thereof.

9. 9,1 0-didehydro-2,6-dimethyl-8p-(2-pyridylthiomethyl)ergoline or an acid addition salt thereof.

10. A compound of claim 8 wherein R1, R2, R3 and X are respectively H, C2Hs, 2-pyridyl, S, or an acid addition salt thereof.

11. A compound of claim 8 wherein R1, R2, R3 and X are respectively CH3, C2Hs, 2-pyridyl, S, or an acid addition salt thereof.

12. A compound of claim 8 wherein Rt, R2, R3 and X are respectively phenyl, CH3, 2-pyridyl, S, or an acid addition salt thereof.

13. A compound of claim 8 wherein RX, R2, R3 and X are respectively H, CH3, p-methylphenyl, S, or an acid addition salt thereof.

14. A compound of claim 8 wherein Ra, R2, R3 and X are respectively H, CH3, phenyl, S, or an acid addition salt thereof.

1 5. A compound of claim 8 wherein R1, R2, R3 and X are respectively H, CH3, p-methylphenyl, 0, or an acid addition salt thereof.

16. A compound of claim 8 wherein R1, R2, Ra and X are respectively H, CH3, CH3, S, or an acid addition salt thereof.

1 7. A compound of claim 8 wherein R1, R2, R3 and X are respectively H, nC3H7, CH, S, or an acid addition salt thereof.

1 8. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use as a pharmaceutical.

19. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use as a neuroleptic.

20. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use in the treatment of cerebral insufficiency.

21. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use against migraine.

22. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use as a vasoconstricting agent.

23. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use against dementia.

24. A pharmaceutical composition comprising a compound of any one of claims 4 to 1 7 or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or diluent.

25. A compound of formula II as defined in claim 2.