FI60865B - FOERFARANDE FOER FRAMSTAELLNING AV 6-METHYL-8-TIOMETYLERGOLENER OCH -ERGOLINER MED CENTRALT DOPAMINERGISKT STIMULERANDE ACTIVITIES OCH MOTVERKAN MOT KATALEPSI FOERORSAKAD MEDELST RESERPIN - Google Patents

Abstract

1497681 6 - Methyl - 8 - mercaptomethylergolenes and ergolines SANDOZ Ltd 10 March 1975 [14 March 1974 23 July 1974] 9807/75 Heading C2 [Also in Division A5] Novel compounds of the Formula I wherein # is the group -CH = CH or and R is hydrogen; cyano; a 5- or 6-membered unsaturated heterocyclic radical attached through a ring carbon atom and having 1 to 3 heteroatoms, the first hetero atom being introgen, oxygen-or sulphur-and the second and third heteroatoms, if present, being nitrogen; or a 2- or 4-pyridyl monosubstituted by C 1-4 alkyl or alkoxy or chlorine, fluorine or bromine, with the proviso that when # is -CH=C< and the side chain in the 8 position has the #- configuration then R is other than 2-pyridyl, and acid addition salts thereof, may be prepared by reacting a compound of Formula II wherein X is a radical capable of being displaced by a thio group with a compound of the formula M5R wherein M is hydrogen or alkali metal or by reducing the -SCN group in a compound of the Formula I in which R is CN to -5N. 6 - Methyl - 8&alpha; - methanesulphonyloxymethyl ergoline-I is prepared by acrylation of 9,10- dihydro-isolysergol I with methane sulphonyl chloride. The compound I excluded by the proviso is the subject of Divisional Specification 1,497,682.

Description

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Patent and registration authorities Anaekan uttajd oc ittl.akriftan publkarad 31.12.8l (32) (33) (31) Pyydetty «TuoikMS —B« glrd prloritet lU. 03.7 ^ 23-07.7 ** Swiss-Swiss (CH) 3563/7 **, 10138/7 ** (71) Sandoz AG, Basel, Swiss-Swiss (CH) (72) Peter Stiitz, Reinach, Paul Stadler, Biel -Benken,

Sve it si -Sc hwei z (CH) (7 * 0 Oy Kolster Ab (5 **) Method for the preparation of 6-methyl-8-thiomethylergolenes and ergolines having a central dopaminergic stimulating activity and a counteraction against reserpine-induced catalepsy - Förfarande för framställning av 6-methyl- 8-biometylergolener och -ergolininer med centralt dopaminergiskt stimulerande activity och motverkan mot katalepsi förorsakad medelst reserpin

The present invention relates to a process for the preparation of 6-methyl-8-thiomethylergolenes and ergolines having dopaminergic stimulating activity and counteractivity against reserpine-induced catalepsy and having the formula

CH0-S-R

Λ ^^^ y \ ^ N_CH3 1 llf N- /

B

2 60865 where x = - = - = y represents the group -CH = C ^. or -CH 2 -CHC. and R is a hydrogen atom or a cyano, pyridyl or thiazolyl group, and for the preparation of their acid addition salts.

When the substituent R is pyridyl, it is especially 2-pyridyl or 1 + pyridyl.

PI Patent Publication No. 1,080,080 discloses compounds with a structure closely related to the invention which inhibit luteotropic pituitary hormone and prolactin and stimulate the secretion of follicle hormone and luteinizing hormone. DK patent publication 12k 51 * 1 + describes an ergoline derivative having an adrenolytic and hypotonic effect. Anti-stress ergoline derivatives are known from CH 2 Patent Publication No. 51 * 5,792. The compounds according to the invention differ from these known compounds both in their structure and in their different pharmacodynamic effects.

The invention is characterized in that a) a compound of formula

CH "-X

rS

vKl3 11

(XX

) LT

B

wherein x = r = y has the same meaning as above and X is halogen or -O-SC 2 -R 4 - having an alkyl group having 1 to 1 carbon atoms or an unsubstituted or substituted phenyl group is reacted with a compound of formula

MS-R III

wherein R is as defined above and M is hydrogen or an early metal, or b) for the preparation of compounds of formula I wherein R is a hydrogen atom, a compound of formula I wherein R is a cyano group is reduced and the compound of formula I thus obtained is recovered as free as a base or an acid addition salt.

The reaction of the compounds of the formula II with the compounds of the formula III can take place in a similar manner as in the preparation of the corresponding compounds by known methods.

3 60865 The residue X is halogen, for example chlorine or bromine. Preferably, the corresponding mesylate or tosylate is used as the compound of formula II.

In general, M in the compounds of formula III is preferably an alkali metal, especially if R is not basic.

The reaction is conveniently carried out in a solvent. Particularly suitable are aprotic, polar solvents which are inert under the reaction conditions, for example amides of organic carboxylic acids, such as dimethylformamide or also hexamethylphosphoric acid triamide or acetonitrile, optionally in admixture with a small amount of water.

Preferably, work is carried out at an elevated temperature, for example at about 50-100 °.

The reaction is conveniently carried out in the absence of oxygen, for example under a nitrogen atmosphere.

Preferably, an excess of a compound of formula III is used, for example about 2-10 moles of a compound of formula III per 1 mole of a compound of formula II.

The reduction according to embodiment b) can take place analogously to the known reduction of rhodanide compounds to mercapto compounds (cf. Methoden der Organischen Chemie, Band IX, Seiten 16, 17; * + · Auflage (1955)). However, it is preferably carried out with lithium aluminum hydride. In particular, an ether such as tetrahydrofuran is used as the solvent.

The reduction with lithium aluminum hydride can be performed at room temperature.

The further processing of the reaction mixtures obtained according to the above process 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 formula I may be in free form or as acid addition salts. Acid addition salts can be prepared from the free bases in a known manner and vice versa.

The starting materials of the formula II in which X = chlorine, O-mesyl or O-tosyl residue are known.

The preparation of the starting material of Example 1 below, 6-methyl-8H-methanesulphonyloxymethylergolene, is described in DE-A-2,223,681.

Compounds of formula II in which X = bromine can be obtained, for example, by reacting a compound of formula 11 60865

CH OH

Λ I! 1

CH3 IV

C/O

B

where x s ^ r = y is as defined above, to react with phosphorus oxybromide.

If the preparation of the starting compounds is not described, these are known or can be prepared according to methods known per se or correspondingly as described herein or correspondingly as known methods per se.

The compounds of formula I, i.e. the compounds of the formula I in free form or in addition salts with physiologically acceptable acids have interesting pharmacodynamic properties in animal experiments. They can be used as drugs.

The compounds of formula I in which x: - = - = y is -CH * Ct ^ have very interesting central dopaminergic resorptor stimulating properties.

R is preferably a 2-pyridyl or cyano group.

The compounds of formula I may be administered in the form of pharmaceutical preparations. For example, the pharmaceutical preparations can be used as tablets, powders, granules, capsules, syrups, elixirs for oral administration, as well as solutions, dispersions and emulsions for parenteral administration.

The preparation of these pharmaceutical preparations can take place in a manner known per se using customary excipients.

A particular formulation thereof is a medicament comprising a compound of formula I and a phosphodiesterase inhibitor. To prepare the latter preparations, a compound of formula I and a phosphodiesterase inhibitor are mixed together. This mixture can then be converted into a dosage form suitable for therapeutic purposes according to methods known per se.

Pharmacological experiments

The compounds of formula I and their salts have not been previously described in the literature. Laboratory experiments on control animals have shown that they have interesting pharmacodynamic properties, in particular their stimulating effect on key dopaminergic receptors.

The effect of the compounds of the formula I on the essential dopaminergic receptors in rats was studied by the method of U. Ungerstedt, published in A, · 5 60865 in the journal Acta Physiol, Scand., Suppl. 367, 69-93 (1971). 6-Hydroxy-dopamine was unilaterally injected into the black groove, which after one week caused unilateral degeneration of the nigrostrial pathways. This lesion, in turn, caused hypersensitivity of the striatal dopaminergic receptors, which, after administration of the stimulant, manifested itself as behavior in which the animal rotated in the opposite direction of the lesion. When the compounds of formula I were administered to the experimental animals subcutaneously at about 0.3 to 3 mg / kg, or orally at about 5 to 10 mg / kg, the compounds were found to clearly stimulate key dopaminergic receptors. Upon oral administration of 6-methyl-8β- (2-pyridylthiomethyl) -β-ergoline and 6-methyl-8/5-thiocyano-β-ergoline at 10 mg / kg, a strong reversal of rotation was observed. Phosphodiesterase inhibitors potentiate the stimulatory effect of the compounds of formula I on key dopaminergic receptors. By phosphodiesterase inhibitors are meant compounds that inhibit the action of phosphodiesterase on the brain. Examples of such compounds are methylxanthine derivatives such as caffeine and theophylline; ethyl carboxylate, 1-ethyl-N-hydrazino-1H-pyrazolo [S, N-b] pyricline N-ethylcarboxylate and 1-ethyl-butylamino-ΙΗ-pyrrolo Solo [3,7-b] pyridine-5-ethylcarboxylate, - (3, 4-dimethoxybenzyl) -2-imidazolidinone and the like, such as U- (3-butoxy-H-methoxybenzyl) -2-imidazolidinone, weak tranquilizers, for example from the series 1,1 + - benzodiazepine such as 7 'chloro-2 -methylamino-5 "phenyl-3H-1,1'-benzodiazepine-U-oxide and 7" chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,1-benzodiazepin-2-one, tricyclic antidepressants such as 1 '- [3- (5H-dibenzo [b, f] azepin-5-yl) propyl-1-piperazineethanol; phenothiazines such as U- (3- [2- (trifluoromethyl) phenothiazin-10-yl) / propyl] -1-piperazineethanol and 2-chloro-10- (3 -dimethylaminopropyl) phenothiazine, 2,6-bis (diethanolamino) -N, 8-dipiperidinopyrimidino [5,6-d] pyrimidine and papaverine. An enhancement of the stimulatory effect of the compounds of formula I is observed when animals are treated with a phosphodiesterase inhibitor, for example by intraperitoneal administration of methylxanthine such as caffeine at a dose of about 5-25 mg / kg before oral administration of compounds of formula I at about 1-5 mg / kg. 6-Methyl-8β- (2-pyridyl-thiomethyl) -β-ergolene shows a 9% potentiation of the key dopaminergic receptor stimulating effect when administered intraperitoneally with 25 mg / kg caffeine 15 min before oral administration of 5 mg / kg of the formula I lost the active ingredient.

The compounds of formula I inhibit reserpine-induced catalepsy in mice. Administration of reserpine intraperitoneally at a dose of 5 mg / kg causes complete catalepsy in mice, manifested as staying in the set position. 17 hours after reserpine administration, the animals are administered 15,60865 test substances subcutaneously and the results are compared with those obtained with control animals. DE n is the dose that inhibits reserpine catalepsy in 50% of animals.

6-methyl-8β- (2-pyridylthiomethyl) -Δ -ergoline and 6-methyl-8β-thiocyano-o ...

for example, methyl Δ -ergoline has a DE5 Q of 0.55 mg / kg and 0.1 mg / kg, respectively, when administered subcutaneously. In general, the compounds of formula I at a subcutaneous dose of about 0.3-3 mg / kg clearly resist reserpine catalepsy.

Due to these properties, the compounds of the formula I can be used therapeutically for the treatment of Parkinson's disease, for the treatment of a disease state following cerebral ischemia, such as apolexia, or for the treatment of extra-pyramidal disorders due to neuroleptic therapy. The compounds are administered daily in a dose of about 1-100 mg in a single dose or in multiple unit doses. They may also be co-administered with a phosphodiesterase, wherein the daily dose of the compound of formula I is about 0.5 to 50 mg and the phosphodiesterase is about 25 to 500 mg, given as a single dose or in several unit doses. The ratio of the amount of compound of formula I to the amount of phosphodiesterase is generally between 1:10 and 1:50.

Acute toxicity:

The acute toxicity of the compounds of formula I was determined in mice. For example, 6-methyl-8H- (2-pyridylthiomethyl) -ergoline had a DLq of more than 100 mg / kg when administered orally.

The compounds of formula I can be administered both as the free base or as a salt having an activity of the same order of magnitude as the corresponding free base.

The compounds of the formula I and their pharmacologically acceptable salts can be used as medicaments, optionally in combination with a phosphodiesterase inhibitor, either as such or as a pharmaceutical composition suitable for oral, rectal or parenteral administration.

The following examples further illustrate the invention. Temperatures are given in degrees Celsius.

Example 1: 6-methyl-β / fr-rhodanomethylergolene

Heat 1.5 g (13.5 moles) of 6-methyl-8H-methanesulfonyloxymethylergolene with 1.5 g (about 1 + 6 moles) of potassium rhodanide in a mixture of 1 + 5 ml of hexamethylphosphoric acid trisamide and 3 ml of water, under a stream of nitrogen at 80 ° C for 20 hours. For work-up, the reaction mixture is poured into 1 + 50 ml of 0.5 N sodium hydroxide solution and filtered. The dry residue is dissolved in methylene chloride / ether while hot and treated with activated carbon. The filtrate is concentrated and the title compound is obtained by crystallization from ethanol as pink-colored prisms with m.p. is 186-188 ° C.

Hydrogen fumarate: methylene chloride / ethanol, m.p. + 182-181 °; [α] 25 D = + 55 ° (c = 0.5, dimethylformamide).

^ 60865

Example 2: 6 -methyl -8ft-mer kapt ome t y yl i e r go 1 e en i

Similarly, as in Example 1, 1.3 g (about 60 moles) of sodium bisulfide · H 2 O are used. After rapid work-up to avoid disulfide formation, the crystalline title compound is obtained from methylene chloride / isopropanol, with a decomposition point of about 200 °, λ max = + 86 °, (c = 0.5 dimethylformamide).

Example 3: 6-methyl-8- [3- (2-pyridyl-thiomethyl) -ergolene

Proceed as in Example 1 but starting from 6 g (5U mmol) of 2-nercaptopyridine. This gives the title compound as light gray crystals.

Sp. 200-201 ° (decomp.).

Tartrate: Sp. 195-196 °; = + 26 ° (c = 1, dimethyl sulfoxide).

Example 6 Methyl-8- (2-pyridylthiomethyl) ergoline

The procedure is as in Example 3, but starting from k, 3 g (13, * + mmol) of 6-methyl-8β-methanesulfonyloxymethylene ergoline. The title compound crystallizes from a mixture of methylene chloride and ethanol as the free base.

Sp. 191-195 °; = -113 ° (C = 1, pyridine).

Example 3 '6-Methyl-8 / 5- (U-pyridyl-thiomethyl) -ergolene

Heat b, 3 g (13.5 mmol) of 6-methyl-8H-methanesulfonyloxymethylene ergolene with 6 g (about k6 mmol) of U-mercaptopyridine in a mixture of b3 ml of hexamethylphosphoric acid trisamide and 3 ml of water under a nitrogen atmosphere at 80 °: for 20 h. For work-up, the reaction mixture is poured into 1 * 50 ml of 0.5N sodium carbonate solution and filtered. The dry residue is dissolved in a mixture of hot methylene chloride and ether and treated with activated carbon. The filtrate is concentrated and the title compound is obtained by crystallization from glacial acetic acid.

Sp. 191-19U0; CoO 2 = + 52.5 ° (c = 1, dimethyl sulfoxide).

Example 6: 6-Methyl-8H- (2-thiazolyl-thiomethyl) -ergolene

The procedure is as in Example 3, but 10 g of 2-mercaptothiazole are used as starting material. The title compound crystallizes from glacial acetic acid.

Sp. 192-195 ° (dec.); ~ + 58.2 ° (c = 1, dimethyl sulfoxide).

Example 7: 6-methyl-γS-rhodanomethyl-ergoline -1

Proceed as in Example 3 but react with h, 33 g of 6-methyl-8-methane-6-sulfonyloxymethylergoline-I and 1.5 g of potassium rhodanide. The title compound crystallizes from glacial acetic acid.

Sp. 189-193 °; ~ 58 ° (c = 1, dimethyl sulfoxide).

Example 8: 6-Methyl-8α-rhodanomethyl-ergoline-I

The procedure is as in Example 7, but starting from 6-methyl-8 ο (-methane-6-sulfonyloxymethylergoline-I). The title compound crystallizes from glacial acetic acid, mp 185-188 °.

The starting material 6-methyl-80f-methanesulfonyloxymethylergoline-I is prepared 8 60865 as follows:

To a stirred suspension of 2.56 g (10 mmol) of 9,10-dihydroisol: ·.-Ergol I (Helv. 32, 19 ^ * 7 (19 * + 9) in 15 ml of absolute pyridine) and in 25 ml of absolute acetonitrile, a solution of 1.95 ml (25 mmol) of methane sulfonyl chloride in 5 ml of absolute acetonitrile is added dropwise at + 10 ° and the mixture is further stirred for 1 hour at room temperature. cooled to 0 °, diluted with methanol until a clear solution is formed and partitioned between 2N-ammonia / methylene chloride after drying and evaporation of the combined organic phases crystallizes into 6-methyl-80f-methanesulfonyloxymethylergoline I ethanolista.

Sp. 139-1 ^ 1 ° ~ 51 *, 6 (c = 1, dimethylformamide).

Example 9: 6-methyl-8,3-mercaptomethylergolene (method b)

To a stirred suspension of 15.1 g (0.1 * mmol) of lithium aluminum hydride in 8 mL of absolute tetrahydrofuran under nitrogen is added portionwise at room temperature 11.8 g (U0 moles) of 6-methyl-8/1-rhodanoethyl-9 ergolene and stir for an additional 1 hour at this temperature. For further processing, decompose with gentle cooling with water and mix with 500 ml of a 5- to 5% aqueous tartaric acid solution. Finally, it is made alkaline with potassium carbonate solution and the aqueous phase is rapidly extracted with methylene chloride containing 10% methanol. After drying over sodium sulfate and distilling off the solvent, the title compound remains.

Decomposes at about 200 °, = (c = °> 5, dimethylformamide).

Claims (1)

Claim: A process for the preparation of 6-methyl-8-thiomethylergolenes and ergolines having dopaminergic stimulating activity and counteracting against reserpine-induced catalepsy and having the formula CH0-S-R Λ y N-CH. I CU Y- * H wherein x rrz y represents a group -CH = C 1 or -CH 2 -CH 2 and R is a hydrogen atom or a cyano, pyridyl or thiazolyl group, and for the preparation of their acid addition salts, characterized in that a) a compound the formula is CIL-X ifS N -CH_ 97 - wherein x --- y is as defined above and X is halogen or -O-SO 2 -R 2 wherein R 1 is an alkyl group containing 1 -U carbon atoms or an unsubstituted or substituted phenyl group , is reacted with a compound of formula MS-R III wherein R is as defined above and M is hydrogen or an early metal, or b) to prepare compounds of formula I wherein R is a hydrogen atom, reducing a compound of formula I wherein R is cyano group, and that the compound of formula I thus obtained is recovered as the free base or acid addition salt.