DK143902B - ANALOGY PROCEDURE FOR PREPARING 8ALFA-ERGOLIN-L DERIVATIVES - Google Patents

Description

ho® I ΉΒΓ (19) DENMARK \ 25-

| J | (12) PUBLICATION MANUAL OR 143902B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 3151/75 (51) lnt.CI.3 C 07 D 457/02 (22) Filing date 10 Jul. 1975 (24) Race day 10 Jul. 1975 (41) Aim. available Jan. 20 1976 (44) Posted Oct 26 1981 (86) International application no.

(86) International Filing Day (85) Continuation Day - (62) Stand Application No. -

(30) Priority 19 Jul. 1974, 9983/74, CH 13-Aug. 1974, 11031/74, CH

(71) Applicant SANDOZ A.G., CH-4002 Basel, GH.

(72) Inventor Peter Stuetz, CH: Theodor Fehr, CH: Paul Stadier, CH.

(74) Plougmann & Vlngtoft's Patent Office.

(54) Analogous procedure for the> => position of 8alpha-ergoline-I-der = 1 levels.

The present invention relates to an analogous process for the preparation of novel 8α-ergoline-I derivatives of the general formula I, CH, -CN

y '^ NLjh nr1 ϊ Λ-Κ

Ό X

wherein X represents hydrogen, chlorine or bromine, and represents methyl or ethyl, in free form or in the form of acid addition salts thereof.

In particular, 2 143902 X represents hydrogen.

R 1 denotes in particular methyl.

The process of the present invention for the preparation of compounds of the general formula I or acid addition salts thereof is characterized in that a compound of the general formula II

HN ^

X

wherein Z represents halogen or an aliphatic or aromatic sulfonyloxy group, and X and R 1 of an acid addition salt.

The reaction of compounds of general formula II to prepare compounds of general formula I may be carried out analogously to known methods, e.g. as disclosed in Belgian Patent Specification No. 712,054.

As the halogen for Z, chlorine or bromine can be used, and as the sulfonyl-oxy group, mesyloxy or p-tosyloxy is preferably used. As a cyano group donor, e.g. an alkali metal cyanide such as sodium or potassium cyanide.

The reaction is preferably carried out in solution. Appropriately, an aprotic solvent such as dimethylformamide, hexamethylphosphoric triamide or acetonitrile is used in admixture with a small amount of water.

3 143902

The reaction is advantageously carried out by heating, e.g. to 50-100 ° C.

The compounds obtained according to the process of the present invention may be in free form as a base or in the form of acid addition salts thereof. Acid addition salts can be prepared from the free bases known per se and vice versa.

The starting compounds are known or can be prepared using methods known per se, e.g. as described in the Examples.

Compounds of general formula I in free form or in the form of physiologically tolerable acid addition salts are characterized by interesting pharmacodynamic properties. The compounds can be used as drugs.

The compounds of formula I have effect on the central dopaminergic receptors, as evidenced by the study method described by U. Ungerstedt in Acta physiol, scand., Suppl.

367, 69-93 (1971) by unilateral injection of 6-hydroxydopamine into substance nigra /, whereby after 1 week, a weekly lateral degeneration of the nigrostrous pathways is obtained. This unilateral lesion causes hypersensitivity to the striated dopaminergic receptors, which, following administration of a stimulant, leads to contralateral scrolls in rats. By intraperitoneal administration of the compound of formula I at doses of between ca. 0.5 and 40 mg / kg, in this experiment, a clear stimulation of the central dopaminergic receptors is obtained. Table I gives the results obtained with some compounds of the general formula I: 4 143 9Ό 2

Table I

Test substance Managed Dose stimulation in mg / kg of the dopaminergic (intraperitoneal) receptors 6-methyl-8 α-cyanomethyl-ergoline I 0.5 +++ 6-ethyl1-8 α-cyanomethyl-ergoline I 1 ++++++ : pronounced effect + +: significant effect.

An effect of the compounds of formula I on central dopaminergic receptors has also been shown in studies of rat behavior; Stimulation of the dopaminergic receptors in the rat induces symptoms of stereotypy such as snuff, licking and wall and floor attacks. The animals are placed in observation cylinders and, after acclimatization, the test substance is administered by intraperitoneal administration. The behavior of the rat is observed for a period of 7 hours as follows: Observations of 2 minutes at 30-minute intervals for the first 2 hours and then at 60-minute intervals for the following five hours. The degree of stereotype is examined by the method described by Costall, Naylor and Olley (Euro.J.Pharmac. 18, 83-94 (1972).) Intraperitoneal administration of the compounds of formula I at doses of between 1 and 40 mg / kg gives a clear stimulation of the central dopaminergic receptors in this experiment.

Thus, the compounds of this invention can be used to treat Morbus Parkinson's because of their dopaminergic properties.

A prescribed daily dose is between ca. 0.5 to 100 mg, especially between 1 and 50 mg, administered at once or in multiple unit doses.

5 143902

The compounds of this invention also have a prolactin secretion inhibitory effect. Prolactin secretion inhibitors may e.g. used for prophylaxis and therapy of physiological lactation and galactoré.

From Danish Patent Specification No. 124,080, Swedish Patent Specification No. 393,111 and the specification to Danish Patent Application No. 1066/74, certain (3-isomers of the compounds of general formula I having the same direction of action) are known. The 8a-cyanomethylergoline derivatives are greatly superior to the known 83 compounds, with the following results obtained with 6-methyl-8-cyanomethyl-ergoline I:

In the Ungerstedt trial, the number of contralateral twists in rats with unilaterally degenerate nigrostrial trajectories is 2607 for the 8a isomer and 1279 for the 80 isomer. The 8a isomer, with an IDsQ value of 0.020 mg / kg, is also subcutaneously in the prolactin secretion inhibition trial of Fliickiger et al. (Postgraduate Medical Journal 52y 57 Suppl. A. 1976) 8 (3-isomer with an ID ^ Q value of 0.060 mg / kg subcutaneously superior.

It is possible to prepare drugs which contain a compound of general formula I in free form or in the form of a physiologically tolerable acid addition salt thereof. Such drugs, e.g. a solution or tablet may be prepared in a manner known per se using conventional adjuvants and carriers.

The process according to the invention is illustrated in more detail by the following examples.

Compounds of general formula I are referred to herein as 8α-ergoline-I compounds or as (5R, 8R, 10R) -8-cyanomethylergoline-I compounds.

6 H3902

Example 1, 6-Methyl 1-8α-cyanomethylergoline-I.

Dissolve 3.35 g (10 mmol) of 6-methyl-8a-mesyloxymethylergoline-I in 20 ml of dimethylformamide and add a solution of 3.25 g (50 mmol) of potassium cyanide in 4 ml of water. After 48 hours at 80 ° C, the mixture is poured into excess 2N sodium carbonate solution and the precipitate, which, after drying in air, is chromatographed on 150 g of alumina with activity steps II - III. The title compound is eluted with 0.2% methanol in methylene chloride and crystallized by methanol. Melting point 160 - 162 ° C, [ct] D = -96 ° (c = 0.3, dimethylformamide).

The 6-methyl-8a-mesyloxymethylergoline-starting material used as starting material is obtained as follows: a) During heating, 100 g of Δ7'-lysic acid methyl ester is dissolved in 900 ml of dimethylformamide, diluted with 1.5 liters of glacial acetic acid and hydrogenated after addition of 10 g of platinum oxide at a temperature of 40 - 50PC at normal pressure until hydrogen is no longer absorbed. The catalyst is filtered off and the filtrate is further hydrogenated after the addition of 5 g of platinum oxide under the above conditions. For working up, filter and evaporate the filtrate to dryness. The resulting resin is dissolved in 1.5 liters of methylene chloride containing 5% methyl alcohol, stirred thoroughly with 20 g of activated carbon, filtered, slowly covered with 1 liter of 2N sodium carbonate solution and shaken gently. The aqueous phase is extracted twice with 500 ml of methylene chloride. After drying the organic phase over sodium sulfate and evaporation to a volume of ca. Dilute 1/5 of the original volume with approx. 500 ml ether and scratch. After standing for 2 hours at 0 ° C, 9,10-dihydroisolysergic acid methyl ester crystallizes. In working up the evaporation residue in a known manner, an additional 9,10-dihydroisolysergic acid methyl ester-I is obtained. The ester, after recrystallization of methylene chloride / ethyl acetate or ethanol, has a melting point of 178-180 ° C, [α] p ^ = -82 ° (c = 1, pyridine).

(b) Under nitrogen, 38 g of lithium aluminium hydride is suspended in 2.5 liters of absolute tetrahydrofuran which is cooled to 0 ° C and, during 7 143902, for 15 minutes, a solution of 200 g of 9,10-dihydroisolic acid methyl ester I is added dropwise to 2 5 liters of absolute tetrahydrofuran. The reaction product is then diluted with 2.5 liters of absolute tetrahydrofuran and stirred for an additional 30 minutes.

For work-up, gently drop 100 ml of ethyl acetate, 100 ml of methanol and 50 ml of water in the order indicated. Then, dilute with 2 liters of 30% methanol in methylene chloride and filter. The residue is then further boiled 4 times with 1 liter of 30% methanol in methylene chloride each time. From the combined filtrates is obtained after evaporation and crystallization of methanol 9,10-dihydroisolysergol-I, mp 189 - 193 ° C. 9,10-dihydroisolysergol-I can be further isolated from the mother liquor by chromatography.

c) 100 g of 9,10-dihydroisolysergol-I is suspended in 500 ml of absolute pyridine and 1.1 liters of absolute acetonitrile, and at 0 ° C is added dropwise with stirring a solution of 80 ml of methanesulfochloride in 200 ml of absolute acetonitrile. After removing the cooling bath, stir for an additional hour at room temperature to give a yellowish precipitate. For working up, cool to 0 ° C and add 2N ammonia solution until alkaline reaction. After scratching, 6-methyl-8α-methanesulfonyloxymethylergoline-I crystallizes with mp 139-141 ° C [α] D = -54.6 ° (c = 1, dimethylformamide).

Proceeding in an analogous manner as above using similar compounds of general formula II wherein Z represents mesyloxy, the following compounds of general formula Ia are obtained:

Example No. X R 2 Melting point in "C

2 Cl CH 2 hydrochloride 267 - 268 3 H C 2 H 5 182 (base).