NO136643B - - Google Patents

Abstract

Analogy method in the production of new therapeutically active ergoline derivatives.

Description

The present invention relates to an anal™-*

in the preparation of nve 8fi « analogue method ig of new Sp-pyridinoaminomethyl-ioa-P,-™! • ^ • spirit level of general formula: ergolmderi-

where R denotes hydrogen or methyl, ;

R-^ and R 2 denote hydrogen, alkyl with 1-3 carbon atoms or phenyl, and where

R 1 denotes hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, phenyl, nitro, amino, acylamino, cyano or carboxamido.

The invention relates to the preparation of compounds of formula (I) by which method dihydrolysergamine or 1-methyldihydrolysergamine is used as starting materials and where the 8j3-guanidinomethyl derivative of 6-methyl- and 1,6-dimethyl-10a-ergoline is obtained as intermediate products, according to the following reaction scheme:

■4 ° i* f f. *y where R, R1, R2 and R3 have the meanings indicated above. J ^00 iO

The starting material used dihydrolysergamine or 1-methyldihydrolysergamine (II) is described in the literature (Gazz.Chim.

•Ita-l.ait, 196"+, P. 936).

6-methyl- or 1,6-dimethyl-8j3-guanidionomethyl-10a-ergoline (III) is obtained by reacting a compound of formula (II) with cyanamide, 1-guanidyl-3,5- dimethyl-pyrazole, S-alkylisothiourea, O-alkylisourea or a salt thereof.

The reaction is carried out in an organic solvent under heating, preferably to the solvent's boiling temperature.

When the reactant used is in the form of a salt, the resulting corresponding salt of 8j3-guanidinomethyl derivative is transferred to the free base by per se known treatment with alkali. The 8|3-guani-dinomethyl derivative (III) is then condensed with an 8j3-dicarbonyl compound of formula

R1-C0-CH(R3)-C0-R2,

where R-p and R^ have the meanings indicated above, in the presence of an organic solvent at a temperature from 10 to 150°C over a period of time from 1 hour to 6 days.

The obtained 8p-pyrimidinoaminomethyl derivative (I) is isolated and purified in a manner known per se by crystallization or chromatography.

The new compounds exhibit a prolonged adrenolytic activity as well as a low toxicity, and are therefore applicable in medical therapy.

The adrenolytic activity was investigated "in vitro" on isolated seminal vesicles from guinea pigs, which were suspended in physiological solution, in comparison with dihydroergotamine. Table I shows the concentration values obtained, which cause a 5% reduction in the spasmogenic effects induced by adrenaline. (I"C,-q)

The adrenolytic activity of the compound of the invention was determined "in vivo" in rats in comparison with dihydroergotamine. In Table II are listed the doses capable of reducing the lethal effect caused by adrenaline to $ 0% by oral (os) and intra-venous (i.v.) administration, compared to dihydroergotamine and nicergoline, i.e. 1,6-dimethyl-8β-.(5'-bromonicotinoyloxymethyl)-10α-methoxyergoline (Br. J. Pharmac. 3^,700, 1968), in mg/kg■(Id^q).

Some of the compounds listed in Table II also had a long-acting effect of up to 2 hours, as listed in Table III.

It is also known that nicérgoline is rapidly converted in the presence

of blood "in vi tro'" (Arcamon et al., Bioch. Pharmac. '21, 2205, 1972), while the compound according to the invention remains practically unchanged under the same conditions. This greater stability was also confirmed by determining the submaximal inhibitory dose that protected 80% of the tested animals (rats) against a single dose of adrenaline (200 mg/kg body weight), injected 8 hours after administration of the test preparations . The results are listed in table IV..

The mean LD^0 t-5-1 of the tested compounds was in rats

greater than >300 mg/kg body weight.

The following examples illustrate the invention further, without limiting it.

Example 1

1,6-dimethyl-8p-[5~nitro-2-pyrimidinoaminomethyl]-10a-ergoline A solution of 5 g of l-methyldihydrolysergamine and h g of 1-guanyl-3,5-dimethylpyrazole nitrate in 200 ml of ethanol was boiled for 7 hours under throwback dress. The mixture was concentrated until crystallization, whereby h g 1,6-dimethyl-8p-guanidinomethyl-10a-ergoline nitrate with melting point 21+2-2Lt-Lt-°C was obtained. To a solution of 3 g of the product thus obtained in 120 ml of methanol, <>>+.8 g of the sodium salt of nitromalondialdehyde (Organic Synthésis 2_7_, 60) and 0.1 ml of piperidine were added.

The mixture was stirred for 8 hours, after which the precipitate formed was collected. Yield: 2.5 g of 1,6-dimethvl7^K5-nitro-2-pyrimidineb-

aminomethyl]-10a-ergoline with melting point 20<1>+-206°C.

Example 2

1,6-dimethyl-8B-[^,6-dimethyl-2-pyrimidinoaminomethyl]-

10cc ergoline

A solution of h g of 1-methyldihydrolysergamine in 1 J0 ml of ethanol was heated under reflux for h hours with 2 equivalents of cyanamide. The mixture was neutralized with nitric acid and concentrated until crystallization started. 2 g of 1,6-dimethyl-8B-guanidinomethyl-1,0a-ergoline nitrate with melting point 2<!>+2-2<1>+<1>+°C were separated. , t

By adding an equivalent of sodium methylate to 1,6-dimethyl-88-guanidinomethyl-10a-ergoline nitrate, the corresponding free base was obtained.

0.9 g of 1,6-dimethyl-8B-guanidinomethyl-1.0a-ergoline base. was lost in

20 ml of acetylacetone and the solution was heated at reflux for 3 hours.

The remaining product was evaporated and chromatographed over clay. 0.6 g of 1,6-dimethyl-8B-[<1>+,6-dimethyl-2-pyrimidinoaminomethyl]-10a-ergoline with a melting point of 129-131°C was obtained.

Example

1,6-dimethyl-8B-[<1>+-methyl-6-phenyl-2-pyrimidinoamino-methyl]-10a-ergoline 1 g of 1,6-dimethyl-8B-guanidinomethyl-10a-ergoline base and 5 g of benzoylacetone were heated for 65 hours at 80°C. The mixture was concentrated in vacuo and the remaining product was chromatographed over clay. 0.5 g of 1,6-dimethyl-8B-[<1>+-methyl-6-phenyl-2-pyrimidinoamino-methyl]-10a-ergoline with melting point 192-19<!>+°C was obtained.

Example h

1,6-dimethyl-8B-[5-chloro-2-pyrimidinoaminomethyl]-

10a-ergoline

2 g of 1,6-dimethyl-8B-guanidinomethyl-10a-ergoline base and 2 equivalents of chloromalondialdehyde (J.Chem.Soc. 19^ 9. P.1550) were heated in butanol for h hours at 110°C. The mixture was concentrated in vacuo and the remaining product was chromatographed over clay. 1.2 g of 1,6-dimethyl-8B-[5-chloro-2-pyrimidinoaminomethyl]-10a-ergoline with melting point 190-192°C was obtained.

Example 5

1,6-dimethyl-8β-[5-nitro-2-pyrimidinoaminomethyl]-10α-ergoline

1 equivalent of 1-methyldihydrolysergamine was reacted with 1 equivalent of S-ethylisothiourea hydrochloride in Q0%-1g ethanol at 50°C over the course of 3 hours. The thus obtained 1,6-dimethyl-83-guanidinomethyl-10a-ergoline hydrochloride was condensed with the sodium salt of nitromalondialdehyde (1:1) in the same way as described in example 1.

Example 6 1,6-dimethyl-83-[5-nitro-2-pyrimidinoaminomethyl-10a-ergoline

In a similar manner to that described in example 5, 1,6-dimethyl-83-guanidinomethyl-10a-ergoline hydrochloride was prepared, although O-ethylisourea hydrochloride was used instead of S-ethylisothiourea.

Example 7 1,6-dimethyl-83-[5-amino~2-pyrimidinoaminomethyl]-10a-ergoline

In a similar manner as described in example 1, 1,6-dimethyl-8|3-[5-amino-2-pyrimidinoaminomethyl]-10a-ergoline was prepared; melting point 17 6 - 178°C.

Example 8 6-methyl-80-[5-nitro-2-pyrimidinoaminomethyl]-10a-ergoline

A solution of dihydrolysergamine and l-guanyl-3,5-dimethylpyrazole nitrate in ethanol was heated for 7 hours under reflux. From the reaction mixture, 6-niethyl-83-guanidinanethyl-10a-ergoline nitrate with a melting point of 235 - 237°C was obtained by crystallization. The product thus obtained was, as described in example 1, reacted with nitromalondialdehyde, whereby 6-methyl-83-[5-nitrcr2-pyrimidiiKDaminomethyl]-10a-ergoline was obtained.

By proceeding as described in Example 1, the following compounds were prepared:

Claims (1)

Analogous process for the preparation of new therapeutically active 83-pyrimidinoaminometh<y>l-lOct-ergoline derivatives of general formula where R denotes hydrogen or methyl, R^ and R 2 denote hydrogen, alkyl with 1-3 carbon atoms or phenyl, and. where R^ denotes hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, phenyl, nitro, amino, acylamino, cyano or carboxamido, characterized in that dihydrolysergamine or 1-methyldihydrolysergamine is reacted with cyanamide, l-guanidyl-3,5-dimethyl- pyrazole, S-alkylisothiourea, O-alkylisourea or a derivative thereof, £>g. that the thus obtained 6-methyl- or 1,6-dimeth<y>l -8B-guanidinomethyl-10a-ergoline is reacted with a B-dicarbonyl compound of general formula R1-C0-CH(R3)-C0-R2, where R1? R 2 and R 3 have the meanings given above, at a temperature of from 10 to 150° C in the course of from 1 hour to 6 days, after which the corresponding 6-methyl- or 1,6-dimethyl-8B-pyrimidinoaminomethyl- 10a-ergoline derivative is isolated and purified.