CS219363B1 - Esters of the n-/5r,85,10r/-6-propyl-8-ergolinyl/carbamo acid and method of making the same - Google Patents

Description

(54) Esters of N - [(5R, 8S, 10R) -6-propyl-8-ergolinyl] carbamic acid and processes for their preparation

The present invention relates to novel N- [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamic esters of the general formula I

in which

R @ ¹ denotes a straight or branched chain alkyl group having from 1 to 5 carbon atoms, a behzyl group or a phenyl group, and

R ² is hydrogen or methyl, and methods of their manufacture. The novel N- (6-propyl-8-ergolinyl) carbamic acid esters of formula (I) exhibit a very potent inhibitory effect on proline and growth hormone secretion in experimental animals and stimulate gonadotropin secretion.

The anti-inhibitory activity of some N- (8-ergolinyl) carbamic acid derivatives, especially their substituted amides, is known. For example, 1 - [(5R, 8S, 10R) -6-methyl-8-ergolinyl] -3,3-diethylurea (Czechoslovak patents 152,153 and 156,178) has a significant inhibitory effect on the depressive secretion. No. 518 of Dec. 14, 76, inter alia, the compounds of the formula include substituted ethyl D-6-methyl and D-6-ethyl-8α-erigolinylcarbamic acid ethyl esters, but without further details of their physicochemical constants and their efficacy. of the present invention found that the introduction of the n-propyl group at the 6-position of the ergoline residue of the 8α-ergolinylcarbamic acid esters leads to an unexpectedly high increase in their inhibitory effect on the depressive secretion.

The compounds of formula I have three chiral centers in their molecule, asymmetric carbons at the 5, 8 and 10 positions. The spatial arrangement of the substituents on these carbons is the same as that of D-9,10-dihydrosolysergic acid [see A. Stoli, Th. Petrzilka, J. Rutschmann, A. Hofman and Hs. H. Gunthard,

Hel v. Chim. Acta 37, 2039 (1954)]: hydrogen on C (5) is in position β (5R configuration), carbamic acid residue on C ₍₈₎ is in position a (SS configuration) and hydrogen on C ₍₁₀₎ is in position and (10R configuration) wherein the linking of rings C and D is trans.

According to the invention, the N- (6-propyl-8-ergolinyl) carbamic acid esters of the formula I can be produced by either:

(a) an isocyanate of the formula II

wherein R ² is as defined above, is reacted with an alcohol of formula III

R ¹ -OH (III) wherein R ¹ represents a straight or branched alkyl group having 1 to 5 carbon atoms or a benzyl group, to give the N- [(5R, 8S, 10R) -6-n-propyl ester -8-ergolinyl] carbamic formula I wherein R ¹ is a straight or branched alkyl group having 1 to 5 carbon atoms or a benzyl group and R ² is as defined above, or

b) (5R, 8S, 10R) -6-n-propyl-8-aminoergoline of formula IV

of formula (II) with an alcohol of formula (III) is conveniently carried out without isolation of the isocyanate by adding an excess (10 to 100 times) of the corresponding alcohol of formula (III) to its solution in an inert solvent and heating the reaction mixture for 0.5 to 2 hours. of said mixture. Suitable inert solvents include those in which the desired isocyanate of formula II is prepared, for example aromatic hydrocarbons such as benzene or toluene, or chlorinated aliphatic hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane or 1,1,2,2-tetrechl. orethane.

According to process b), the reaction of the 8-aminoergoline of the formula IV with the halo-formic acid ester of the formula V is conveniently carried out in an inert organic solvent such as an aromatic hydrocarbon such as benzene or toluene in a chlorinated aliphatic hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, or; in an ether such as diethyl ether, tetrahydrofuran or dioxane in the presence of an acid acceptor. As the acid acceptor, inorganic bases such as sodium or potassium hydroxide or sodium or potassium carbonate or an organic base, preferably a tertiary organic amine, for example triethylamine, diisopropylethylamine, pyridine, N-ethylpiperidine and the like can be used. The reaction can be carried out in a temperature range of from -10 ° C to the boiling point of the reaction mixture, preferably at 0 ° C to + 10 ° C.

The required starting (5R, 8S, 10R) -6-n-propyl-8-aminoergoline of formula IV can be prepared, for example, by Curtius degradation of the azide of formula VI

wherein R ² is as defined above. The reaction can advantageously be carried out by introducing an aqueous solution of the azide hydrochloride of the formula VI as obtained by treatment with (5R, 8S, 10R) -6-n-propyl-8-ergolinylcarboxylic acid hydrazide (cf. author's certificate 206 192). reacted with dilute hydrochloric acid, preferably at a temperature of 80 to 100 ° C.

Esters of N- (6-propyl-8-ergolinyl) carbamic of formula I are colorless, practically insoluble in water crystalline material of basic character which may be from the reaction mixture by conventional seve wherein R ² is as defined above, indicate reactions with DO- a haloformic acid ester of formula VI

X - COOR ¹ (V) wherein R ¹ is as defined above and

X represents a bromine or chlorine atom, to give carbamates of the formula I.

In process a), the isocyanate reaction is carried out by steaming and purification processes, for example by shaking, chromatography and / or crystallization. For therapeutic purposes, they can be used in the form of their water-soluble salts with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, sulfuric, methanesulfonic, ethanesuliphonic, maleic, malic, tartaric, citric and the like.

The inhibitory activity of the novel N- (6-propyl-8-ergolinyl) carbamic acid esters of formula I on the secretion of a proline in the adenohypophysis of female rats was investigated as an anti-lactation and antinidative effect.

The anti-lactation efficacy was tested in lactating rats of the Wistar strain (Konarovice), which were administered the test substances orally in the form of aqueous solutions of acid tartaric bases, daily for four consecutive days, starting on the fifth postpartum day. The effect on milk production was monitored both by the weight gain of the suckling pups and by the degree of milk saturation of the pups, by the estimation of the size and intensity of the pups' milk spots [for methodology see E. Fluckiger and H. R. Wagner, Experientia 24, 1130 [1968]; M. Aušková, K. Řežábek and M. Semonský, Arzneimittelforschung 4, 617 (1973). In this evaluation, one of the most potent compounds was ethyl N- [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate of formula Ia

which, as shown in Table 1, showed about one-fold higher anti-lactation activity than lisuride [1- (D-6-methyl-8α-ergolinyl) -3,3-diethylurea and about 350-fold higher activity than bromocryptine compared to known prolactin-inactivating active substances. (2-bromo-α-ergocryptine).

The antinidative activity of the compounds of formula (I) was also tested in rats of the Wistar strain (Konárovice), to which the compounds were applied in the form of a solution of the respective acid tartrate base in a single administration.

p. o., on the fifth day after the coupling; between days 14-16, females were sacrificed by ligament dissection and the number of live and resorbed fetuses was subtracted in hysterecomia [for methodology, see A. Cerny, K. Rezabek, M. Seda, V. Trcka and M. Semonsky, Collection Czech. Commun. 41, 1042 (1976)]. As shown in Table 1, Compound 1a showed about 3.5-fold greater potency than lisuride in this assay.

In the therapy, the above pharmacological effects of the N- (6-propyl-8-ergolinyl) carbamic esters of the general formula I can be utilized wherever it is desirable to reduce the secretion of a depressant or growth hormone or to increase the secretion of gonadotrophins in humans or animals. . They can be used in human therapy, for example, in arresting postpartum lactation, in the treatment of galactorrhoea, amenorhoea, hyperprolactinemia, acromegaly, pituitary tumors, breast cancer, parkinsonism, prostate hypertrophy, prostate cancer, some gonadal hypofunctional states and others. In the veterinary field, the compounds of formula I can be used, for example, in sows to arrest lactation and induce estra in the early postpartum period, to induce heat in heifers, cows and null gilts, and in cattle to induce and synchronize oestras, or reduce anestral conditions; in lower vertebrates, for example, in fish, to induce genital activity, and in birds to induce egg laying.

TABLE 1

Inhibitory activity of ethyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergoline] carbamate (1a) on prolactin secretion compared to lisuride and bromo octyl

Compound Antilactic activity Antinidative activity

ED50 (mg / kg) ^a ) (mg / kg) ^b ) la lisuride bromocryptine ⁰ ) about 0.010 0.1

0.050 0.35

3.5 1.5 ^b ) minimum 100% effective dose in mg / kg after single administration ^c ) single sc administration (E. Fluckiger, cited above) ^a ) by weight gain of offspring at

p. o. administered daily for 4 days, compared to baseline

213363

The preparation of the N- (6-propyl-8-ergolinyl) carbamate esters of formula (I) is illustrated by the following non-limiting examples, the melting points of the compounds being determined on the Kofler block and given as other temperature data, The specific rotation values given are for crystal-free substances, and yields are given in percent by weight.

Example 1

Ethyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate

To a solution of 1.56 g (5 mmol) of (5R, 8S, 10R) -6-n-propyl-8-ergolinecarboxylic acid hydrazide in 50 ml (5 mmol) of 0.1 M hydrochloric acid was stirred and cooled under stirring. 5 ml (5 mmol) of 1 M sodium nitrite solution is added and then, dropwise at the same temperature of the reaction mixture,

27.5 ml (5.5 mmol) of 0.2 M hydrochloric acid. The mixture is stirred for an additional 15 minutes at this temperature, then made alkaline with 20 ml (20 mmol) of 1M sodium bicarbonate solution and the precipitated azide base is taken up in 200 ml of carbon tetrachloride. The organic extract was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was heated to reflux for about 15 minutes, excluding air humidity. To the hot isocyanate solution is added 10 ml of ethanol, the mixture is heated under reflux for 1 hour, and the solvents are then distilled off under reduced pressure. The residue (1.5 g, yield 88%) was purified by silica gel column chromatography (5 g), using chloroform as eluent. From the combined uniform front fractions, the solvent was distilled off under reduced pressure and the crude product was crystallized from a mixture of benzene and cyclohexane. The title carbamate is obtained, mp 87-91 °, [α] _D 20 + 3.2 ° (c = 0.2, pyridine).

Example 2

Benzyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate

To a solution of (5R, 8S, 10R) -6-n-propyl-8-aminoergoline (0.27 g, 1 mmol) in chloroform (27 mL) was added triethylamine (0.12 g, 1.2 mmol) with stirring. with stirring and cooling, at a reaction temperature of 0 to + 5 °, a solution of 0.205 g (1.2 mmol) of benzyl chloro carbonate in 2 ml of chloroform was added dropwise. The reaction mixture was stirred at room temperature for 24 hours, then washed with dilute ammonia (1:10) and water, the organic portion was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product (0.36 g, yield 90%) is obtained after purification by silica gel column chromatography using chloroform with increasing amounts of methanol (up to 5%) as eluent, and after recrystallization of the residue containing a uniform substance from a mixture of benzene and cyclohexane, the title compound.

Example 3 Butyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate

In the same manner as in Example 2, but using a target. butyl chlorocarbamate instead of benzyl chlorocarbonate, a target is obtained. butyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate.

Example 4

In the same manner as in Example 1, but using the appropriate alcohols instead of ethyl alcohol, the following carbamates were prepared:

methyl N - [(5R, 8S, 10R) -6-propyl-8-ergolinyl] carbamate propyl N- [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] isopropyl-N- carbamate [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate butyl-N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate

Example 5

Ethyl [(5R, 8S, 10RJ-1-methyl-6-n-propyl-8-ergolinyl) carbamate

In the same manner as in Example 1, but using (5R, 8S, 10R) -1-methyl-6-n-propyl-8-ergolinecarboxylic acid hydrazide instead of (5R, 8S, 10R) -6-n- propyl-8-ergolinecarboxylic acid gave ethyl N - [(5R, 8S, 10R) -1-methyl-6-n-propyl-8-ergolinyl] carbamate.

Example 6 (5R, 8S, 10R) -6-n-Propyl-8-aminoergoline

A solution of (5R, 8S, 10R) -6-n-propyl-8-ergolinecarhoxylic acid azide in dilute hydrochloric acid prepared from the acid hydrazide (1.56 g, 5 mmol) as described in Example 1 was added dropwise with stirring to boiling solution of 0.1 N hydrochloric acid (100 ml). The reaction mixture is stirred for about 2 minutes at the boiling point of the mixture, then the solution is cooled, basified with 1M sodium hydroxide solution to pH 8-9 and the product is taken up in chloroform. After drying the chloroform extract with anhydrous sodium sulfate and distilling off the solvent, the crude product obtained (0.25 g, yield 92%) is recrystallized from methanol. To afford the title compound, mp 223-225 °, [a] ²⁰ _D - 42.2 ° (c =

Claims (15)

SUBJECT N- [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamic acid esters of the general formula I in which: R ¹ represents a straight or branched alkyl group having 1 to 5 carbon atoms, a benzyl group or a phenyl group, and R ² represents a hydrogen atom or a methyl group, ·. 2. Methyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl) carbamate. 3. Ethyl N-E (5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate. 4. Propyl N- [η (5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate. 5. Isopropyl-N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate. 6. Butyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate. 7th target. Butyl N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate. 8. Benzyl-N- [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate. 9. Phenyl-N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamate. 10. A process for the preparation of N- [('5R, 8S, 10'R) -6-n-propyl-8-ergolinyl] carbamic acid esters of the general formula I according to claim 1, characterized in that (5R, 8S, 10R) -6-n-propyl-8-ergolimocyanate of formula II R 1 = OH (ΠΙ). wherein R ¹ represents a straight or branched chain alkyl group having 1 to 5 carbon atoms or; benzyl group to form N- [(5R, 8S, 10R) -6-n-propyl-8-erigolinyl] carbamic acid ester wherein R ¹ is a straight or branched alkyl group having 1 to 5 carbon atoms or benzyl and R ² is as defined above. 11. A process for the preparation of N - [(5R, 8S, 10R) -6-n-propyl-8-ergolinyl] carbamic acid esters of the general formula I according to claim 1, characterized in that (5R, 8S, 10R) -6 -n-propyl-8-aminoergolin formula IV wherein R ² has the above meanings, is reacted with a halogenated carbonic acid ester of the formula V X - COOR ¹ (V) wherein R ¹ is as defined above and X represents a bromine atom or a chloro atom to form a carbamate of formula I wherein R ¹ and R ² are as defined above. 12. A process according to claim 10 wherein the reaction of the isocyanate of formula II with an alcohol of formula ΪΙΙ is carried out in an inert solvent such as benzene, toluene, carbon tetrachloride, 1,2-dichloroethane or 1,1,2,2,2. tetrachloroethane, at the boiling point of the reaction mixture, using a 10 to 100-fold excess of alcohol. 13. The process of claim 11 wherein the reaction of the 8-aminoergoline of formula (IV) with a halogenated carbonic acid ester is carried out in an inert organic solvent and in the presence of an acid reporter. 14. The method of item 13 wherein the inert organic 'solvent is an aromatic hydrocarbon such as benzene or toluene ·, a chlorinated aliphatic hydrocarbon such tetrachlorve which R ² has the above meanings, is reacted with an alcohol of formula ΙΓΙ methane , chloroform or methylene chloride, or an ether such as diethyl ether, tetrahydrofuran or dioxane. 15. A process according to claim 13, wherein the acid acceptor is an inorganic base such as sodium or potassium hydroxide or carbonate, or an organic base such as a tertiary organic amine, for example triethylamine, diisopropylethylamine, pyridine or N-ethylpiperidine.