CS240396B1 - 2-halogen derivatives of n,n-diethyl-n-(1,6-dialkyl-8 alpha-argolinyl) ureas and methods of their production - Google Patents

Abstract

The present invention relates to 2-halogen derivatives of N, N-diethyl-N '- (1,6-dialkyl-8a-ergolinylurea). of formula (I) wherein R 1 represents an alkyl group with one up to three carbon atoms, optionally allyl, R2 denotes an alkyl group with one with up to three carbon atoms, X represents an atom chlorine or bromine as well as their methods production, either by halogenation of compounds of general interest of formula I in which. X represents a hydrogen atom, or by alkylation of compounds of the general formula I wherein R 1 is hydrogen. Compounds Formula I can be used as spasmolytics, prolactin secretion inhibitors and to affect central nervous disorders including parkinsonian syndromes.

Description

The present invention relates to 2-halogeno derivatives of N, N-diethyl-N - (1,6-dialkyl-8α-ergolinyl) ureas of general formula I

in which

^R1 - represents an alkyl group having one to three carbon atoms or allyl,

R ² represents alkylov.ou group having one to three carbon atoms;

X represents a chlorine or bromine atom, and processes for their preparation. '·

In the 1-position of the unsubstituted N, N-diethyl-N '-( 2-halogenergolinyl) urea (of formula I above) wherein R @ ¹ is hydrogen and the urea residue at position 8 is bound by either 8-a or 8- (3) are known (EP 56 358, NSR prior. 14/01 81) The compounds of the invention have some new and more advantageous pharmacological properties.

According to the invention, the 2-halogeno derivatives of N, N-diethyl-N- (1,6-dialkyl-8α-ergolinyl) urea of the formula R ¹ , R ² and X as defined above can be produced by either of formula (I) as defined above, wherein R @ ¹ and R @ ² , in which X is hydrogen, are reacted with halogenating agents in an inert solvent medium;

b) reacting a compound of the formula I with the meaning of R ² and X in which R ¹ is a hydrogen atom with an alkylating agent of the formula II

R ¹ -Y (II) wherein R ¹ has the abovementioned meaning and Y represents halogen or the residue of an ester-linked aliphatic or aromatic sulfonic acids or ester-linked radical of sulfuric acid.

The starting materials used in the production methods of the invention are known (cf. AO 231 214; EP 56 358; Beran M. et al., Collect. Czech. Chem. Commun. 42, 1417 [1977]).

In process (a), bromine in the presence of boron trifluoride etherate, N-bromosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, N-bromoacetamide, N-bromophthalimide, N-2,6-trichloro-4-nitroacetanilide or sulfuryl chloride may be used as halogenating agents. presence of boron trifluoride etherate.

As inert solvents, aprotic ethers such as dioxane, dimethoxyethane or chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-diethiorethane or dipolar aprotic solvents such as acetonitrile or mixtures of said solvents may be used.

In the process b), the alkylation is carried out by treatment with 1-5 molar equivalents alkylaěního agent of formula II to a solution of the compound of formula I in which R ² and X have the above meanings and R ¹ is hydrogen, in an inert solvent in the presence of a base to scavenge acids released.

Alkyl halides, preferably alkyl iodides, or allyl bromide, or alkyl esters of sulfuric acid such as dimethyl sulfate or diethyl sulfate or alkyl esters of aliphatic or aromatic sulfo acids such as alkyl methanesulfonates or alkyl-4-tolylsulfonates can be used as the alkylating agent of formula II.

As inert solvents, polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide or acetone or liquid ammonia can be used.

As the base for binding the liberated acid, strong bases can be used, for example sodium or potassium amide, lithium dialkylamides, sodium methylate or alkali metal hydroxides.

The reactions may be carried out in a temperature range of from -50 ° C, or from the melting point of the reaction mixture to 80 ° C, or to the boiling point of the reaction mixture, if this is within said interval.

The compounds of the formula I can be isolated from the reaction mixture by conventional separation methods, for example by shaking, evaporating the solvents and chromatography and / or crystallization. They are substances of a basic nature which give strong salts with strong inorganic or organic acids. For therapeutic purposes, the water-soluble salts of the compounds of formula I with pharmaceutically acceptable, non-toxic acids such as hydrochloric, sulfuric, methanesulfonic, ethanesulfonic, maleic, malic, tartaric, citric and the like are preferred. Said salts may be prepared by treating at least 1 mol equivalents of acid to 1 mol equivalents of a compound of formula I in a suitable inert solvent, preferably methanol, ethanol, acetone, water or mixtures thereof.

The compounds of the present invention exhibit, among other effects, effects due to their action on dopaminergic and adrenergic receptors, particularly in the central nervous system and in the endocrine system.

The substances act as agonists and antagonists in the functions mediated by the influence on dopamine receptors in the central nervous system. For example, it causes a pronounced in240396 hibiscus prolactin secretion, as evidenced both by direct determination of prolactin in rat serum using RIA and by monitoring of prolactin-dependent physiological events, ie lactation and nidation of fertilized eggs in the uterus. In contrast to the effects of, for example, apomorphine or lisuride, these substances do not induce increased motility and stereotyped movements; A reduced agonist effect on dopaminergic receptors is also manifested in an assay for the effect on body and temperature of rats and mice, where, unlike apomorphine and lisuride, the compounds of the present invention cause a slight decrease in temperature. In reserpinized mice, then they do not induce reversal of hypothermia after reserpine (2.5 mg / kg 18 hours in advance) as apomorphine and, conversely, inhibit the effect of apomorphine; they therefore act as antagonists. These compounds weakly inhibit neuroleptic-induced catalepsy (perfenazine, 1.5 mg / kg) in rats. Supersensitivity of dopamine receptors in denervated striatum occurs in rats with unilateral lesion of nigrostriatal doparainergic pathways following application of 6-hydroxydopamine to substantia nigra. The model acts by stimulating dopamine receptors with subsequent rotation contralateral to the lesion, thus acting similarly to apomorphine or lisuride.Other model was prepared by a unilateral electrolytic lesion of rat striatum, in these animals dopaminergic agonists such as apomorphine or lisuride rotate the animals ipsilaterally with respect to the lesion side In this model, where the effect on normal striatum receptors is monitored, the compounds of the invention do not induce any rotation and inhibit the rotation after apomorphine, thus acting as antagonists. Minor receptors in rat striatum were demonstrated by inhibition of 0.5 nM ⁵ H-spiperone binding. The action on adrenergic receptors was demonstrated by inhibiting the lethal effect of i. V. Injection of 0.4 mg / kg adrenaline.

One of the compounds of this group, N, N diethyl-N '- (2-bromo-1,6-dimethyl-8α-ergolinyl) urea of formula I, wherein R ¹ and R ^{2 are} methyl and X is bromine, has shown remarkable affinity Its ICho (concentration causing 50% inhibition of ³ H-spiperone binding) was 11.4 nM, which corresponds approximately to the IC 50 of haloperldol (10.8 nM) and is indicative of a higher affinity than terguride ( IC50 = 23.4 nM], chlorpromazine (881.4 nM), clozapine (288.5 nM) or nicergolm (5,347 nM), which further significantly reduced the locomotor activity of mice at doses of 1 and 10 mg / kg. At 2 and 4 mg / kg sc, it slightly decreased the temperature of normal mice, did not affect reserpinal-induced hypothermia, and at 2 and 4 mg / kg, it inhibited the reversal of this hypothermia induced by apomorphine.

lesion of nigrostriatal pathways with 6-hydroxydopamine at 1 mg / kg s. c. In rats with an electrolytic lesion, the striatum was at 1 mg / kg s. c. without effect and inhibited apomorphine-induced ipsilateral rotation. The anti-cataleptic effect was observed at a dose of 1 to 2 mg / kg s.c. It also reduced prolactinemia in rats at a dose of 0.075 mg / kg and, from a dose of 0.5 mg / kg, prevented rats from fertilizing eggs in the uterus.

Depending on the biological effects observed, the compounds of the invention may be used as sympatholytics, prolactin secretion inhibitors, and to affect central nervous system disorders including parkinsonian syndromes and certain neuroleptic-induced side effects.

For therapeutic use, the compounds of the invention may be formulated into conventional pharmaceutical preparations for enteral or parenteral administration. The pharmaceutical preparations comprise an active compound of the formula I and an inert carrier suitable for the intended mode of administration, for example gelatin, acacia, sugars, starches, talc, magnesium stearate, water, saline, vegetable oils, polyalkylene glycols and other excipients such as preservatives , stabilizers, wetting or emulsifying agents. Said pharmaceutical preparations may be prepared in the form of a solid, such as tablets, capsules, dragees or suppositories, or in the form of a liquid, such as injections, solutions, suspensions or emulsions.

The following non-limiting examples illustrate the preparation of the compounds of formula (I). Melting points are determined on a Kofler block and are reported in ° C. The values of specific rotation [α] _D ²⁰ refer to crystal-free substances.

Example 1

N, N-diethyl-N‘-chloro-1,6-dimethyl-Sor-ergolinyl) urea

To a solution of 355 mg (1 mmol) of Ν, Ν-diethyl-N '- (1,6-dimethyl-8α-ergolinyl) urea in 20 ml of absolute acetonitrile cooled to -5 ° C was added 5 ml of dichloromethane containing 0 ml in the dark. 34 g (2.44 mmol) of boron trifluoride etherate and after stirring for 2 minutes, a further 5 ml of dichloromethane solution containing 0.34 g (2.5 mmol) was added for a further 30 minutes and then poured into 0 ° C cold. The organic extract was washed with water (3 x 50 ml), dried over sodium sulfate, the desiccant was filtered off and the filtrate was evaporated in a water pump vacuum at 30 ^DEG C. The residue was chromatographed on a column. Silica gel using chloroform with increasing ethanol content and a homogeneous fraction containing pure product were combined and evaporated in a water-jet vacuum to give the title compound as a foamy residue.

¹ H-NMR spectrum (chloroform solution, tetramethylsilane as internal standard, 80 MHz):

6.70 to 7.30 (m, 3H, ArH),

5.58 (bd, J = 8.0 Hz, 1H, NH-CO),

4.20 (m, 1H, C5-H),

3.68 (s, 3H, Ni-CH 3),

3.25 (q, J = 7.0Hz, 4H, CONCH2),

2.40 (s, 3H, N 1 - CH 3),

1.55 (dt, J = 13.3, 4.8 Hz, 1H, Cs-H),

1.10 (t, J = 7.0 Hz, 6H, COCH 2 CH 3).

Example 1 a d 2

N, N-Diethyl-N- (2-bromo-1,6-dimethyl-8H-ergolinyl) urea

To a solution of 355 mg (1 mmol) of N, N-diethyl-N '- (1,6-dimethyl-8α-ergolinyl) urea in 10 mL of absolute dichloromethane was added 346 mg (2.44 mmol of boron trifluoride etherate) with stirring at room temperature. and after 2 minutes 5 ml of a dichloromethane solution containing 192 mg (1.2 mmol of bromine) is added dropwise. The reaction mixture is stirred for 10 minutes at room temperature, shaken with 20 ml of aqueous sodium bicarbonate solution and shaken with 10 ml of dichloromethane. The organic fractions were combined and evaporated to dryness under a water pump vacuum The residue was chromatographed on a silica gel column using 1% ethanol in chloroform, the homogeneous fractions were combined, the solvents were evaporated in vacuo and the residue was crystallized from acetone to give the title compound. compound as white crystals, mp 80-85 ° C, _{[a] D} 20 = + 23.8 ° (c 0.2, chloroform).

In the same manner as in Example 2, but using the corresponding starting N, N-diethyl-N 1 ^; - (1,6-dialkyl-8α-ergolinyl urea) is prepared by:

N, N-diethyl-N1 ^; - (lallyl-2-bromo-6-methyl-8α-ergolinyl) urea, non-crystallising oil, [ _.alpha. ] _D @ ²⁰ = + 8.0 DEG (c 0.2 chloroform),

N, N-diethyl-N '- (2-bromo-6-methyl-propyl-8a-ergolinylJ urea, non-crystallizing oil, [αι] ο ²⁰ = + 3.1 ° (c 0.2, chloroform)

N, N-diethyl-N1 ^; - {2-bromo-1-methyl-6-propyl- (K-ergolinyl) urea, non-crystallising oil, [α] D ²⁰ = + 10.0 ° (c 0.2 chloroform),

N, N-diethyl-N '- (2-bromo-1,6-dipropyl-8α-ergolinyl) urea, non-crystallizing oil, [α] ²⁰ D + 0.2 ° (c 0.2 chloroform).

Claims (3)

SUBJECT N-N-diethyl-N - (1,6-dialkyl-8α-ergolinyl) ureas of formula (1): R ¹ represents an alkyl group having one to three carbon atoms or an allyl group, R ² represents an alkyl group having one to three carbon atoms; X represents a chlorine or bromine atom. 2. A process for producing 2-halogenated N, N-diethyl-N'- (l, 6-dialkyl-8a-ergolinyl) urea of formula I for the above known výVYNALEZU R ^1, R ² and X according to claim 1, characterized in that the process comprises reacting a compound corresponding to formula 1 having the above meanings of R ¹ and R ^2, where the point X is hydrogen, with a halogenating agent introducing a chlorine or bromine in an inert solvent *. 3. A process for the preparation of the 2-halogeno derivatives of N, N-diethyl-N '-( 1,6-dialkyl-8.alpha.-ergolinyl) ureas of the general formula R < ¹ &^gt; by reacting a compound of formula (I) of the above-mentioned meanings R @ ² and X, in which R @ ¹ is hydrogen, with an alkylating agent of formula (II) R ¹ -Y (II) wherein R ¹ has the abovementioned meaning and Y represents halogen or the residue of an ester-linked aliphatic or aromatic sulfonic acids or ester-linked radical of sulfuric acid.