CS262283B1 - 13-acetyl-2-brom- and 2-acetyl-13-bromderivatives of ergoline and process for preparing them - Google Patents

Description

The present invention relates to ergoline 13-acetyl-2-bromo derivatives of formula (I) and to 2-acetyl-13-bromo derivatives of formula (II)

in which

R represents a group diethylaminoureidovou (-NHCON (C ₂ H ^) ₂₎ ^{Configuration} 8-alpha (i.e. 8S> or a methoxycarbonyl group (COOCH ^) Configuration 8-beta (i.e. 8R) and their preparation.

Compounds of formula I and II exhibit significant in vitro effects on Afla _n 3 ¹ -adrenergic receptors, manifested by marked inhibition of binding of alpha--receptor- H-prazosin.

The ergoline derivatives of formulas I and II have three chiral centers in the molecule, asymmetric carbons at the 5, 8 and 10 positions, with the hydrogen atom on C (5) having the beta position (5R configuration), in accordance with formulas I and II, the alpha or beta position and the hydrogen atom on C (10) has the alpha position (10R configuration).

According to the invention, the 13-acetyl-2-bromo and 2-acetyl-13-bromo derivatives of the ergoline of the general formula I and of the formula I can be used. II to prepare from the known 2-bromo-13-H-derivatives of ergoline of the general formula III,

in which R is as defined above, by Friedel-Crafts acetylation of these precursors with acetyl chloride under catalysis with Lewis acids.

The reaction is preferably carried out by adding excess catalyst, Lewis acid, e.g., aluminum chloride or bromide, titanium tetrachloride or tin tetrachloride, to the solution of the substrate in a non-polar solvent, preferably in absolute 1,2-dichloroethane, with stirring and preferably under inert. atmosphere, such as under nitrogen or argon. The catalyst / substrate ratio is 3.0 to 10.0. After the time required to form the complex, 5 to 15 minutes, acetyl chloride is added to the reaction mixture in an acetyl chloride / substrate molar ratio of 1.0 to 5.0.

Alternatively, a catalyst may be added to the mixture of substrate and acetyl chloride in the solvent, maintaining the above ratios.

The resulting reaction mixture is then stirred for a period of time, depending on the nature of the substrate, the catalyst, and the reaction temperature (which may range from -15 ° C to +80 ° C, depending on the nature of the substrate and catalyst), usually 30 minutes to 5 hours.

The reaction mixture is then quenched with water. containing an addition of alkali, e.g. concentrated aqueous ammonia, or a saturated solution of a compound, forming soluble complexes with an catalyst in an alkaline medium, e.g. sodium ammonium tartrate with addition of alkali, or an acid e.g. eg by pouring into water optionally containing a base such as ammonia, by sucking and / or shaking the products into a water-immiscible solvent such as chloroform or dichloromethane and evaporating the extract obtained. The product obtained is purified by chromatography and / or crystallization from a suitable solvent or solvent mixture. Similarly, the two isomers, i.e. 13-acetyl-2-bromo derivative (Formula I) and 2-acetyl-13-bromo derivative ( of formula (II).

The obtained 13-acetyl-2-bromo derivatives and 2-acetyl-13-bromo derivatives of ergoline of formulas I and II are colorless, high melting crystalline substances, weakly basic and forming salts with strong inorganic and organic acids. For pharmaceutical purposes, water-soluble salts with pharmacologically acceptable acids can be used, such as hydrochloric, sulfuric, methanesulfonic, acetic, maleic, tartaric, citric and the like.

The process for the preparation of ergoline 13-acetyl-2-bromo derivatives I and ergoline 2-acetyl-13-bromo derivatives II is explained in more detail in the following examples, which are not intended to limit the scope of the invention.

Melting points of the products are determined on a Kofler block and are given in ° C.

Structure of compounds was confirmed by infrared, ultraviolet and NMR spectra, composition by elemental analysis.

Example 1

To a suspension of 7.26 g (20 mmol) of methyl 2-bromo-9,10-dihydrolysergate in 200 mL of abs. 1,2-Dichloromethane is added under stirring under nitrogen atmosphere to 10 g (75 mmol) of anhydrous aluminum chloride powder. The black reaction mixture was stirred for 5 minutes, then 3.1 mL (42 mmol) of acetyl chloride was added and the resulting reaction mixture was stirred for 30 minutes, then quenched by the addition of 100 mL of sat. sodium ammonium tartrate solution and 25 ml conc. aqueous ammonia, the heterogeneous mixture is stirred for 15 minutes, then the organic phase is separated and the aqueous is extracted with 3x100 ml of chloroform. The combined organic phases were dried freely. Na 2 SO 4, evaporated and separated by chromatography on silica gel (eluent mixture of chloroform, ethyl acetate and triethylamine, 50: 50: 0.2, with increasing methanol content). Qualitatively identical fractions were combined and crystallized from ethyl acetate to give 5.1 g (63%) of methyl 13-acetyl-2-bromo-9,10-dihydrolysergate, m.p. 230 DEG-233 DEG C. and 1.55 g (19%) of methyl 2-acetyl-13-bromo-9,10-dihydrolysulfate, m.p.

208 ° C to 215 ° C.

Example 2

Using the procedure described in Example 1 but employing 840 mg (2 mmol) of 2-bromo-terburide, 1.32 g (10 mmol) of anv. aluminum chloride and 0.31 ml (4.2 mmol) acetyl chloride in 20 ml abs. 1,2-dichloroethane, after work-up, 340 mg (36.8%) of 13-acetyl-2-bromo-terburide, m.p. 245 DEG-250 DEG C. (dec.) And 170 mg (18%) of 2-acetyl-13-bromo-terburide, m.p. 210 DEG-214 DEG C. (with decomposition).

Example 3

To a suspension of 3.41 g (9.4 mmol) of methyl 2-bromo-9,10-dihydrolysergate in 100 mL of abs. Acetyl chloride (2.1 ml, 28.5 mmol) was added dropwise to 1,2-dichloroethane and the mixture was stirred under nitrogen for 10 minutes. Then 5.1 g (38 mmol) of anhydrous ethyl acetate are added. aluminum chloride and stirred for an additional 1 hour. The mixture was then quenched with 50 mL sat. sodium ammonium tartrate solution and basified with conc. aqueous ammonia to pH 7.5. The mixture is then worked up as described above. There was thus obtained 1.92 g (52%) of methyl 13-acetyl-2-bromo-9,10-dihydrolysergate and 1.55 g (42%) of 2-acetyl-13-bromoisomer.

Claims (4)

OBJECT OF THE INVENTION An ergoline 13-acetyl-2-bromo and 2-acetyl-13-bromo derivative of the general formulas I and II in which: R is an 8-alpha, i.e., 8S, diethylamino-rimide group, or an 8-beta, i.e., 8R, methoxycarbonyl group. 2. A process for the preparation of Claims I and II wherein the 2-bromo-13-H precursor The compound of formula (R) as defined in claim 1, wherein the formula (III) in which R is as defined above is acetylated with acetyl chloride under catalysis by Lewis. acid. 3. A process according to claim 2, wherein the molar ratio of catalyst / substrate is 3.0 to 10.0 and the molar ratio of acetyl chloride / substrate is 1.0 to 5.0. 4. The process according to claim 3, wherein the catalyst is anhydrous aluminum chloride, anhydrous aluminum bromide, anhydrous titanium tetrachloride or anhydrous tin tetrachloride.