CS229948B2 - Processing method of erotderivative - Google Patents

Abstract

A process for the preparation of anilides in the ergoline series of the general formula <IMAGE> in which R1 denotes a hydrogen, chlorine or bromine atom, R2 denotes an alkyl group having 1 to 4 carbon atoms, X denotes the group R2, a free or substituted phenyl group, a free amino group or an amino group which is mono- or disubstituted by the radical R2, a group of the general formula NR'R'', in which R' represents a hydrogen atom or the radical R2, an acyl group having 1 to 4 carbon atoms or R' and R'', together with the nitrogen atom to which they are bonded, represent a 5- or 6-membered saturated or unsaturated heterocyclic ring, in which a CH2 or CH group can be substituted by N, O or S, denotes a mercapto group substituted by R2 or the phenyl radical or denotes the group OR2, by reaction of corresponding lysergic acid methyl ester or lysergic acid ethyl esters with a dimethylaluminium anilide in an inert solvent is described. The compounds which can be prepared according to the process are useful pharmacologically active compounds.

Description

BACKGROUND OF THE INVENTION The present invention relates to ergotivatives for a process for the preparation of the novel formula I

wherein n is hydrogen or alkyl having 1 or 2 carbon atoms.

Lysergic acid and 9,10-dihydrolysergic acid anilides are known as valuable pharmaceuticals. A number of lysergic and 9,10-dihydrolysergic derivatives are known from U.S. Pat. No. 4,101,552 which have an antihypertensive effect on blood pressure. Substituted lysergic acid and 9,10-dihydriclysergic acid anilides are known from U.S. Pat. No. 3,904,633 to have an antiserotonin effect, a central nervous system depressant effect, or an antidepressant effect similar to a tricyclic antidepressant.

It has now surprisingly been found that compounds of the general formula Γ

a single bond —C — C or a double bond —C = C—,

R ² is hydrogen, chlorine or bromine,

R 5 alkyl of 1 to 3 carbon atoms,

X is methyl, methoxy, hydrogen, fluoro, chloro, an amino acid, or a group of formula

- C0-NR‘R ', where R ‘and R' are the same or different;

in which ^C f-^- ^C 10 denotes a single bond C-C a

X hydrogen or halogen at the 4-position have antihypotonic activity.

In particular, 6-methyl-ergoline-8/1-carboxylic acid anilide and 4-flucranilide acid 6 in the Timmermanns trial model (Timmermanns, W. MWM, Kwa, W. van Zwieten, PA, Naunyn-Schmiederbergs Arch. Pharmacol. 310) [1979] 189-193) in despimalized rats increased mean arterial blood pressure, peripheral vascular cdpor, and cardiac minute volume. Normoton male rats weighing 280-320 g were used for the experiments. The animals were decerebrated, spinalized, bilaterally vagotized and ventilated with a small animal ventilation apparatus. The compounds of the invention were administered intravenously in animals (dose: 0.1 to 1.0 mg / kg). Blood pressure was measured through a catheter in A. femoralis and heart rate was determined by a recording electrocardiogram (lead A according to Spoerri, H., Arch. Wiss. Prakt. Tiherrhilkunde 79 [1944] 1 to 57). Cardiac minute volume was determined by cardiac thermodilution (Mannesmann, G. u. Muller, B., J. Pharmacol. Meth. 4 [1980] 11-18).

In addition, a cold catheter catheter was placed in the right V. jugularis and a thermistor in the abdominal aorta to inject the cold solution. Peripheral vascular resistance was determined according to the following formula ___6 x P _M

V _m (ml / min / 100 g KGj) where P _M represents mean arterial blood pressure and V _m heart rate.

The test compounds show a significant blood pressure-enhancing effect at both experimental doses, which goes hand in hand with an increase in peripheral vascular resistance and cardiac minute volume. After a dose of 1 mg / kg of these compounds, blood pressure was still elevated at half an hour to one hour after injection. This increase was 100% above baseline. Heart rate was unaffected. The effects found can be antagonized by doses of m receptor blocker such as prazosin.

Both compounds are therefore useful as low blood pressure therapeutics.

The compounds of the invention are used by methods known in the art for the manufacture of medicaments for oral administration. For this purpose, they are used either in free form as a base or in the form of physiologically acceptable acid addition salts, for example in juices, syrups, in dragees, in tablets or capsules, optionally in conjunction with customary auxiliaries and / or carriers. The acid addition salts are obtained by reacting the free bases with an acid, for example tartaric, maleic or benzoic acid, and then purified by recrystallization and / or chromatography.

The dosage of the compounds according to the invention is in the range of 5 to 109 mg / day in humans and the dosage form contains 1 to 20 mg of active ingredient.

Known manufacturing methods (DAS 28 02 023, U.S. Pat. No. 3,904,633, U.S. Pat. No. 4,101,552 and DE Patent No. 659,085) are based on lysergic acid of the general formula

R 6 = C 1 -C 4 -alkyl,

R ² = H, Br, Cl, which is first converted into a reactive functional derivative thereof such as the chloride, azide or a mixed anhydride which is then reacted with an appropriately substituted aniline to vžílikú desired anilide.

The known methods are generally well applied to 9,10-dihydrolysergic acid, but often fail with lysergic acid alone, as already determined by comparative experiment by W. L. Garbrecht, J. Org. Chem. 24, 368 (1959).

The thermal and chemical instability of lysergic acid leads to the fact that known processes for the production of lysergic acid anilides usually proceed with poor chemical yields and even in cases where good chemical yields are achieved, the reaction and / or processing conditions lead to isomerization to C-8 molecular skeletons to obtain lysergic acid anilide mixtures. Although isomer separation is possible, the yield of the desired product is reduced.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the production of anilides in the ergoline series which provides the desired anilides stereospecifically in high yield.

It has now been found that ergo derivatives of the aforementioned general formula (I) can conveniently be prepared according to the invention by reacting equimolar amounts of trimethylaluminum and free aniline or aniline derivative of general formula

III dl č

223048 where

X is as previously defined, wherein the resulting intermediate of formula IV (IV) wherein

X 'is as previously defined, is reacted with a lysergic ester of formula II

in which

R ² and R ⁶ are as previously defined, and

R is methyl or ethyl, in an inert solvent.

The reaction is carried out in a temperature range of 0 to 40 ^° C, preferably at room temperature.

The alkyl or C1-C3 alkoxy groups are derived from alkanes such as methane, ethane, propane and isopropane.

The process according to the invention is carried out by reacting trimethylaluminum in an inert solvent with cooling with aniline or an aniline derivative of the formula III under cooling and then slowly adding the lysergic ester of the formula II.

Solvents include, in addition to toluene, benzene, hexane and methylene chloride.

It is expedient to work under a shielding gas such as nitrogen or argon.

After. The reaction mixture is worked up to give the free base or the free base salt as desired. Suitable salts are, in particular, the tartaric acid salt. However, i. other. salts such as phosphoric acid,. hydrochloric acid, acetic acid, benzenesulfonic acid and maleic acid.

The advantage of the process according to the invention lies in the ease of reaction and processing, the high chemical yield and, in particular, the surprising fact that the reaction of the lysergic esters does not result in isomerization, i.

isolysergic anilides are not formed as undesirable by-products.

This finding is not in. by no means obvious, considering that trimethylaluminum and derivatives thereof are used as highly active Lewis acids. So would the Lewis character. of the compounds of formula II could hardly have assumed that the reaction of the lysergic acid esters was carried out while maintaining the configuration. Even high chemical yields are surprising to the person skilled in the art, since the ergoline backbone exhibits another grouping (N-1, C-3, N-6) that could react with Lewis acid.

The following example illustrates the process of the invention.

Example

To a solution of 16.7 ml of a 10% solution of trimethylaluminum (19.2 mmol) in toluene, 1.83 ml of 4-fluoroaniline in 10 ml of toluene was added dropwise under cooling with ice water and under argon, then stirred for 30 minutes at room temperature. 2.72 g (9.6 mmol) of lysergic acid methyl ester in 20 ml of toluene and 20 ml of methylene chloride are added dropwise, and the reaction solution is then stirred at room temperature for 1.5 hours.

The reaction mixture can be worked up in two ways.

Variant A:

While cooling with ice water, excess reagent is decomposed by dropwise addition of 10 ml of water. The reaction solution was then diluted with 50 mL of methylene chloride and 50 mL of methanol, filtered through celite, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-diisopropyl ether gave 3.35 g of lysergic acid p-fluoroanilide (96.2%), m.p. 203-206 ° C (dec.).

Variant. B:

8.5 g of solid sodium fluoride are added portionwise to the reaction solution at room temperature, stirred for 30 minutes, filtered through celite, the filter residue is washed with methylene chloride and the filtrate is concentrated. The crude product obtained is dissolved in about 20 ml of methanol, 1.0 g of 1 (+) tartaric acid is added and crystallized overnight at -5 ^DEG C. 4.4 g (89.2%) of p- 152 DEG-155 DEG C. (decomposition).

The following are produced analogously:

(a) lysergic anilide, hydrogen tartrate, m.p. 144-149 ° C [decomposition], yield 91%;

(b) lysergic acid 4-methoxyanilide, hydrercartrate, melting point 155-158 ° C (decomposition), yield 100%;

(c) 6-methyl-ergoline-8β-carboxylic acid 4-methylanilide, m.p. 241-244 ° C, yield 95%;

d) 2-aiiiinoamiid acid 6-methyl-ergoline-8 / f-carboxylic acid, mp 249-253 C. ^a yield of 85 ° / o

e) 6-methyl-etgoline-β-carboxylic acid anilide, m.p. 231 ° C, yield 100 proc.,

(f) 2,6-Dimethyl-6-methyl-ergoline-8/3-carboxylic acid, m.p. 262 ° C (decomposition), yield 86%;

(g) 6-methyl-ergoline-8-carboxylic acid 4-fluoroanilide, m.p. 251-255 ° C, yield 98%;

(h) 6-methyl-ergoline-8/3-carboxylic acid 4-chloroanilide, m.p. 247-251 ° C, yield 100%;

(i) N-9,10-dihydrolysergyl-m-aminobenzoic acid diethylamide, m.p. 138-141 ° C, yield 97%;

j) 6-methyl-ergolm-S1-carboxylic acid 3-difluoromethylanilide. melting point 130 ° C, yield 88 ° / o,

(k) 9,10-Didehydro-6-n-pyl-8'-ergolinecarboxylic acid 4-fluoroanilide, hydrogen tartrate, m.p. 138-142 ° C (dec.), 92% yield ,

(l) 2-Chloro-lysergic acid 4-oxo-oxyanilide, hydrogen tartrate, m.p. 146-148 ° C, yield 87%.

Claims (1)

pRedmet vynalezu A process for the preparation of ergotivatives of the formula I by means of a single C-C bond or a double C-C bond, R ² is hydrogen, chlorine or bromine, R ⁶ alkyl of 1 to 3 carbon atoms, X is methyl, methoxy, hydrogen, fluoro, chloro, amino or a group of the formula —CO — NR‘R ”where R‘ and R “, which are the same or different, denote hydrogen or alkyl having 1 or 2 carbon atoms, characterized in that equimolar amounts of trimethylaluminum and free aniline or aniline derivative of the general formula III (III) are reacted wherein X is as previously defined, wherein the resulting intermediate of formula IV (IV) wherein X, as previously defined, is reacted with a lysergic ester of formula II COOR in which R ² 'and R 6 are as previously defined and R is methyl or ethyl, in an inert solvent. Seveeografia, n. P., Závod 7, Most price 2,40 CZK