SK277964B6 - Method of production of 2-substituted ergolines - Google Patents

Abstract

2-substituted ergolines is prepared so, that quarternary salts with general formula IIa is reduced on compound with general formula I, where R/exp_2/ is methyl and gained methylergolines can be transmissed on thioureas or addition salts with acids can origin or treating isomers are separated.

Description

Technical field

The invention relates to a process for the preparation of 2-substituted 2-ergolinylurea derivatives.

BACKGROUND OF THE INVENTION

2-substituted derivatives of ergolinyl urea are known from EP-A-160 842 and EP-A-250 357, wherein the described 2-substituted derivatives are particularly suitable as neuroleptics by virtue of their apomorphine antagonist activity and / or α-receptor blocking effect. Surprisingly, it has now been found that the introduction of a long chain hydrocarbon residue at the 6-position of 2-substituted ergolinyl urea derivatives shifts the effect from dopamine antagonist to dopamine antagonist while maintaining or improving the metabolic stability of the compounds.

The invention relates to a process for the preparation of compounds of the formula I

(i) where they are

C2 C3 and C9 - - - - C10 single or double bond X oxygen or sulfur; R ² methyl; R ⁴ C 1-6 -alkyl, C 3-5 -alkenyl or C 1-4 -cycloalkylalkyl, as well as their acid addition salts and isomers.

If C 9 C 10 represents a single bond, then the hydrogen atom at the 10-position is always and, if C 2 -C 8 represents a single bond, then the hydrogen atom at the 3-position is always β. The compounds of the formula I can act as E- or Z-isomers.

The term alkyl refers to both a straight-chain and branched-chain alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, 12-dimethylpropyl, 2-methylbutyl, 3-methylbutyl and the like.

Alkenyl is now, for example, vinyl, 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, 1-butenyl, methylalyl.

R ⁴ represents a cycloalkylalkyl group, for example cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and the like.

As a radical R ⁴ is a suitable alkyl, alkenyl and cycloalkylalkyl having up to 4 carbon atoms.

Physiologically acceptable acid addition salts are derived from known inorganic or organic acids, such as hydrochloric acid, sulfuric acid, hydrobromic acid, citric acid, maleic acid, filmaric acid or tartaric acid.

The compounds of formula I and their pharmaceutically acceptable acid addition salts exhibit pharmacological effects, in particular central dopaminergic activity, and can therefore be used as medicaments.

The dopamine antagonist effect was determined by the method described by Borowski, based on the automatic registration of stereotypes in rats (Arzneim. Forsch. 12, 2281-2286, 1978), immediately after intraperitoneal administration of test substance or vehicle, male Wistar rats (90-120 g). ) are placed one at a time in acrylic glass enforcement cages. Using the electrodynamic sensing system arranged in front of the animal's head, the number of touches on the steel cup with the center metal rod is registered over 60 minutes as a result of the stereotypes of chewing, licking and biting movements. The mean + SEM of the number of touches over 60 minutes is calculated for sperm groups of 12 animals each, and significant differences are found between the mean values of the different doses of the test substance compared to the vehicle-treated control group using a simple variation analysis in conjunction with Dunnet's test.

Since the compounds of the invention are characterized by dopamine antagonistic activity, they are particularly suitable for the treatment of Parkinson's disease.

For the use as medicaments of the compounds of the formula I according to the invention, they are converted into a pharmaceutical preparation which contains, in addition to the active ingredient for enteral or parenteral administration, suitable pharmaceutical organic or inorganic carrier materials such as water, gelatin, acacia, milk sugar, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols and others. The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules or in liquid form, for example in the form of solutions, suspensions or emulsions. In addition, they may optionally contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting the osmotic pressure or buffers.

SUMMARY OF THE INVENTION

Compounds of formula (I) are prepared by quaternary salt of formula (IIa)

(II ·), wherein R ⁴ , X and C ₉ Z 2 are C 10 as defined above, and R ⁷ and R ^{7 is} C 1-6 -alkyl or, together with the nitrogen atom, a 5- to 6-membered unsaturated heterocycle which may optionally be interrupted by an oxygen atom, is reduced to a compound of formula I wherein R ² is methyl. The 2-methylergolines thus obtained may optionally be converted into thioureas or acid addition salts may be formed or the resulting isomers separated.

Suitable 5- to 6-membered saturated heterocycle -NR ⁷ R ^e , which may optionally be interrupted by an oxygen atom, is, for example, piperidine, morpholine or pyrrolidine.

The reaction of the compounds of the formula IIa can be carried out according to the methods described in EP-A 250 357. For example, the quaternary salt of the disubstituted aminomethyl compound with sodium borohydride in polar solvents such as alcohols can be reduced to the 2-methyl compound.

The optional introduction of the double bond can be accomplished by conventional dehydration methods, via sulfonates or acetates, such as methanesulfonic acid chloride in polar solvents, in ethers in the presence of a base, and optionally by heating.

The conversion of urea derivatives into thiourea derivatives can be carried out, for example, as described in EP-A-217 730 by reaction with a POCl 3 thiolating agent. The reduction of the double bond at the 2-3 position can be carried out, for example, as described in EP-A-286 575 by organosilanes in the presence of an acid such as trifluoroacetic acid or sodium borohydride. The compounds of formula (I) are isolated either in the free base form or in the form of their acid addition salt.

For salt formation, the compound of formula I is dissolved, for example, in a little methanol or methylene chloride and made up with a concentrated solution of the desired acid.

Mixtures of isomers may be separated by conventional methods, for example by crystallization, chromatography or by salt formation into diastereomers or E / Z isomers.

The compounds of formulas IIa are valuable intermediates for the preparation of pharmacologically active compounds. The conversion of the intermediates to the active compounds is carried out according to the methods described above.

Unless the production of the starting compounds is described, they are known or can be prepared in analogy to known compounds or in a manner analogous to that described.

Production of starting compounds

1. General working instructions for the Mannich reaction of 3- (6-alkyl-8d-ergolinyl) -1,1-diethylureas.

mmol of ergoline 24.0 g (0.19 mol) of morpholine hydrochloride, 4.5 g (0.15 mol) of paraformaldehyde and 220 ml of dry dimethylformamide are mixed in that order and the mixture is stirred for 30 minutes in an oil bath preheated to 100 ° C. . For work-up, the reaction solution was poured onto ice, basified with 25% ammonia solution and extracted with toluene. After drying over sodium sulfate and distilling off toluene in vacuo, the crude product obtained is dissolved in 100 ml of trifluoroacetic acid and stirred for 30 minutes at 60 ° C. The reaction mixture was then poured onto ice and basified with 25% ammonia solution. Extraction with dichloromethane, drying over sodium sulfate and evaporation of the solvent in vacuo gave a dark oil which was purified by chromatography.

The following compounds were produced:

1,1-Diethyl-3- (2-morpholinylmethyl-6-n-propyl-8α-ergolinyl) urea.

Yield after chromatography (SiO 2, dichloromethane 97: 3): 78-89%, (x x) d + 11.3 ((c = 0.5 in chloroform).

1,1-Diethyl-3- (2-morpholinylmethyl-6-n-propyl-8α-ergolinyl) urea, L-hydrogen tartrate.

Yield: 84% (crystalline) (<x) d + 1.6 '(c = 0.5 in methanol).

1,1-Diethyl-3- (2-morpholinylmethyl-6-cyclopropylmethyl-8α-ergolinyl) urea.

Yield after chromatography (SiO 2, dichloromethane / methanol 99: 1-97: 3): 66%, (a) _D = 0.8 '(c = 0.5 in chloroform).

3- (6-Allyl-2-morpholinylmethyl-8a-ergolinyl) -1,1-diethylurea.

Yield after chromatography (SiO 2, dichloromethane-1,1-diethylurea).

Yield after chromatography (SiO 2, dichloromethane / methanol 97: 3): 71-97%, (36-59%) (crystalline), (α) + 2.4 ((c = 0.5 in chloroform).

1.1 -Diethyl-3- (6-ethyl-2-morpholinylmethyl-8a-ergolmyl) urea.

Yield after chromatography (SiO 2, dichloromethane / methanol 99: 1-95: 5): 81%, (46% crystalline), (a) + + 4.0 (c = 0.5 in chloroform).

3- (6-Cyano-9,10-dihydro-2-morpholinylmethyl-8α-ergolinyl) -1,1-diethylurea.

Yield after chromatography (acetic acid esterMethanol 98: 2 - 96: 4): 46 (24% crystalline from acetic acid ester), (<x) d + 301.6 '(c = 0.5 in chloroform).

2. General guideline for the quartemization of the Mannich Compound of Ergoline mmoles is dissolved in about 200 ml of tetrahydrofuran and supplemented with 4.0 ml (65 mmol) of methyl iodide. It is allowed to stir at room temperature for 17-22 hours. The mixture, from which the product starts to precipitate after about 4 hours, is cooled in an ice bath and 100 ml of diisopropyl ether is added dropwise. After 30 minutes at 0'C the salt is aspirated. The material so obtained was used for the next reaction without characterization.

The following compounds were prepared: N- (8a) -3,3-diethylureido (6-n-propyl-2-ergolinylmethyl) -N-methylmorpholinium iodide. Yield: 99-70%.

N- (6-cyclopropylmethyl-8a (3,3-Diethylureido) -2-ergolinyl> N-metylmorfolíniumjodid.

Yield: 64-80%.

N- (6-ethyl-8a- (3,3-Diethylureido) -2-ergolinyl) -N-metylmorfolíniumjodid

Yield: 87%.

N- (6-cyano-9,10-dehydro-8a- (3,3-Diethylureido) -2-ergolinyl) -N-metylmorfolíniumjodid.

Yield: 82%.

3. Bromination of 1,1-diethyl-3- (8α-ergolinyl) urea. 3- (2-Bromo-8a-ergolinyl) -1,1-diethylurea. For production and data see EP 56 358.

4.1.1-Diethyl-3- (2-ethyl-8α-ergolinyl) -urea.

Dissolve 1.00 g (2.47 mmol) of 3- (2-bromo-8α-ergolinyl) -1,1-diethylurea in 10 ml of toluene and make up to 90 mg (0.12 mmol) of 1,1'-bis chloride - (diphenylphosphino) ferrocene-palladium (II) and stirred at room temperature for 15 minutes. Then, 5.5 ml of triethylborane (1M solution in tetrahydrofuran) and 2.5 ml of 4N potassium hydroxide are added and the mixture is heated at reflux for 4 hours. The reaction mixture was acidified with hydrochloric acid, basified with concentrated ammonia and extracted with dichloromethane. The crude product obtained after drying the organic phases (sodium sulfate) and distilling off the solvent in vacuo is chromatographed on silica gel (dichloromethane / methanol 98: 2). Yield after crystallization (acetic acid ester): 307 mg (35%).

(a) o + 47.6 * (c = 0.5 in chloroform).

5. Cyanamide reduction was performed according to published methods ¹ *.

¹¹ A. Ceniy et al .: Collection Czechoslovak Chem. Commun., 1984, 49, 2828.

The following compounds were prepared from the 6-cyano derivatives:

3- (9,10-dehydro-2-methyl-8α-crgolinyl) -1,1-diethylurea

3- (9,10-Dehydro-2-methoxymethyl-8a-ergolmyl) -1,1-diethylurea

3- (9,10-Dehydro-2-methylthiomethyl-8a-ergolmyl) -1,1-diethyl urea

3- (9,10-dehydro-2-hydroxymethyl) -8a-ergolinyl) -1,1-diethylurea

3- (9,10-Dehydro-2-ethyl) -8a-ergolinyl) -1,1-diethyl urea

DETAILED DESCRIPTION OF THE INVENTION

Example 1

General working instructions for the reduction of quaternary salts with sodium borohydride.

Dissolve 1.00 mmol of ergoline in 35 mL of dry ethanol, make up 184.6 mg (5.00 mmol) of powdered NaBfL and stir at room temperature. After completion of the reaction, the mixture was poured onto ice and extracted with dichloromethane. The crude product obtained after drying over sodium sulfate and distilling off the solvent in vacuo is purified by chromatography or crystallization.

The following compounds were prepared: 3- (6-Cyclopropylmethyl) -2-methyl-8α-ergolinyl) -1,1-diethylurea.

Yield after crystallization (acetic acid ester / diisopropyl ether): 61%, (a) 0-52 (c ⁼ 0.5 in chloroform).

3- (6-Allyl-2-methyl-8α-ergolinyl) -1,1-diethylurea. Yield after chromatography (SiO 2, dichloromethane / methanol 95: 5): 67%, (35% crystalline), (a) _D -2.8 * (c = 0.5 in chloroform).

1,1-Diethyl-3- (6-ethyl-2-methyl-8α-ergolinyl) -urea. Yield after chromatography (SiO 2, dichloromethane / methanol 97: 3): 33%, (13% crystalline), (α) + 32 * (c = 0.5 in chloroform).

3- (6-n-Propyl-2-methyl-8α-ergolinyl) -1,1-diethylurea Yield after crystallization (acetic acid ester / diisopropyl ether): 63%, (a) n + 34 * (c = 0.5 in pyridine).

Example 2

General procedure for the production of thioureas from ureas.

At -20 ° C it is dissolved in 5 ml of dichloromethane in the same sequence of 0.13 ml of freshly distilled POCl 3 (1.4 mol) and 0.23 mmol of ergolinyl urea. The mixture is stirred overnight at room temperature, then the volatiles are carefully distilled off under vacuum and the residue is dissolved in 10 ml of acetonitrile. A solution of 205 mg of potassium methylxanthate (1.4 mmol) in 20 mL of acetonitrile was added to the mixture at room temperature, stirred at room temperature for 2 hours, and was quenched with ice and concentrated ammonia solution. The mixture is extracted with dichloromethane, the organic phases are chromatographed together with sodium sulfate, ethyl acetate and recrystallized from acetic acid ester / diisopropyl ether.

The following compounds were prepared: 3- (9,10-Dehydro-2-ethyl-6-n-propyl-8α-ergolinyl) -diethylurea.

Yield: 15% (a) of + 373 ® (0.25% in chloroform).

3- (9,10-dehydro-2-methyl-6-n-propyl-8a-ergolinyl) -dietyltiomočovina.

Yield: 39% (a) of + 419 '(0.5% in chloroform).

1,1-Diethyl-3- (2,6-di-n-propyl-8α-ergolinyl) thiourea.

Yield: 61% (a) by + 91 '(0.25% in chloroform).

1,1-diethyl-3- (2-methyl-6-n-propyl-8α-ergolinyl) thiourea.

Example 3

1,1-Diethyl-3- (9,10-dehydro-2,3H-dihydro-2,6-methyl-6-n-propyl-8a-ergolinyl) urea

980 mg of 3- (9,10-didehydro-2-methyl-6-n-propyl-8α-ergolinyl) -1,1-diethylurea (2.3 mmol) are dissolved in trifluoroacetic acid and after 5 minutes at room temperature add 1.48 ml of triethylsilane in three equal portions. It is then stirred for 60 minutes, then ice is added first and then, with cooling, a 25% ammonia solution and the alkaline solution is shaken with dichloromethane. The organic phase is dried and evaporated. The yield after chromatography is 378 mg. Crystallization from acetic acid ester (diisopropyl ether is 106 mg) (12%), (ajo = + + 204 '' (0.5% in chloroform).

1,1-Diethyl-3- (2,3-p-dihydro-2-methyl-6-n-propyl-8α-ergolinyl) urea.

Yield: 63%.

1,1-Diethyl-3- (2,3-p-dihydro-6-ethyl-2-methyl-8α-ergolinyl) urea.

Yield: 34%, (a) c = + 50 '(0.5% in chloroform).

l, l-Diethyl-3- (2,3P-dihydro-2,6-di-n-propyl-8a-ergolinyl) urea.

Yield: 33%, (<i) d = + 63 '(0.57% in chloroform).

1,1-Diethyl-3- (2,3-p-dihydro-6-ethyl-2-methyl-8α-ergolinyl) thiourea.

Yield: 29%, (? X) d = + 70 ° (0.5% in chloroform).

Claims (2)

Process for the preparation of 2-substituted ergolines of the general formula I Bé (1), wherein C ₂ X ₂ is: C 3, C 2 z 2 of C 10 single or double bond; X is oxygen or sulfur; R * methyl; R ⁶ C ₂ . C1-alkyl, C3-alkenyl or C1-cycloalkylalkyl as well as their acid addition salts and isomers, characterized in that the quaternary salt of the general formula H and (III ') wherein R ⁶ , X, C 5 -C 10, R ⁷ and R ⁸ are as defined above, is reduced to a compound of formula I wherein R ² is methyl and the methylergolines obtained are optionally converted to thioureas or acid addition salts are formed or the isomers obtained separated. The end of the document (IIa), wherein R ⁶ , X and Cs C 10 are as defined above and R ⁷ and R ⁷ are C 1-6 alkyl or together with the nitrogen atom a 5- to 6-membered heterocycle which may optionally be interrupted by an oxygen atom, is reduced to a compound of formula I wherein R ² is methyl and the resulting 2-methylergolines are optionally converted to thioureas, or acid addition salts are optionally formed, or the resulting isomers are separated. A process for the preparation of 2-substituted ergolines of the general formula I according to claim 1 (i). wherein C _9, C 2, C 2, X, R ² , R ⁴ are as defined above and C ₂ - C 3 is a single bond as well as their acid addition and isomer addition salts according to claim 1, characterized in that: Quaternary salt of formula Ra