CZ60191A3 - Process for preparing 2-substituted ergolines - Google Patents

Abstract

(A) Ergoline derivs. of formula (I) and their isomers and acid-addn. salts are new, where, the C2-C3 and C9-C10 bonds are single or double; X = O or S; R2 = 1-10C alkyl, 2-10C alkenyl, 2-10C haloalkenyl, CH2YR3, CR12(OR4)R5, CH2CH(R9)COR10 or COR12; Y = O or S; R3 = H, 1-4C alkyl, phenyl, 2-5C acyl or phenyl (1-4C) alkyl; R4 = H or 2-5C acyl; R5 = 1-9C alkyl; R9 = acetyl or 2-5C alkoxycarbonyl; R10 = 1-4C alkyl or 1-4C alkoxy; R12 = H or 1-9C alkyl; R6 = 2-10C alkyl, 3-10C alkenyl or (3-7C)cycloalkyl(1-3C)alkyl. (B) Intermediates of formula (IIa) are also new (see 'Preparation').

Description

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

BACKGROUND OF THE INVENTION

2-substituted ergolinyl urea derivatives 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 blocking effect of the α 1 -receptor. Surprisingly, it has now been found that by introducing a long chain hydrocarbon residue at the 6-position of 2-substituted ergolinyl urea derivatives, the effect shifts from dopamine antagonism to dopaminagonism while maintaining or improving the metabolic stability of the compounds.

The invention relates to compounds of formula I ξίΗ - CX - N / C ₂ H _5/2 ^'?

- στ / 1 / where ° ₂ mp _{3 is a} double bond and C, '10 is single or

-2X oxygen or sulfur

R ² . C _1-8 -alkyl, C ₂ -C ₅ -alkenyl, CR ¹² / OR ⁴ / R ⁵ , CH 2 OH,

CH-O-C ^^ - alkyl, CH-O-Cg ^^ - ^^ alkanoyl.CHg OC alkyIfenyl, CH-SC _1-4 -alkyl,

R ^{4 is} hydrogen, R ⁴ -C 5 -alkyl and R 4 -H or C 1-6 -alkyl,

R ⁶ C _2w5 -alkyl, _{C "5} -alkenyl or C ₄ -5 - y ° ^kloal cycloalkylalkyl, as well as their acid addition salts and isomers.

When C ^ * * * * C ^ o represents a single bond, then the hydrogen atom at the 10-position is always O ^ »if Cg ** * * C ^ represents a single bond, then the hydrogen atom at the 3-position 3θ always (¾. they may act as E- or Z-isomers or, if a hiral center is present in the radical R?, they may act as diastereomers and mixtures thereof.

The term alkyl refers to both a linear and branched chain alkyl radical, such as methyl, ethyl, pyridyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. butylpentyl, hexyl, heptyl, octyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl and others - Alkenyl now means, for example, vinyl, 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, 1- butenyl, methalyl.

p

The alkenyl radical R may be substituted one or two times with a halogen such as fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

When R is cycloalkylalkyl, it is meant, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and the like.

Suitable radicals R are alkyl, alkenyl, and cycloalkyl of up to 4 carbon atoms. The residues S ³ and S should not have more than 9, preferably more than 6, carbon atoms.

The physiologically acceptable acid addition salts are derived from known inorganic or organic acids, such as sulfuric acid, sulfuric acid, broccinic acid, citric acid, maleic acid, fumaric acid or tartaric acid.

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

Dopaminantagonisic effect was determined using 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 the test substance, in the case of a vehicle, male Wistar rats (90-120 g) were placed one at a time in acrylic glass coil cages. by means of an electrodynamic sensing system arranged in front of the animal's head, the number of contacts on the steel cup with the center metal rod is regionated for 60 minutes as a result of the stereotypes of chewing, licking, and biting movements. The average value of S.B.M. The number of touches during 60 minutes is calculated for the? groups of 12 animals each, and significant differences were found between the mean values of the different doses of the test substance compared to the vehicle-shaken control group, by simple variation analysis and in connection with the Dunnet test.

Since the compounds of the invention are characterized by dopaminantagonist activity, they are particularly suitable for the treatment of Farkinson's disease.

For the use as medicaments of the compounds of the formula X according to the invention, they are converted into a pharmaceutical preparation containing, in addition to the active substance for enteral or paienteral 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 IIIa

NH - CX - N / C ₂ H _5/2

/ IIa / wherein the means X and Cg * * * * C _1Q it _has the above meaning and jj _and ⁸ ^ 1-6 "alkyl or together with the nitrogen atom a five- or six-membered unsaturated heterocycle which may optionally be interrupted by oxygen , is reduced to a compound of formula I wherein R 1 is methyl. The 2-methylergolines thus obtained may optionally be converted into thioureas or may be formed by addition of a safe acid or the resulting isomers separated.

A 5-6 membered saturated heterocycle -NR ^ R®, which may optionally be interrupted by an oxygen atom, is suitable, 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 amino methyl compound with sodium or hydrate in polar solvents such as alcohols can be reduced to the 2-methyl compound.

Eacultative introduction of the double bond may be accomplished by conventional dehydration methods such as sulfonates or acetates such as methanesulfonic acid chloride in polar solvents such as ethers in the presence of a base and optionally with heating.

If the R substituent contains an exocyclic double bond, it can be reduced in the usual manner to the corresponding alkyl derivative. The reduction can be carried out, for example, catalytically with palladium on carbon or Raney nickel at room temperature in aliphatic alcohol or by reduction in liquid ammonia in sodium. an inert solvent such as cyclic and non-cyclic ethers in the presence of a proton donor such as aliphatic alcohols.

If R * contains a 2-hydroxyl group, it can be reduced, for example by reaction with NaBH4 in glacial acetic acid, to the corresponding 2-alkyl derivative.

Conversion of urea derivatives to thiourea derivatives can be carried out, for example, by the method described in EP-A-217 730 by reaction with phosphorus oxychloride and a thioling agent. The reduction of the double bond in the 2-3 position can be carried out, for example, as described in EP-A-286,575 organylsilanes in the presence of an acid such as trifluoroacetic acid or trium borohydride. The compounds of formula I are isolated either in free base or acid addition salts.

For salt formation, the compound of formula (I) is dissolved, for example, in a little methanol or methylene chloride. and make up with a concentrated solution of the required acid ·

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

Compounds of formulas IIIa are valuable intermediates for the preparation of pharmacologically active compounds. The conversion of the intermediates to the active compounds is carried out as described above.

If the preparation of the starting compounds is not described, then these are known or can be prepared analogously to known compounds or in a similarly described manner.

Production of starting compounds

1. General working instructions for the Mannich reaction of 3/6-alkyl-8 (.alpha.-eggolinyl) -1,1-diethylmolamine ergoline mmol, 24.0 g (0.19 mol), morpholine hydrochloride, 4.5 g (0.15) mole / paraformaldehyde and 220 ml of dry dimethylformamide are combined, and the mixture is stirred for 30 minutes in an oil bath preheated to 100 ° C. For working up, the reaction solution is poured on ice, basified with 25% ammonia solution and extracted with toluene. After drying over sodium sulfate and distilling off the toluene in vacuo, the crude product obtained is dissolved in 100 ml of trifluoroacetic acid and stirred at 60 DEG C. for 30 minutes. The reaction mixture is then poured onto ice and basified with 25% ammonia solution. Extraction with dichloromethane, drying over sodium sulfate and removal of the solvent in vacuo gave a dark oil which was purified by chromatography.

The following compounds were produced:

1,1-Diethyl-3- / 2-morpholinomethyl-6-n-propyl-8o-6-ergolinylurea

Yield after chromatography (SiO 2, dichloromethane / methanol 97 S 3): B 8 - 89% (mp + H 3) (c = 0.5 in chloro form).

-71.1- diethyl-3- (2-morpholinomethyl-6-n-propyl-8 ergolinyl) -urea, 1-hydrogen tartrate

Yield = 84 $ / crystalline /, / «* C / _D + 1.6 ⁰ / c = 0.5 in methanol /.

1,1-Diethyl-3- (2-morpholinomethyl-6-cyclopropylmethyl-8H-ergolinyl) -urea

Yield after chromatography / Si0 _2, dichloro »rmethan / mexha Nol 99: 1-97: 3/66 $ / OC / - ~ 0.8 ^0/0 $ c = 5; chloroform /.

3- (6-allyl-2-morpholinomethyl-8qL-ergolinyl) -1,1-diethylamine

Yield after chromatography (SiO ₂ , dichloromethane) -1.1 diethylurea

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

1,1 - Die-ethyl-3- / 6-ethyl-2-morpholinomethyl-80C- ergolinyl / -urea

Yield after chromatography (SiO ₂ , dichloromethane / methanol 99 µl - 95: 5): 81 $ (46 $ crystalline), [α] _D + 4.0 ⁰ (0 = 0.5 in chloroform)

3- (6-cyaro-9,10-dihydro-2-morpholinomethyl) -80- (4-oxolinyl) -1,1-diethylurea

Chromatography yield (acetic acid ester / methanol 98: 2 - 96: 4): 46/24 (crystalline from acetic acid ester), (δ L) + 301.6 ⁰ (c = 0.5 in chloro form) /.

2. General formula for the quaternization of the Mannich ergol mmol compound is dissolved in about 200 ml of tetrahydrofuran and supplemented with 4.0 ml (65 ramoles) of methyl iodide. After stirring for 17 to 22 hours at room temperature. after about 4 hours, the product is precipitated, cooled in an ice bath and 100 ml of diisopropyl ether is added dropwise. After 30 minutes, the quaternary salt was aspirated at 0 ° C. The material so obtained was used for the next reaction without characterization.

The following compounds were produced:

N- (80t) -3,3-Ethylureido] -6-n-propyl-2-ergolinyl methyl] -N-methylmorpholinium iodide

Yield 59-70

N- (6-cyclopropylmethyl-8O) - (3,3-diethylureido) -2-ergolinylmethyl] -N-methylmorpholinium iodide

Yield: 64 - 80

K- (6-ethyl-8 (N) - (3,3-ethylureido) -2-ergolinylmethyl) -methylmorpholinium iodide

Yield: 87%

N- (6-cyano-9,10-didehydro-8O- [3,3-diethylureido] -2-ergolinylmethyl) -N-methylmorpholinium iodide yield: $ 82

3. Bromination of 1,1-diethyl-3- (8'-ergolinyl) -urea

3- (2-bromo-8O) -ergolinyl] -1,1-diethylurea For production and data see EP 56 358

4. 1,1-Diethyl-3- (2-ethyl-8H-ergolinyl) urea

Dissolve 1.00 g (2.47 mol) of 3- (2-bromo-3 H -ergolinyl) -1,1-diethylurea in 10 ml of toluene and make up to 90 mg (0.12 mmol) of 1,1 * -bis Then, 5.5 ml of triethylborane (1M solution in tetrahydrofuran) and 2.5 ml of 4N potassium hydroxide solution are added and the mixture is heated under reflux for 4 hours. The reaction mixture was acidified with hydrochloric acid, basified with concentrated ammonia and extracted with dichloromethane. Crude product obtained after

The dried organic phases (sodium sulfate) and, after distilling off the solvent in vacuo, are chromatographed on silica gel (dichloromethane / methanol 23: 2). Yield after crystallization / acetic ester / 307 mg / 35 $ / · / ⁰ ^ / ^ + 47.6 0 / c = 0.5 in chloroform /

5. Cyanamide reduction was performed according to published net

1 / A. Cerny et all. Collection Czechoslovak Chem. Commun., 1984, 49, 2828.

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

3- (9,10-didehydro-2-methyl-1- [α] 8-ergolinyl) -1,1-diethyl urea

3- (9,10-Didehydro-2-methoxymethyl-8o-ergolinyl) -1,1-diethylurea

3- (9,10-didehydro-2-methylthiomethyl-8oC -ergolinyl) 1,1-diethylurea

3- (9,10-Didehydro-2-hydroxymethyl) -8Qfc-ergolinyl / 1,1-diethylurea

3- (9,10-didehydro-2-ethyl-8o-4-ergolinyl) -1,1-diethylmorea

DETAILED DESCRIPTION OF THE INVENTION

Example 1

General working instructions for the reduction of quaternary salts with sodium trihydride

Dissolve 1.00 mmol of ergoline in 35 ml of dry ethanol, make up 184.6 mg (5.00 mmol) of powdered KABl and stir at room temperature. After completion of the reaction (DG), pour onto ice and extract with dichloromethane. The crude product obtained after drying over sodium sulfate and distilling off the solvent in vacuo is purified by chromatography or crystals.

-10zací.

The following compounds were produced:

3- / 6-O7klop _rO p% methyl / i-methyl-8 _ffie <* .- ergolinyl / _-l> diethylurea

Yield after crystallization / ethyl acetate / diisopropyl ether / 61 #, / Ot / _D - 5.2 ⁰ / c = 0.5 in chloroform /.

3- (6-allyl-2-methyl-80) (-ergolinyl) -1,1-diethylurea

Yield after chromatography (SiO ₂ , dichloromethane / methanol 95: 5) · 67 $ (35 # crystalline), [?] _D = 2.0 ° (c =

0.5 in chloroform /

1,1-diethyl-3/6-ethyl-2-methyl-8 O ^s ergolinyl / urea

Yield after chromatography (SiO ₂ · CHCl 3 / methanol 97: 3): 33% (13% crystalline), (0C) _D + 3.2 ^° (c = 0.5 in chloroform)

3- (6-n-propyl-2-methyl-8'-ergolinyl) -1,1-diethylurea

Yield after crystallization (acetic acid ester / diisopropyl ether) 65% (O + P + 34 ^° C = 0.5 in pyridine) Example 2

General procedure for the production of thioureas from ureas

At -20 ° C, 0.13 ml of freshly distilled phosphorus oxychloride (1.4 mmol) and 0.23 mmol of ergolinyl urea are dissolved in 5 ml of dichloromethane in the above sequence. The mixture is stirred overnight at room temperature, then the volatiles are carefully distilled off in vacuo and the residue is dissolved in 10 ml of acetonitrile.

The mixture is extracted with dichloromethane, the organic phases are chromatographed with sodium sulphate sulphate and recrystallized from acetic acid ester / diisopropyl ether.

The following compounds were produced:

3- / 9,10-Didehydro-2-ethyl-6-n-propyl-8C-ergolinyl / diethylurea

Yield: 15 $ (C 25 -) _D = + 373 ° (0.25% in chloroform)

3- / 9,10-Didehydro-2-methyl-6-n-phenyl-3α-ergolinyl / diethylthiourea

Yield: 39 / & · / $ ⁸⁸ $ 419 ⁰ / 0.5 fy in chloroform /

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

Yield: 61% - + 91 ° (0.25 fy in chloroform)

1,1-Diethyl-3- (2-methyl-6-n-propyl-80t-ergolinyl) -thio urea

Example 3;

1,1-diethyl-3- (9,10-didehydro-2,3) i-dihydro-2H-methyl-6-n-propyl-80H -ergolinyl] urea

880 mg of 3- (9,10-didehydro-2-methyl-6-n-propyl-1H-ergolinyl) -1,1-diethylurea (2,3 mmol) was dissolved in trifluoroacetic acid and spaced at room temperature at a temperature of 5 DEG C. 1.58 ml of triethyl silane was added in three equal portions. After stirring for 60 minutes, ice was added first, followed by cooling with 25% ammonia solution and the alkaline solution was shaken with dichloromethane. The organic phase was dried and evaporated. Crystallization from acetic acid ester / diisopropyl ether is 106 mg / 12 fy.

-12teor./, / ou / P = ⁰ 204 + / 0.5 ° ^C in chloroform t /.

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

Yield: $ 63

1,1-Diethyl-3- (2,3-dihydro-6-ethyl-2-methyl-8-fit ergolinyl) -urea

Yield: 34 DEG, .delta. = + 50 DEG (0.5% in chloroform)

1,1-diethyl-3- / 2,3-p-dihydro-2,6-di-n-propyl-80 (ergolinyl) -urea

Yield 33 $ i, / r / ^ = 63 + ⁰ / $ 0.57 in chloroform /

1,1-diethyl-3- (2,3) -4-dihydro-6-ethyl-2-methyl-80-ergolinyl / thiamouline

Yield: 28 $, / r / ^. »+ 70 ⁰ / 0.5 $ in chloroform /

7 (/ (’ΟΪχ.ί'Λέ

-13V. 3 Ci <4 i: *? Í'Á? ‘;.> i ´; eiSŽjJJS SS

-J, XJ i r! ?> o!

i · i O c · <

: a · w;

<.-. - ':>

O • U '

Μ »

O, τ

Claims (2)

CLAIMS 1. A process for the preparation of 2-substituted ergolines of the general formula I (I), wherein they are R ^f is a double bond and a single or double bond oxygen or sulfur; C _1-3 -alkyl, C ₂ _ ₅ alkenyl, CR ¹² / 0R ⁴ / R ^5, CH ₂ 0H, CH ₂ -0-C _{1 -4} alkyl, _CH2 -0-C _2-5 -alkenyl, CH _{2 -0-C-4} / -alkyl-phenyl, CH ₂ -SC ^ _ ₄ -alkyl, hydrogen, R 0 _{1 to 5} -alkyl and R ¹² = H or 0 · ^ _ ₄ alkyl C 1-4 -alkyl, C 1-4 -alkenyl or C 1-4 -cycloalkylalkyl, as well as their acid-salt and isomeric salts thereof, characterized in that the quaternary salt of the general formula II C _1-4 -alkyl wherein R ⁶ , X and C 8-6 O 2 O ₁₀ have the above meanings and R ⁷ and R ⁸ represent C _1-6 -alkyl or, together with the nitrogen atom, a 5- or 6-membered heterocycle which is optionally interrupted by an oxygen atom, is reduced to a compound of formula I wherein R is methyl and the methylergolines obtained are optionally converted into thioureas or optionally forming acid addition salts or resolving the isomers obtained. 2. A process for the preparation of 2-substituted ergolines of the general formula 1 d> where ^{»χ» R2} »^ ^fi6 Aji defined above and is a single bond, and their acid addition salts and isomers according to claim 1, wherein the quaternary salt of formula IIa / IIa / -16kde ΙΙ ^, X, and B ⁸ are as defined above known, is reduced to a compound of formula I wherein R is methyl and the resulting ergoline optionally Take the joints in thiomččoviny or optionally formed acid addition salts or the isomers are separated .