DD146460A1 - PROCESS FOR PREPARING 1-BENZYLATED ERGOMETRIN DERIVATIVES - Google Patents

Abstract

1. 1-Benzylated ergometrine derivatives of the general formula I see diagramm : EP0029082,P11,F1 wherein A ... B is -CH=C< or -CH2 -CH< and R**1, R**2 and R**3 are simultaneously or independently H, halogen, lower alkyl, trifluoromethyl or alkoxy, at least one of the substituents R**1, R**2 and R**3 not being H, and their salts with physiologically acceptable acids.

Description

-A-

Title of the invention

Process for the derivation of new 1-benzylated ergometrine derivatives

Field of application of the invention

The invention relates to a method for Herateilung new 1-benzylated Ergoraetrinderivate that should find use as therapeutics, especially for the treatment of therapeutic migraine forms.

Characteristic of the known technical solutions

It is known that, in addition to the native peptide alkaloids of ergot, also semisynthetic ergoline derivatives such as "B ₈ der !!" (D-δ-methyl-S-isoergolenyl) -!], ^ - diethylharnate (A, Cern $ "u · M. Semonsky, Collect · czechoslov.chem.commun. £ 7 (1962), 1585, CS-PS 100832) show the serotonin antagonism important for migraine therapy »

It is further known that some, preferably uterotonic ergolines such as D-Lysergsäurebutanolaraid or D-Lyaergsäurepropanolamid can be converted by 1-methylation into valuable migraine therapeutics with pronounced serotoninantagonistischer V / effect.

(W.Richtzenhain, medical practice 21 (1965), 1738; GB-PS 982737)

However, all the preparations introduced are limited in their application, partly by lifting effects, partly by inadequate action in certain migraine cases. "Attempts to favorably influence the effect of ergometrine derivatives by introducing substituted benzyl radicals in the 1-position have not yet been described."

Object of the invention

The aim of the invention is the provision of new, highly effective serotonin antagonists with low toxicity, wide range of application and reduced side effects, which can be found particularly for the treatment of treatment-resistant migraine forms' application · With these new derivatives to be opened by influencing the spectrum of action new applications

Explanation of the essence of the invention

For the Herateilung the 1-benzylated Ergometrinderivate of the formula I in which AB c £ or -CH -CH- ₀ for the bonds -CH = and in which the radicals R -R may be the same or different is hydrogen, halogen lower, Alkyl, trifluoromethyl or alkoxy, but with at least one mono-substitution, the

transferred to eich known method of 1-alkylation of compounds of formula II by means of alkyl halide and sodium amide in liquid ammonia to corresponding nucleus-substituted benzyl halides V * Since in this reaction, a number of by-products, preferably the 8-alkylated derivatives, (Troxler, F * and A ₄ Hofmann, HeIv chim "Acta 40 (1957), 1721-32; Hempel, R, Grawert, W * and Ch. Dauth, Pharmacie 3 (1979) H 5/6, p Achievement of high yields> the observance of a certain molar ratio of the reactants required · For the benzylation, a molar ratio of ergoline base: NaHH ₂ * benzyl halide of 1: 1.4 ϊ 1.2 was determined as optimum «For the conversion of lysergic acid and 9,10- Dihydrolysergic it is glinetiger, a molar ratio of lysergic acid or 9,10-dihydro lysergic acid: UaIiH ₂ ^J benzyl halide of 1: 3: 4 su. In practice, the reaction is carried out by preparing by adding sodium in liquid ammonia in the presence of catalytic amounts of iron (III) nitrate a sodium amide solution, the ergoline base of formula II enters and then the solution of the substituted benzyl halide s in a little ether to flow quickly. The residue is stirred in aqueous tartaric acid and the solution is purified by shaking with ether. After alkalization, the base of the end product is filtered off with suction or extracted by extraction and converted into a physiologically acceptable salt

A practicable variant of the method is that instead of alkanolamides II a lysergic acid of general formula III as described above aryl-alkylated, the derivatives of formula IV isolated by blunting the tartaric solution to pH 5.5 to 7.0, with one of the methods customary in peptide chemistry, for example, converted by reaction with DMF / SO-p in an activated form and coupled with aminopropanol in T) IiF «

Especially for the preparation of the dihydro derivatives _s d · h # Compounds of the formula I in which A ~ B represents the bond -CH ₂ -CH- can also be obtained from a product of the formula I in which A "B for the bond -CH = C- can be assumed © reduction (9,10-hydrogenation) is carried out catalytically with Raney-Ni in lower alcohols or dioxane at 70 ^° C. and 50 atm hydrogen pressure ·

Another preparation method of the compounds I in which AB is the bond -CH ₂ -CH ^ consists in the conversion of II with excess alkali hydroxide and V preferably in a dipolar aprotic solvent.

The derivatives of the formula I prepared according to the invention and their salts with physiologically tolerated acids have some valuable pharmacological properties, for example as shown in the table below. Thereafter, the compounds 1- (3- ^t- fluorobenzyl) -ergometry-jj-maleinate and 1- (4- ^t- chlorobenzyl) -ergometrine-bimaleinate at the serotonin edema after winter on the rat show a potency comparable to the methysergide *

Table: Average antianerotonin effect on rat serotonin edema calculated as a percentage inhibition to the control group. (Experimental arrangement after winter ₉ C _e H ,, Risley, E "A" and HusSjGeWo, Proc * Soc "Exp" Biol * ^Med * IH (1962). 54)

Doaia; 0.05 dg / kg i.p », values statistically secured *

Substance number of % inhibition after administration of d serotonin each animal 10 30 90 150 210 270 min,

1- (3 '-Pluorbonzyl) - 44. 50 36 55 56 ergometrinbiaa- leinat 1 "(4i-chlorobenzyl) - 44 45 46 61 58 ergometrinbima- 68 60 36 34 46 leinat methysergide

Exercise Examples Example 1

400 ml of ammonia are liquefied in a 1.5 l sulfonating flask with stirrer, dropping funnel, dry ice flask as before with an exhaust pipe after filling the cooling bag with acetone / dry ice. "To this is added 65 mg of iron (III) nitrate and then In portions, 395 mg of Ia as the blue color disappears again. Then 4.0 g of dry ergometrine base are added and the mixture is stirred for 20 minutes, and the solution of 2.82 g of 2-fluorobenzyl bromide in 5 ml of dry ether is added infuse rapidly. The mixture is stirred at reflux for a further 30 min and then worked up as follows:

Kach completely distilling off the ammonia, the dry residue is dissolved in 250 ml of 3% aqueous tartaric acid, the solution washed twice with 100 ml of ether and separated the water phase · It is underlaid with 150 ml of chloroform, adjusted with ammonia water to pH 9 and repeated after phase separation, the chloroform extraction * The total extract is washed with water, dried over Ha ₂ SO ₄ and distilled to dryness in a vacuum rotary evaporator. Then the crude base (5.22 g) is dissolved in 15 ml of methanol and the bimaleinate is precipitated with ethereal maleic acid solution. 5.17 g of 1- (2-fluorobenzyi) -ergometrine bimaleinate * C ₂₆ H ₂₈ PIi ₃ O _{2 are obtained} C ₄ H ₄ O ₄ (mol. Wt. 549.6); Mp. 167.5 ^0C; foCJ ^ ⁰ * + 3,1 ° (C = 0,2 methanol)

In an analogous manner were obtained;

1- (3 -Pluorbenzyl ^t) -ergometrinbimaleinat, mp 184.6 ⁰ * C ^ oC "7p ° = + 4.2 ° (C = 0.2, methanol) 1 '- (4 ^l" Pluorbenzyl) -ergometrinbimaleinat, Schmpo 170.0 ⁰ C 1- (2'-bromobenzyl) -ergometrine bimaleinate, Schrnp, 192.0 ⁰ C K7 I! ₆ = + ⁶ »1 ° (C = 0.4 pyridine)

1 -. (2-methylbenzyl ^l) -ergometrinbimaleinat, mp "184.5 ⁰ C = + 4.6 ° (C = 0.2, methanol)

Example 2

4.0 g of Ergometrinbaae are reacted with 2.38 g of 4-chlorobenzyl chloride analogously to Example 1. »This gives 4.7 g of crude base and 4.45 g of 1- (4'-chlorobenzyl) -ergometrine bimaleinate therefrom

₃ O ₂ (mol, wt. 566.04), m.p. »175.0 ⁰ C,

= + 2.3 ° (C = 0.2 methanol)

Example 3

Aue 300 ml of liquid ammonia, 80 mg of iron (III) nitrate and 630 mg of Na, as described in Example 1, prepared a Na-amide solution · Are added to 5.14 g of 9,10-dihydroergometrine base and after 15 The solution of 5.78 g of 2-fluorobenzyl bromide in 10 ml of dry ether is then stirred for a further 30 minutes and worked up in analogy to Example 1. Substitution of the ischen-carbonated methanolic solution with essential tartaric acid gives the 1- (1) 2 ^f -fluorobenzyl) -

9 »10 dihydroergometrin as bitartrate, ^C 26 ^H 30 ^PH 3 ° 2 'G ₄ H ₆ O ₆ (M.W. · 585.6). Mp »126.0 ⁰ C; p ^ j \ ° = + 2.5 ° (C = 0.2 methanol)

Example 4

5.0 g of the prepared according to Example 1 1- (3 ^f -fluorobenzyl) -ergometrine are dissolved in the form of the base in 200 ml of methanol, mixed with 4 g of Raney nickel catalyst and 2 hours at 70 ⁰ C and 50 atm hydrogenated. After suction filtration of the catalyst the Löaung is distilled to dryness in vacuo and the crude base with ethereal tartaric acid in the bitartrate transferred "to give 4.3 g of 1- (3'-fluorobenzyl) -9,10-dihydroergometrinbitartrat · C ₂₆ H ₃₀ FK ₃ O ₂ . C ₄ H ₆ O ₆ (mol. Wt. 585.6);

Mp * 124.0 ⁰ C; C ° Cj ^ = - 37.8 ° (C = 0.2 methanol) Example 5

In an apparatus as described in Example 1, to 400 mg of liquefied ammonia as indicated 360 mg of Fe (NO ₃ J ₃ .9 H ₂ O, 2.4 g of sodium, 9.4 g of lysergic acid and 29 g of p-Chlorbenzyibromid given After the filtration and phase separation, the aqueous phase is concentrated to about 1/3 of the initial volume and precipitated with 20% sulfuric acid to pH 1 as sulfate.

The precipitate obtained is separated off, washed with a little water and dried at ⁰ ° C. for 5 hours. This gives 12.5 g of a light brown crystal powder. The substance is dissolved in aqueous alkali, cleaned with activated carbon as usual and precipitated again as sulfate. The thus pre-purified substance is chromatographed in aqueous alkaline solution in 20 times the amount of Sephadex ^. From the filtrate, the 1- (4-chlorobenzyl-d-lysergic acid) C ₂ -, H ₂ .ClCl ₂ O ₂ (M.W., 392.6), mp = 136 - 140 ° C at pH 5.5-6.0 with 10% acetic acid. After recrystallization with acetone Scbsip _e 144 - 146 ⁰ C. The sulfate ^C 23 ^H 21 ^C1N 2 ° 2 * ^H 2 ^S0 4 ( ^MoleGew · 490.6) melts at 171 ⁰ C.

Analogously, for example, were obtained: 1- (4-fluoro-benzyl) -d-lysergoic acid; C ₂₃ H ₂ -Pi ₂ O ₂ Schrnp. Sulphate: 178 ⁰ C

1- (4 '~ chlorobenzyl) -9,1O-dihydrolysergic acid; Schmpo as sulphate: 209 ⁰ C, 1 "OCJ ^ ⁰ - - 45,3 ° (C β 0,2 methanol)

Match 6

A solution of 5.14 g dried in vacuo 1- (4 -Chlorbenzyl ^f) d-lysergic acid and 310 mg of dried lithium hydroxide in 50 ml of methanol is concentrated under vacuum to incipient separation of Lithiumlysergates. The concentrate is immediately mixed with 200 ml of anhydrous dimethylformamide and distilled

In an oil pump vacuum at about 40 ^° C. bath temperature up to 60 ml. Then, with stirring and ice-cooling, 26 ml of a 1 molar DMP.sub.2 SO.sub.4 complex solution are added and the mixture is poured after 20 minutes into 6.2 ml (+ ) -2-aminopropanol-O). After stirring for a further 20 minutes, 340 ml of deat-water are added and, after 10 minutes, 340 ml of 20% aqueous tartaric acid are added. The mixture is first extracted 3 times with 100 ml of chloroform and, after subsequent alkalization with conc. Ammonia solution (pH 9-10) again 3 times with 200 ml of ethyl acetate. The ethyl acetate extracts are combined, washed with water and evaporated to dryness over Ha ₂ SO ₄ in vacuo to a syrup. The residue is dissolved in just required amount of methanol and with a solution of 2.5 g of maleic acid in 5 ml of methanol to pH 4 offset · The crude product thus obtained (3.1 g) is purified by Umkrietallisation with methanol / activated carbon · One obtains 2.9 g of 1- (4 ~ ^f chlorobenzyl) -ergometrinbimaleinat · '

^C 26 ^H 28 ^C1II 3 ⁰ 2 ^{β C} 4 ^H 4 ° 4 (M.W. 566.04.); M.p · 175 ⁰ C * In an analogous manner was obtained z * B *: 1- (4'-chlorobenzyl) ~ 9,10-dihydroergometrinbitartrat, ^C 26 ^H 30 ^CIN 3 ⁰ 2 · ^C 4 ^H 6 ° 6 ^"(mol * ^weight * 601.8); C ⁰ ^ Jt? ^Baae = -. 68.8 ° (C = 0.4, methanol) Melting point 124 ⁰ C of 1- (4 ^t -Chlorbenzyl) -9 "10-dihydrolysergic acid (see Example 5) ·

11 - 1

Example 7

A mixture of 1 g of 9-10-dihydroergometrine and 0.65 g of triturated UaOH in 65 ml of dimethylformamide is stirred for 30 min at room temperature. With further stirring, 1.4 g of p-chlorobenzyl bromide, dissolved in 10 ml of dimethylformamide, added dropwise. The workup can be done in 2 variants: Variant A.

The reaction mixture is brought to dryness in a vacuum rotary evaporator at 40 ⁰ C. bath temperature in an oil pump vacuum "The obtained residue (ca * 1.9 g) is added to the necessary amount CHCIo and at the 50-fold amount of Al ₂ Oo, Activity I neutral with chloroform ala eluent chromatographed after elution of by-products, which will result in no blue staining with Secale reagent daa 1- (4'-chlorobenzyl) -9 "1O-dihydroergometrin washed into the filtrate · from methanol needles m.p · 201 ⁰ C. the mixed melting point with the according to example 6 recovered base showed no depression.

Variant B

Bas reaction mixture is concentrated in a vacuum rotary evaporator at 40 ⁰ C bath temperature in an oil pump vacuum to about «1/3 of the initial volume and then treated with 20% tartaric acid to pH 4. It is then extracted 3 times with the same volume of chloroform and after alkalization with conc. Ammonia solution (pH 9-10) extracted 3 times with chloroform as above

The organic extracts of the aqueous-alkaline phase are combined, washed with water, dried over sodium sulfate and brought to dryness in a vacuum rotary evaporator at 35 ⁰ C bath temperature. The residue is dissolved after drying in acetone and mixed with the calculated quantity of solid tartaric acid · Hach stand for 12 hours at 3 ⁰ C is suction filtered and the precipitate washed with ether · Recrystallization from acetone / ether yields 1- (4 ^f -Chlorbenzyl) ~ 9,1O-dihydroergometrinbitartrat which melts at 124 ⁰ C * = - 38.1 ° (C = 1 methanol) (see example 6 *).

O CH-OH

H ι

C-NH-CH

I N-CH

0 CH-OH

C-NH-CH

CH. N-CH.

COOH

COOH

N-CH,

Claims (4)

ErfindungaansprUche 1 3 halide of the formula V in which R-R has the abovementioned meaning and X is halogen, or b) a lysergic acid of the general formula III, wherein A-B has the abovementioned meaning, arylalkylated in the same way and the reaction product IV in activated form with L - (+) - 2-aminopropanol-1 coupled, or -AH- c) an ergometrine of general formula II, wherein A-3 is the bond -CH ₂ -CH ^. is at room temperature in dimethylformamide mixed with powdered alkali metal hydroxide and a solution of V in dimethylformamide added dropwise, 1 · A process for the preparation of novel 1-benzylated ergometrine derivatives of general formula I, wherein the 13
Radicals R - R, which may be identical or different, may stand for hydrogen, halogen, lower alkyl, trifluoromethyl or alkoxy, but at least one monosubstitution being present, as well as A ¹ B for the bonds -CH = C- or -CH ₂ -CKi, characterized in that a) an ergometrine derivative of the general formula II in which A-B has the abovementioned meaning, in liquid ammonia at its boiling point with sodium amide and a substituted benzyl 2 _# Method according to item 1, characterized in that a reaction product of the formula I in which Α-Έ for the bond. -CH = CC is converted to the corresponding 9,10-dihydro derivative by catalytic hydrogenation on Raney nickel. 3. The method according to item 1, characterized in that the synthesis of I via the intermediate IV takes place, being used as the activated form of IV, preferably the mixed anhydride with sulfuric acid. 4 · Method according to item 1 and 2, characterized in that the resulting bases with physiologically acceptable acids in their salts, preferably Maleinate, tartrates or methanesulfonates überfuhrt. For this ... // ropes formulas