DD140044A1 - PROCESS FOR PREPARING LYSERGYL ENKEPHALINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of O.ligopeptide derivatives such as analogs and derivatives of enkephalin with d-lysergic acid, d-isolysergic acid and 9,10-Dihydrolysergsäure and their derivatives as Να-acyl component, wherein the amide formation by means of a Combination of dicyclohexylcarbodiimide and N-hydroxybenzotriazole is achieved in suitable polar organic solvents and the Peptidkomponente preferably in carboxyl-protected ester or Amide form is used. Gentler and easier Reaction is here the formation of by-products largely avoided, with the desired lysergyl-peptide derivatives be obtained in high yield and good purity. The on this Manner by modification of Lysergsäure- like peptide part in the Basic Structure of the Formula Scheme Available Class of the Lysergyl enkephalins and related compounds interesting, therapeutically utilizable properties.

Description

Process for the preparation of lysergyl-enkephalin derivatives

Int. Cl ² . CO7B 457/06

Area of application of the invention . ,

The invention relates to a process for the condensation of lysergic acid, isolysergic acid and 9,1o-bihydrolysergic acid with peptides and enkephalin-type peptide derivatives which have novel pharmacological properties.

C characteristic of "known technical solutions

Of the endogenous pentapeptides, methionine-enkephalin and leucine-enkeühalin ^f; have recently been a number of analogs and derivatives synthesized ^{J 'y,} under which • D-Met ^2, Pro ⁵ amides ^{5' 6} ^ and some D-Ala ² Met ⁵ - (O) - ole '' as anaigetisch proved particularly effective. In contrast, the lysergic acid amides a broad,? ^Yj by modifying the Lysergsäure- as Amida estes largely variable pharmakologisch.es spectrum and diverse therapeutic properties *

d ~ Lysergsäure-, d-Isolysergsäure- and 9,1o-dihydrolysergic derivatives could previously only von'Aminosäuren "and very simply structured, short-chain oligopeptides produced v / ground ^ö _{'9)} W} obei conventional classical methods

/ | _o \ ΊΊ ^)

the. Peptide chemistry, such as the azide _^y} acid chloride · ^w,

^ 14 ")

ip 1 ^ 14- ")

Mixed anhydride " ^JJ , dicyclohexylcarbodiimide- ^J or active ester method. have been transferred to this specific issue. Corresponding lysergic acid derivatives of higher, more complex structured oligopeptides v; ie those of

-Jd-

Enkephalin types could not yet be obtained by these methods because, because of the facile epimerization possibility at the co of the lysergic acid component, unfavorable solubility ratios, decomposability of the required reaction conditions or side reactions on the additional functions of the peptide component complex

more cleanable mixtures are formed. "*.. ...

In DD Patent No. 1227985 'a process for the preparation of amides and peptides of drLysergsäure and 9 »10 di-. hydro ~ d-lysergic acid, which describes the amide formation between the two components by means of dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole in anhydrous, polar organic solvents.

Object of the invention

Gis

The aim of the invention is to find a method for N-acylation of complex structured oligopeptides and oligopeptide derivatives by lysergic acid and its conversion products, which is easy to carry out, leading to pure end products and high yields.

Explanation of the essence of the invention

The object of the invention is to develop a new route for the synthetic development of lysergyl enkephalins and related compounds for the purpose of systematic investigation of this pharmacologically interesting class of substances.

It has been found that for the preparation of lysergyl-enkephalin derivatives of the general formula

CO - Tyr-Gly-GLy-'Rbe-Met-OMe

with oligopeptides of the bnkephalin type as amide and d-lysergic acid, d-isolysergic acid and 9i1.o ~ dihydrolysergic acid.

/ if

as N-acyl Xomponente the amide is formed with dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole using Verv / endung of polar organic solvents and the peptide component is hereby preferably used in ester or Amidforra.

This method has the advantage of being suitable for use with higher, more complex, structured oligopeptides, e.g. Pentapeptides with the basic structure of the enkephalin and derivatives derived therefrom is particularly suitable and leads to significant process mixtures advantages such as high yields and uniform products, especially if the peptide component in carboxyl-protected, so. in Ister- or amide ^ orra, with which lysergic acid asrivate is reacted. The solvents used here are polar organic solvents having good solubility properties for the two reactants. Additional functions in the peptide part generally do not need to be covered by temporary protective groups. If d-lysergic acid and its derivatives are used, different proportions of the respective d-isolysergyl compound are formed, depending on the reaction times used, which can be conveniently separated by chromatographic methods. In this way, a broad spectrum of oligopeptide derivatives of the enke-, phalin-type with d-lysergic acid, d-lsolysergsäure, 9} 1o-Dihydrolysergsäure and their derivatives as N -Acylkomponente

,accessible. Among these are some with pharmacologically interesting properties.

embodiments

1. d-lysergyl and d-isolysergyl-met-enkephalin

2.68 g (Ιο, ο.πιΜοΙ) d-lysergic acid / Zers.- point: 2o5 ° C, / cC / ψ = + 12.6 ° (c = 1, o in pyridine) /, 2, o6 g ( 1o, o mmol) bicyclohexylcarbodiimide, 1.8o g (15 »o mmol) F-hydroxybenzotriazole and 6.24 g (10, o mmol) of met-enkephalin methyl ester hydrochloride (mp 143-145 ° C, / oC / ^ ⁰ = + 12.4 ° (c = 1, o ifi methanol) are dissolved in 5o ml of BMF, treated with 1.1 ml (1o, o mmol) of N-methylmorpholine and stirred for 2o Std. "At 2o ° ö in the dark The dicyclohexylurea is then filtered off, the solvent is stripped off at 1 Torr, and the crude product obtained in 60% yield is washed with ethyl acetate, followed by saponification of this mixture of d-lyserglyl and d-isolyserylglycerol. Met-Snkephalinmethylester with o, 1 η NaOH in Bioxan / H ₂ 0 3: 1 3o minutes at 2o ° C. Then the solution with 1 η Hol brought to pH 5, concentrated at 1o Torr, the residue taken up with absolute ethanol , separated by chromatography on silica gel, the two isomers u and reprecipitated from methanol / ether

 d-lysergyl-met-enkephalin: decomposition point: 162-164 ° C,

/ oC / ψ = + 23.7 ° (c = o, 2 in methanol) d-isolysergyl-met-enkephalin: dec. point: 169-171 ⁰ C,

/ y / ^ ° = + 1o, o ° (c = o, 2 in methanol)

2 5

2. d-lysergyl and d-isolysergyl-D-Met, Pro ^ -encephalin

ethylamide,.

1o, o mmol d-lysergic acid, 1 o, o mmol dicyclohexylcarbodiimide, 15, o, mmol of N-hydroxybenzotriazole and 1o, o mmol

2 5

D-Met, Pro - ^ - Enkephalin-ethylamide hydrochloride / Tyr-D-Met-aiy-Phe-Pro-mi-C ₂ H ₅ .HCl, mp: 78-8 ° C, / n /> = ~ 13> 7 (c - o, 8 in ethanol) / are reacted as in Example 1 in DMF and that in 5o - 6oproz. Yield obtained crude reaction product separated into the isomers. The eluates are concentrated at 15 Torr to pH 5 with a

-5 -

saturated methanolic maleic acid solution, the bimaleate precipitated with ether and recrystallized from methanol / ether.

2 5

d-lysergyl-D-Met, Pro ^ -Bnkephalin-ethylamide-bimaleate:

Mp: 138 - 14o ° C, / cC / ^ ° = + 127.8 ° (c = o, 1o in ethanol)

2 5 'd-isolyseryl-D-Met, Pro ^ -enkephalin-ethylamide-bimaleate: mp: 13o - 132 ⁰ C, / öC / ^ = ~ 39.5 ° (c = o, 1o in ethanol) -.

2 5 9j1o-dihydrolyseryl-D-Met, Pro ^ -enkephalinamide

9,1o-dihydrolysergic acid / Zers.- point:> 28o ° G, / ^ / ^ ° = -124.3 ° (c = o, 15 in pyridine) / v, in the same quantitative ratio as in Example 1 and 2 with Dicyclohexylcarbo-

2 S diimide, N-hydroxybenzotriazole and D-Met, Pro ^ -Snkephalin

amide hydrochloride (mp: I38-140 ° C, / cC / ^ = -12 ° C (c = 0.5 in methanol) for 2h at 2o ° C in DPiF Solvent at o, 1 Torr is washed with ethyl acetate and the crude product is purified by silica gel chromatography The Bluat is concentrated at 15 Torr, added to the pH 5 nii ^ a saturated methanolic maleic acid solution, precipitated with ether the Biinaleat and from methanol / Ether recrystallized.

2 5

9,1o-Dihydrolysergyl-D-Met, Pro ^ -Bnkephalin amide bimaleate:

Decomposition point: 2oo ° C, / aC / ψ - -18.7 ° (c = 0.6 in methanol)

Claims (1)

invention claim Process for the preparation of lysergyl-enkephalin derivatives characterized in that with oligopeptides of the
Enkephalin-type as amide and d-lysergic acid, d-isolysergic acid and 9 »1o-Dihydrolysergsäure as N-acyl component, the amide formation with Dicyclohesqylcarbodiiiaid in the presence of N-hydroxybenzotriazole using polar organic solvents takes place and the peptide component here
is preferably used in ester or amide form. GO-Type-GIy-GIy -