NO133670B - - Google Patents

Description

Procedure for the preparation of lysergamides of general formula I:

where :F"*"y "denotes a -CH=C- or -CH2~CH group,

R^ denotes a hydrogen atom or a methyl group and

R2 denotes an allyl group, a phenyl, pyridyl or pyrimidyl group which optionally has one or more met

oxy, halogen, trifluoromethyl and/or nitrosubstituents, an n-propyl or n-butyl group which optionally has one or more carbomethoxy and/or nitroguanidino substituents, or a glycol-tyrosinol group.

In this description, the term "lysergic acid" means a completely general statement, and thus the term can refer to isolysergic acid, as well as D and Ir antipodes or the racemic forms of the acids. The R 2 group in the compounds of general form I may likewise be derived from optically active or inactive substituted amines.

It is well known that lysergamides are compounds of great medical importance. Thus, e.g. all of the ergot alkaloids that exist in nature are lysergamides. The semi-synthetic methods that start from lysergic acid in most cases concern the production of lysergamides and lysergalkanolamides, since these compounds greatly extend the therapeutic applicability of the lysergic acid derivatives.

Several methods have been developed for the semi-synthetic production of lysergamides. The first of the widely used methods was developed by A. Stoll and A. Hofman (Helv.Chim. Acta 26, I9U-3). According to this procedure, lyserg peptides cleaved to form lyserg hydrazide which was converted to lyserg azide, and this compound was used in the acylation of various amines. However, a major disadvantage of this so-called azide method is that it proceeds with a low yield, and a significant amount of by-products are also formed.

Another known method is the so-called mixed anhydricT coupling method. According to this method, a mixed anhydride from lysergic and trifluoroacetic acid is formed (US patent no. 2,736,728)

or from lysergic acid and sulfur trioxide (German Patent No. 1.0^0.560), and the resulting mixed anhydride is used in the acylation of alkanol amines. However, this method does not allow the production of identical lysergalcanolamides.

According to another known procedure, the acylation is carried out with lyser halides. Production of the respective lyser halides is described in Hungarian patent documents No. 150A25 and 151.8^7. However, these methods are disadvantageous in many respects, so e.g. the acid chloride formation is only carried out under extremely aggressive reaction conditions (e.g. using phosphorus trichlorA3 as solvent and phosphorus oxychloride and phosphorus pentachloride as chlorinating agents), the resulting acid chloride contains a large amount of impurities (first of all lysergic acid, inorganic phosphorus compounds and lysergic chloride also chlorinated in 2 position), and finally no method has been developed for purifying the acid chloride. Furthermore, the acylation using lysergic chloride can only be carried out with a maximum yield of 70$, and the impurities of the lysergic chloride also appear in the lysergamides produced in this way.

Austrian Patent No. 216,679 describes a process for the preparation of monosubstituted lysergamides, according to which lysergic acid and a primary amine are condensed with each other in the presence of carbodiimides. Using this method, however, significant yields cannot be obtained, since the optically active lysergic acid is practically completely converted to the racemic form during the course of the reaction.

Of further known methods for the production of lysergic acid canolamides, mention should be made of the direct condensation of lysergic acid with amino alcohols (Collection 3ij 3^15, 1966), and amidation of lysergic acid methyl ester (Collection 22, 101^, 1957). However, these methods require very high temperatures (190 to 200°C) and

long reaction times (8 to 10 hours), and they proceed with very low yields.

The present invention provides a new method for the production of lysergamides, free from the disadvantages with which the hitherto known methods have been affected, and where a very pure product is produced with a good yield by an easily carried out reaction without the formation of by-products.

■ The method according to the invention is based on the discovery that lysergamides are formed in a completely pure state when active lysergic acid esters are reacted with compounds containing a primary or secondary amino group. Neither isomerization nor racemate formation takes place during the course of the reaction, and the synthesis proceeds with a practically quantitative yield. This method can be used without exception in the preparation of any acid amide of lyserg-

acid, N-alkyl-lysergic acids, 9,10-dihydro-lysergic acids and N-alkyl-9,10-dihydro-lysergic acids.

The present invention therefore relates to a new process for the production of lysergic acid amides of general formula I, and their acid addition salts, which process is characterized by an active lysergic acid ester of general formula II:

where x~^"y and R-, have the previously indicated meanings^ Z denotes

halogen atoms and/or nitro groups, and n is a factor from 1 - 55 is amidated with a compound containing a primary or secondary amino group, and if desired, the resulting compound of general formula I is converted into an acid addition salt by reaction with a pharmaceutically acceptable acid.

A group of the new compounds exhibits specific antiserotonic activity. According to experiments carried out on isolated organs under in vitro conditions, these compounds inhibited the smooth muscle contraction activity induced by serotonin, while under in vivo conditions they acted as antagonists at low doses to the inflammation-inducing and circulation-influencing effects of serotonin. Another group of the new compounds exhibited a significant depressant activity on the central nervous system, thus suppressing the spontaneous motility of test animals and acting as an antagonist to the stimulating activity evoked of psychostimulant pharmaceuticals, e.g. amphetamine. A further group of compounds with antidepressant activity exhibited activities similar to the tricyclic antidepressants. In "experiments carried out on rats and mice, they acted as antagonists to the neuroleptic activities elicited by reserpine and potentiated the psychostimulant activity of amphetamine . However, these compounds differ from the tricyclic antidepressants in that they do not increase the vasopressor activity of norepinephrine.

The compounds of general formula II, which are used as starting materials in the process according to the invention, can be prepared by reacting lysergic acids of general formula III: where R-, and have the previously indicated meanings, with phenols of general formula IV:

where Z and n have the previously stated meanings, in the presence of dehydrating agents.

Among the active lysergic acid esters, pentachlorophenolates can preferably be used. The reaction is preferably carried out in the presence of an inert solvent, such as tetrahydrofuran, acetonitrile, methylene chloride or dimethylformamide. The active lysergic acid esters can be used in isolated form, but the reaction can also be carried out using the reaction mixture in which these active esters are formed.

As amino reagents, any substituted amine compound can be used such as mono- or polyhydric amino alcohols, mono- or di-substituted alkyl amines, amino acids, di- or tri-peptides, mono-substituted piperazines, aryl amines, e.g. aniline and aniline derivatives, aminopyridines etc_

The invention reveals several advantages, among which the following should be particularly mentioned: a) the new method can be carried out without exception in the preparation of any substituted lysergamide.

b) the reaction can be carried out in a simple process,

c) no by-products are formed during the course of the reaction,

d) the reaction proceeds with a high yield,

e) the compounds are of high purity and exhibit valuable properties

pharmacological properties.

The invention shall be further illustrated by the following examples.

Example 1

Preparation of l- methyl- 9. 10- dihydro- d- lysergic acid- C^- methoxy)- anilide

5.53 g of l-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester was dissolved in 100 ml of dry chloroform with stirring, then the solution was quenched with ice water and 1.35 g of p-methoxy-aniline was dissolved in 10 ml of chloroform was added dropwise. The solution was stirred at room temperature for one hour, then it was extracted - with 6x25 ml of 1% aqueous tartaric acid solution. The aqueous extracts were combined, and the pH of the mixture was adjusted to 8 by the addition of a few milliliters of 10 µg aqueous ammonium hydroxide solution. The aqueous solution was shaken with 5x50 ml of chloroform. The chloroform solution was combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in 10 ml

benzene and the benzene solution was poured into 300 ml of dry petroleum ether. The separated precipitate was filtered off, washed with a small amount of petroleum ether and dried in vacuo. The product was subjected to chromatography on an aluminum oxide column, using an 8:2 mixture of chloroform and benzene as eluent. In this way, 3.56 g (91$) of 1-methyl-9,10-dihydro-d-lysergic acid-(^-methoxy)-anilide with a melting point of 159°C were obtained.

The starting material, l-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester was prepared as follows: 1.1+3 g of l-methyl-9,10-dihydro-d-lysergic acid free of water was suspended in a mixture of 60 ml of absolute tetrahydrofuran and 60 ml of absolute dichloromethane, after which 1.35 g of pentachlorophenol was added. The resulting solution was cooled with stirring to a temperature between 0° and 5°C, and 1.25 g of dicyclohexylcarbodiimide was added in small portions over the course of 2 hours. The solution was gradually heated to 20° and stirred for several hours. Dicyclohexylurea separated in crystalline form was filtered and washed with 10 ml of tetrahydrofuran. The filtrate and washings were combined and evaporated to dryness under reduced pressure. The dry residue was dissolved hot in 5 ml of benzene and the solution obtained was poured under stirring into 50 ml of petroleum ether. The resulting suspension was treated with ice for 2 hours, after which the product was filtered, washed with 20 ml of cold petroleum ether and dried under vacuum.

Yield: 2.0 g ($75), (a>p° = -20° (c- = 0.5 ethanol).

Example 2

Preparation of d-lysergic acid-(^-methoxy)-anilide

This compound was prepared as described in Example 1, from 5.37 g of d-lysergic acid pentachlorophenol ester and 1.5 g of p-methoxyaniline. The product was obtained in a yield of 8% (3.1 g) and melted at 127°C.

The starting compound, d-lysergic acid pentachlorophenol ester was prepared from d-lysergic acid and pentachlorophenol in a similar manner as described in Example 1.

Yield: 62$(a)^° = +31° (c = 0.5 ethanol).

Example 3

Preparation of 9. 10-dihydro-d-lysergic acid-(1+-methoxy)-anllide This compound was prepared as described in Example 1 from 5.39 g of 9,10-dihydro-d-lysergic acid pentachlorophenol ester and 1.5 g of p- methoxyaniline. 3.1 g (82.5$) of the title compound was obtained, m.p. 16k°C.

The starting compound 9,10-dihydro-d-lysergic acid pentachlorophenol ester was prepared from 9,10-dihydro-d-lysergic acid and pentachlorophenol in a similar way as described in Example 1.

Yield: 69.5$, (a)^° = +3° (c = 0.5 ethanol).

Example h

Preparation of d-lysergic acid-6-(If-chloro-5-nitropyimidine)-amide

This compound was prepared as described in Example 1

from 5.37 g of d-lysergic acid pentachlorophenol ester and 2.0 g of ^-chloro-5-nitro-6-amir.o-pyrimidine. 3.2 g (7*+$) of the title compound were obtained, m.p. 2<>>+0°C.

The starting compound, d-lysergic acid pentachlorophenol ester was prepared as described in Example 2.

Example 5

Preparation of 9,10-dihydro-d-lysergic acid-2-(5-bromo-pyridine)-amide

The compound was prepared as described in Example 1 from

^.70 g of 9,10-dihydro-d-lysergic acid-(2,1f,5-trichlorophenol)-ester and 2.0 g of 2-amino-5-bromopyridine. 3.5 g (80$) of the title compound was obtained, m.p. 132°C.

The starting materials 9,10-dihydro-d-lysergic acid-(2,^1-,5-trichlorophenol)-ester were prepared from 9,10-dihydro-d-lysergic acid and trichlorophenol in a similar manner as described in Example 1.

Example 6

Preparation of l- methyl- 9. 10- dihydro- d- lysergylglycyl- tyrosinol

This compound was prepared as described in Example 1

from 5.53 g of l-methyl-9,10-d-lysergic acid pentachlorophenol ester and 2.8 g of glycyl-tyrosinol. There was obtained ^.5 g (89$) of the title compound, m.p. 152°C.

The starting material, 1-methyl-9,10-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 1.

Example 7

Preparation of 9. lO- dihydro- d- lysergic acid- (3- trifluoromethyl)- anilide

This compound was prepared as described in Example 1 from 5.39 g of 9,10-dihydro-d-lysergic acid pentachlorophenol ester and 2.0 g of 3-trifluoromethyl-aniline. 3.1 g (72$) of the title compound was obtained.

Sm.p. 130°C.-

The starting material 9,10-dihydro-d-lysergic acid pentachlorophenol ester was prepared as described in Example 3"

Example 8

Preparation of l-methyl-9,10-dihydro-d-lysergic acid-(3-trifluoromethyl)-anilide

This compound was prepared as described in Example 1

from ^.05 g of 1-methyl-9,10-dihydro-d-lysergic acid-(^-nitro-phenol ester and 2.0 g of 3-trifluoromethylaniline. 2.9 g (68$) of the title compound was obtained Melting point 2l+2°C.

The starting material, l-methyl-9,10-dihydro-d-lysergic acid (l-nitrophenol) ester was prepared from l-methyl-9,10-dihydro-d-lysergic acid and ^-nitrophenol as described in Example 1, with the exception that the amidation was carried out in the solution of active ester obtained after filtering off dicyclohexylurea.

Example 9

Preparation of d-lysergic acid allyl amide maleate

The free base was prepared as described in Example 1 from

5.37 g of d-lysergic acid pentachlorophenol ester and 1.0 g of 1-allylamine. The free base obtained after chromatography was dissolved in 20 ml of hot ethanol, and 1.2 g of maleic acid dissolved in 5 ml of ethanol was added to the solution. The separated crystalline salt was filtered off, washed with one liter of ethanol and used. 3.6 g (8^-$) of the title compound were obtained, m.p. 179°C.

The starting material, d-lysergic acid pentachlorophenol ester, was prepared as described in Example 2.

Example 10

Preparation of 1-methyl-9,10-dihydro-d-lysergic acid allylamide

This compound was prepared as described in Example 1 from 5.53 g of 1-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester and 1.0 g of 1-allylamine. 3.1 g ($96) of the title compound was obtained. Sm.p. 189°C.

The starting material, 1-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 1.

Example 11

Preparation of d-lysergic acid-2-(1-hydroxy-butane)-amide maleate

This compound was prepared as described in Example 9

from 5.37 g d-lysergic acid pentachlorophenol ester and 1.1 g (+)-1-hydroxy-.2-amino-butane. 3.85 g (8^.5$) of the title compound was obtained. Sm.p. 200°C; (a)^° +^7.0° (c = 1.0 in water).

The starting compound d-lysergic acid pentachlorophenol ester was prepared as described in Example 2.

Example 12

Preparation of l-methyl-d-lysergic acid-2-(l-hydroxybutane)-amide maleate

This compound was prepared as described in Example 9

from 5.51 g of 1-methyl-d-lysergic acid pentachlorophenol ester and 1.1 g of (+)-1-hydroxy-2-aminobutane. ^jl2 g (85$) of the title compound was obtained, m.p. 183°C, (cOp = +^2.0° (c = 0, k in water).

The starting compound, 1-methyl-d-lysergic acid pentachlorophenol ester was prepared from 1-methyl-d-lysergic acid and pentachlorophenol in a similar way as described in Example 1.

Yield: 68$, (a)^° = + lk° (c = 0.5, ethanol).

Example 13

■Preparation of 9,10-dihydro-d-lysergic acid-(If-p-hydroxypropyl)-piperazide maleate

This compound was prepared as described in Example 9

from 5.39 g of 9,10-dihydro-d-lysergic acid pentachlorophenol ester and 1.75 g of p-hydroxy-propyl-piperazine. U-.9 g ($93) of the title compound was obtained. Sm.p. 207°C; ( a)^ ° = - k9° (c = 0.5 in 50$ aqueous ethanol).

The starting compound, 9,10-dihydro-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 3-

Example lh

Preparation of l-methyl-9,10-dihydro-d-lysergyl-uj-nitro-L-arglnine methyl ester

5.53 g of l-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester was dissolved in a mixture of 50 ml of chloroform and 50 ml of tetrahydrofuran with stirring, and 3?5 g of L-u)-nitro-L-arginine methyl ester hydrochloride was dissolved in a mixture of 20 ml chloroform and 8 ml triethylamine was added to the cooled solution". The reaction mixture was stirred at room temperature for 2 hours, then it was extracted with 5 x 30 ml 1% aqueous tartaric acid. The procedure then proceeded as described in Example 1. h, 2 g (86.5$) of the title compound was obtained.

220°C.

The starting compound 1-methyl-9,10-dihydro-d-r.lysergic acid pentachlorophenol ester was prepared as described in Example 1.

Example 15

Preparation of d-lysergic acid dimethylamide

This compound was prepared as described in Example 1 from 2.7 g d-lysergic acid pentachlorophenol ester and 0.5 g dlmethylamine.- 1.3 g

■ (88$) of the title compound was obtained, (a>^0 =-+30° fi-pyridine).

The starting compound, d-lysergic acid pentachlorophenol ester, was prepared as described in Example 2.

Example 16

Preparation of d-lysergyl-L-( + )-cc- aminosuccinic acid methyl ester maleate

1.7 g of L-(+)-2-amino-butyric acid methyl ester hydrochloride (m.p. 9<*>+-96°C; (a)p° = +21° (c =-5, i- 20$ hydrochloric acid ) was suspended in 150 ml of chloroform, and the suspension was cooled to 10°C. 1 ml of triethylamine was added dropwise to the stirred suspension, then 5.37 g of d-lysergic acid pentachlorophenyl ester was sprinkled into the obtained suspension, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with 30 µl chloroform and extracted with 2 x 50 ml 1% aqueous tartaric acid. The pH of the combined aqueous extracts was adjusted to 7 to 7.5 using 10 µl aqueous ammonium hydroxide, and this watery one

solution was extracted with h x 50 ml chloroform. The organic phases were combined, dried over anhydrous magnesium sulfate. filtered and evaporated to dryness in vacuo. The residue was dissolved in 30 ml of hot ethanol and 1.6 g of maleic acid dissolved in 6 ml of ethanol was added to this solution.

nothing. The obtained suspension was cooled in ice for several hours, after which the precipitate was filtered off, washed with 10 ml of ethanol and dried in vacuum. 3.17 g (86$) of the title compound was obtained. Sm.p. 200°C (decomposition), (oc)^ ° = +35° (c = 1, in 50$ aqueous ethanol).

The starting compound, d-lysergic acid pentachlorophenol ester,. was prepared as described in Example 2.

Example 17

Preparation of l-methyl-d-lysergyl-L-(+)-α-aminosuccinic acid methyl ester maleate

This compound was prepared as described in Example 16, from 5.55 g of 1-methyl-d-lysergic acid pentachlorophenol ester and 1.7 g of L-(+)-2-aminosuccinic acid methyl ester hydrochloride. It was obtained

3.21 g (8^f$) of the title compound. Sm.p. 178°C (decomposition);

(oc)p° = +17.3° (c = 1, in 50$ aqueous ethanol).

The starting compound, 1-methyl-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 12.

Example 18

Preparation of d-lysergyl-l-alanine methyl ester

This compound was prepared as described in Example 1

from h, 82 g of d-lysergic acid-2,1+, 5-trichlorophenyl ester and 1.6 g of 1-alanine methyl ester hydrochloride. 3.1 g ($88) of the title compound was obtained. (a) D = -6^-° (c = 1 in chloroform),

The starting material, d-lysergic acid-2,k,5-trichlorophenyl ester, was prepared from d-lysergic acid and 2,*+,5-trichlorophenol as described in Example 1 with the exception that the amidation was carried out in solvent

of the active ester obtained after filtration of dicyclohexylurea.

Claims (3)

1. Procedure for the production of lysergamides of general formula I: where x y denotes a -CH=C- or -CH2~CH group, R-^ denotes a hydrogen atom or em methyl group, and R denotes an allyl group, a phenyl-, pyridyl-, or pyrimidyl group- which optionally has one or more methoxy-r-halogen, trifluoromethyl 1- and/or nitro-substituents, an n-propyl- or n-butyl group which optionally has one or more cajrbomethoxy- and/or nitroguani- dino-substituents, or a glycol-tyrosinol group, characterized by an activ-lysergic acid ester of general formula II: where x~*~^y and JL have the previously stated meanings, Z denotes halogen atoms and/or nitro groups, and where n is a factor from 1 - 5, is amidated with a compound containing a primary or secondary amino group, and if desired, the obtained compound of general formula I is converted into an acid addition salt by reaction with a pharmaceutically acceptable acid. 2. Procedure according to claim 1, characterized in that the corresponding pentachlorophenol ester is used as active lysergic acid ester. 3. Method according to claim 1 or 2, characterized in that the amidation is carried out directly in the reaction mixture in which the active lysergic acid ester is formed, without isolation of the active ester.