IL41409A - Lysergic acid amides and process for their preparation - Google Patents

Description

nnasn^ "pVnni n'-nT'1? nxom *?w O'TDR Lysergic acid amides and process for their preparation Richer Gedeon ¾egyeszeti Gyar RT 2 - 41409/2 ..

This invention relates to novel lysergic amides having the general formula I wherein x , y represents a ^CHeQ- or -CHg-CH- group, represents a hydrogen atom or a methyl group, and ' H9 stands for hydrogen «5 stands for .'J."5 i. an allyl group m il. a phenyl, 2-pyridyl or pyriAidyl group optionally substituted by one or more methoxy, trifluoromethyl, nitro groups and/or a halogen atom ill. an n-propyl or n-butyl group having one or more carbomethoxy and/or nitroguanidine substituent(e) ; iv. a glyco-tyrosinyl group; v. Rg and R- together with the adjacent /nitrogen form a N-hydroxy propyl j&perazine group; and their pharmaceutically acceptable acid addition salts Furthermore, the invention relates also to a process for preparing the lysergio aoid amides of the general formula I. - 2a - . 41409/2 In the specification the termnlysergic acid" is to be interpreted in complete generality; thus it may also denote isolysergic acid, as well ao the D and L antipodes or the racemic forms of the acids. The Hg group of the compounds having the general formula X can similarly be derived from optically active or inactive substituted amines..

It is veil known that lysergic amides are compounds of great medical importance. Thus, e.g. all of the ergot alkaloldes occurring in the nature are lyserglo amides. The semisynthetic processes starting from ¾ eergio acid relate, in the majority of the cases, to the preparation of lysergic amidea and lysergic alicanolamides , since these compounds may broaden the therapeutical applicability of the lysergic acid derivatives to a great extent.

Several processes have been developed . for the semisynthetic preparation of lysergic amides. The first of the widely used methods was elaborated .by A. Stoll and A. Hoffma (Helv. Chim. Acta 26, 944 /1943/). According to this' process lysergic peptides were split to yield lysergic hydrazide, this latter was converted to lysergic azide, and this compound wa3 used for the acylation of different amines. A great disadvantage of this so-called azide method is, however, that it proceeds with a poor yield, and a substantial · amount of by-products is also formed.

Another known process is the 30-called mixed anhydride coupling method. According to this method a mixed anhydride is formed from lysergic acid and trifluoroacetic acid (US Patent Specification No. 2 736 728; or from lysergic acid and sulphur trioxide (German Patent Specification No. 1 040 560), and the obtained- mixed anhydride ig used for the acylation of alk:anolami es . This process, however, does not allow the preparation of uniform lysergic alkanolamides .

According to another known method the acylation.. is carried oat with lysergic halides. The preparation of the respective lysergic halides is described in Hungarian Patent Specifications Nos . 150 25 and 151 847. These processes, however, are disadvantageous in many respects: thus, e.g. the acid chloride formation, can only be carried out unde extremely aggressive reaction conditions (e.g. using phosphorous trichloride as solvent and phosphorous oxychlpride and phosphorous pentachloride as chlorinating agent), the obtained acid chloride contains a high amount of impurities (first of all lysergic acid, inorganic phosphorous compounds and lysergic chloride chlorinated also in the 2 position), and finally no process is known for the purification of the acid chloride* Moreover, the acylation using lysergic chloride can only be carried out with a yield of maximum 70 , and the impurities of the lysergic chloride appear also in the lysergic amides prepared in this way.

Austrian Patent Specification No. 216 679 describes a process for the preparation of monosubstituted lysergic amides, acoording to which lysergic acid and a primary amine are condensed with each other in the presence of oarbodiimides. Using this reaction, however, an appreciable yield cannot be obtained, since the optically active lysergic acid almost completely converts into the racemic form in the course of the reaction.

There are still further processes known for the preparation of lysergic alkanolamides, namely the direct con- ' densation of lysergic acid with aminoalcohols (Coll* of Czechoslovak Chemical Communications 31. 3415 /1966/), and the amidation of lysergic acid methyl ester (Coll. of Czechoslovak Chemical Communications 22, 1014 /1957/). These processes, however, require very high temperatures (190 to 200°C) and long reaction times (8 to 10 hours), and they run with extremely low yields.

Israel patent specifications Nos. 10,438, 15,470, 41409/2 - 4a - tioned above for preparing lysergic acid amides differing from the claimed compound and having pharmaceutical, mainly aiitiserotonine, effects.

Nov it has been found that the new lysergic acid amides according to the invention show considerable neuroleptic and, respectively, antidepressant activities.

This invention aims also at the elaboration of a new process for the preparation of lysergic amides, free of the disadvantages of the hitherto known methods, and capable to provide an extremely pure product with a good yield in a - 5 - 41409 2 - smooth reaction, without the formation of by-produc s.

The process according to the invention is based on the recognition that lysergic amides are formed in a completely pure state when "active lysergic acid esters are reacted with compounds containing a primary or secondary amino group* Neither isomerlzation nor racemization oocurs in the course of the reaction, and the synthesis proceeds with a almost quantitive yield. This process can be applied, in complete generality, for the preparation of any acid amides of lysergic acid, N-alkyl-lyeergic acids, 9,10-dihydro-lysergio acid and H-alljyl-9,10-dlhydro-lyeerglc acids, respectively* Accordingly, this invention relates also to a novel process for the preparation of lysergic acid amides having the general formula I, nd their acid addition salts, in which an active lysergic acid ester of the general formula II wherein , Z represents hydrogen and/or halogen atoms and/or nitro groups, and n is an integer from 1 to 5» is amidated with a compound containing a primary or secondary amino group and, if desired, the obtained compoiand of general' formula 1 is converted into an aid addition salt by reacting with a pharmaceutically acceptable acid.

, , ¾ : The process according to the invention can be used for the preparation of any known or new lysergic amides. Examples 1 to 10 describe the preparation of new lysergic amides, possesing valuable pharmacological activities.

A group of the new compounds possesses specific anti-serotonine activity. According to experiments carried out on isolated organs i under in vitro conditions these compounds inhibit the smooth muscle contracting ^activity of serotonine while under in vivo conditi ons they antagonize in low doses the oedema-inducing and circulation- influencing effects of serotonine. Another group of thenew compounds exerts a significant depressive activity on the c.mtral nervous s¾stem; thus, e.g. they suppress the spontaneous motility of test animals and antagonize the stimulant activity of psychostimulant pharmacons, e.g. of amphetamine. A further group of the compounds having antidepressant activity shows effects similar to that of the tricyclic antidepressants, thus e.g. in tests carried out on rates and mice they antagonize the neuroleptic properties of reserpine and potentiate the psychostimulant activity of amphetamine. These compounds, however, differ from the tricyclic antidepressants in that they do not increase the vasopressor activity of noradre-ine.

The compounds of the general formula II, used as starting substances in the process of the invention, can be prepared by - 7 - wherein R and x have the same meaning aa above, with phenols of general formula IV wherein Z.'and n have the same meaning as above, in the presence of dehydrating agents.

Jimong the- active lysergic acid esters the pentachlo.ro-phenolates can be used with particular advantages. The reaction is preferably carried out in the presence of an inert solvent, such as tet ahydrofuran, acetonitrile , methylene chloride or dimethyl formamide. The active lysergic acid esters can be used in isolated form, but the reaction can also be carried out using the reaction mixture where these active esters, were formed.

As amino reagents, any substituted amine compound can in which the substituent ie within the definition of R^given above be used, /such as/mono- or polyhydroxylic aminoalcohols , certain mono- &*-^a-substituted alkrylamines , amino' acids, di-peptides, monosubstituted piperazines , arylamine3, e.g. aniline and aniline derivatives, aminopyridines , etc.

The invention involves several advantages, among which - 8 - the following are to be mentioned: a) the new process can be applied in complete generality for the preparation of any substituted lysergic amides, b) the reaction can be carried out in a simple process , c) no by-products are formed in the course of the reaction; d) the reaction proceeds with a high yield; e) the compounds are of high purity grade and' possess valuable pharmacological properties.

The invention is furt er illustrated by the aid of the following non-limiting Examples .

Example 1 Preparation of i-methyl-9 ,10-dihydro-d-lysergic acid- -( -methox )-anilide 5.53 g. of l-methy.1-9 , 10-dihydro-d-lysergic acid-pentachlorophenXl ester are dissolved in 100 ml. of dr chloroform while stirring, thereafter the solution is cooled with ice wate and 1.35 g. of p-methoxy-aniline dissolved in 10 ml. of chloroform are added dropwise. The solution is 3ti.rred at room temperature for one hour, thereafter it is extracted with 6x25 ml. of 1% aqueous tartaric acid solution. The aqueous extracts are combined, and the pH of the combined extracts is adjusted to 8 b adding some' ml. of 10% aqueous ammonium hydroxide solution. The aqueous solution is shaken with 0 ml. of chloroform. The chloroform solutions are combined, dried over sodium sulphate, filtered,, and evaporated in vacuo. ' The residue is dissolved in 10 ml. of benzene, and. the benzene solution - 9 - is poured into 300 ml. of dry petroleum ether. The geparated precipitate is filtered off, washed with a small amount of petroleum ether, and dried in vacuo. The product is subjected to chromatography on an aluminium oxide column, using a 8;2 mixture of chloroform and benzene as eluting agent. In this way 3.56 g. (91%) of l-methyl- , 10-dihydro-d-lysergic acid-( 4-methoxy )-anilide are obtained; m.p.: 159 °C.

The starting compound, l-methyl- > 10-dihy/dro-d-lysergIc acid-pentachlorophenol ester is prepared as follows: 1.43 g. of l-methyl-9 ,10-dihydro-d-lysergic acid free of water are suspended in admixture of 60 ml. of abs . tetra-hydrofurane and 60 ml. of abs. dichloromethane , then 1.35 g. of pentachlorophenol are added. The obtained solution Is cooled while stirring to a temperature between 0 °C and 5 °C, and in small portions 1.2,5 g. of dicyclohexyl carbodiimide are added during 2 hoars. The solution is gradually warmed to 20 °C and stirred for further 2 hours. The dl-cyclohexyl urea separated in crystalline form is filtered and washed with 10 ml. of tetrahydrofurans. The filtrate combined and the washing liquid is -u*A4-el and evaporated to dryness under reduced pressure. The dry residue is dissolved while hot in ml. of benzene and the obtained solution is poured while stirring In 0 ml. of"'"petroleum' ether . The obtained suspension is treated with ice during 24 hours, thereafter the product is filtered, washed with 20 ml. of cold petroleum ether and dried under vacuum.

Yield: 2.0 g. ('75¾)·? -20° (c = 0.5, ethanol). . - 10 ~ Example,, 2 Preparation of d-l sergic acid-( -methox ) -anilide This compound is prepared as described in Example 1, starting from '5 «37 g» of d~lyse.rgic acid pentachlorophenol ester and l„5"g. of p-methox -aniline . The product is obtained with a yield; of 84 1o (3.14 g.), and melts at 127 °C.

The starting compound, d-lysergic acid pentachlorophenol y ester, is prepared from d-lysergic acid and pentachlorophen-el in the way as .descri ed in Example 1.

Yield: 62 $· (fi )j° = +31° ( c = 0.5,' ethanol).

Example 3 Preparation of 9 , 10-dihydro-d -lysergic acid--( 4-methoxy )-anilide .· ■ s ."This" compound is prepared as described in Example 1, starting, from 5.39 g. of , 10-dihydro-d-lysergic acid pentachlorophenol ester and,, 1.5 g. of p-methoxy-aniline. 3.1 g. (82.5 ) of the title compound are obtained ; m.p . : 164 °C.

The starting compound, > 10-dihydro-d-lysergic acid pentachlorophenol ester i3 prepared from 9 » 10-dihydro-^d-lysergic acid and pentachlorophenol in the way as described in Example 1.

Yield:. .5' %; (< )p° = †3° ("c = 0.5, ethanol).

Example 4 Preparation of d-lysergic acid-6-( -chloro-5-nitro- -6-dyl py imidin-e ) -amide This compound, is prepared, as described in Example 1, starting from 5.37 g. of d-lysergic acid pentachlorophenol ester and, 2.0 g." of 4-chloro~5-nitro-6-amino-pyrimidine . 3.2 g. (74 ). of the tit'Le compound are obtained; m.p.: 240 °C. - 11 - The starting compound, d -lysergic acid pentachlo.ro- phenol ester, is prepared as described in Example 2.

■ ' Example 5 Preparation of 9 , 10-dihydro-d-lysergic acid-2-N -( 5-bromo-pyridine ) -amide The compound is prepared as described in Example 1, starting from 4.70, g. of 9 » 10-dihydro-d-lysergic acid- (2,4,5-trichlorophen^l)-ester and .0-g.. of 2-amino-5~bromo- pyridine. 3.4 g. (SO y¾) of the title compound are obtained; m.p.: 132 °C.

The starting compound, 9 , 10-dihydro-d-lysergic acid . (2,4,5-trichlo.rophen¾l)-ester, is prepared from ,10-dihydro- d-^lysergic acid and trichlorophenol in the way aa described in Example 1.

Example 6 Preparation of 1-methy -9 10-dihydro-d-lysergyl- ■■-e gly cyl -t rosins* This compound is prepared as described in Example 1, starting from 5.5 . g. of 1-methy1-9,10-d -lysergic acid penta- e chlorophenol ester and 2.8 g. of glycyl-tyrosinei . 4.5 g. (89' ) of the title compound are obtained; m.p.: 152 °C.

■ The starting compound, l-methyl~ , 10-d-lysergic acid y pentachlorophen-el ester, is prepared in the way as described in Example U Example 7 Preparation of ' ,10-dihydro-d-lysergic acid-(3-tri- fluoromethyl ).-anilide .

This compound is prepared as described in Example 1 starting from 5.39 g. of 9, 0-dihydro-d-lysergic acid penta- - 12 - 3.1 g. (720) of the title compound are obtained; m.p.: 130 °C.

The starting compound, 9 T10-dih dro-d-lysergic acid pentachlorophenol eater, is prepared as described in Example 3.

Example 8 Preparation of l-methyl-9 ,-10-dihydro-d-lysergic acid- ( 3-trifluoromethyl )-anilide This compound is prepared as described in Example 1, starting from 4.05 g. of l-methyl- , 10-dihyd.ro-d-lysergic y acid-( 4-nitro-phei©l )-e3te.r and 2.0 g, of 3-trifluoromethyl-aniline. 2.9 g. (6δό) of the title .compound, are obtained; m.p.: 242 °C.

The starting compound, l-methyl-9 , 10-dihydro-d-lysergic acid-( 4-nitro-phen^l ) -ester , is prepared from l-methyl- 110-dihydro-d-lysergic acid and 4-nitrophenpl in the way as described in Example 1, with the. difference that the amidation is carried out in the solution of the active eater obtained after filtering off the dicyclohexyl urea. .

Example 9 Preparation of d-lysergic acid-allylamide maleate The free base is prepared as described in Example 1, starting from 5.37 g. of d-lysergic acid pentachlorophenol ester and 1.0 g. of 1-ally lamine . The free base obtained after the chromatography is dissolved in 20 ml. of hot ethanol, and 1.2 g. of maleic acid d 33olved in 5 ml. of ethanol are added to the solution. The separated crystalline salt is filtered off, washed with a small amount of cold ethanol, and dried. 3.6 g. (84%) of the title compound are obtained; m.p.: 179 °C. - 13 - 41409 2 The starting compound, ώ-lysergic acid pentachloro-phenol ester, is prepared as described in Example 2.

Example 10 Preparation of l-methyl-9»10-dihydro-d-lysergic acid-allylamide.

This compound is prepared as desoribed in Example 1, stalling from 5·53 g of l-methyl-9,10-dihydro-d-lysergic acid pentaohlorophenol ester and 1,0 g of 1-allylamine. 3.1 g(96#) of the title compound are obtained; m.p.i 189°0.

The starting compound, l-methyl-9,10-dihydro->d-lysergic acid pentaohlorophenol ester, is prepared as described in Example 1.

Example 11 Preparation of 9,10-dihydro-d-lysergio acid-(4-P-hydroxy- n propyl)-piperazi e maleate.

This compound is prepared as described in Example 9, starting from 5·39 g of 9fl0-dihydro-d-lysergio acid pentaohlorophenol ester and 1.75 g of β-hydroxy-propyl-piperazine. 4.9 g(93#) of the title compound are obtained; m.p. : 207°0; ( o )p° e -49° (o 0. ; in 50 aqueous ethanol).

The starting compound, 9TlO-dihydro-d-lysergic acid pentaohlorophenol ester, is prepared as described in Example 3.

Example 12 Preparation ofl-methyl- ,10-dihydro~d-lysergyl-j - nitro-L-arginine methyl ester. 5.53 g of i-methyl-a,10-dihydro-d-lysergic acid penta-chloropheno- ester are dissolved in a mixture of 50 ml of - 14 41409/2 trlethylamine, are added to the cooled solution. The reaction mixture is stirred at room temperature for 2 hours thereafter it is extracted with 5x30ml of 1% aqueous tartaric acid.

Thereafter one prooeeds as described in Example 1. 4.2 g (86.5#>r ) of the title compound are obtained} m.p.: 220°C.

The starting compound, l-methyl-9,10-dihydro-d-lysergic acid pentaohlorophenol ester, is prepared as described in Example 1.

Example J.? .

Preparation of l-methyl-d^lyeergyl-] .(< )^-amin0«-butyrio acid methyl ester maleate.

:T;his compound is prepared starting from 5·55 g of l-methyl-d-lyeergic acid pentaohlorophenol ester and 1.7 g of L-(+)~2-amino-butyrio acid methyl ester hydrochloride. 3.21 (84 ) of the title compound are obtained; m.p.: 178°C(under decomposition) (a )g0 « +17.3° (o If in 5 > aqueous ethaholj. ' The starting compound, l-methyl-d-lysergic acid pentaohlorophenol ester, is prepared as described in Example|¾L.'

Claims (1)

1. Lysergic amideβ of the general formula I wherein represents a or represents a hydrogen atom or a methyl stands for hydrogen stands for an group mid ii a or group optionally substituted by one or more nitro groups a halogen atom an nrpropyl or group having one or more methoxy a and together with the adjacent nitrogen form a piperazine and their pharmaceutically acceptable aoid addition 16 A or the preparation of lysergic amides having the general formula X wherein x and have the same meaning as in Claim 1 in which an active lysergic acid ester of the general formula II π wherein y and have the as defined Z represents hydrogen halogen atoms nitro and n ie an integer from 1 to anidated with a prinary or secondary amino group if the obtained compound of general 1 ie converted into an acid addition by reacting with a phanaaoeutically acceptable A as in claim in the active lysergic acid the corresponding A proceae claimed in 2 or in which the amidation carried out directly in reaction mixture where the active lysergic acid ester without isolating the active 18 A process as claimed any claims 2 to substantially as herein A process as claimed in any of 2 to substantially as herein with reference to the Exampleso The product of the process of any the preceding Lysergic amides of general formula as described herein with reference to the acid of general henever prepared b a prooess as claimed in any of claims 2 to Pharmaceutical compositions comprisin a compound as claimed in any of claims 1 and 7 to in association with a pharmaceutical For the Applicants Yitzhak Hess insufficientOCRQuality