GB2106505A

GB2106505A - Tryptamine derivatives and processes for their preparation

Info

Publication number: GB2106505A
Application number: GB08216547A
Authority: GB
Inventors: Csaba Czantay; Lajos Szabo; Lajos Dancsi; Gyorgy Kalaus; Laszlo Szporny; Egon Karpati; Tibor Keve
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1978-07-12
Filing date: 1979-07-12
Publication date: 1983-04-13
Also published as: HU177727B; GB2106505B

Abstract

Compounds of the general formula:- <IMAGE> [wherein F represents a hydrogen atom or the group -COCHR<2)<CH2)3OH (in which R<2> represents a C1-6 alkyl group); and G represents a hydrogen atom, a carboxyl group or the group -COOR<4> (in which R<4> represents a C1-6 alkyl group); with the proviso that G represents a hydrogen atom when F represents the group -COCHR<2)<CH2)3OH] and where G represents a hydrogen atom or a carboxyl group, the pharmacologically acceptable acid addition salts thereof and where G represents the group -COOR<4> the hydrogen halide salts thereof possess interesting physiological activity and serve as useful intermediates in the preparation of indologuinolisine derivatives which derivatives possess vasodilatory activity.

Description

SPECIFICATION Tryptamine derivatives and processes for their preparation The present invention relates to tryptamine derivatives and to processes for their preparation. The tryptamine derivatives of the present invention possess interesting physiological activity and, in addition, serve as useful intermediates in the preparation of other compounds possessing interesting physiological activity; in particular indoloquinolisine derivatives possessing vasodilatory activity as described and claimed in our copending British Patent Application No. (Serial No.

and 1 O-bromo-vincaminic acid esters of interest in the treatment of behavioural disorders as described in our copending British Patent Application No. 7924355 (Serial No. 2036732).

According to the present invention there is provided a compound of the general formula:

[wherein F represents a hydrogen atom or the group CO CHR2(CH2)30H (in which R2 represents a C,-6 alkyl group); and G represents a hydrogen atom, a carboxyl group or the groupCOOR4 (in which R4 represents a C18 alkyl group); with the proviso that G represents a hydrogen atom when F represents the group -COCHR2(CH2)30H] and where G represents a hydrogen atom or a carboxyl group, the pharmacologically acceptable acid addition salts thereof and where G represents the group -COOR4 the hydrogen halide salts thereof.

The present invention thus includes within its scope compounds of formula I as follows:- a) compounds of formula I wherein F represents a hydrogen atom and G represents the group --COOR4 (in which R4 is as defined in claim 1) and the hydrogen halide salts thereof such as for example ethyl-5-bromo-tryptam ine-2-carboxylate or its hydrochloride; b) compounds of formula I wherein F represents a hydrogen atom and G represents a carboxyl group; c) compounds of formula I wherein F and G each represent a hydrogen atom; and d) compounds of formula I wherein F represents the group -CO-CHR2-(CH2)3-OH and G represents a hydrogen atom.

The compounds of the present invention may be prepared by the following processes: a p-halo-aniline of the formula (II),

is subjected to diazotization, the resuting diazonium salt is reacted with a malonate compound of the general formula (III),

(wherein R4 is an alkyl group of 1 to 6 carbon atoms and Y stands for halogen) in an alkaline medium, the resulting phenylhydrazone derivative of the general formula (IV),

(wherein R4 and Y are as defined above) is subjected to ring closure, the resulting 5-bromotryptamine derivative of the general formula (VIII)

(wherein R4 and Y are as defined above) is either subjected to hydrolysis in an alkaline medium and the resulting 5-bromo-tryptaminecarboxylic acid of the formula (Va)

is decarboxylated in an acidic medium, or the ester of the general formula (V) is hydrolysed and decarboxylated in one step in an acidic medium, the resulting 5-bromo-tryptamine of the formula (VI),

is reacted, optionally after converting it into an acid addition salt, with a pentanolide derivative of the general formula (VII),

(wherein R2 is as defined above), to form a trypatmaine derivative of the general formula (VIII)

(wherein R2 is as defined above).

If desired, a racemic end product of the general formula VIII is resolved in a manner known per se to yield the pure optically active isomers, or, if desired, the optically active compounds of the general formula are prepared by resolving the racemic intermediates of the general formulae (Va) or (Vi) and performing the subsequent reaction step(s) with the respective optically active intermediate. If desired, the free bases of the general formula (I) can be converted into their pharmaceutically acceptable acid addition salts.

In the above formulae R2 may stand for straight-chained or branched C15 alkyl groups, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, nhexyl and isohexyl groups.

The tryptamine derivatives of formula VIII can be prepared according to the process of the invention from new, easily available starting substances in easily performable reaction steps through simple new intermediates. The process of the invention provides the end-products in high yields and in pure state.

The compound of formula (II), used as a starting substance is a known and easily accessible material. The malonate compounds of general formula (III), used as reactants, can be prepared according to the method of E. Fischer and H. Bergmann (Ann. 398, 120/1 913).

The bromoaniline derivative of formula (II) can be diazotized with an alkali metal nitrite, primarily sodium nitrite, in an aqueous, preferably concentrated aqueous solution of a strong mineral acid, particularly in concentrated aqueous hydrochloric acid, at a temperature of --100C to +50C.

The resulting solution of the diazonium salt of the bromoaniline starting substance is then reacted with a solution of a compound of the general formula (III) in an inert organic solvent. As inert organic solvent preferably an aliphatic alcohol, such as dry ethanol, can be used. The reaction is performed in an alkaline medium, preferably in the presence of an alkaline agent such as an alkali metal hydroxide, e.g. potassium hydroxide or sodium hydroxide. The alkaline agent is preferably added to the alcoholic solution of the formula (III) compound before introducing it into the acidic solution of the diazonium salt.

The product of the above reaction, i.e. the phenylhydrazone derivative of the general formula (IV), is obtained in the form of a cis-trans isomeric mixture. It is not necessary to separate the individual isomers from one another at this stage, since in the subsequent cyclization step both isomers are converted into the same compound of the general formula (V).

The cyclization can be performed in an organic solvent, such as in an aliphatic alcohol (preferably n-butanol) at elevated temperatures, preferably at 40-1 800 C, optionally in the presence of a small amount of water.

The compounds of the general formula (V), obtained as described above, can be converted into the 5-bromo-tryptamine derivative of the formula (VI) in two different ways. According to one of these methods the compounds of the general formula (V) are subjected first to alkaline hydrolysis, and the resulting 5-halo-trypatamine-2-carboxylic acid of formula (Va) is decarboxylated by heating it in an acidic medium. The alkaline hydrolysis is performed preferably by heating the ester in a solution, desirably in an aqueous-alcoholic (such as aqueous-ethanolic) solution, of an inorganic base, preferably sodium or potassium hydroxide. When the reaction is conducted at the reflux temperature of the mixture, hydrolysis is complete within a few hours. The subsequent decarboxylation can be performed e.g. by boiling the carboxylic acid in aqueous sulfuric acid.

According to the other method the compounds of the general formula (V) are hydrolysed and decarboxylated in a single step in an acidic medium. The reaction is performed in a solution of a strong mineral acid, such as in 10 to 20% aqueous sulfuric acid, by boiling the mixture for several hours.

The 5-halo-tryptamine derivative of the formula (VI), obtained according to one of the above methods, is then reacted with a 2-alkyl-pentanolide of the general formula (VII) generally in an organic solvent which does not effect the reaction. It is preferred to use an aromatic hydrocarbon, such as xylene, toluene or benzene, as inert organic solvent. The reaction is generally performed with heating, preferably at the reflux temperature of the mixture, and is complete within about 2 to 6 hours.

The reaction mixtures formed in the individual steps of the above synthesis can be processed by conventional methods. Depending on the nature of the compound and on the solvent used the intermediates and the end-products can be isolated from the reaction mixtures e.g. by filtration or by evaporating the solvention optionally under reduced pressure. If desired, the isolated substances can be purified by recrystallization from an appropriate inert organic solvent. The solvents to be used for this purpose are selected in accordance with the solubility conditions and crystallization properties of the compounds in question.The reaction mixtures can also be processed by extracting the product from the mixture with an appropriate inert organic solvent, such as dichloromethane, dichloroethane, etc., drying and evaporating the solution, and, if necessary, crystallizing the residue from an appropriate solvent. In some instances the product can also be precipitated from the reaction mixture with an appropriate inert organic solvent, such as ether, and isolated by filtration. If desired, the resulting racemic or optically active compounds can be purified further by additional conventional operations, such as by recrystallization.

The products obtained by the process of the invention can also be purified by preparative layer chromatography. For this purpose it is preferred to apply silica gel, such as Merck PF254+366 grade silica gel, as adsorbent; various solvent mixtures can be utilized as eluting agents.

If desired, the racemic or optically active compounds of the general formulae (Va), (VI) and/or (VIII) obtained according to the method of the invention can be converted into their pharmaceutically acceptable acid addition salts by reacting the free bases with appropriate acids. Examples of the acids applicable for this purpose are mineral acids, such as hydrohalic acids (e.g. hydrochloric acid, hydrobromic acids, etc.), sulfuric acid, phosphoric acid and perhaloic acids (e.g. perchloric acid): also organic carboxylic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicyclic acid, lactic acid, benzoic acid and cinnamic acid; sulfonic acids, such as methanesulfonic acid, ptoluenesulfonic acid and cyclohexylsulfonic acid; and amino acids such as aspartic acid, glutamic acid, N-acetyl-aspartic acid, N-acetyl-glutamic acid, etc.

The salt formation is performed preferably in an inert solvent, particularly in an aliphatic alcohol, such as methanol, by dissolving the free base of the general formulae (Va), (Vl) and/or (VIII) in the solvent and acidifying the solution slightly (to about pH=6) with the selected acid. The resulting salt separates from the reaction mixture, or it can be precipitated with an appropriate organic solvent, such as ether.

The compound of general formula VIII contains an asymmetric carbon atom, and consequently exists in the form of optically active isomers and racemic mixtures. The process of the invention also encompasses the preparation of the optically active isomers of the end-products. The optically active compounds of the general formula (VIII) can be prepared either by resolving the corresponding racemic mixtures in a manner known per se, or by utilizing optically active starting substances. If desired, any of the optically active compounds prepared according to the invention can be converted into the respective racemic mixtures by methods known per se.

The compounds of the general formulae IV, V, Va, and VIII are novel compounds and are biologically active substances possessing interesting pharmacological properties.

The invention also encompasses the methods in which one of the above intermediates is applied as starting substance and only the remaining steps of the synthesis are carried out.

It is to be mentioned that the intermediates formed in the process of the invention need not be isolated necessarily, but the next step of the synthesis can be performed directly on the mixtures containing the intermediates in question. This latter method is also embraced by the scope of the invention.

The invention is elucidated in detail by the aid of the following non-limiting Examples.

Example 1 Ethyl 5-bro mo-trypta mine-2-carboxylate hydrochloride 23.70 9 (0.10 mmoles) of diethyl 3-chloropropylmalonate are dissolved in 70 ml. of abs. ethanol, and a solution of 6.40 g. (0.11 mmoles) of potassium hydroxide. in 70 ml. of abs. ethanol is added dropwise to the mixture under stirring and exclusion of atmospheric moisture. The mixture is stirred for further 2 hours, then it is cooled to --50C, and a diazonium salt solution, precooled to -50C is added to the mixture. The diazonium salt solution is prepared as follows: 17.20 g. (0.10 mmoles) of p-bromoaniline are dissolved in mixture of 100 ml. of water and 27 ml. of concentrated aqueous hydrochloric acid.The solution is cooled to 0-30C, and a solution of 7.00 g (0.11 mmoles) of sodium nitrite in 1 5 ml. of water is added dropwise. When diazotization terminates, the pH of the solution is adjusted to 6 by introducing about 77 ml. of 10% aqueous sodium carbonate solution, and the resulting solution is cooled to -50C.

After introducing the diazonium salt solution the pH of the mixture is adjusted to 7.4 to 7.5 with about 1 5 ml. of 10% aqueous sodium carbonate solution, and the mixture is stirred for one hour at OOC under nitrogen atmosphere. Thereafter the mixture is acidified to pH=6 with acetic acid, and allowed to stand at room temperature overnight. The separated deep red oil is extracted with dichloromethane.

The organic phase is washed first with 2N aqueous sodium hydroxide solution and then thrice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated to dryness in vacuo. The oily residue, which is a cis-trans isomeric mixture of 2-oxo-5-chloro-valeric acid ethyl ester p-bromo-phenylhydrazone, is separated into the individual isomers by preparative layer chromatography (adsorbent: Silicagel Merck PF254+366; eluding agent: a 14:2 mixture of benzene and methanol). Ref=0.85 (isomer A) and 0.77 (isomer B).

IR spectrum (in KBr pellets): Isomer A: 3250 (NH), 1 738 (-COOC2H5), 1 680 (C=N), 1 605 (aromatic) cm-1.

Isomer B: 3300 (NH), 1 735 (-COOC2H5), 1 700 (C=N), 1 608 (aromatic) cm~'.

The oily substance obtained as described above is dissolved in 1 60 ml. of n-butanol. Some drops of water are added, and the mixture is refluxed under nitrogen atmosphere for 24 hours. Thereafter the solution is cooled to OOC, the precipitated ethyl 5-bromo-tryptamine-2-carboxylate hydrochloride is filtered off, washed with a small amount of n-butanol, and dried. 12.50 g. (34.8%) of the above compound are obtained; m.p.: 248-2490C (after recrystallization from ethanol).

IR spectrum (in KBr pellets): 3340 (NH), 1705 (ester CO) cm-1.

Mass spectrum, m/c%: 312 (M+, 19.6), 283 (100), 237 (54.5), 208 (25.6), 127 (34), 101 (13.1).

1H-NMR spectrum (in CDCI3): 6=7.82--7.28 (3H, m, aromatic protons), 4.44 (2H, ester, -CH2-CH3), 1.42 (3H, t, ester, -CH2-CH3).

Example 2 5-Bromo-tryptamine-2-carboxylic acid 1.00 g. (2.87 mmoles) of ethyl 5-bromo-tryptamine-2-carboxylate hydrochloride are boiled for 2 hours in a mixture of 10 ml. of ethanol and 10 ml of 4N aqueous sodium hydroxide solution. The mixture is cooled with ice, acidified to pH 6 with glacial acetic acid, and the separated crystals are collected by filtration. 0.75 g. (91%) of 5-bromo-tryptamine-2-carboxylic acid are obtained; m.p.: 248-249 0C.

IR spectrum (in KBr pellets): 3320 (NH), 1 585 (COO~) cm~1.

Analysis: calculated for C11H11N202Br(M.wt.: 283.13): C: 46.63%, H: 3.91%, N: 9.98% found: C: 46.52%, H: 3.85%, N: 9.92% Example 3 5-Bromo-tryptamine A mixture of 1.00 g. (3.53 mmoles) of 5-bromotryptamine-2-carboxylic acid and 80 ml. of 10% aqueous sulfuric acid is stirred and refluxed for 30 hours. The pH of the mixture is adjusted to 9 with concentrated aqueous ammonia under cooling in an ice bath, and the alkaline mixture is extracted with 4x20 ml. of chloroform. The organic extracts are combined, washed with 5% aqueous sodium hydroxide solution and then with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. 0.48 g. (58%) of 5-bromo-tryptamine are obtained as an oily residue.

A part of the oily residue is dissolved in ethanol and converted into the formate by introducing formic acid. The formate salt melts at 1 75-1 760C after recrystallization from ethanol.

Analysis: calculated for Cr,Hr2N202Br(M.wt.: 284.14): N: 9.86% found: N: 9.71% Example 4 N-(a-Ethyl-8-hydrnxy-valeroyl)-5-bromo-tryptamine 0.48 g. (2.0 mmoles) of 5-bromo-tryptamine and 0.30 g. (2.3 mmoles) of 2-ethyl-pentanolide are dissolved in 5 ml. of abs. xylene, and the solution is refluxed for 4 hours. The reaction mixture is evaporated in vacuo, the residue is triturated twice with 3 ml. each of petroleum ether, thereafter it is dried in a desiccator. 0.59 g. (80%) of N-(-ethyl-a-hydroxy-valeroyl)-5-bromo-tryptamine are obtained.

IR spectrum (in KBr pellets): 3320 (NH, OH, broad), 1640 (acid amide CO) cm~1.

Claims

1. A compound of the general formula:

[wherein F represents a hydrogen atom or the group -COCHR2(CH2)30H (in which R2 represents a C18 alkyl group); and G represents a hydrogen atom, a carboxyl group or the group --COOR4 (in which R4 represents a C16 alkyl group); with the proviso that G represents a hydrogen atom when F represents the group -COCHR2(CH2)30H] and where G represents a hydrogen atom or a carboxyl group, the pharmacologically acceptable acid addition salts thereof and where G represents the group ---COOR4 the hydrogen halide salts thereof.

2. A compound as claimed in claim 1 wherein F represents a hydrogen atom and G represents the group --COOR4 (in which R4 is as defined in claim 1) and the hydrogen halide salts thereof.

3. A compound as claimed in claim 1 wherein F represents a hydrogen atom and G represents a carboxyl group.

4. A compound as claimed in claim 1 wherein F and G each represent a hydrogen atom.

5. A compound as claimed in claim 1 wherein F represents the group -CO-CHR2-(CH2)3-OH and G represents a hydrogen atom.

6. Ethyl-5-bromo-tryptamine-2-carboxylate or its hydrochloride.

7. A compound as claimed in claim 1 as herein specifically disclosed.

8. A process for the preparation of a compound as claimed in claim 1 (in which F represents the group -CO-CHP2-(CH2)3-OH and G represents a hydrogen atom) which comprises reacting a compound of the formula:

or an acid addition salt thereof, with a compound of the formula:

(wherein R2 is as defined in claim 1) to form a compound as claimed in claim 1 in which F represents the group -CO-CHP2-(CH2)3-OH and G represents a hydrogen atom.

9. A process for the preparation of a compound as claimed in claim 1 (in which F and G each represent a hydrogen atom) which comprises decarboxylating a compound as claimed in claim 1 in which F represents a hydrogen atom and G represents a carboxyl group in the presence of an acidic medium.

10. A process for the preparation of a compound as claimed in claim 1 (in which F represents a hydrogen atom and G represents a carboxyl group) which comprises hydrolysing a compound as claimed in claim 1 (in which F represents a hydrogen atom and G represents the group --COOR4) or a hydrohalide salt thereof in the presence of an alkaline medium.

11. A process for the preparation of a compound as claimed in claim 1 (in which F and G each represent a hydrogen atom) which comprises the hydrolysis and decarboxylation of a compound as claimed in claim 1 (in which F represents a hydrogen atom and G represents the group --COOR4) or a hydrohalide salt thereof in the presence of an acidic medium.

1 2. A process as claimed in claim 10 or claim 11 wherein the compound as claimed in claim 1 (in which F represents a hydrogen atom and G represents the group --COOR4) or a hydrohalide salt thereof, is first prepared by the ring closure of a compound of the formula:

(wherein R4 is as defined in claim 1 and Y represents a halogen atom) to form a compound as claimed in claim 1 (in which F represents a hydrogen atom and G represents the group --COOR4).

1 3. A process as claimed in claim 12 wherein the compound of formula IV is first prepared by diazotisation of p-bromo aniline followed by reaction of the diazonium salt thus obtained with a compound of the formula:

(wherein R4 is as defined in claim 1 and Y is as defined in claim 12) to form a compound of formula IV as defined in claim 12.

14. Each and every novel compound and process herein disclosed.