IE43464B1 - Derivatives of 9h-pyrido /3,4-b/ indole, process for their preparation and compositions incorporating them - Google Patents

Description

This invention relates to derivatives of 9H-pyrido[3,4-b] indole, processes for their preparation and compositions incorporating them.

In particular, it concerns certain l-(3'-indolyl-methyl) - 1,2,3,4 - tetrahydro - 9H - pyrido-[3,4,-bjindoless which may be of use in human or veterinary medicine.

In one aspect this invention provides the derivatives of 9H-pyrido[3,4-b]indole of the general formula: wherein R and R , which may be the same or different, each 3' represent a hydrogen atom, a halogen atom, a hydroxy radical, an alkoxy radical containing from 1 to 5 carbon atoms or a benzyloxy radical, with the proviso that R does not represent a hydroxy radical when r' represents a halogen atom, an alkoxy radical or a benzyloxyl radical; and acid addition salts thereof.

When [J and/or represents a halogen atom it is desirably a fluorine, chlorine or bromine atom, and the preferred halogen atom is chlorine. 2 When R and/or R represents an alkoxy radical it may be, for example a methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy or t-butoxy radical. A preferred alkoxy radical is the methoxy radical.

Amongst the derivatives of the invention a preferred class of compounds are those derivatives of the general formula I Ί 2 wherein R and R , being the same or different, each represent a hydrogen atom, a chlorine atom, a hydroxy radical, a methoxy radical or a benzyloxy radical (subject, of course, to the proviso set out hereinbefore) and their acid addition salts.

The acid addition salts may be formed with any convenient acid, including inorganic acids, such as hydrochloric, hydrobromic, hydriodic, nitric, sulphuric and phosphoric acid, and organic carboxylic acids such as acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids such as methanesulphonic acids and arylsulphonic acids such as benzenesulphonic acid. Particularly preferred acid addition salts are the hydrochlorides and fumarates.

The particularly preferred derivatives of the invention include:1 - (5' - methoxy - 3' - indolyl - methyl)- 1,2,3,4 tetrahydro - 6 - methoxy - 9H - pyrido j3,4-bjindole and its hydrochloride; - (5' - methoxy - 3' - indolyl - methyl) - 1,2,3,4 tetrahydro - 9H - pyrido[3,4-bj- indole and its hydrochloride; G41 - (3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 - hydroxy - 9H - pyrido [3,4-b] indple and its fumarate; - (3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 - chloro - 9H - pyrido f3,4-b] - indole; and - (5' - hydroxy - 3‘ - indolyl - methyl) - 1,2,3,4 - tetrahydro - 9H - pyrido [3,4-b] - indole and its hydrochloride.

The invention also provides a process for the preparation of the derivatives of general formula I wherein I? is as defined p hereinbefore and R represents a hydrogen atom, a halogen atom, an alkoxy radical containing from 1 to 5 carbon atoms or a benzyloxy radical, in which an appropriate compound of the general formula 2 (wherein R is as defined hereinbefore and R^ represents a hydrogen atom, a halogen atom, an alkoxy radical containing from 1 to 5 carbon atoms or a benzyloxy radical) is decarboxylated to give the desired compound of general formula I.

The decarboxylation may be carried out by means of a strong mineral acid and hydrochloric acid is preferred. The decarboxylation is conveniently effected at an elevated temperature, and typically the reaction mixture is heated to a temperature of 95° to 110°C (or a convenient reflux temperature) from 2 to 6 hours.

The compound of general formula IV may be prepared by reacting an appropriate tryptamine of the general formula: (Π) (wherein is as defined hereinbefore) with a suitable derivative of 3-indole-pyruvic acid of the general formula (III) ? (wherein RA is as defined hereinbefore) to give the desired compound of general formula IV.

-Chloro-3-indole-pyruvic acid is a new compound.

When it is desired utlimately to prepare a product of general formula I wherein R^ represents a hydroxy radical, it is advantageous to prepare the appropriate compound of general formula IV from a tryptamine of general formula II wherein R^ represents a hydroxy radical in the form of a complex with creatinine sulphate.

The reaction of the compounds of general formulae II and III is preferably carried out either in an aqueous medium or in an anhydrous medium, and optionally in the presence of an alkanol of low molecular weight (preferably containing 1 to 5 carbon atoms), such as butanol. The reaction mixture is conveniently heated to a temperature between 50°C and the boiling temperature of the reaction mixture, preferably for a period of 48 hours to 7 days.

The starting materials of general formula III have not all been previously described, and the compounds III wherein 2 Ra represents a halogen atom, a hydroxy radical or an alkoxy radical containing from 1 to 5 carbon atoms may be prepared by !0 subjecting an appropriate compound of the general formula: {wherein Rg represents a halogen atom, a hydroxy radical or an alkoxy radical containing from 1 to 5 carbon atoms) to alkaline hydrolysis to give the desired compound of general formula III.

The compounds of general formula VIII used as starting material 5 in this process are novel; they may be prepared by condensing an appropriate 3-formyl-indole of the general formula: I H p (wherein Rg is as defined hereinbefore) with hydantoin to give the desired compound of general formula VIII.

The condensation may be carried out in the presence of a base, and preferably anorganic nitrogenous base such as piperidine.

The invention also provides a process for the preparation of derivatives of general formula I wherein R^ represents a hydrogen atom or a benzyloxy radical and R represent a 15 benzyloxy radical in which an appropriate compound of general formula; (wherein represents a hydrogen atom or a benzyloxy radical and Alk represent an alkyl radical containing from 1 to 3 carbon atoms) is hydrolysed and decarboxylated to give the desired derivative of general formula I, which is a compound of the general formula It is preferred that when it is desired to prepare a compound ρ of general formula I wherein R represents a benzyloxy radical this latter process is employed, where applicable.

The hydrolysis and decarboxylation of compoumd VI is preferably 5 effected by an alkali-metal hydroxide, such as sodium or potassium hydroxide, in an alkanol of low molecular weight (preferably containing from 1 to 5 carbon atoms) such as ethanol. The reaction is most conveniently effected at the boiling temperature of the reaction mixture. Naturally, the normal work-up procedures may be employed to isolate the desired product, as would be appreciated by the man skilled in the art.

The compound of general formula VI may be prepared by reacting an appropriate tryptamine of the general formula: (Π') (wherein Rft1 is as defined hereinbefore) with a suitable compound of the general formula: i JiCd H (wherein Alk is as defined hereinbefore) to give the desired product of general formula VI.

This reaction of compounds II' and V may advantageously be carried out in an alcohol of low molecular weight (preferablycontaining from 1 to 5 carbon atoms) such as ethanol. The reaction mixture is conveniently heated to a temperature between 50°C and its boiling temperature, preferably for a period of 48 hours to 7 days.

The starting materials of general formula V may be prepared by ) a process in which an appropriate compound of the general formula: (wherein Aik is as defined hereinbefore) is hydrolysed and decarboxylated to give the desired product of general formula V.

A secondary product of the hydrolysis and decarboxylation 2 is the compound of general formula III wherein R^ represents 5 a benzyloxy radical which may be isolated, and naturally if isolated may be used in the process described hereinbefore.

The hydrolysis and decarboxylation is preferably effected by acetic acid, and in a particularly preferred process the hydrolysis and decarboxylation is effected by a 10:1 acetic acid: water mixture. The reaction mixture is also preferably heated, most conveniently at reflux.

The compound of general formula X may be prepared by condensing the methyl ester of 5 - benzyloxy - 3 - indole acetic acid of the formula: with an appropriate alkyl oxalate to obtain the desired product of general formula X.

The condensation is preferably carried out in the presence of a base, a preferred base being sodium ethoxide, and this preferred base is conveniently prepared in situ by reacting sodium with ethanol. 43484 This invention also provides a further process, for the preparation of derivatives of general formula I wherein R^ represents a 2 hydrogen atom or a hydroxy radical and R represents a hydroxy radical, in which an appropriate compound of general formula 1' as defined hereinbefore (a compound of general formula I wherein R1 is and represents a hydrogen atom or a benzyloxy radical and R represents a benzyloxy radical) is hydrogenolysed to give the desired compound of general formula I.

The hydrogenolysis replaces the or each benzyloxy radical of compound I* by a hydroxy radical. Hydrogenolysis is a treatment wellknown in the art, and in the above preparation it is preferably effected by means of gaseous hydrogen in the presence of a suitable catalyst. Preferred catalysts include platinum and palladium.

The derivatives of general formula I are of a basic nature, and it is possible to prepare their acid addition salts. Accordingly, this invention also provides a process for the preparation of the acid addition salts of the derivatives of general formula I, in which the appropriate derivative of general formula 1 is reacted with a suitable acid to form the desired acid addition salt. Preferably, the derivative and the acid are reacted in substantially stoichiometric proportions. It is not necessary to isolate the derivative to prepare the acid addition salt; instead the salification may be performed on a reaction product containing the appropriate derivative, the formed salt then being isolated. 43484 Naturally, the derivative of General formula I used in the salification is preferably prepared by a process as described herein.

The compounds of general formula I and their acid addition salts have very interesting pharmacological properties; in particular they possess remarkable tranquil!ising properties. Certain products have, in addition, properties antagonistic with regard to serotonine and properties antagonistic to platelet aggregation caused by collagen.

These properties may make the derivatives of 9H-pyrido{3,4-bJ indole of general formula I and their pharmaceutically acceptable acid addition salts useful as medicaments. These medicaments may be useful, for example, in the treatment of anxiety, hyperemotivity, psychomotor agitation, irritability, sleep disturbances, true migraine and related vasomotor cephalalgia. However, before the compounds are used in medicine they are preferably formed into compositions.

Thus, the invention further provides pharmaceutical compositions which contain, as active principle, one or more 9H-pyrido-[3,4-bJ indole derivative of general formula I and/or one or more pharmaceutically acceptable acid addition salt thereof in association with a suitable pharmaceutical vehicle.

The active principle is preferably one or more of those derivatives and/or their salts mentioned hereinbefore as being preferred. - (5' - hydroxy - 3' - indolyl - methyl)-1,2,3,4 - tetrahydro - 9H - pyrido[3,4-bj indole hydrochloride is particularly preferred as the active principle. 43454 The terms pharmaceutical and pharmaceutically-acceptable are used herein to exclude any possibility that the vehicle or the acid addition salt, considered in relation to the route by which the composition is intended to be administered, could be harmful rather than beneficial. The choice of a suitable mode of presentation, together with an appropriate vehicle, is believed to be within the competence of those accustomed to the preparation of pharmaceutical formulations.

The compositions of this invention may be administered by digestive or parenteral routes, and thus may be administered orally, perlingually, transcutaneously or rectally. In respect of these modes, the pharmaceutical vehicle is preferably:a) the ingestible excipient of a tablet, coated tablet, sublingual tablet or pill; the ingestible container of a capsule or cachet, the ingestible pulverulent solid carrier of a powder; or the ingestible liquid medium of a syrup, solution, suspension or elixir. b) a sterile injectable liquid solution or suspension medium, or c) a base material of low melting point capable of releasing !0 the active ingredient to perform its pharmacological function, which base material when appropriately shaped forms a suppository.

Whilst the modes of presentation just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities.

The compounds of this invention may preferably be administered in the form of tablets or sugar-coated tablets; of injectable solutions or suspensions dispensed in single-dose ampoules or multi-dose phials; of gelatin capsules; of granules; and of suppositories or implants.

The pharmaceutical vehicle may comprise one or more of the excipients conventionally employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives or glycols.

In addition, the compositions may comprise various wetting, dispersing or emulsifying agents, and/or preservatives.

The dosages employed will depend upon the route of administration, the active material used, the subject treated and the complaint concerned. Nevertheless, by way of example, it may be said that the useful dose ranges from 5 mg to 100 mg of active principle per day, by oral route in man.

The following Examples and Formulations are now given, though only by way of illustration to show preferred details of various aspects of the invention. 43404 Example 1 - (5' - methoxy - 3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 - methoxy - 9H - pyrido [3,4-b] indole hydrochloride.

Under an atmosphere of nitrogen, 2.74 g of 5-methoxy tryptamine and 14.4 cm of N hydrochloric acid were introduced q into 70 ctrr of normal butanol and 3.7 g of 5-methoxy-3indole-pyruvic acid were added.

The mixture was heated with agitation for 48 hours at 95°C, cm of concentrated hydrochloric acid were added, then the agitation was continued for 5 hours at 95°C and the reaction mixture distilled to dryness under vacuum. 7 g of crude product were recovered and purified by chromatography on silica. After eluting with 8:2 chloroform/methanol mixture, 2.7 g of product were recovered and crystallised from 10 cm of ethyl acetate.

After vacuum-filtration, 2 g of product were recovered and dissolved in 40 cm3 of methanol, the solution was filtered, q cm of ethyl acetate were added and the whole was concentrated q to 30 cm . After vacuum-filtration, 1.55 g of l-(5'-methoxy-3'indolyl-methyl)-l,2,3,4-tetrahydro - 6 - methoxy - 9H-pyrido[3,4-b|indole ’0 hydrochloride were obtained in the form of a white crystalline product. M.Pt = 225-230° C.

Analysis: CggH^NgOg.HCl = 397.89 Calculated: C% 66.41 H% 6.08 N% 10.56 Cl% 8.91 Found: C% 66.1 H% 6.1 N% 10.3 CU 8.9 Example 2 - 5' - methoxy - 3' - indolyl - methyl)-!,2,3,4 - tetrahydro - 6 - hydroxy - 9H - pyridoj3,4-b]indole.

Under agitation and under an atmosphere of nitrogen, 10 g of - methoxy - 3- indole - pyruvic acid, 14.7 g of serotonineo 3 creatinine sulphate, 150 cm of normal butanol and 150 cm of water were heated for 5 days at 100°C. 30 cm3 of concentrated hydrochloric acid were then added, and the mixture was agitated for 5 hours at 100°C and distilled to dryness under vacuum. 27 g of crude product were recovered and purified by chromatography on silica. After eluting with a 7-3 chloroform/methanol mixture, 6 g of product were recovered and dissolved in 160 cn? of water at 80°C. This solution was filtered, cooled and neutralised by the addition of sodium bicarbonate. It was left to stand for 15 hours and vacuumfiltered. 3.9 g. of l-{5‘-methoxy - 3' - indolyl - methyl) - 1,2,3,4tetrahydro - 6 - hydroxy - 9H - pyrido[3,4-b]indole were obtained and recrystallised from methanol. A yellow crystalline product was recovered. M.Pt— 170°C.

Analysis: ^1^21^2 = 34?.4Ο Calculated: CSS 72.60 HSS 6.09% N% 12.10 Found: CSS 72.6 H% 6.0 NSS 12.1 Example 3 - (3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 - methoxy - 9H - pyrido[3,4-b]-indole hydrochloride.

Under an atmosphere of nitrogen, 14.3 g of 5-methoxy tryptamine were dissolved in 75 cm of N hydrochloric acid, 100 cm of water and 75 cm3 of normal butanol, and 15.3 g of 3-indole-pyruvic acid were added.

The mixture was heated under agitation for 54 hours at 100°C q and 25 cm of concentrated hydrochloric acid were added. The mixture was then agitated for 2 hours 30 minutes at 100°C and distilled to dryness under vacuum. 32 g of crude product were recovered and purified by chromatography on silica. After eluting with a 7:3 chloroform/methanol mixture, 10 g of product were recovered and crystallised from 30 cm of ethyl acetate.

After vacuum-filtration, 8.8 g of product were recovered and 3 dissolved in 140 cm of methanol, this was filtered, 150 cm of ethyl acetate were added, and the whole was concentrated. After vacuum-filtration, 7.8 g of 1 - (3‘ - indolyl - methyl) - 1,2,3,4tetrahydro - 6 - methoxy - 9H - pyrido-[3,4-bJindole hydrochloride were obtained in the form of a yellow crystalline product.

M.Pt — 250°C.

Analysis:C21 H21N3O.HC1 = 367.87 Calculated: C% 68.56 H% 6.03 N% 11.42 CU 9.64 Found: c% 68.3 6.1 N%. 11.7 CU 9.8 Example 4: - (57 - chloro - 3' - indolyl - methyl)-1,2,3,4 tetrahydro - 9H - pyridojl·,4-b] -indole hydrochloride Under an atmosphere of nitrogen, 9.5 g of 5-chloro-3-indolepyruvic acid and 7.8 g of tryptamine hydrochloride were dissolved in 0 50 cm of normal butanol and 50 cm of water.

The solution was agitated for 55 hours at 100°C, 10 cm·5 of 3 4 6 4 concentrated hydrochloric acid were added, and the solution was agitated again for 4 hours at 100°C. It was distilled to dryness under vacuum, and the product obtained was crystallised from 50 cm3 of isopropanol and vacuum-filtered. 4 g of product were obtained. M.Pt = 270°C.

The mother liquors were chromatographed on silica, eluting with a 7:3 chloroform/methanol mixture. 3 g of product were recovered and crystallised from isopropanol. 2.2 g of product were obtained (m.Pt. = 270° C) to which were added the 4 g obtained previously, and the mixture was dissolved in 600 cm3 of methanol at reflux, q ο filtered and concentrated to 100 cm . 300 cm of methylene chloride were added and the solution was concentrated to 100 cm3. After vacuumfiltration, 4.2 g of 1-(5'-chloro-3'-indolyl-methyl )-1,2,3,4 tetrahydro - 9H - pyridojj,4-bj-indole hydrochloride were recovered in the form of a colourless crystalline product.

M.Pt·^ 270°C.

Analysis: C2qH18C1N3.HC1 = 372.28 Calculated: 0% 64.52 HX 5.14 Cl% 19.05 NX 11.29 Found: C% 64.5 HX 5.4 CU 19.1 NX 11.2 -ch1oro-3-indole-pyruvic acid can be prepared as follows: 23.8 g of 5-chloro-3-formyl-indole, 13.2 g of hydantoin and 25 cm3 of piperidine were agitated for 30 minutes in a bath at 135°C and under nitrogen. 50 cm3 of water and 25 cm3 of acetic acid were added, and the mixture was left to cool and vacuum-filtered. .8 g of product were obtained, which was used as follows: .8 g of product, prepared above, in 700 cm3 of a soda solution containing 20 g soda per 100 cm were agitated for 5 hours at reflux and under nitrogen. The mixture was cooled and extracted with ether, the aqueous phase was acidified with concentrated hydrochloric acid, and the precipitate formed was extracted with ethyl acetate. It was dried over magnesium sulphate, filtered and distilled to dryness under vacuum. 8.7 g of 5-chloro-3-indole-pyruvic acid were obtained in the form of a yellow crystalline product.

M.Pt^Si 180°C.

Example 5: - (5' - methoxy - 3' - indolyl - methyl)-1,2,3,4 tetrahydro - 9H - pyrido[3,4 bJ-indole hydrochloride. 8.6 g of tryptamine hydrochloride and 10.2 g. of -methoxy-3-indole-pyruvic acid in 370 cm of water were heated for hours under agitation at 100°C and under an atmosphere of nitrogen. □ cm of concentrated hydrochloric acid were added. The mixture was heated again for 5 hours at 100°C, and distilled to dryness under vacuum, and 21 g of crude product were obtained and purified by chromatography on silica. It was eluted with a 7:3 chloroform/ methanol mixture and 5.8 g of product were recovered and crystallised from isopropanol. After vacuum-ftitration, 3.2 g of 1 - (5'-methoxy-3'-indolyl-methyl) - 1,2,3,4 - tetrahydro -9Hpyrido-[3,4-bJ indole hydrochloride were obtained and recrystallised successively from isopropanol, a 50:50 methanol/ethyl acetate mixture, then again from isopropanol. A colourless crystalline product was obtained. M.Pt = 270°C. Analysis: C21H2]NgO.HCl = 367.87 Calculated: C% 68.56 H% 6.03 Found: CSS 68.8 H% 6.1 N% 11.42 Cl % 9.64 N% 11.1 Cl% 9.6 Example 6: - (3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 hydroxy - 9H - pyrido|3,4-b] - indole fumarate. g of 3-indole-pyruvic acid, 24 g of 5-hydroxy tryptamine 3 3 creatinine sulphate, 150 cm of water and 150 cm of butanol were agitated for 68 hours at 90°C and under an atmosphere of nitrogen. 30 cm of concentrated hydrochloric acid were added and the mixture was agitated for 5 hours at 100°C. It was distilled to dryness under vacuum, and 42 g of crude product were recovered and purified by chromatography on silica. It was eluted with a 7:3 chloroform/methanol mixture, and 12 g of product were recovered and dissolved in 1 litre of water at reflux. This was filtered, cooled and rendered alkaline by the addition of sodium bicarbonate.

The precipitate formed was extracted with ethyl acetate, dried over magnesium sulphate, filtered and distilled to dryness under vacuum. 7 g of l-(3'-indolyl-methy1)-l,2,3,4-tetrahydro - 6 hydroxy - 9H - pyridoj3,4-bj -indole were recovered in the form of a brown oil.

Preparation of the fumarate: g of l-(3'-indolyl-methyl)-l,2,3,4-tetrahydro - 6 hydroxy - 9H - pyrido[3,4-b] - indole were dissolved in 50 cm3 of isopropanol, and 2.56 g of fumaric acid in solution in a minimum of methanol were added, drop by drop.

The mixture was vacuum filtered and 7 g of product were obtained and recrystallised from methanol. 3.5 g of 1-(31-indolyl-methyl )-1,2,3,4 - tetrahydro - 6 - hydroxy - 9H pyrido[3,4-bj indole fumarate were recovered in the form of a colourless crystalline product.

M.Pt.~ 270°C.

Analysis: C20H19N30-C4H4°4 = 433.45 Calculated: C% 66,50 H% 5.35 N% 9.70 Found: CSS 66.3 H5S 5.4 9.6 Example 7: - (3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 chloro - 9H - pyrido |3,4-bJ - indole g of 5-chloro-tryptamine hydrochloride were dissolved in q 200 cnr of water, under an atmosphere of nitrogen, then, over a period of 4 days, 13 g of 3-indole-pyruvic acid were added (4 g at the beginning, 2 g after 8 hours, 2 g after 24 hours, g after 2 days, 2 g after 3 days and 1 g after 4 days). 43434 The mixture was first agitated for 6 days at 100°C, then 20 cm3 of concentrated hydrochloric acid were added, and the mixture was agitated again for 5 hours at 110°C. It was distilled to dryness under vacuum, and 26 g of crude product were obtained and purified by chromatography on silica. It was eluted with a 7:3 chloroform/methanol mixture, and 10 g of a product were recovered which was purified again by chromatography, operating under the same conditions. The product obtained was crystallised from ethyl acetate, and 2.3 g of 1-(3’-indolyl-methyl )-1,2,3,410 tetrahydro - 6 - chloro - 9H - pyrido |^3,4-b]-indole hydrochloride were obtained. The hydrochloride was recrystaliised from isopropanol. M.Pt = 255°C.

Preparation of the base: 2.6 g of 1-(31-indolyl-methyl )-1,2,3,4-tetrahydro-6-chloro15 9H-pyridojj3,4-b]-indole hydrochloride were dissolved in 400 cm3 of water at 80°C, copied, filtered and rendered alkaline by the addition of a solution of sodium bicarbonate. The solution was vacuum filtered and dried under vacuum. 2 g of 1-(31-indolyl-methyl )-1,2,3,4tetrahydro - 6 - chloro - 9H - pyrido[3,4-0indole were obtained in the form of a colourless crystalline product.

M.Pt.= 120uC.

Calculated: Found: Analysis: CiS 71.53 C% 71.4 C20H18C1N3 335.82 H% 5.40 N% 12.51 H« 5.6 N% 12.7 Cl% 10.56 Cl% 10.9 464 Example 8 - (5' - benzyloxy - 3' - indolyl - methyl )-1,2,3,4 tetrahydro - 9H - pyrido ]3,4-b] - indole hydrochloride Stage A: - ethoxycarbonyl - 1 - (5' - benzyloxy - 3* - indolyl - methyl) - 1,2,3,4 - tetrahydro-9H-pyrido[3,4-b]-indole.· 233 mg of ethyl 5-benzyloxy-3-indole pyruvate and 333 mg of tryptamine hydrochloride in 23 cm of absolute ethanol were agitated for 5 days at reflux. This was then distilled to dryness under vacuum.

The crude product obtained was chromatographed on silica. It was eluted with a 9:1 chloroform/methanol mixture, and 320 mg of amorphous product obtained, of Rf 0.65. The product obtained was crystallised from a minimum of ether, vacuum-filtered and washed with isopropyl ether. The product was recrystallised from isopropyl ether. 225 mg. of 1 - ethoxycarbonyl - 1 - (5' - benzyloxy - 3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 9H - pyrido(3,4-6]indole were obtained in the form of a clear yellow crystalline product.

M.Pt. = 120-125°C (melting slow towards 75-80°C) Analysis:C30H29N3°3 = 479.56 Calculated: C% 75.13 •H% 6.10 M 8.76 Found: C% 75.2 M 6.4 N% 8.9 Stage B: - (5' - benzyloxy - 3' - indolyl - methyl)-1,2,3,4 - tetrahydro - 9H - pyrido [3,4-b] -indole hydrochloride: 4.8 g of l-ethoxycarbonyl-l-(5‘-benzyloxy-3'-indolyl-methyl) 24 1,2,3,4 - tetrahydro - 9H - pyrido[3,4-bj indole in 150 cm3 of 3 ethanol and 20 cm of N soda were agitated for 45 minutes at 3 reflux. 5 cm of concentrated hydrochloric acid were added. The refluxing was continued for 5 hours and the mixture distilled to dryness under vacuum. 5.1 g of crude crystalline product were obtained and taken up with isopropyl ether and vacuum-filtered. 3.5 g of - (5' - benzyloxy - 3' - indolyl-methyl) - 1,2,3,4 tetrahydro - 9H - pyrido [3,4-bJ -indole hydrochloride were recovered in the form of a beige crystalline product.

M.Pt = 270 - 280°C.

Analysis: Cg/HggNjO.HCl = 443.96 Calculated: CX 73.04 HX 5.90 NX 9.46 C1X 7.99 Found: CX 73.0 HX 5.9 NX 9.4 C1X 8.1 Ethyl 5-benzyloxy-3-indole-pyruvate can be prepared as follows: Stage A: Ethyl α-methoxycarbonyl-(5-benzyloxy-3-i ndole)-pyruvate: 2.55 g of sodium were introduced into 80 cm of absolute ethanol. This was agitated at ambient temperature until the sodium disappeared, then 16.1 g of ethyl oxalate were added, all at once. The mixture was agitated for 5 minutes at ambient temperature, then, over 15 minutes, the solution formed by 29.5 g of 5-benzyloxy-3-indole acetic acid methyl ester in 150 cm of anhydrous ether was added.

The mixture was agitated for 3 more hours at ambient temperature, and 46 4 poured onto 600 cm of water, the neutral fraction was extracted with ether, the mother liquors were acidified with concentrated hydrochloric acid and the whole was extracted with methylene chloride.

It was dried over magnesium sulphate, filtered and distilled to dryness under vacuum. 33.2 g of ethyl α-methoxycarbonyl(5-benzyloxy-3-indole)-pyruvate were obtained in the form of a brown oil. The product was used as follows: Stage B: Ethyl 5-benzyloxy-3-indole-pyruvate: 14.8 g of ethyl a-methoxycarbonyl-(5-benzyloxy-3-indole)3 3 pyruvate were dissolved in 75 cm of acetic acid and 7.5 cm of water.

The mixture was agitated for 4 hours 15 minutes at reflux. It ί was distilled to dryness under vacuum, the product was taken up in benzene and vacuum-filtered, and 3.1 g of ethyl 5-benzyloxy-3-indolepyruvate were obtained in the form of a beige product which was recrystallised from ether.

M.Pt. = 169-170°C.

Thin-layer chromatography carried out upon the reaction product (before recrystallisation from ether) revealed the presence of 5-benzyloxy-3-indole-pyruvic acid (Rf = 0.15) in addition to ethyl 5-benzy1oxy-3-indole pyruvate (Rf =0.70). 3 4 6 4 Example 9: - (5' - hydroxy - 3' - indolyl - methyl )-1,2,3,4-tetrahydro - 9H - pyrido ^3,4-b J -indole hydrochloride. 4.6 g of l-fS'-benzyloxy-S'-indolyl-methyl)-1,2,3,4 - tetrahydro - 9H - pyrido )3,4-b] - indole hydrochloride (obtained in example 8) were suspended in 460 cm of absolute ethanol, and 2.3 g of 10% palladium on charcoal were added.

The mixture was hydrogenolysed under agitation for 5 hours (volume of hydrogen absorbed: 200 cm3). It was filtered, rinsed with ethanol, then with methanol. It was distilled to dryness under vacuum, and 3.7 g of crude product were obtained and crystallised from ethyl acetate.

After vacuum-filtration, 3.4 g of l-(5'-hydroxy-3‘indolyl - methyl) - 1,2,3,4 - tetrahydro - 9H - pyrido[3,4-bj indole hydrochloride were recovered and recrystallised from methanol. A clear beige crystalline product was obtained.

M.Pt = 280°C. Analysis: C20H19N30,HC1 = 353.84 Calculated: Ci 67.88 Hi 5.70 N« 11.87 Cli 10,02 Found: Ci 67.8 Hi 5.7 Ni 11.6 Cli 10.2 Example 10: 1,2,3,4 indole hydrochloride - (5' - benzyloxy - 3' - indolyl - methyl) tetrahydro - 6 - benzyloxy - 9H - pyridoT3,4-bJ Stage A: - ethoxycarbonyl - 1 - (5' - benzyloxy - 3' - indolyl-methyl)1,2,3,4 - tetrahydro - 6 - benzyloxy - 9H - pyrido p,4-bj indole: 43454 Preparation of 5-benzyloxy-tryptamine hydrochloride: q g of 5-benzyloxy-tryptamine were dissolved in 200 cm of isopropanol at 20°C, and a saturated solution of hydrochloric acid in ethyl acetate was added, until pH = 1.2.

The mixture was vacuum filtered, washed with ethyl acetate and dried under vacuum. 11.3 g of 5-benzyloxy-tryptamine hydrochloride were obtained. M.Pt. = 250°C.

Condensation: g of ethyl 5-benzyloxy-3-indole-pyruvate and 9g of 5-benzyloxy-tryptamine hydrochloride were introduced into 250 cm3 of absolute ethanol.

The mixture was agitated for 3 days at reflux and distilled to dryness under vacuum. 17 g of crude product were obtained and chromatographed on silica gel. It was eluted with a 9:1 chloroform/methanol mixture, and 12 g of crude product were recovered and crystallised from ether, after treatment with active charcoal. 10.3 g of l-ethoxycarbonyl-l-(5'-benzyloxy-3’-indolyl-methyl)-1,2,3,4tetrahydro - 6 - benzyloxy - 9H - pyrido f3,4-bJindole were recovered in the form of a beige product melting at 125°C.

Analysis: ^7^35^3^4 = 585.57 Calculated: « 75.87 H% 6.02 N% 7.18 Found: C% 75.8 5.8 N% 6.8 Stage B: - (5' - benzyloxy - 3' - indolyl - methyl)-1,2,3,4 - tetrahydro - 6 - benzyloxy - 9H -pyrido{3,4-bJindole hydrochloride: .3 g of 1-ethoxyearbonyl-1-(5'-benzyloxy - 3' - indolyl meth - 1,2,3,4 - tetrahydro - 6 - benzyloxy - 9H - pyrido [3,4-bJ 3 3 -indole were suspended in 103 cm of ethanol and 34 cm of N soda.

The suspension was agitated for 30 minutes at reflux, and 9.7 cm of concentrated hydrochloric acid were then added all at once. The refluxing was continued for 6 more hours. The mixture was cooled, vacuum-filtered, and washed with water, then with ethanol. 8.3 g of crude product were obtained and dissolved in 2 litres of methanol at reflux, 1 litre of water was added, and the solution filtered and concentrated to about 400 cm3. It was left to stand for one night, vacuum filtered, washed with water and dried under vacuum. 6.9 g of l-(5'-benzyloxy-3'-indolyl-methyl) -1,2,3,4 - tetrahydro - 6 - benzyloxy-9H-pyrido[3,4-b] indole hydrochloride were obtained in the form of a clear yellow crystalline product. M.Pt = 252-254°C. Analysis: C34H31N3O2.HC1 = 550.08 Calculated: C% 74.23 H« 5.86 N% 7.64 CU 6.45 Found: C% 74.1 H% 5.9 N% 7.4 CU 6.3 Example 11 - (5‘ - hydroxy - 3' - indolyl - methyl)-1,2,3,4 - tetrahydro - 6 hydroxy - 9H - pyrido[3,4-b] indole hydrochloride. 1.5 g of 10% palladium on charcoal were washed 3 times with 20 cm3 of 0.5 N hydrochloric acid, then 4 times with 50 cm of water and finally 4 times with 50 cm of methanol. 300 cm of anhydrous methanol are then added, followed by 3 g of 1-(51-benzyToxy-31-indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 benzyloxy-9H-pyrido [j?>4-b]indole hydrochloride. 434G4 The mixture was hydrogenolysed under agitation (absorption of q 260 cm of hydrogen in 1 hour).

The mixture was filtered in a flask containing a trace of butyl hydroxy anisole, rinsed with methanol and distilled to dryness under vacuum. g of l-(5'-hydroxy-3'-indolyl-methyl)-1,2,3,4 - tetrahydro - 6 hydroxy - 9H-pyrido[3,4-bJindole hydrochloride were obtained in the form of a pink powder. M.Pt^250°C. The product obtained was kept in an inert gas Formulation 1: Tablets were prepared, corresponding to the formula: l-(5-methoxy-3'-indolyl-methyl)-1,2,3,4-tetrahydro-6methoxy-9H-pyrido [3,4-b]indole hydrochloride 5 mg; Excipient q.s. for a tablet up to 100 mg.

(Oetail of the excipient: lactose, starch, talc, magnesium stearate).

Formulation 2: Tablets were prepared, corresponding to the formula: l-(5'-hydroxy-3'-indolyl-methyl)-1,2,3,4-tetrahydro-9H-pyridojjj,Q-b]indole hydrochloride 5 mg; Excipient q.s. for a tablet up to 100 mg.

(•Detail of the excipient: lactose, starch, talc, magnesium stearate).

Formulation 3: Tablets were prepared, corresponding to the formula 1-(5'-hydroxy-3'-indolyl-methyl )-1,2,3,4-tetrahydro-9H-pyrido[j,4-b] indole hydrochloride 5 mg: Excipient q.s. for a tablet up to 100 mg.

(Detail of the excipient: lactose, starch, talc, magnesium stearate).

Claims (54)

1. CLAIMS •j 3 ·4 6 *1

1. A derivative of 9H-pyrido[3,4-b]indole of the general formula wherein and R 2 , which may be the same or different, each represent a hydrogen atom, a halogen atom, a hydroxy radical, an alkoxy radical containing from 1 to 5 carbon atoms or a benzyloxy radical. ο with the proviso that R does not represent a hydroxy radical when R represents a halogen atom, an alkoxy radical or a benzyloxyl radical; or an acid addition salt thereof.

2. A derivative or salt as claimed in claim 1, wherein R and/or R c represents a chlorine atom.

3. A derivative or salt as claimed in claim 1, wherein R and/or R £ represents a methoxy radical.

4. A derivative or salt as claimed in claim 1, wherein R 1 and 2 R , which may be the same or different, each represent a hydrogen atom a chlorine atom, a hydroxy radical, a methoxy radical or a benzyloxy radical. „1

5. An acid addition salt as claimed in any of the preceding claims, wherein the salt is formed with hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic or aspartic acid, methanesulphonic acid, or benzenesulphonic acid.

6. 1 - (5' - Methoxy - 3' - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 - methoxy - 9H - pyrido [3,4-bJ indole or its hydrochloride.

7. 1 - (5' - Methoxy - 3' - indolyl - methyl) - 1,2,3,4 tetrahydro - 9H - pyrido [3,4-bJ - indole or its hydrochloride.

8. 1 - (3' - Indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 hydroxy - 9H - pyrido - ^3,4-bJindole or its fumarate.

9. 1 - (3‘ - indolyl - methyl) - 1,2,3,4 - tetrahydro - 6 - chloro - 9H - pyrido -[^3,4-bJ indole.

10. 1 - (5' - Hydroxy - 3' - indolyl-methyl) - 1,2,3,4 - tetrahydro - 9H - pyrido (3,4-bJindole or its hydrochloride.

11. A process for the preparation of a derivative of general Ί ? formula I wherein R is as defined in claim 1 and R represents a hydrogen atom, a halogen atom, an alkoxy radical containing from 1 to 5 carbon atoms or a benzyloxy radical, in which process as appropriate compound of the general formula:

12. 1 2 (wherein R is as defined in claim 1 and R ft represents a hydrogen atom, a halogen atom, an alkoxy radical containing from 1 to 5 carbon atoms or a benzyloxy radical) is decarboxylated to give the desired compound of general formula I. 5 12. A process as claimed in claim 11, in which the decarboxylation is carried out by means of a strong mineral acid.

13. A process as claimed in claim 12, in which the strong mineral acid is hydrochloric acid.

14. A process as claimed in any of claims 11 to 13, in which 10 the reaction mixture is heated to a temperature of 95° to 110°C for 2 to 6 hours.

15. A process as claimed in any of claims 11 to 14, in which the compound of general formula IV is prepared by reacting an appropriate tryptamine of the general formula: R. (Π) (wherein R is as defined in claim 1) with a suitable derivative of 3-indole-pyruvic acid of the general formula: (ΠΙ) (wherein R^ is as defined in claim 11) to give the desired compound of general formula IV.

16. A process as claimed in claim 15 for the preparation of a compound of general formula I wherein R^ represents a hydroxy radical, in which the appropriate compound of general formula IV is prepared from a tryptamine of general formula II wherein represents a hydroxy radical in the form of a complex with creatinine sulphate.

17. A process as claimed in claim 15 or 16, in which the reaction of the compounds of general formulae II and III is carried out either in an aqueous medium or in an anhydrous medium, and optionally in the presence of an alkanol containing 1 to 5 carbon atoms.

18. A process as claimed in claim 17, in which the alkanol is butanol.

19. A process as claimed in any of claims 15 to 18, in which the reaction mixture is heated to a temperature between 50°C and the boiling temperature of the reaction mixture.

20. A process as claimed in c.laim 19, in which the reaction mixture is heated for a period of 48 hours to 7 days. ti 3 sl ii 4

21. A process as claimed in any of claims 15 to 20, in which when R a 2 represents a halogen atom;, a hydroxy radical or an alkoxy radical containing from 1 to 5 carbon atoms, the compound of general formula III is prepared by subjecting an appropriate compound 5 of the general formula p (wherein Rg represents a halogen atom, a hydroxy radical or an alkoxy radical containing from 1 to 5 carbon atoms, to alkaline hydrolysis to give the desired compound of general formula III. 10

22. A process as claimed in claim 21, in which the compound of general formula VIII used as starting material is prepared by condensing an appropriate 3-formyl-indole of the general formula: (VII) 3 Ί S 4 (wherein R g is as defined in claim 21) with hydantoin to give ine desired compouna of general formula VIZ.

23. A process as claimed in claim 22, in which the condensation is carried out in the presence of piperidine.

24. A process for the preparation of a derivative of general formula I wherein R 1 represents a hydrogen ato radical and R represents a benzyloxy radical an appropriate compound of general formula: m or a benzyloxy , in which process I H (VI) (wherein R^ represents a hydrogen atom or a benzyloxy radical and Alk represents an alkyl radical containing from 1 to 3 carbon atoms) is hydrolysed and decarboxylated to give the desired compound of the general formula: wherein is as defined hereinbefore.

25. A process as claimed in claim 24, in which the hydrolysis and decarboxylation of compound VI is effected by an alkali-metal 5 hydroxide in an alkanol containing from 1 to 5 carbon atoms.

26. A process as claimed in claim 25, in which the alkali-metal hydroxide is sodium or potassium hydroxide.

27. A process as claimed in claim 25 or claim 26, in which the alkanol is ethanol. 10

28. A process as claimed in any of claims 24 to 27, in which the hydrolysis and decarboxylation is effected at the boiling temperature of the reaction mixture.

29. A process as claimed in any of claims 24 to 28, in which the compound of general formula VI is prepared by reacting an appropriate 15 tryptamine of the general formula: ,3464 ι (wherein (Π 1 ) NH, is as defined in claim 23) with a suitable compound of the general formula (wherein Alk is as defined in claim 24) to give the desired product of general formula VI. 434G4

30. A process as claimed in claim 29, in which the reaction of compounds II' and V is carried out in an alkanol containing from 1 to 5 carbon atoms.

31. A process as claimed in claim 30, in which the alkanol is ethanol.

32. A process as claimed in any of claims 29 to 31, in which the 5 reaction mixture is heated to a temperature between 50°C and its boiling temperature.

33. A process as claimed in claim 32, in which the reaction mixture is heated for a period of 48 hours to 7 days.

34. A process as claimed in any of claims 29 to 33, in which the starting 10 material of general formula V is prepared by a process in which an appropriate compound of the general formula: COO-Alk (X) (wherein Alk is as defined in claim 24, is hydrolysed and decarboxylated to give the desired product of general formula V. 4 3 4 3 4

35. A process as claimed in claim 34, in which, as a secondary product, the compound of general formula III wherein R^ 2 represents a benzyloxyl radical is isolated.

36. A process as claimed in claim 34 or claim 35, in which the hydrolysis and decarboxylation is effected by acetic acid.

37. A process as claimed in any of claims 34 to 36, in which the compound of general formula X is prepared by condensing the methyl ester of 5-benzyloxy-3-indole-acetic acid of the formula: (IX) with an appropriate alkyl oxalate to obtain the desired product of general formula X.

38. A process as claimed in claim 37, in which the condensation is carried out in the presence of sodium ethoxide. «3434

39. A process for the preparation of a derivative of general formula I wherein represents a hydrogen atom or a hydroxy radical o and R represents a hydroxy radical, in which an appropriate compound of general formula 1' as defined in claim 24 is hydrogenolysed to give the desired compound of general formula I.

40. A process as claimed in claim 39, in which the hydrogenolysis is effected by means of gaseous hydrogen in the presence of a suitable catalyst.

41. A process as claimed in claim 40, in which the catalyst is platinum and palladium.

42. A process as claimed in any of claims 39 to 41, in which the compound of general formula 1' is prepared by a process as defined in any of claims 24 to 38.

43. A process for the preparation of a derivative of general formula I, as claimed in claim 1, substantially as described herein with reference to the Examples.

44. A process for the preparation of an acid addition salt of a derivative of general formula I, in which the appropriate derivative of general, formula I is reacted with a suitable acid to form the desired afcid addition salt,

45. A process as claimed in claim 44, in which the derivative and the acid are reacted in substantially stoichiometric proportions.

46. A process as claimed in claim 44 or claim 45, in which the derivative of general formula I is prepared by a process as claimed in any of claims 11 to 43.

47. A process as claimed in any of claims 44 to 46 and substantially as described herein with reference to the Examples.

48. A derivative of general formula I or an acid addition salt thereof, whenever prepared by a process as claimed in any of claims 11 to 47.

49. A pharmaceutical composition which contains, as active principle, one or more 9H-pyrido|_3,4-bJindole derivative of general formula I and/or one or more pharmaceutically acceptable acid addition salt thereof in association with a suitable pharmaceutical vehicle.

50. A pharmaceutical composition as claimed in claim 49, in which the active principle comprises one or more derivatives and/or one or more salts as claimed in any of claims 2 to 10.

51. A pharmaceutical composition as claimed in claim 50, in which the active principle comprises l-(5'-hydroxy-3'-indolyl-methyl) - 1,2,3,4 - tetrahydro - 9H - pyrido-[3,4-bJindole hydrochloride.

52. A pharmaceutical composition as claimed in any of claims 49 to 51 in which the vehicle comprises one or more of talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives and glycols.

53. A pharmaceutical composition as claimed in claim 52, in which the vehicle also comprises a wetting, dispersing or emulsifying agent, and/or a preservative.

54. A pharmaceutical composition as claimed in any of claims 49 to 53, and substantially as described herein with reference to the Formulations.