GB2035310A

GB2035310A - Indole-s-carbaxamides and this anologues

Info

Publication number: GB2035310A
Application number: GB7935208A
Authority: GB
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1978-10-12
Filing date: 1979-10-10
Publication date: 1980-06-18
Also published as: US4252803A; DE2940687A1; GB2035310B; ES484980A0; FI793071A; DK425579A; DE2940687C2; JPS6358817B2; ES492114A0; IT1142170B; NZ191802A; FR2438651A1; AU531783B2; AU5165779A; IE49304B1; BE879381A; SE7908443L; SE448628B; ES8106142A1; JPS5562063A

Description

1 -10 GB 2035310 A 1

SPECIFICATION

Heterocyclic compounds This invention relates to certain heterocyclic compounds, to processes for their preparation, to pharmaceu- 5 tical compositions containing them and to their medical use.

Thus, the present invention provides an indole of the general formula (I):

R1 X 4 Alk-N R2 6 R6 R5 R3 R4 (1) wherein R, and R2, which may be the same or different, each represents a hydrogen atom, or an aryl,aralkyl, cycloalkyl, fluoroalkyl or alkyl group, which alkyl group may be unsubstituted or substituted by an alkenyl group or by a group -OR7 or by a group -W-R7 -1 R8 where R7 and RB, which may be the same or different, each represents a hydrogen atom, an alkyl, aryl or 25 aralkyl group; or R, and R2 together with the nitrogen atom to which they are attached form a saturated monocyclic 5 to 7 membered ring which may contain a further hetero function (viz oxygen or the group -H or - Me); R3 and R4, which may be the same or different, each represents a hydrogen atom, or an aryi, aralkyl, cycloalkyl, fluoroalkyl or alkyl group, which alkyl group may be unsubstituted or substituted by an alkenyl group or by a group -OR7 or by a group R7 -N-.R8 where R7 and R8 are as previously defined; 40 or R3 and R4 may together form an aralkylidene group; or R3 and R4together with the nitrogen atom to which 40 they are attached form a saturated monocyclic 5 to 7 membered ring which may contain a further heterto function (viz oxygen or the group -H or - Me); R5 represents a hydrogen atom or an alkyi or aralkyl group; R6 represents a hydrogen atom or an aryl or Cl-C3 alkyl group; Alk represents an alkylene group of one to four carbon atoms in chain length, which group may be unsubstituted or substituted at one or more of its carbon atoms, by one to three Cl-C3 alkyl groups; and 50 X represents an oxygen or sulphur atom, and its physiologically acceptable salts, hydrates and bioprecursors.

The compounds according to the invention include all optical isomers thereof and their racemic mixtures.

Referring to the general formula (1), the alkyl group may be a straight chain or branched chain alkyl group preferably containing from 1 to 6 carbon atoms unless otherwise specified. The cycloalkyl group preferably 55 contains 5 to 7 carbon atoms. The fluoroalkyl group is a Cl-C3 alkyl group substituted with not more than three fluorine atoms which may be attached to one or more of the carbon atoms. The term aryl used.as such or in the term aralkyl preferably means phenyl which may be substituted by one or more alkyl groups (for example, methyl), halogen atoms (for example, fluorine), hydroxy groups or methoxy groups. The alkyl moiety of the aralkyl group preferably contains 1 to 6 carbon atoms. The alkenyl groups preferably contains 2 60 to 4 carbon atoms. The aralkylidene group is preferably an aryimethylidene group.

In the general formula (1), R, and R2 are preferably both hydrogen atoms.

It is preferred that one or both of R3 and R4 are hydrogen or Cl-C3 alkyl groups or R3 is a hydrogen atom and R4 is an aralkyl group. R5 and R6 are preferably both hydrogen atoms.

The group represented by Alk is preferably a C2-C3 alkylene group which is preferably unsubstituted.

2 GB 2 035 310 A 2 X is preferably oxygen.

In the embodiment wherein R, and R2 or R3 and R4togetherwith the nitrogen atom to which they are attached form a saturated monocyclic ring, the monocyclic ring is preferably morpholino According to a particular embodiment of the present invention it is preferred that R, is a hydrogen atom and that R2 is a hydrogen atom, an aralkyl group preferably benzyi, a cycloalkyl group preferably cyclopentyl, 5 an unsubstituted alkyl group preferably methyl or an alkyl group substituted by an alkenyl group or the group -OR7 preferably hydroxymethyl or allyl.

According to another embodiment, it is preferred that R3 is a hydrogen atom or an alkyl group preferably methyl or n-propyl and that R4 is a hydrogen atom, a fluoroalkyl group preferably trifluoroethVI, an unsubstituted alkyl group preferably methyl or n-propyl or an aralkyl group preferably benzyi or a group CH3CH(C1-12)pPh wherep is 1, 2 or 3 and the phenyl group (Ph) may be substituted by a p-chloro group.

Alternatively, it is preferred that R3 and R4tOgether form an aralkylidene group preferably benzylidene or together with the nitrogen atom to which they are attached form a saturated monocyclic 5 to 7 membered ring containing a further hetero function preferably morpholino or piperazino.

According to another embodiment, it is preferred that Rs is a hydrogen atom, an alkyl group preferably methyl or a benzyi group.

According to a further embodiment, it is preferred that R6 is a hydrogen atom or an alkyl group preferably methyl.

According to a further aspect of the invention it is preferred that Alk is an alkylene group containing 2 or 3 carbon atoms and is preferably unsubstituted.

According to a particularly preferred embodiment of the invention R, is a hydrogen atom and R2 is a hydrogen atom or a methyl or hydroxymethyl group.

According to another particularly preferred embodiment R3 is a hydrogen atom or a methyl group and R4 is a hydrogen atom or a methyl, trifluoroethyl or benzyi group or a group CH3CH(C1-12Th (where Ph represents an unsubstituted phenyl group). Alternatively it is particularly preferred that R3 and R4together 25 with the nitrogen atom to which they are attached represent a benzylidene or morpholino group.

it is particularly preferred that R5 represents a hydrogen atom or a methyl group.

According to a further particularly preferred embodiment R6 represents a hydrogen atom.

It is further particularly preferred that Alk represents an unsubstituted alkylene chain containing 2 or 3 carbon atoms.

In the particularly preferred embodiment of the invention X is preferably an oxygen atom.

Preferred compounds according to the invention are:

3-(2-aminoethyl)-1H-indole-5-carboxamide; 3-[2-[(1-methy]-3-phenylpropyl)amino]ethyil-1H-indole-5-carboxamide; 3-[2-(di methyl ami no)ethyll-1 M ndo le-5-carboxamide; 3-[2-(methylamino)ethyil-1H-indole-5-carboxamide; 3-12-(4-morpholinyl)ethyi]-1H-indole-5-carboxamide; 3-(2-aminoethyi)-1H-indole-5-carbothioamide; 3-(3-ami nopro pyl)-1 H-i n do 1 e-5-ca rboxa mid e; 3-[2-(2,2,2-trifluoroethyi)aminoethyll-1H-indole-5-carboxamide; and their physiologically acceptable. salts.

Suitable physiologically acceptable salts of the indoles of general formula (1) are acid addition salts formed with organic or inorganic acids, for example, hydrochlorides, hydrobromides, sulphates, fumarates, maleates and creatinine sulphate adducts.

The compounds of the invention have been shown to have selective actions on blood vessels such that they may be useful in the treatment of cardiovascular disorders such as hypertension, Raynaud's disease and migraine.

The antihypertensive properties of the compounds of the invention have been demonstrated bytheir abilityto lower blood pressure in tests performed on hooded rats made hypertensive by DOCA implantation and by replacement of their drinking water with isotonic saline for 8 weeks. The compounds of the invention 50 when administered intraperitoneally were found to lower blood pressure in conscious hypertensive rats in some instances fora period of several hours.

The potential use of certain compounds of the invention in the treatment of migraine is indicated by the fact that they have a selective contractile action on the dog isolated ear artery. Methysergide, which is known to be useful in the treatment of migraine, shows this same action (M Fenluk, P.P.A. Humphrey and G.P. Levy, 55 Br. J Pharmacology 1977, 61, 466).

Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound selected from indole derivatives of the general formula (1), their physiologically acceptable salts, hydrates and bioprecursors adapted for use in human orveterminary medicine, and formulated for administration by any convenient route.

Such compositions may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Such compositions may also contain other active ingredients, e.g. conventional P-blocking agents, such as propranolol.

Thus the compounds according to the invention may be formulated for oral, buccal, parenteral or rectal administration. Oral administration is preferred.

10.

1 1 3 GB 2035310 A 3 For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, capsules, solutions, syrups or suspensions prepared by conventional means with physiologically acceptable excipients. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

The compounds of the invention maybe formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compounds may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glyceride.

A proposed dose of the compounds of the invention for oral administration to man, in order effectively to lower the blood pressure, is 5 mg - 500 mg total daily dose which may be administered, for example, in up to 4 or 5 doses per day.

The compounds of general formula (1) may generally be prepared by an appropriate combination of reactions by which the desired substituents are introduced into suitable intermediates, either before or after cyclisation to form the indole nucleus.

The following are given as examples of processes for the preparation of the compounds of the invention. It may be necessary or desirable to perform a sequence of two or more reaction steps in order to obtain the 20 desired substitution. Where necessary, other substitutent groups already present on the indole nucleus may be protected in conventional manner, during a reaction to introduce or modify another substituent.

According to one process, for the preparation of a compound of general formula (1) in which X is an oxygen atom, an activated carboxylic acid derivative of general formula (1l):

25 Y0C,' Alk-N R3 N R4 30 1 1 R6 (11) R5 where Alk, R3, F14, R5 and R6 are as previously defined and Y is a leaving group, is reacted with a reagent of general formula RIFI2NH in which R, and R2 are as previously defined.

Suitable activated carboxylic acid derivatives represented by the general formula (11) include acyl hlaides (e.g. acid chlorides), esters (e.g. methyl, p-nitrophenyl or 1- methylpyridinium esters), acid anhydrides (in particular mixed acid anhydrides), and the products formed by reaction of the appropriate carboxylic acid corresponding to general fomula (11), in which Y is a hydroxyl group, with a coupling agent such as carbonyl 40 diimidazole or dicyclohexyi-carbodiimide. These activated carboxylic acid derivatives may be formed from the corresponding acid by well known procedures. For example, acid chlorides may be prepared by reaction with phosphorus pentachloride, thionyl chloride or oxalyl chloride; esters (e.g. alkyl esters) may be prepared by reaction with an alcohol (e.g. methanol) in the presence of an acid catalyst such as a mineral acid (e.g.

hydrochloric acid), and 1-methylpyridinium esters (1l,y=)may conveniently be prepared by reactionwith IZz N 0 1 (D --, Me 50 a 2-halo-l -methyl pyridiniu m iodide in the presence of an amine (e.g. triethylamine); and mixed acid anhydrides may be prepared by reaction with an appropriate acid anhydride (e.g. trifluoroacetic anhydride), an acid chloride (e.g. acetyl chloride or 1- [(diphenylamino)carbonyllpyridinium chloride) or an alkyl or aralkyl haloformate (e.g. ethyl or benzy] chloroformate).

The conditions under which the activated carboxylic acid derivative of general formula (11) is formed and subsequently reacted with the reagent of formula R1R2NH will depend upon the nature of the activated derivative and the reagent R1R2NI-1. Thus the reaction between an ester of formula (11) and the reagent of formula R1R2NH may conveniently be carried out in a solvent such as water of an alkanol (e.g. methanol), or the reagent may itself also act as solvent. Atemperature appropriate to the reaction is used, which may be 60 up to and including the reflux temperature of the mixture.

Where it is desired to prepare a compound of general formula (1) in which one or both of R3 and R4 represent hydrogen it is frequently necessary, in the above reactions, to protect the group N113R4, for example as a phthalimide (in the case of a primary amine), an N-benzyl derivative, and N-benzyi-oxycarbonyl derivative or an N-trichloroethyl urethane. Such protection is essential when the activated derivative 65 4 GB 2035310 A 4 represented by formula (11) is an acid chloride or acid anhydride. Subsequent cleavage of the protecting group is achieved by conventional procedures. Thus a phthalimido group may be cleaved by treatment with hydrazine hydrate or a primary amine for example methylamine, and Nbenzyl or N-benZY1OXYcarbonyl derivative may be cleaved by hydrogenolysis in the presence of a catalyst, for example, palladium. An 5 Nbenzyloxycarbonyl group may also be cleaved by treatment with hydrogen bromide in acetic acid.

According to another process for preparing a compound of general formula (1) in which R, and R2 are both hydrogen, the -CXNH2 group is introduced by reaction of a nitrile of general formula (Ill):

R NC Alk-N R4 N R6 1 R5 (X) 1Q wherein Alk, R3, R4, R5 and R6 are as previously defined, with a suitable oxygen- or sulphur-containing compound.

According to one embodiment of this process for preparing a compound of general formula (1) wherein X is oxygen, a nitrile of general formula (111) may be hydrolysed with acid or alkali under controlled conditions 20 to yield the desired 5-carboxamide. Thus, for example, the nitrile of formula (111) may be heated under reflux in a mixture of concentrated sulphuric acid, acetic acid and water (1: M) or with acetic acid containing boron trifluoride. Another possibility is to treat the nitrile of formula (111) with the hydroxide form of an anion exchange resin (e.g. Amberlite IRA 400) in a solvent such as ethanol or water are reflux or with a base, for example potassium hydroxide or potassium tertiary butoxide, in a solvent, for example tertiary butanol, at 25 reflux.

According to another embodiment of this process for preparing a compound of general formula (1) wherein X is sulphur, a nitrile of general formula (111) may be treated with, for example, hydrogen sulphide in a solvent (e.g. dimethylformamide or pyridine).

In this embodiment of the process, when R3 and/or R4 is a hydrogen atom, the -NR3R4 group should preferably be protected, for example as the N-phthalimide, during the treatment with hydrogen sulphide with subsequent removal of the protecting group to yield the desired 5- thioamide.

A compound of general formula (1) according to the invention may also be prepared by conversion of another compound of the general formula (1).

For example, a compound of general formula([), wherein R5 andlor R3 and R4 are hydrogen atoms, maybe 35 converted into another compound of general formula (1), wherein R5 and/or at least one of R3 and R4 is other than hydrogen, by a variety of alkylation procedures. Thus, it is possible, according to the present invention, selectively to introduce by alkylation either the R5 group or one or both of the groups R3 and R4, it being understood that when preparing a compound of general formula (1) in which R5 is a hydrogen atom it may be '40 necessary to replace this hydrogen atom by a protecting group which may subsequently be removed. - Similarly, when preparing a compound of general formula (1) wherein either or both of R3 and R4 are hydrogen atoms then a protecting group may be necessary.

Thus, a particularly useful procedure for the preparation of a compound of general formula (1) in which X is oxygen and one of R3 and R4 is hydrogen is reductive alkylation of the corresponding compound of formula (1) in which R3 and R4 are both hydrogen with an appropriate ketone or aldehyde (e.g. acetone or benzaldehyde) in the presence of a suitable catalyst (e.g. 10% palladium on charcoal). Alternatively the aldehyde or ketone may be condensed with the primary amine and the intermediate thus formed may subsequently be reduced using, for example, sodium borohydride or sodium cyanoborohyd ride or hydrogen in the presence of a metal catalyst (e.g. palladium).

According to another possibility, alkylation (e.g. methylation) maybe effected by treating a primary amine 50 of general formula (1) (i.e. in which R3 and R4 are both hydrogen) with formaldehyde and formic acid (the Eschweiler-Clarke procedure). This method is particularly suitable for the preparation of N,N-disubstituted products of general formula (1), in which R3 and R4 are both the same and other than hydrogen. Alternatively a secondary amine (i.e. in which R3 is hydrogen and R4 is other than hydrogen) may be used, to give a tertiary amine of general formula (1) in which R3 and R4 may be the same or different.

A further possibility is to react a primary amine of formula (1) (i.e. in which R3 and R4 are both hydrogen) with an appropriate halide (e.g. iodoethanol) in a solvent such as acetone and preferably under reflux, followed by treatment with a base (e.g. sodium hydroxide) to produce an Nsubstituted amine of general formula (1) in which at least one of R3 and R4 is other than hydrogen.

In another process, treatment of a primary amine of general formula (1) (i.e. where both R3 and R4 are 60 hydrogen) with an aromatic aldehyde (e.g. benzaldehyde) followed by reaction with an alkyl halide (e.g.

methyl iodide) in a solvent (e.g. aqueous 95% ethanol) gives, after heating under reflux, an N-substituted amine of general formula (1) where one of R3 and R4 is other than hydrogen.

Compounds of general formula (1) in which the moiety NR3R4 forms a heterocyclic ring may be prepared by treating the corresponding primary amine of general formula (!) (i.e. in which R3=R4=H) with, for 65 t 1 GB 2035310 A 5 example, an a,w-dihalocompound such as an a,o)-dihaloalkane (e.g. 1,5- dibrornopentane) or an umdihalodialkyl ether (e.g. 2,2'-dichlorodiethyl ether).

The introduction of an alkyl group represented by R5 may be carried out by alkylation with an appropriate alkyl or aralkyl halide or dialkyl sulphate preferably in the presence of a base such as sodium hydride in a 5 solvent such as dirnethylformarnide.

According to another process the group Alk NR3R4 may be interconverted to another group of formula Alk NR3R4 by reduction. For example, a compound of general formula (1) wherein R3 is a benzy] group may be reduced in the presence of a suitable catalyst such as palladium on charcoal in a solvent such as ethanol to yield a compound of general formula (1) wherein R3 is a hydrogen atom.

The aminoalkyl substituent (-Alk-NR3R4) may be introduced into the indole nucleus by a variety of 10 conventional techniques which may, for example, involve modification of a substituent in the 3-position, direct introduction of the aminoalkyl substitutent into the 3-position or introduction of the aminoalkyl substitutent prior to cyclisation to form the indole nucleus. In general the processes involved are based on methods referred to in'A Chemistry of Heterocyclic Compounds - Indoles Part IV, chapter V1(3), edited by

Willi amJ. Houiihan (1972),Wileyinterscience NewYork.

A compound of general formula (1) in which X is an oxygen atom and Alk is a 2-carbon chain may be prepared by reduction of a compound of general formula OV):

R1 R2 NCO W 1 20 N R6 1 (77) R5 where R,, R2, R5 and R6 are as previously defined and W represents the group -CHR9M, CH2CHR9NO2 -CH=CR9N02 or -COCHR9Z (where R9 is a hydrogen atom or a Cl - C3 alkyl group and Z is an azido group N3 or an amino group NIR3134) with the proviso that, except where W represents the group -COCHR9Z and Z is an amino group NIR3134, R3 and R4 in the resulting compound of general formula (1) are both hydrogen atoms.

According to a modification of this process the 5-substitutent may be a group convertible to a F11132NCOgroup. Thus, for example, according to a first embodiment, a compound of general formula (1) in which R3 and R4 are both hydrogen and Alk is a 2-carbon chain which may be unsubstituted or substituted by a C1-3 alkyl group on either carbon atom, may be prepared by catalytic reduction of a corresponding nitrile of general formula (V) or by reduction of a nitro-compound of general formula (V1) with Raney nickel and hydrogen 0 11 46 R1R21\4C CHR9CN 40 Rr, (V) R5 45 0 11 R1R21C 2CHR9NO2 ic" 50 Rr' (TT) RS in which IR,, R2, R5, R6 and R9 are as defined previously.

According to a second embodiment, an aminoethyl derivative of general formula (1), in which R3 and R4 are 55 both hydrogen and the carbon atom adjacent to the amino group may be unsubstituted or substituted by a C1-3 alkyl group, may be prepared by reduction (e.g. using hydrogen in the presence of a catalyst such as palladium) of a corresponding 3-nitrovinylindole of general formula (Vii):

R1R2NCO Ip, 1 1 z11 07] N' R6 1 R5 HCRQN05) 6 GB 2035310 A in which IR,, R2, Rs, R6 and R9 are as defined previously.

According to a third embodiment of the reduction process, a compound of general formula (1) in which Alk is a 2-carbon chain which may be unsubstituted or substituted with a C1-3 alkyl group at the carbon atom 9 adjacent to the amino group-NR3R4, may be prepared by reduction of an azidoketone or aminoacylindole of general formula (V110:

6 R1R2NCO COCHR9Z R6 R5 in which R,, R2, R5, R6, R9 and Z are as defined previously.

This reduction may, for example, be effected catalytically or by the use of sodium borohydride in propanol.

When an azidoketone (V]H, Z = N3) is reduced the product is a 2aminoethyl derivative in which R3 and R4 are 15 both hydrogen; reduction of an aminoacylindole Will, Z = NIR3R4) affords a 2-aminoethyl derivative in which one or both of R3 and R4 may be other than hydrogen.

According to a modification of this process where Z is NR3R4 then the 5substituent may be a group convertible into a R, R2NCO-group, for example a cyano group, wherein the reduction reaction is followed by conversion of the 5-substitutent into the desired R1R2NCO-group for example by hydrolysis with acid or 20 alkali.

The starting materials for the first embodiment of the reduction process described, having the general formula (V) or (V1), may be prepared by quaternisation of the appropriate compound of formula (IX):

R1R2NCO CHR9NR3R4 25 Rr, H5 wherein R,, R2, R3, R4, R5, R6 and R9 are as previously defined with an alkyl halide of general formula R10Hal (where Rjo represents an alkyl group), and subsequent reaction of the quaternary salt of general formula (X):

(D E) 35 R1R2NCO CHR9rNR3R4 R10Hal Rr, (X) 40 R5 with either an alkali metal cyanide or an alkali metal salt of a nitroalkane to give the corresponding nitrile (V) or nitro compound (V1) respectively. Alternatively the nitrocompound M) may be prepared by reaction of the Mannich base (IX) with an alkali 45 metal salt of a nitroalkane. The 3-aminomethyl derivative of general formula (R) may be prepared by subjecting an indole of formula (Xl):

t R1R2NCO 1-1 1 1 50 R6 R5 55 wherein R,, R2, R5 and R6 are as previously defined to a Mannich reaction using a primary or secondary amine of formula R3R4NH and an aldehyde of formula R9CHO (where R9 is a hydrogen atom or a Cl-C3 alkyl group) e.g. formaldehyde.

The nitrovinylindole used as starting material forthe second embodiment of the reduction process, having the general formula (V11) may be obtained by the action of a nitroalkane of general formula R9CHN02 on a 60 corresponding 3-formylindole of general formula (Xli):

Q z 1 7 GB 2035310 A 7 R1R2NCO CHO Rr, R5 in which IR,, R2, Rr, and R6 are as previously defined. The compound of general formula (XII) may be prepared by carrying out a Vilsmeier reaction (e.g. using 10 phosphorus oxychloride and dimethylformamide) on an indole of formula (Xlil):

R11 02C is 1R6 R5 wherein R,, is a lower alkyl group with subsequent conversion of the ester into the amidic group -CONIR1R2, thereby giving the Vormylindole of formula (X11) as just defined.

The azicloketone or aminoacylindole starting material for the third embodiment of the reduction process, having the general formula, (VIII), may be obtained from a corresponding haloacylindole of general formula (VII0 in which Z represents a halogen atom, by treatment with sodium azide or an amine of formula R3R4NH 25 respectively.

The haloacylindole (Vill, Z = Hal) may be prepared by halogenation (e.g. bromination) using N-bromosuccinimide) of the corresponding acylindole (VIII, Z = H), which may itself be obtained from an indole of general formula (M) by treatment with, for example, an acyl halide of formula R9CH2COHal.

Compounds of formula (1) in which Alk represents an akylene chain containing one, two, three orfour carbon atoms may, in general, be prepared by application of the Fischer- indole synthesis, whereby a phenylhydrazone of general formula (XIV):

R1R2NCO 35 NRO==CR6CH2AlkQ in which Q is the group NR3R4 or a halogen atom (e.g. chlorine), is cyclised by a variety of methods, 40 When Q is the group NR3R4 the phenylhydrazone of formula (M) is cyclised by heating in the presence of an appropriate catalyst such as zinc chloride.

When Q is a halogen atom cyclisation is effected by heating in an aqueous alkanol (e.g. methanol) to give a product of formula (1) in which R3 and R4 are both hydrogen.

The phenylhydrazone of formula (M) in which Q is NR3R4 maybe prepared by reacting a phenylhydrazine 45 of formula (XV):

R1R2NCO 1 50 (7v) 50 NR5NH2 with an appropriate aldehyde or ketone of formula (XVI):

R6COCH2Alkl\1R3R4 (XVI)55 (or a derivative thereof such as an acetal or ketal) in a suitable solvent (e.g. aqueous acetic acid).

The phenylhydrazone of formula (M) in which Q is a halogen atom may be prepared by condensing a substituted phenylhydrazine of formula (XV) with a haloketone R6COCH2Alk Hal (in which Hal is e.g. chlorine) 60 in a solvent (e.g. ethanol).

According to a modification of the above process the 5-substituent may be a group convertible to a R1R2NCO-group, e.g. a cyano group, wherein the cyclisation step is followed by conversion of the 5-substituent into the desired R1R2NCO-group.

In the above synthesis, when Q is the group NR3R4 and R3 and/or R4 are hydrogen, the amino group NR3R4 65 is preferably protected (e.g. as a phthalimide or N-benzyl derivative) as described previously.

8 GB 2035310 A A further general method for preparing compounds of general formulaffi involves displacement of the halogen function from a 3-halo-alkylindole of formula (XVII):

8 R1 R2 NCO"' 1 R6 R.5 AikHal in which R,, R2, R5, R6 and Alk are as defined for formula (1) and the halogen function, Hal is, for example, 10.

chlorine, by reaction with ammonia or an amine of formula R3R4NI-1.

The haloalkylindole starting material of general formula (XVII) may be prepared by condensing a substituted phenylhydrazine of formula (XV) with a haloketone R6COCH2AlkHal (in which Hal is e.g. chlorine) in a solvent (e.g. ethanol), with heating and in the presence of an acid (e.g. hydrochloric acid).

Where it is desired to isolate a compound of the invention as a salt thismay be achieved by treating the free base of general formula (1) with an equivalent amount of an appropriate acid, or with creatinine sulphate in a suitable solvent (e.g. aqueous acetone).

The carboxylic acid derivatives represented by general formula (11) in which the group Y mayfor example be an alkoxy group, the corresponding carboxylic acids, and the nitriles of formula (111) may in general be 20 prepared by suitable application of one or more of the above described processes for introducing the substituent -AlkNIR3R4 either before or after cyclisation to form the indole nucleus.

Thus, for instance, a nitrile of formula (111) may conveniently be prepared by application of the Fischer-indole synthesis described above by heating a hydrazone of general formula (XVIII):

NC NN--CCH2AikNR3R4 1 1 R5 R6 (--TM) with a catalyst (e.g. polyphosphoric ester) in a solvent (e.g. chlorobenzene).

Hydrazones of formula (XVIII) are prepared from the corresponding hydrazines (XIX):

"--NNH2 1 R5 and an aldehyde or ketone of formula (XVI) as previously defined or a derivative thereof such as an acetal or 45 ketal according to the general procedure previously described.

In another process affording a nitrile of formula (111), a haloindole of general formula (XX) is treated with cuprous cyanide in a solvent such as N-methylpyrrolidine at an elevated temperature (e.g. 200OC).

Hal AWNR3R4 R 6 R5 In the above formula (M), AlkNIR3R4, R5 and R6 are as defined for general formula (1) and Hal represents a halogen atom (e.g. bromine). When preparing nitriles of formula (111) in which R3 andlor R4 represents hydrogen, it is necessary to protect the amino group NR3R4 (e.g. as a phthalimide or an N-benzyl derivative) as described previously.

The haloindole (XX) may be prepared from a halo-substituted pheny[hydrazine of general formula (XXI): 60 Hal is 1 so z i M5NH2 9 GB 2035310 A 9 by application of the Fischer indole synthesis as described previously.

If desired a nitrile of formula (111) may be hydrolysed to a carboxylic acid corresponding to formula (11) (Y OH) by prolonged reflux in either acid or alkali, or converted into an ester of formula 01) (Y = alkoxy) by treatment with an appropriate alkanol (e.g. methanol) in the presence of an acid (e.g. gaseous hydrogen 5 chloride).

In addition a carboxylic acid corresponding to general formula (11) (Y = OH) in which R3, R4, R5 and R6 are hydrogen, and Alk represents a 2carbon chain, may conveniently be prepared by application of the Abramovitch synthesis, in which a substituted benzenediazonium salt is coupled with a 3-carboxy-2piperidone to give a hydrazone of formula (XXII):

Y 1 0C "'laNH - R9 N-- NH 0 is wherein R9 is as previously defined and Y' may be, for example, a hydroxy or alkoxy group, which is then cyclised to a 1,2,3,4-tetrahydro-1 -oxo-p- carboline of general formula (XXIII):

Y10c 'aN ' NH R9 1 H 0 Hydrolysis of the oxocarboline (XXIII) followed by decarboxylation of the resulting indole-2-carboxylic acid 30 gives the desired 3- aminoethylindole derivative.

The invention is illustrated by the following Examples.

EXAMPLES OF PHARMACEUTICAL PREPARATIONS Tablets

These maybe prepared by direct compression or by wet granulation. The direct compression method is 35 preferred but may not be suitable in all cases as it is dependent upon the dose level and physical characteristics of the active ingredient.

1 A. 40 Direct compression mg/tablet

10.0 Active ingredient Microcrystalline Cellulose B.P.C.

89.5 Magnesium Stearate Compression Weight 0.5 100,0 The active ingredient is sieved through a 250 Itm sieve, blended with the excipients and compressed using 6.0 mm punches. Tablets of other strengths may be prepared by altering the compression weight and using 50 punches to suit.

B. Wet Granulation mg/tablet

Active ingredient 10.0 Lactose B.P.

74.5 Starch 13.P.

10.0 Pregelatinised Maize Starch B.P.

5.0 Magnesium Stearate B.P.

0.5 Compression Weight 100.0 GB 2 035 310 A The active ingredient is sieved through a 250 lim sieve and blended with the lactose, starch and pregelatinised starch. The mixed powders are moistened with purified water, granules are made, dried, screened and blended with the magnesium stearate. The lubricated granules are compressed into tablets as described for the direct compression formula.

The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxypropyl 5 methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.

Capsules. mglcapsule Active ingredient 10.0 10 STA-13X 1500 89.5 Magnesium Stearate 13.P. 0.5 is Fill Weight 100.0 15 A form of directly compressible starch supplied by Colorcon Ltd., Orpington, Kent, England.

The active ingredient is sieved through a 250 gm sieve and then blended with the other ingredients. The mix is filled into No. 2 hard gelatin capsules using a suitable filling machine. Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.

Sustained release tablets mg/tablet

Active ingredient 50.0 25 Cutina H.R. 20.0 Lactose B.P. 128.0 30 Magnesium Stearate B.P. 2.0 Compression Weight 200.0 Cutina HR is a grade of microfine hydrogenated castor oil supplied by Sipon Products Ltd., London.

The bctive ingredient is sieved through a 250gm sieve and blended with the Cutina HR and lactose. The mixed powders are moistened with Industrial Methylated Spirits 74 O.P., granules are made, dried, screened and blended with the magnesium stearate. The lubricated granules are compressed using 8.5mm punches to produce tablets with a hardness of not less than 101(p (Schleuniger tester).

Syrup mg/5mi dose Active ingredient Sucrose B.P. 2750.00 Glycerine 13.P. 500.00 Buffer Flavour As required Colour Preservative Distilled water 5.00 mi z 11 GB 2035310 A 11 The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water, and the glycerine is added. The remainder of the water is heated to 80,C and the sucrose is dissolved in this and cooled. The two solutions are combined, adjusted to volume and mixed. The syrup produced is,clarified by filtration.

Injection for Intravenous Administration. %W/V Active ingredient 0.20 Water for injections 13.P. to 100.00 10 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability using either dilute acid or alkali.

The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass.

The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the 15 solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen.

PREPARATION 1 3-[[(Phenylmethoxy)carbonyllaminolethyll-1H-indole-5-carboxylic acid Avigorously stirred solution of 3-(2-amino-ethyi)-1H-indole-5-carboxylic acid (50g) in aqueous sodium hydroxide (1 M, 450mi) was cooled in an ice-bath and benzyi chloroformate (60m1) and aqueous sodium hydroxide (1 M, 430mi) were added simultaneously dropwise over a period of 1 hour so as to maintain the pH >1 0. The reaction mixture was stirred at ca 5'C for 1.25 hour and then a further portion of aqueous sodium hydroxide (1 M, 130 mi) was added. After a further 2 hour. the reaction mixture was extracted with ether (2 x 25 500 mi) and the aqueous layer treated with sodium chloride (200g), acidified to pH 1 with concentrated hydrochloric acid (80mi) and extracted with ethyl acetate (3 x 500mi). The combined extracts were washed with aqueous sodium chloride (10%, 2 x 500 mi), dried (M9S04) and evaporated to dryness to give the title compound as a white solid (61.8g) mp 186.5 - 188'.

Analysis Found: C, 67.4; H, 5.4; N, 8.1% C191-118N204 requires: C, 67.5; H, 5.3; N, 8.3%.

PREPARATION 2.

[2-[5-(Aminocarbonyl)- 1H-indol-3-yllethyllcarbamic acid, phenyImethyl ester, compound with 2-propanol 35 W 1) A solution of 3-[2-[[(phenyimethoxy)carbonyi]aminolethyl]-1H-indole-5- carboxylic acid (1.7 g) and triethy lamine (2.0 mi) in acetonitrile (100 mi) was added to a stirred suspension of 2-iodo-1-methyi-pyridinium iodide (3.5g) in acetonitrile (100 m]) and the mixture was warmed to 50'for 90 mins. Ammonia was bubbled through the reaction mixture for 10 mins. After 30 mins, the resulting yellow solution was evaporated to dryness and partitioned between ethyl acetate (200 mi) and sodium hydroxide solution (1N, 100 mi). The organic phase was washed with dilute sulphuric acid (2N, 3 x 100 mi), water (100 mi), dried (Na2SO4) and evaporated to dryness to give a colourless foam (1.7g) which was crystallised from 2-propanol to give the title amide as a white crystalline solid (1.2g) m.p. 134.5 -135.5'C.

A sample for analysis was recrystallised from 2-propanol m.p. 135-70C.

Analysis Found: C, 66.4; H, 63; N, 10.7% C191-119N303C31-180 requires: c, 66.5; H, 6.8; N, 10.6% PREPARATION 3 3-[2-(1,3-Dihydro1,3-dioxo-2H-isoindol-2-yl)ethyll- 1H-indole-5- carbonitrile i) 4-[2-[4-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2yl)butylidenelhydrazinolbenzoni trile.

A solution of 4-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yil-butanaI diethyl acetal (1 3.7g) in ethanol (100 mi) was added dropwise to a suspension of 4-cyanophenylhydrazine hydrochloride (8g) in aqueous acetic acid (50%) at 800C. After 1 hour the solvent was evaporated off and the residue was triturated with water (200 mi). 55 The solid produced was filtered off, washed with water and was dried, (13. 4g) m.p. 129-1320C. Crystallisation from ethanol gave a sample m.p. 132-1340C.

Analysis Found: C, 685; H, 5.0; N, 16.3%; C191-118N402 requires: Q68.5: H, 4.8; N, 16.75% fl) 3-[2-(1,3-Dihydro- 1,3-dioxo-2H-isoindol-2-yl) ethyl]1H-indole-5- carbonitrile, compound with water (4: 1) The crude 4-[2-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2yi)butylidenelhydrazinelbenzoni trile (8g) was added to polyphosphoric acid ethyl ester (40g) in chloroform (200 mi), and the resulting mixture was heated under reflux for 16 hours. The chloroform was evaporated off and the oily residue was partitioned between 65 12 GB 2035310 A aqueous 2N sodium carbonate solution (150 mi) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (2 x 30 m]) and the combined organic extracts were washed (H20), dried (M9S04) and evaporated. Trituration of the residue with ethanol produced a yellow powder (2.1 g) which was filtered off.

The filtrate was evaporated and the residual orange oil was chromatographed on silica (Merck 60 mesh).

Elution with light petroleum (b.p. 40-60'C)-ethyl acetate (11: 1) gave the title compound as a pale yellow solid 5 (3.6g) m.p. 223-2250C.

Analysis Found: C, 71.65; H, 4.3; N, 12.8% C19H13N302'0.25H20 requires: C, 71.35; H, 4.25; N, 13.1 % PREPARATION 4 3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyll-1Hindole-5-carbonitrile 1) 2-[2-(5-Bromo- 1H-indol-3-yl)ethyll- 1Hisoindole-1,3(2H)-dione 4-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yi]butanaI diethyl acetal (11.69) was added with vigorous stirring to a solution of 4-bromophenylhydrazine hydrochloride (9.0g) in 50% aqueous acetic acid (370 mi). The mixture was heated on a steam bath for 4 hours and was then diluted with water, while still hot, to 1 1. The mixture was cooled and an orange yellow precipitate was filtered off and dried in vacuo. The solid was boiled in ethanol (250 m]) for 1 hour and residual solid filtered off and dried to afford the title compound as a yellow solid (9.5g) m.p. 206-2090C. Crystallisation of a portion of this solid (0.59) from ethanol (25 mi) gave a sample (0.259) m.p. 208-212'C.

Analysis Found: C, 58.5; H, 3.75; N, 7.6% C181-11313M202 requires: C, 58. 55; H, 3.55; N, 7.6% fl) 3-[2-(1,3-Dihydro1,3-dioxo-2H-isoindol-2-yl)ethyll- 1H-indole-5- carbonitrite A mixture of 2-[2-(5-bromo-1H-indol-3-yi)ethyil-1H-isoindole-1,3(2M-dione (4.0g), cuprous cyanide (1.1g) and N-methy]-2-pyrrol id i none (10 mi) was heated at reflux for 1 hour. The reaction mixture was poured onto ice (30g) and concentrated ammonia (15 m]) was added and the suspension was stirred for 0.75 hour. The solid was filtered off, washed with water and methanol and was crystallised from aqueous acetone to give the title compound (2.7g) as a fawn solid m.p. 217-221'C. T.L.C. Silica ether Rf 0.44.

PREPARATION 5 [2-[5-[[[(Diphenylamino)carbonylloxylcarbonyll- 1H-indol-3Yllethyllcarbamic acid, phenyImethyl ester A solution of 1-[(diphenylamino)carbonyilpyridinium chloride (1.1g) in water (10 mi) was added rapidly to a stirred solution of 3-[2-[[(phenyimethoxy)carbonyllaminolethyll-1H- indole-5-carboxylic acid 0 g) and triethylamine (0.6 ml) in water (15 mi). After 0.5 hour, an amorphous yellow solid (1.7g) was filtered off. A sample (0.5g) was crystallised from a mixture of ethyl acetate and cyclohexane to give the title compound (0.3g) as a cream crystalline solid m.p. 137-138.5'C.

Analysis Found: C. 72.0; H, 5.1; N, 7.75% C32H27N305 requires: C, 72.05; H, 5.1; N, 8.0% PREPARATION 6 3-(2-Aminoethyl)-1H-indole-5-carboxylic acid, methyl ester, hydrochloride Thionyl chloride (25 mi) was added to Analar methanol (84 mi) at WC over a period of 1 hour under nitrogen. 3-(2-Aminoethyi)-1H-indole-5- carboxylic acid hydrochloride (2.5g) in Analar methanol (35 mi) was added at OOC and the mixture was heated at reflux under nitrogen for 2.5 hour, cooled to ca. 450C and dry diethyl ether (200 mi) was added. The mixture was cooled and left overnight at O'C giving the title compound (1.99) as white microcrystals m.p. 265.5-2670C. T.L.C. Silica, ethyl acetate: 2- propanol:water: ammonia (25:15:8:2) Rf 0.46 Analysis Found: C, 56.8: H, 5.9: N, 11.0% C12H14N20-HCI requires: C, 56. 6: H, 5.9: N, 11.0% PREPARATION 7 Amberlite Resin (IRA 400 OH-) Amberlite Resin (IRA 400 C[-) (20g) was stirred at room temperature for 1 hour in aqueous sodium hydroxide (2N, 150 m]) and then allowed to stand overnight. The mixture was filtered and the resin washed with water (50 mW This resin was used in some of the following Examples.

PREPARATION 8 3-[2-(1,3-Dihydro- 1,3-dioxo-2H-isoindol2-yl)ethyll11-14ndole-S- carboxamide i) 3-[2-(1,3-Dihydro1,3-dioxo-2H-Isoindol-2-yl)ethyll- 1H-indole-5- carboxylic acid, 4-nitrophenyl ester.

Polyphosphoric acid ethyl ester (40 mO and 4-nitrophenol (6.3 g) were added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yi)ethyil-1H-indole-5carboxyiic acid (159) in dimethyl-formamide65 12 A0 so.

13 G-13 2 035 310 A 13 (70 mi) and the mixture was stirred at WC for 24 hours. More polyphosphoric acid ethyl ester (20 mi) was added and the mixture stirred at WC for 3 hours. The mixture was cooled, poured into ice and water (900 mi) and stirred for 1 hour with ice cooling. The resulting solid was filtered off and washed with boiling ethanol )l 500 mi) and hot water)600 mi) to give the title compound (12.5g) as pale yellow crystals m.p. 248-251'C.

T.L.C. Silica, ethyl acetate:2-propanol:water: ammonia (25:15:8:2) Rf 0.9 ii) 3-[2-(1,3-Dihydro- 1,3-dioxo-2H-isoindol-2-yl)ethyll- 1H-indole-5carboxamide Ammonia (0.88,0.2m]) was added to a solution of 3-[2-(1,3-dihydro-1,3- dioxo-2h-isoindol-2-yi)ethyi-1Hindole-5-carboxylic acid, 4-nitrophenyl ester (0.3g) in warm (50'C) dimethylformamide (3mi). The mixture was stirred at WC for 4 hours., poured into water (40 m]) and stirred for a further 0.5 hours. The precipitate 10 (0.21 g) was collected and crystallised from ethanol to give the title compound (0.1 2g) as an off-white solid m.p. 254-60C. T.L.C. Silica, Ethyl acetate: 2-propanol:water: ammonia (25:15:8:2) Rf 0.75.

EXAMPLE 1 i) a [2-[5-[[(Phenylmethyl)amino)carbonyl]1H-indol-3-yllethyllcarbamic acid, pheny/methyl ester, quarter 15 hydrate.

Triethylamine (3.6 mi) was added to a stirred mixture of 2-ch 1 oro-1 methyl pyridiniu m iodide (4.5g) and 3-[2-[[(phenyimethoxy)carbonyllaminolethyil-1H-indole-5-carboxylic acid (3.0g) in dry acetonitrile (200 mi).

After 1 hour at room temperature, benzylamine (3.9 m[) was added and stirring was continued for a further 24 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (200 mi) 20 and sodium hydroxide (1 N, 250 mi). The aqueous phase was further extracted with ethyl acetate (2 x 100 mi) and the combined extracts were washed with sodium hydroxide (1 N, 100 mi), sulphuric acid (1 N, 2 x 150 mi) and brine (200 mi), dried (Na2S04) and evaporated in vacuo to give a dark oil (3.7 g), which after treatment with a mixture of methanol and ethyl acetate gave the title compoundas an off-white solid (1.2 g) m.p.

129-130.5'C.

Analysis Found: C, 72.2; H, 5.8; N, 9.6% C261-125N303'1/41120 requires: C, 72.3; H, 5.9; N, 9.7% The following compounds were similarly prepared from 3-[2- [[(phenyimethoxy)carbonyllaminolethyil-1H- 30 indole-5-carboxylic acid (A) and the appropriate amine:

i)b 2-propylamine (2 mO and A (1.0g) gave [2-[5-[[(1methylethyi)amino]carbonyi]-1H-indol-3yilethyi]carbamic acid, phenyimethyl ester (0.45g) m.p. 136-7'C (from ethyl acetate).

Analysis Found: C, 69.1; H, 63; N, 11.1% C22H25N303 requires: C, 69.6; H, 6.6; N, 11.1% i)c Morpholine (3 mi) and A (2.5g) gave [2-[5-[(4-morphol i nyl)carbonyll- 1 H-indol-3-yll ethyl]ca rbam ic acid, phenyimethyl ester (1.7g) as light brown foam. T.L.C. silica, ethyl acetate: cyclohexane 1:1 Rf 0.36.

i)d Aniline (5.4 m]) and A (10.0g) gave [2-[5-[(phenylamino)carbonyil-1Hindol-3-yilethyllcarbamic acid, phenyimethyl ester (1.3g) m.p. 136.5 137.50Cfrom ethyl acetate: petroleum ether (b.p. 40-60'Q after purification on a silica column (Kieselgel 60,400g) eluted with chloroform containing 5% methanol.

Analysis Found: C, 72.1; H, 5.4; N, 9.7% C25H23N303 requires: C, 72.6; H, 5.6; N, 10.2% i)e Cyclopentylamine (1.2 m]) and A (2.0g) gave [2-[5[(cyclopentylamino)carbonyil-1H-indol-3- yllethyllcarbamic acid, phenyImethyl ester hernihydrate (1.2g) m.p. 165- 7'C.

Analysis Found: C, 70.4; H, 6.6; N, 10.3% C24H27N303'1/2H20 requires: C, 70.3; H, 6.8; N, 10.25% so i)f 2-Methoxyethylamine (0.8 m]) and A (3.0g) gave [2-[5-[[(2- methoxyethyi)aminolcarbonyil-1H-indol-3yilethyllcarbamic acid, phenyimethyl ester (2.3g) as a yellow oil after purification by chromatography on a silica column (Kieselgel 60,60g) eluted with ethyl acetate. T.L.C. silica, ethyl acetate Rf 0.25.

ii)a 3-(2-Aminoethyl)-N-(phenylmethyl)- 1H-indole-5-carboxamide, compound with creatinine, sulphuric acid and water 0: 1: 1) A solution of [2-[5-[[(phenyl methyi)aminolcarbonyll-1 H-indol-3- yilethyi]carbamic acid, phenyimethyl ester, quarter hydrate (0.8g) in ethanol (40 mi) was hydrogenated at room temperature and pressure over palladium oxide on charcoal (10%; 400 mg; pre-reduced) until hydrogen uptake ceased. The mixture was filtered through a Hyflo (diatomaceous earth) pad and the filtrate evaporated in vacuo to give a dark yellow oil (0.8g). A portion (0.6g) of the oil was dissolved in hot ethanol (10 mi) and a solution of creatinine sulphate65 14 GB 2035310 A in water (2M; 1:1; 1.5mi) was added. The precipitate that formed was filtered off and crystallised from aqueous ethanol to give the title compound (0.21 g) as a white solid m.p. 206-80C.

Analysis Found: C, 50.2: H, 5.5: N, 16.2% 5 C18H19N30'C4H7N30-1-12S04.1--120requires: C, 50.6; H, 53; N, 16.1% 14 The following compounds were similarly prepared by hydrogenation of the intermediates stated followed by formation of the appropriate salt:- jo ii) b [2-[5-[[0 -M ethylethVI)a m i nolca rbonyl 11 i ndol-3-yilethyl carbamic acid, phenyl methyl ester (0.4 g) gave 10 a 3-(2-aminoethyl)-N-(1-methylethyi)-1H-indole-5-carboxamide, maleate (0. 25g) as a white crystalline solid m.p. 174-5'C (from methanollethyl acetate) Analysis Found: C, 59.8; H, 6.4; N, 11.6% 15 C14H19N3O'C4H404 requires: C, 59.8; H, 6.4; N, 11.6% Mc [2-[5-[(4-Morpholinyi)carbonyil-1H-indol-3-yilethyllcarbamic acid, phenyImethyl ester (1.5g) gave 4-[[3(2-aminoethyl)-1H-indol-5yilcarbonyi] morpholine, compound with creatinine, sulphuric acid and water (1: 1:11) (0.65 g) as a white crystalline solid m.p. 178-1181'C (from aqueous ethanol) Analysis Found: C, 453; H, 53; N, 16.4% C,5H19N302C4H7N3O.H2S04.H20 requires: C, 45.4; H, 6.0; N, 16.7% ii)d [2-[-[(Phenylamino)carbonyil-1H-indol-3-yi]ethyllearbamic acid, phenyimethyl ester (1.06g) gave 3-(2 aminoethyi)-N-phenyi-11-1-indole-5-carboxamide hydrochloride (0.23 g) as a white crystalline solid m.p. 261.5 25 - 2630C (from methanollethyl acetate) Analysis Found: C, 64.6: H, 5.8; N, 13.0% C17H17N30-HCI requires: C, 643; H, 5.4; N, 13.3% ii)e [2-[5-[(Cyciopentylamino)carbonyi]-1H-indol-3-yilethyllcarbamic acid, phenyimethyl ester (0.9g) gave 3-(2-aminoethyi)-N-cyclopentyl-IH-indole5-carboxamide, quarter hydrate as an off-white solid (0.6 9) m.p. 22222WC (dec.) Analysis Found: C, 69.4; H, 8.0; N, 15.2% C16H21 N30.1/4H20 requires: C, 69.7; H, 73; N, 14.7% ii)f [2-[5-[[(2-Methoxyethyl)aminolcarbonyil-1H-indol-3-yilethyllcarbamic acid, phenyimethyl ester (2.09) gave 3-(2-aminoethyl)-N-(2-methoxyethyi)1H-indole-5-carboxamide, compound with creatinine, sulphuric acid and water 0AA:2) (0.89) as a white crystalline solid m.p. 193-50C (from aqueous ethanol) Analysis Found: C, 42.7; 1-1, 6.1; N, 16.7% C14H19N302C4H7N3O.H2S04.2H20 requires: C, 42.5; H, 63; N, 16.5% EXAMPLE 2 3-(2-Aminoethyl)-N-(4-methoxyphenyl)-1H-Indole-5-carboxamide, hydrate i) [2-[5-[[(4-Methoxyphenyl)aminolcarbonyll- 1H-indol-3- yllethyllcarbamic acid, phenylmethyl ester A mixture of [2-[5[[[(diphenylamino)carbonylloxy]carbonyll-1H-indol-3-yi]ethyllcarbamic acid, phenyImethyl ester (2,59) and 4-methoxyaniline (3.0g) was heated at 1 OWC for 0.25 hour, and the resulting liquid was partitioned between hydrochloric acid (1 N; 100 mi) and ethyl acetate (100 mi). The organic layer was washed successively with hydrochloric acid (1 N; 100 mi), sodium bicarbonate solution (8%; 2 x 100 ml), and brine (2 x 100 mi), dried (magnesium sulphate), and evaporated in vacuo affording a red solid (2.6g). The solid was triturated with ether (150 mi) to give a pale red solid (1.6g) which was purified by chromatography on a silica column (Kieselgel 60; 40g) eluted with chloroform-methanol (99: 1) to give the title compound as an off-white solid (1.28g). T.L.C. Silica, chloroform: methanol (39: 1) Rf 0.25 Analysis Found: C, 70.6; H, 53; N, 9.5% C26H25N304 requires: C, 70.4; H, 53; N, 9.5% z is GB 2035310 A is ii) 3-(2-Aminoethyl)-N-(4-methoxyphenyl)-1H-indole-5-carboxamide, hydrate Following the method of Example 1 (ii) a [2-[5-[[(4methoxyphenyi)amino]carbonyll-1 H-indol-3yllethyllcarbamic acid, phenyimethyl ester (0.7259) was hydrogenated to give an orange oil which crystallised on standing. Trituration with dry ether gave the title amide as an off-white crystalline solid (0.25 5 9) m.p. 163-60C (dec.) Analysis Found: C, 66.5; H, 6.0; N, 12.5% C181-119N302H20 requires: C, 66. 0; H, 6.5; N, 12.8% EXAMPLE 3

3-(2-Aminoethyl)-N-(2,2,2-trifluoroethyl) 11-14ndole-5-carboxamide, compound with creatinine, sulphuric acid and water (2:2:2:3) 1) [2-[5[[(2,2,2- Trifluoroethyl)aminolcarb on yll- 1 H-indol-3-yllethyllcarbamic acid, phenyImeth y/ ester A mixture of [2-[5-[[[(diphenylamino)carbonylloxylcarbonyll-1 H-indol-3- yll ethyl Ica rbamic acid, pheny- lmethyl ester (0.5 9) and 2,2,2-trifluoroethylamine (0.4 mi) was heated at 1 WC for 10 mins. in an autoclave. is The mixture was cooled in an ice bath and triturated with cyclohexane (70 mi) to give a cream solid (0.3g) which was crystallised from ethyl acetate and cyclohexane to give the title compound as an off-white crystalline solid (0.29) m.p. 138-140'C.

Analysis Found: C, 59.6; H, 4.7; N, 9.7% C211-120F3N303 requires: C, 60.1; H, 4.8; N, 10.0% fl) 3-(2-Aminoethyl)-N-(2,2,2-trifluoroethy)1H-indole-5-carboxamide, compound with creatinine, sulphuric acid and water (2:2:2:3) Following the method of Example 1 (ii) a [2-[5-[[(2,2,2trifluoroethyi)aminolcarbonyil-1H-indol-3yllethyllcarbamic acid, phenyimethyl ester (0.5g) was hydrogenated and the produce converted to the creatinine sulphate salt to give the title compound (0.5 g) as a white crystalline solid m.p. 234-7'C (dec.) (from aqueous ethanol) Analysis Found: C, 383; H, 4.9; N, 15.9% C13H14F3N30-C4H,N30-H2S01'1 1/2H20 requires: C, 39.0: H, 5.0; N, 16.05% EXAMPLE 4

3-(2-Aminoethyl)-N-(prop-2-enyl)-1H-indole-5-carboxamide, hydrobromide, hemihydrate i) [2-[5-[prop-2-enylamino)carbonyll1H-indol-3-yl)ethyllcarbamic acid, phenylmethyl ester, quarter hydrate 35 A mixture of [2-[5-[[ [(di phenyl a mi nolcarbonyl loxylca rbonyll-1 H-i ndol-3-yll ethyl Ica rbamic acid, pheny Imethyl ester (1.0 g) and allylamine (1 m]) was stirred at room temperature for 1 hour. The excess allylamine was removed by evaporation under reduced pressure and the residue triturated with dichloromethane (10 m]). The resulting solid was filtered off, washed with diethyl ether and dried to give the title compound (0.25 g) as a white solid m.p. 136-7'C.

Analysis Found: C, 68.95; H, 53; N, 11.0%; C12H23N303.0.25H20 requires: C, 69.2; H.61; N, 11.0% fl) 3-(2-Aminoethyl)-N-(prop-2-enyl)11-14ndole-5-carboxamide, hydrobromide, hemihydrate [2-[5-[(Prop-2-enylamino)carbonyi]-1H-indol-3-yilethyi]carbamic acid, phenyimethyl ester, quarter hydrate (0.5 9) was treated with hydrogen bromide in glacial acetic acid (45%,3 m]), at room temperature, with stirring, for 0.33 hour and diluted with diethyl ether (24 mi). The resulting solid was filtered off, washed with ether (3 x 5 mi) and recrystallised from a mixture of ethanol and cyclohexane to afford the title compound (0.25 g) as a white crystalline solid m.p. 224-227'C.

Analysis Found: C, 50.55; H, 5.4; N, 12.4%; C14H17N3O.HBr.1/2H20 requires: C, 50.5; 1-1,535; N, 12.6%.

so EXAMPLE 5

3-(2-Aminoethyl)-N,N-dimethyl- ffl-indole-5-carboxamide, compound with creatinine, sulphuric acidand water (2.2:2:3) i) [2,[5-[(Dimethylamino) carbonyll- 1 H-indol-3-yllethyllcarbamic acid, phenylmethyl ester, hydrate A stirred solution of 3-(2-aminoethyi)-1H-indole-5-carboxylic acid hydrochloride (2.6 g) in dry dimethylfor mamide (700 mi) was treated with triethylamine (5.0 g) followed by benzyl chloroformate (17.0 g). After 1 60 hour at room temperature, dimethylamine in ethanol (30%,50 m[) was added and the yellow solution kept at room temperature for 18 hours before evaporating to small volume (approx. 100 m]). The mixture was poured into water (1 litre), acidified with dilute hydrochloric acid and extradted with ethyl acetate (5 x 200 mi). The combined extracts were washed with water (5 x 100 mi), dried (Na2S04) and evaporated to dryness to give a yellow oil which was purified on a silica column (Kieselgel 60, 100 g) eluted with ethyl 16 GB 2 035 310 A 16 acetate/cyclohexane (1:1) to givethe titleamide (1.1 g) as a paleyellowfoam. T.L.C. Silica, ethyl acetate Rf 0.35 Analysis Found: C, 66.0; H, 6.3; N, 10.7%, C21H23N303-1-120 requires: C, 65.8; H, 6.6; N, 11.0%.

fl) 3-(2-Aminoethyl)-NN-dimethyl- 1H-indole-5-carboxamide, compound with creatinine, sulphuric acidand water (2:2:2:3) Following the method of example 1 (ii) a 12,-[5-1(dimethylamino) carbonyl]-1H-indol-3-yilethyllcarba mic acid, phenyimethyl ester, hydrate (1.0 g) was hydrogenated and the product converted to the creatinine sulphate salt to give the title compound (1.0g) as a white crystalline solid m.p. 192-CC.

Analysis Found: C, 43.5; H,6.0; NJ 8.2% C13H17N30-C4H7N3O.H2S04'1 1/2H20 requires: C, 43.5; H,6.1; NJ 7.9% EXAMPLE 6 3-(2-Aminoethyl)1H-indole-5-carboxamide, compound with creatinine, sulphuric acidand water (1: 1: 1:2) 3-(2-Aminoethyi)-1H- indole-5-carboxylic acid, methyl ester, hydrochloride (1.0 g) in ammonia (0.88 cl, 50 mO was heated at 500C for 48 hours. The reaction mixture was evaporated in vacuo and the resulting crude oil was purified by chromatography on silica gel (Hopkins & Williams WC, 50 g). Elution with ethyl acetate: 2-propanol:WATER: ammonia (25:10:8:2) gave the amide (0.86 g) as a colourless oil which was converted into its creatinine sulphate salt in aqueous acetone to give the title compound (0. 7 g) as colourless microcrystals m.p. 215-225'C(dec.)Analysis Found: C, 40.9; H,6.0; N,19.1% C11H13N30C4H7N30-1-12S04.21-120 requires: C, 40.9; H, 53; N,19.1% EXAMPLE 7

3-(2-Aminomethyl)-N-methyl-1H-indole-5-carboxamide, hydrochloride 3-(2-Aminoethyi)-1H-indoie-5-carboxylic acid, methyl ester, hydrochloride (2 g) was dissolved in aqueous 30 methylamine solution (40%, 100 mi) and stirred at 50-60'C under nitrogen for 4.5 hours. The reaction mixture was evaporated to dryness in vacuo and the resulting white solid (2.2 g) was purified by column chromatography on silica gel (40 g). Elution with ethyl acetate: 2- propanol:water: ammonia 25:15:8:2 gave the amide as a pale brown oil (1.2 g) which was converted into the hydrochloride salt with ethereal hydrogen chloride to give the title compound (1.15 g) as white microcrystals m.p. 182-WC. T.L.C. Silica ethyl acetate: 35 2-propanol:water: ammonia (25:15:8:2) Rf 0.44.

EXAMPLE 8

3-(2-Aminoethyl)-N-(hydroxyethyl)- 1H-indole-5-carboxamide, compound with creatinine, sulphuric acid and water (2.2.2:5) Following the method of example 6,3-(2-aminoethyl)-1H-indole-5-carboxylic acid, methyl ester, hydroch loride (0.6 9) was heated with ethanolamine (10 mi) at 750C for 24 hours. The product was converted to its creatinine sulphate, salt in aqueous acetone to give the title compound (0.55 g) as colourless microcrystals m.p. 227-2300C (foam) softened 17WC.

Analysis Found: C, 403; H, 6.0; N, 17.2% C13H17N302C4H7N3O.H2S04.2.5H20 requires: C, 40.6; H, 6.2; N, 16.7% EXAMPLE9

50!)a 3-[[Methyl(phenylmethyl)aminolacetyll- 1H-indole-5-carbonitrile 3-(Bromoacetyi)-1H-indole-5-carbonitrile (5.0 g) was added to a solution of the methyl benzylamine (4.85 g) in 2-propanol (175 m]) and the mixture was refluxed with stirring under nitrogen for 2.5 hours. The resulting solution was allowed to cool to room temperature overnight. The title compound (4.8 g) crystallised from solution and was collected, washed with 2-propanol and ether, and dried m.p. 195-205'C. A portion of the product was recrystallised from 2-propanol to afford colourless needles m.p. 200-2OWC.

Analysis Found: C, 74.9; H, 5.6; N, 13.6%, C19H17N30 requires: C, 75.2; H, 5.6; N, 13.85%; so The following compounds were similarly prepared from 3-(bromoacetyi)-1H- indole-5-carbonitrile(A) and the 60 appropriate amine:

i)b Di-n-propylamine (8 mi) and A (5 9) gave 3-[(di-propylamino) acetyil1H-indole-5-carbonitrile (5 g) as a yellow solid. T.L.C. Silica, ethyl acetate: methanol (191) Rf 0.17.

z 4 17 GB 2035310 A 17 i)c Piperazine (1.0 g) and A (3.0 g) gave 3-[1-piperazinyi)acetyil-1H- indole-5-carbonitrile (1.85 g)m.p. 241-273OC(dec.). T.L.C. Silica, ethyl acetate: 2-propanol:water:ammonia (25:15:8:2) RfO.38.

Od 2,2,2-Trifiuoroethylamine (3.0 mi), A (1.0g) and butanone (30 mi) at 1000C in an autoclave for 3.75 hours gave 3-[(2,2,2-trifluorethylamino)acetyil-1H-indole-5-carbonitrile, hydrobromide, hemihydrate (1.22 g) m.p. 5 248-253'C(dec.).

Analysis Found: C, 42.2; H, 3.2; N, 11.1%, C13H1OF3N3O.HBr.0.5H20 requires: C, 42.1; H, 3.3; N, 11.3%.

fla 3-[2-[Methyl)phenylmethyl)amino[ethyll- 1H-indole-5-carbonitrile A mixture of 3-[[methyl (phenyl methyi)amino]acetyll-1 H-indole-5carbonitrile (4.5 g) and sodium borohy dride (10.0 g) in 1-propanol (200 mi) was refluxed under nitrogen for 2 hours. The resulting white paste was cooled to room temperature and then treated with a mixture of ethyl acetate (200 mi) and water (200 mi). The aqueous layer was separated and extracted with ethyl acetate (2 x 200 mi). The combined ethyl acetate solutions were then extracted with 2N hydrochloric acid (3 x 250 m]). The acid extracts was basified to pH 14 with 2N sodium hydroxide with ice-bath cooling and then extracted with ethyl acetate (3 x 200 m]). The combined extracts were dried (M9S04), filtered and evaporated in vacuo to give an oil (2.7 g). Evaporation of the ethyl acetate solution which had been extracted with aqueous acid gave a further quantity of impure material (2.1 g). Chromatography of the combined products on silica gel (60 mesh; 200 g) with a mixture of 20 ethyl acetate; 2-propanol (10: 1) as eluent gave the title compound (2.0 9) as a yellow crystalline solid m.p.

77-81.50C.

Analysis Found: C, 78.6; H, 63; N, 14.4%, C19H19N3 requires: C, 78.9, H, 6.13; N, 14.5%.

The following compounds were similarly prepared by reduction of the intermediates (i)b-d with sodium borohydride ii)b 3-[(Di pro pyla m in o)acetyl 1-1 H-indol e-5-ca rbon itrile (4.5g) and sodium borohydried (1 l g) gave 3-[2-(dipropylamino)ethyi]-1H-indole-5-carbonitrile, hydrochloride, hemihydrate (1.07g) m.p. 204-WC.

Analysis Found: C, 65.0; H, 8.2; N, 13.3%; C17H23N3.HCI.0.5H20 requires: C, 64.95; H, 8.0; N, 13.4% ii)c 3-M -Piperazinyi)acetyil-1H-indole-5-carbonitrile (1,859) and sodium borohydride (2.85g) gave 3-[2-0 piperazinyi)ethyil-1H-indole-5-carbonitrile (1.19) as a brown oil. A portion of this material was converted into 35 its maleate salt (97 mg) as a colourless crystalline solid m.p. 95-970C.

Analysis Found: C, 52.8; H, 5.4; N, 10.4%; C,5H,8N4,2C4H404.2H20 requires: C, 52.85; H, 5.8; N, 10.7% 40 ii)d 3-[(2,2,2-Trifluoroethylamino)acetyil-1H-indole-5-carbonitrile (0. 85g) (obtained from the hydrobromide (1.19g) and sodium borohydride (2.1 g) gave 3-[2-(2,2,2-trifluoroethylamino)ethyil-1H-indole-5-carbonitrile (0.64g) m.p. 102.4C. T.L.C. Silica, ethyl acetate RfOA8 iffia 3-[2-[Methyl(phenylmethyl)aminolethylj- 1H-indole-5-carboxamide, compound with creatinine, sulphur- 45 ic acid, acetone, ethanol and water (20:20.20:12: 1) A mIxture of 3-12-(methyl (phenyl methyi)a m i nolethyl 1-1 H-i ndo 1 e-5- ca rbonitril e (2.5g), Amberlite resin (Preparation 7, 20g) and water (50 mi) was refluxed for 10 hours. The cooled mixture was filtered and the resin thoroughly washed with hot ethanol (200 mi). The combined solutions were evaporated to afford an oil 1 50, (1.35g) which solidified in vacuo.

Analysis Found: C, 74.55, H, 7.2; N, 13.25%; C191-121N30 requires: C, 74.25; H, 6.9; N, 13.65% T.L.C. Silica, ethanol Rf 0.65 55 The following compounds were similarly prepared by hydrolysis of the intermediates (ii)b-d with Amberlite resin (Preparation 7) followed by formation of the appropriate salt.

iii)b 3-[2-(Dipropylamino)ethyi]-1H-indole-5-carbonitrile (2.3g) and Amberlite resin (60g) gave a gummy oil (1.05g) which crystallised from a mixture of ethyl acetate and etherto give 3-[2-dipropylamino)ethyil-1Hindole-5-carboxamide, quarter hydrate (0.288g) as a colourless crystalline solid m.p. 157-80C.

Analysis Found: C, 69.8; H, 8.65; N, 14.35%; C17H25N304'0.25H20 requires: C, 69.95; H, 8.8; N, 4.4% 18 GB 2035310 A 18 iii)c 3-[2-(1-Piperazinyi)ethyil-1H-indole-5-carbonitrile (0.49) and Amberlite resin (4g) gave 3-[2-(lpiperazinyi)-ethyi]-1H-indole-5- carboxamide, dimaleate, hernihydrate (0.09g) as a brown crystalline solid m.p. 151-1540C (dec.) T.L.C. Silica, ethyl acetate: 2- propanol:water:ammonia (25:18:8:2) Rf 0.3 iii)d A stirred suspension of 3-[2-(2,2,2-trifluoroethyl amino) ethyl]-1H- indole-5-carbonitrile (0.599g) and Amberlite resin (1 Og) in water (50 mi) was heated at reflux for 18.5 hours. The mixture was filtered hot and the filtrate was evaporated to dryness. The resulting white solid was extracted into hot methanol (4 x 50 m]) which was evaporated to give the amide as a pale yellow oil (0.19g). This was dissolved in ethyl acetate (25 mO, diluted with dry ether (25 m]) and treated with ethereal hydrogen chloride to give 3-[2-(2,2,2 trifluoroethylamino)-ethyil-1H-indole-5-carboxamide, hydrochloride, 1.25 hydrate as an amorphous off- lot white solid (0.15g) m.p. 225-9'C (dec).

Analysis Found: 45.25; H, 4.7; N, 11.8%; C13H14F3N30-HCI.1.25H20 requires: C, 45.35; H, 51; N, 12.2%; iffle 3-[2-(4-Morpholinyl)ethyll1H-indole5-carboxamide A stirred mixture of 3-[2-(4-morpholinyi)ethyi]-1H-indole-5-carbonitrile (1.0g),Amberlite resin (log) and water (30 mO was heated at reflux under nitrogen for 4 hours. The reaction mixture was filtered and the resin was washed with hot water (50 mi). The aqueous solution was allowed to cool to room temperature to give 20 the title compound (0.3g) as a colourless solid m.p. 205-206.50C.

Analysis Found: C, 65.9; H, 7.1; N, 15.4%; C19H19N302 requires: C, 65.9; H, 7.1; N, 15.4%; iffif 3-[2-(Dimethylamino)ethyll1H-indole-5-carboxamide compound with creatinine, sulphuric acid, water, 25 ethanol and acetone (1: 1: 1:2:0,25:0. 18) A mixture of 3-[2-(di methyl am i no)ethyll-1 H-i ndole-5-carbon itri le (0.79) water (30 m]) and Amberlite resin (20g) was heated under reflux for 18 hours. The resin was filtered and the filtrate evaporated to give an oil which was dissolved in a mixture of methanol and ethyl-acetate (1:2; 15 mi), filtered and evaporated to give a yellow oil (0.22g). The resin was continuously extracted with ethanol (150 mi) for 2 hours and the extract 30 was evaporated to afford a further 0.1 g of crude product.

Column chromatography on silica gel (60-120 mesh, 15g) using ethyl acetate: 2-propanol; water:O.88 ammonia (25:15:4:1) as eluent gave a yellow oil (0.17g). Conversion of the oil into its creatinine sulphate salt gavethe title compound (0.27g) as a colourless crystalline solid m.p. 115- 120'C (dec.). T.L.C. Silica, ethyl acetate: 2-propanol:water: ammonia (25:15:8:2) Rf 0.5 EXAMPLE 10 a) 3-[2-(1-Methyl-2-phenylethyl)aminolethyll- 1H-indole-5-carboxamide A mixture of [2-[5-(aminocarbonyi)-1H-indol-3-yil-ethyi]carbamic acid, phenyimethyl ester (lg), phenyl acetone (2 mi) and palladium on carbon (10%, 0.2g) in ethanol (50 mO was stirred under a hydrogen atmosphere for 18 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. Trituration of the residue with ether gave the title compound as a white micro- crystal line solid (0.45g) m.p. 150-1520C Analysis Found: C, 74.5 H, 7.15; N, 12.75%; C20H23N30 requires: C, 74.75; H, 7.15; N, 13.1 % b) 3-[2-fl-Methyl-4-phenylbutyl)aminolethyll-1H-indole-5-carboxamide was prepared in a similar mannerto that described in Example 10a from [2-[[5-(aminocarbonyi)-1H-indol-3- yilethyllearbamic acid, phenyimethyl ester (1.09), palladium on carbon (10%, 0.59) and 5-phenyl-pentan-2-one (5 mi) to give the title compound (0.4g) as a colourless crystalline solid, m.p. 146-9'C after purification on a silica column (Kieselgel 60 mesh, so 100g) eluted with a mixture of ethyl acetate: 2-propanol:water:ammonia (25:15:8:2) and crystallisation from a mixture of ethyl acetate and light petroleum (b.p. 60-80'C).

Analysis Found: C, 75.2; H, 7.65; N, 11.8%; C22H27N30 requires: C, 75.6; H, 7.8; N, 12.05% 1 c) 3-[2-(Dimethylamino)ethyll-N-(hydroxymethyl)1H-indole-5-carboxamide, compound with ethanol (10: 1) A mixture of [2-[5-(aminocarbonyi)-1H-i ndol-3-yl]-ethyl Jca rbam ic acid, phenyimethyl ester (3.0g) aqueous formaldehyde (36%, 20 mi) and palladium oxide on charcoal (10%, 1.6g) in ethanol (200 mO was hydrogenated at room temperature and 45 p.s.i. for 24 hours. The catalyst was filtered off and the filtrate 60 evaporated to give a white paste which was purified on a silica column (Kiesegel 60,200g) eluted with ethyl acetate: 2-propanol:water: ammonia (25:15:4: 1) to give a pink, waxy solid (1.2g). This material was triturated with boiling acetone to give the title compound (0.44g) m.p. 148-151'C.

19 1 50 GB 2 035 310 A 19 Analysis Found: C, 64.05; H, 7.6; N, 15.9%; C14H19N302'O'l C2H60 requires: C, 641; H, 7.5; N, 15.9% EXAMPLE 11 a) 3-[2-[(1-Methyl-3-phenylpropyl)aminolethylj-1H-indole-5-carboxamide, compound with water (4: 1) A solution of 3-(2-aminoethyl-1H-indole-5_carboxamide (0.59) in ethanol (100 mi) containing benzyl acetone (2 mi) was stirred over pre-reduced palladium oxide on carbon catalyst (10%, 0.5g) under a hydrogen atmosphere at room temperature and atmospheric pressure. After 16 hours the catalyst was filtered off and the filtrate was evaporated in vacuo. The resulting oil was dissolved in ethyl acetate (20 mi), and was added drop-wise to rapidly-stirred light petroleum (b.p. 40-60'C) (80 mi).A finely divided white amorphous solid precipitated and was collected and dried (0.8g). Reprecipitation using the same volumes of ethyl acetate and light petroleum (b.p. 40-60'C) afforded the title compound as a white solid (0.51 g) m.p.

110-1170C.

Analysis Found: C, 74.3; H, 7.7; N, 12.6% C21 H25N30.1/4H20 requires: C, 74.6; H, 7.6; N, 12.4% b) 3-[2-[(1-Methylethyl)aminolethyll1H-indole-5-carboxamide, compound with creatinine, sulphuric acid and water (4:4:4:5) in a si milar manner to that described in Example 11 a, 3-(2-aminoethyi)- 1 H-indole-5-carboxamide (0.4g) 20 and acetone (10 mi) were hydrogenated in ethanol (150 mi) at 40 p.s.i. for 4 hours to give, after conversion into the creatinine sulphate salt, the title compound (0.27 g) as a colourless crystalline solid m.p. 220-228"C (dec.A is Analysis Found: C, 44.8; H, 6.3; N, 17.65% C14H,,N30C4H7N3O.H2S04'1.25H20 requires: C, 45.15 EXAMPLE 12 3-[2-[[3-(4-Chlorophenyl)1-methylpropyllaminolethyll- 1Win - ca acidand water (1:1: 1) A mixture of 3-(2-aminoethyl)-1H-indole-51carboxamide (0.7g), 4-(4chiorophenyl)butan-2-one (1 mi) and sodium cya noborohyd ride (0.31 g) in methanol (30 mi) was kept at 20C for 4 days. The solution was maintained at pH 6 by addition of aqueous 2 N hydrochloric acid solution. Excess ethereal hydrogen chloride was added and the solid produced was filtered off and discarded. The filtrate was evaporated to dryness and the residue was made basic with concentrated aqueous ammonia (10 mi). The mixture was extracted with 35 ethyl acetate 3 x 30 mi) and evaporation of the washed (H20) and dried (M9S04) organic extracts gave a pale yellow gum. The-gum was redissolved in absolute ethanol (10 mi) and maleic acid (0.5 g) was added.

Addition of dry ether (100 mi) afforded the title compound (0.27 g.) as a pale yellow solid. m.p. 126-1300C.

H, 6.4; N, 17.55% -J^I- tr- A,,,,amir]P- compound with maleic Analysis Found: C, 59.75; H, 5.65; N, 8.6% C21H24C[N30'C4H404.H20 requires C, 59.6; H, 5.95; N, 8.35% EXAMPLE 13

3-[2-(Phenylmethylamino)ethyll- 1H-indole-5-carboxamide, compound with creatinine, sulphuric acid, etha nol and water (3:5:4:2:6) i) 3-[2-(Phenyl methyl idenea m i no)ethyll-1 H-indole-5-carboxamide, compound with water (4:3) Freshly distilled benzaldehyde (0.6 g) in benzene (3 ml) was added to 3- (2-aminoethyl)-1H-Indole-5 carboxamide (1.2 g) at room temperature. A gummy oil separated out and the mixture was stirred manually for 15 min. before being left at room temperature overnight. The mixture was evaporated to an orange gum which was triturated with an ether-benzene mixture (1: 1, 200 mi) to give the title compoundas an off-white so solid (1.1 g) m.p. 152-157'C.

Analysis Found: C, 71.0; H, 6.0; N, 13.8% C1,1-11,N30,3/4H,0 requires: C, 70.9; H, 6.1; N, 13.8% ii) 3-[2-(Phenylmethylamino)ethyll1H-indole-5-carboxamide, compound with creatinine, sulphuric acid, ethanol and water (3:5:4:2:6) Sodium borohydride (0.05 g) was added with stirring to a solution of 342 (phenyl methyl i denea mi no)ethyll-1 W ndole-5-carboxa mi de (0.75 g) in absolute ethanol (2.5 mi) at O-WC. The reaction was stirred at 3 to 100C for 2 hours and then acidified to pH 34 with 2 N hydrochloric acid. The mixture was extracted with chloroform (3 x 10 mi). The aqueous phase was evaporated to dryness in vacuo and the residue was washed with ethyl acetate and ethanol. The organic washings were combined and evaporated in vacuo to give an oily solid (0.3 g). Purification by preparative layer chromatography on silica (20 x 20 x 0.2 cm) using a mixture of ethyl acetate: 2-propanol:water: ammonia (25:15:8: 1.5) as eluent gave a yellow oil (0.15 g). Conversion of the oil into its creatinine sulphate salt gave the title compound (0.14 g) as a65 GB 2 035 J31 0 A colourless crystalline solid m.p. 190-2000C.

Analysis Found: C, 46.35; H, 5.75; N, 16.15% Cl,Hi9N301.66C4H7N30'1 -33H2S04'0.66C2H60.2H20 requires: C, 45.95; H, 6.1; H, 16.5% EXAMPLE 14

3-[2-(Methylamino)ethyll- 1H-indole-5-carboxamide compound with ethanol (10: 1) A solution of 3-[2-[(methyi(phenyimethyi)amino]ethyi]-1H-indole-5carboxamide (1.05g) in absolute ethanol (200 mi) was hydrogenated over pre-reduced palladium oxide on charcoal (10%, 0.5 g) for 2.5 hours at room temperature and pressure. The catalystwas filtered off and the filtrate evaporated in vacuo to give the title compound(O.7 9) as a colourless crystalline solid. T.L.C. Silica, ethanol:water (1:1) Rf 0.3 Analysis Found: C, 66.3; H, 73; N, 18.7% C12H15N30'01 MC2H60 requires: C, 66.0; H, 7.1; N, 18.9% EXAMPLE 15

3-(2-Aminoethyl)-1H-indole-5-carbothioamide, compoundwith creatinine, sulphuric acid and water (4:5.4.10) i) 3-[2-(1,3-Dihydro1,3-dioxo-2H-isoindol-2-yl) ethyl]- 1H-indole-5- carbothioamide Hydrogen sulphide gas was passed through a stirred solution of 3-[2-(1,3dihydro-1,3-dioxo-2H-isoindol-2- 20 yi)ethyil-1H-indole-5-carbonitrile (4g) and triethylamine (3 m]) in dry dimethylformamide (100 mi) for 6 hours. and the reaction mixture was stirred for a further 7 days. Hydrogen sulphide gas was passed through the reaction mixture for 0.5 hours on each day. Water (200 mi) was added and the mixture was extracted with ethyl acetate (3 x 200 mi). Evaporation of the washed (H20) and dried (M9S04) extracts gave a yellow residue which gave a yellow powder (4.1 g). on trituration with ether. A sample was crystallised from ethanol to give 25 the title compound as yellow microcrystals m.p. 195-8'jC (dec.) Analysis Found: C, 65.05; H, 4.3; N, 11.65% C19H15N302S requires: C, 65.3; H, 4.3; N, 12.0% 0 3-12-(Phenylmethylideneamino)ethyll1H-indole-5-carboxamide, compound with water (4:3) (4:5..4:10) A solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyil-1Hindole-,-carbothioami de (2 g) in etha nolic methylamine (33%,30 m]) was kept at 20.048C for 3.5h. and then was evaporated to dryness. The residue was chromatographed on silica (m.f.c. 60g), eluted with ethyl acetate: 2-propanol:water: ammonia 35 (25:15:4:U.5) to give the major component of the reaction mixture as a yellow gum (0.45 g). This was redissolVed in hot aqueous ethanol (20%,20 mi) and treated with aqueous creatinine and sulphuric acid solution (2M, 1.0 mi) Pale yellow microcrystals (0.41 g) of the title compound m.p. 202-5'C (dec) separated out on cooling.

Analysis Found: C, 37.9; H, 5.3; N, 18.75% C11H13N3S.1 -25C4H7N3OmH2S04.2. 5H20 requires: C, 38.15; H, 5.7; N, 18.85% EXAMPLE 16

3-(2-Aminoethyl)- 1-(phenylmethyl)- 1H-indole-5-carboxamide, compound with maleic acid and water (4.4: 1) 45 i) 3-[2-(1,3-Dihydro1,3-dioxo-2H-isoindol-2-yl) ethyl]- 1- (phenylmethyl)1H-indole-5-carbonitrile Sodium hydride (0.16 9) was added to a solution of 3-[2-(1,3-dihydro-1,3- dioxo-2H-isoindol-2-yi)ethyil-1Hindole-5-carbonitrile (2.0 9) in dry dimethylformamide (40 mi) under nitrogen. After 0.5 hour. benzyl chloride was added and after a further 2 hours the mixture was diluted with water (150 mi) and extracted with ethyl acetate (3 x 40 ml). Evaporation of the washed (H20) and dried (M9S04) extract gave a red oil which was 50 triturated with ether and then crystallised from ethanol to give the title compound as yellow microcrystals (1.2 g) m.p. 1824C. T.L.C. Silica, ether Rf 0.45.

fl) 3-(2-Aminoethyl)-1-(phenylmethyl)- 1H-indole-5-carbonitrile, compoundwith maleic acidandwater (4.4. 1) A mixture 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yi)ethyil-1 -(phenyl methyl)-1 H-i ndol e-5-carbonitri le (1 55 g) and hydrazine hydrate (1 mi) in ethanol (40 m]) under nitrogen was heated at 60'Cfor 2 hours. The solvent was evaporated off and the residue was treated with aqueous 2N sodium carbonate solution (40 mi) at 500C for 0.5 hour. The mixture was extracted with ethyl acetate (3 x 40 m[) and the combined organic extracts were washed (H20) dried (M9S04) and concentrated to ca. 50 mi. A solution of maleic acid (0.3 g) in ethyl acetate (10 mi) was added to give the title compoundas a yellow crystalline solid (0.7 9) m.p. 182-4C Analysis Found: C, 66.4; H, 5.4; N, 10.9% C18H17NTC4H404'0.25H20 requires: C, 66.75; H, 5.45; N, 10.6% 1 21 GB 2 035 310 A 21 fli) 3-(2-Aminoethyl)1-(phenylmethyl)- 1H-indole-5-carboxamide, compound with maleic acid and water (4:4:1) Following the method of Example 9(iii)a, treatment of 3-(2-a m i noethyl)- 11 -(phenyl methyl)-1 H-i ndo le-5carbonitrile (0.6 g) with Amberlite resin (5 g) gave the title compoundas brown microcrystals (0.15 g) m.p. 5 188-90C.

Analysis Found: C, 63.15; H, 5.85; N, 10.4% C181H19N30C4H40A.25H20 requires: C, 63.15; H, 5.85; IN, 10.05% EXAMPLE 17

3-(2Aminoethyl)-1-methyl-1H-indole-5-carboxamide, compoundwith maleicacid, methanol and water (4:4:4:1) i) 3-[2-(1,3-Dihydro- 1,3-dioxo-2Hisoindol2-yl) ethyl]- 1-methyl- 1H-indole-5-carbonitrile, compound with ethyl acetate (10: 1) Following the method Example 16(i), 3-[2-(1,3-dihydro-1,3-dioxo-2H- isoindol-2-yi)ethyil-1H-indole-5carbonitrile (3g) and methyl iodide (1 m]) gave the title compoundas pale yellow microcrystals (1.8 g) m.p. 212-40C Analysis Found: C, 71.8; H, 4.5; N, 12.5% C2oEll,N302-O'l C4H802 requires: C, 72.11; H, 4.65; IN, 12.35% fl) 3-(2-Aminoethyl)- 1-methyl- 1H-indole-5-carbonitrile, compound with maleic acid and ethyl acetate (4:4: 1) Following the method of Example 16(ii),3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yi)ethyi]-1-methyl1Hindole-5-carbonitrile (1.0 g) and hydrazine hydrate (1 mi) gavethe title compoundas pale yellow needles (0.6 g) m.p. 163-50C.

Analysis Found: C, 603; H, 5.4; N, 12.5% C12H131\13'C41-1404'0.25C4H802 requires: C, 60.5; H, 6.0; N, 12.6% iii) 3-(2-Aminoethyl)- 1-methyl1H-indole-5-carboxamide, compound with maleic acid, methanol and water 30 (4:4:4:1) Following the method of Example 1605), treatment of 3-(2-aminoethyi)-1- methyi-1H-indole-5-carbonitrile' maleate (0.4g) with Amberlite resin (5 g) gave the title compound as pale yellow needles (0.23g) m.p.

161-30C.

so Analysis Found: C, 54.5; H, 5.6; N, 11.45% C12H,5N30'C4H40,4-CH30H.O. 25H20 requires: C, 55.1; H, 6.0; N, 11.2% EXAMPLE 18

3-(3-Aminopropyl)- 1H-indole-5-carboxamide, compound with water and ethyl acetate (10:5. 1) i) 5-Bromo-3-(3-chloropropyl)- 1H-indole 5-Chloropentanal (ca. 70% pure, 8.0g) was added to a suspension of 4bromophenylhydrazine hydrochloride (13.4 g) in aqueous acetic acid (50%,300 m]). The mixture was heated rapidly to boiling with vigorous stirring and maintained at reflux for 7 hours. The resulting dark brown solution was cooled to room temperature, diluted with water (300 mi) and extracted with ethyl acetate (4x 150 mi). The combined extracts 45 were washed with water (200 mi) and saturated aqueous sodium hydrogen carbonate (4x 250mi), dried (M9S04), filtered and evaporated to a dark brown oil (14.7g), which was purified on a silica column (Kieselgel 60, 200 g) eluted with ethyl acetate: light petroleum (b.p. 60-80') W2) followed by bulb to bulb distillation twice in vacuo to give the title compound as a yellow oil (4 g) b.p. 2000C, 0.5 mm, which rapidly darkened on storage.

Analysis Found: C, 48.2; H, 4.11; N, 5.2% C11H11BrON requires: C, 48.5; H, 4.1; N, 5.1% ii)2-[3-[5-Bromo-1H-indol-3-yljpropyll-1H-isoindole-1,3-(2H)-dione A mixture of 5-brom o-3-(3-ch 1 oro pro pyl)-1 W ndol e (1.35 g), potassium phthalimide (0.93g) and potassium iodide (1.3 g) in dry dimethylformamide (20 mi) was warmed with stirring at 105'Cfor 3 hours. The mixture was cooled and diluted with water (30 mi). An oil precipitated which crystallised over the next 5 min. The resulting solid was collected and washed thoroughly with water. The produce was recrystallised from 2-propanol (50 mi) to afford the title compound as a pale yellow crystalline solid (1.1 g) m.p. 168.5-1700C. 60 Analysis Found: C, 59.9; H, 4.0; N, 7.2% C191115BrN202 requires: C, 59.5; H, 3.95; N, 7.3% 22 GB 2035310 A 22 ifi) 3-[3-(1,3-Dihydro- 1,3-dioxo-2H-isoindol-2-yl)propyll1H-indole-5- carbonitrile 2-[3-[5-Bromo-1H-indol-3-yilpropyil-1H-isoindole-1,3-(2H)-dione (8.43g) and cuprous cyanide (3.2g) were added to N-methy]-2-pyrrol idi none (20 mi) under a nitrogen atmosphere. The stirred mixture was heated to ref lux over 25 min. and maintained at reflux for 45 min. It was then cooled to room temperature and poured onto ice-water (300 g). Concentrated aqueous ammonia (40 mi) and ethyl acetate (300 mill were added and 5 the mixture was stirred vigorously for 20 min. The brown organic layerwas separated from the blue aqueous phase. The aqueous phase was then extracted with ethyl acetate (3 x 100 mi). The combined organic solutions were washed with water (3 x 100 mi) until the washings were colourless, dried (M9S04) and evaporated in vacuo to afford a fawn solid (6.85g), which was recrystallised from a mixture of isopropyl acetate (300 mi) and 2-propanol (100 mi) to afford the title compound as a pale fawn solid (5.2 g) m.p.

193-1950C.

2 Analysis Found: C, 73.3; H, 4.85; N, 12.3% C20H15N302 requires: C, 73.0; H, 4.6; N, 12.8% iv) 3-(3-Aminopropyl)- 1H-indole-5-carbonitrile, hydrochloride.

Hydrazine hydrate (5.25 mi) was added to a suspension of 3-[3-(1,3dihydro-1,3-dioxo-2H-isoindol-2- yi)propyil-1H-indole-5-carbonitrile (4 g) in absolute ethanol (120 mi) at WC. The mixture was heated between 60-80'C for 2 hours. After 20 min. the solid had dissolved but a heavy cream precipitate formed after 40 min. The reaction mixture was cooled and evaporated in vacuo to a cream paste which was taken up into 20 2N aqueous sodium carbonate (100 mi) and warmed at 40-50'C for 30 min. The solution and oil thus obtained was extracted with ethyl acetate (3 x 75 mi) and the combined extracts were washed with water (50 mi) dried (M9S04) and evaporated to afford an orange brown oil which crystallised on standing (2.27 g) m.p. 80-850C.

A portion of the product (0.79) was dissolved in ethyl acetate (25 mi) and treated with ethanolic hydrogen chloride. An off-white solid was precipitated which was collected, washed with ethyl acetate and recrystallised from a mixture of ethanol (20 mi) and ethyl acetate (35 mO to afford the title compound as a finely-divided off-white solid m.p. 232-237'C.

Analysis Found: C, 60.9; H, 6.0; N, 17.7% C121-113NTI-IC1 requires: C, 61.1; H, 6.0; N, 17.8% v) 3-(3-Aminopropyl)-1H-indole-5-carboxamide, compound with waterand ethylacetate (10:5. 1) A mixture of 3-(3-aminopropyi)-1H-indoie-5-carbonitrile (1.45 g) and Amberlite resin (17 g) in water (100 mi) was heated at refluxfor 4.5 hours. The resin was filtered off and the clear colourless filtrate evaporated in vacuo to afford a white solid (0.7 g) m.p. 18WC. Recrystallisation of the solid from a mixture of ethanol (15 35 mi), ethyl acetate (85 m]) and light petroleum (bp 60-80'C) (150 mi) gave the title compound as a very pale yellow solid (0.5 g) m.p. 188-1940C.

Analysis Found: C, 63.5; H, 6.8; N, 17.9% C12H15N30.0.5H20'0'1 C4H802 requires: C, 63.1; H, 7.2; N, 17.9% EXAMPLE 19 3-(2-Aminopropyl)-1H-indole-5-carboxamide, compoundwith maleic acid and water (2.2: 1) i) 3-(Dimethylaminomethyl)-1H-indole-5- carboxamide, compoundwith creatinine, sulphuric acid and water (2..2:2:3) A mixture of aqueous formaldehyde (36%,0.56 g) and aqueous dimethylamine (40%,0.76) was added to solution of 1H-indole-5-carboxamide (1 g) in glacial acetic acid (50 mi) and the reaction mixture was stirred at 2WC for 2 hours. The solvent was evaporated at reduced pressure and the residue was treated with aqueous 2N sodium hydroxide (15 m]) at 1 O'C. The mixture was extracted with ethyl acetate (3 x 30 mi) and evaporation of the washed (H20) and dried (M9S04) extracts gave a white foam (0.7 g). This was redissolved in hot aqueous ethanol (80%, 50 m]) and the solution was treated with a solution of creatinine sulphate (0.8 g) in water (10 mi). Dilution with ethanol (100 mi) and cooling gave the title compoundas white needles (0.8 g). m.p. 165-WC Analysis Found: C,42.1;H,6.2;N,18.8% C12H,5N30C4H7N30-H2S04'1.5H20 requires:C,42.2;H,5.9;N,18.5% 4h z ii) 31(2-Methyl-2-nitro)ethyll- 1H-indole-5-carboxamide Sodium (0.1 g) was added to dry nitroethane (50 m]) and the mixture was stirred under nitrogen until all the sodium had dissolved (0.5 hour). A solution of 3-(dimethylaminoethyi)- 1H-indole-5-carboxamide (2.5 g) 60 in nitroethane (50 m]) was added and the reaction mixture was heated under refluxfor 5hours. The nitroethane was removed by distillation at reduced pressure, and the residue was redissolved in ethyl acetate (100 mi). Evaporation of the washed (2N HCI, H20) and dried (M9S04) ethyl acetate solution gave the title compoundas a pale yellow solid which crystallised from tolueneethanol as cream microcrystals (2.21 g) m.p. 164-WC.

* 23 GB 2035310 A 23 Analysis Found: C, 58.6; H, 5.7; N, 16.6%, C12H13N303 requires: C, 58.3; H, 5.3; N,17.0%.

iffi 3-(2-Aminopropyl)-1H-indole-5-carboxamide, compound with maleic acidandwater (2:2: 1) A mixture of 3[(2-methyi-2-nitro)ethyil-1H-indole-5-carboxamide (1 g), Raney nickel (19) and ethanol (100 mi) was stirred in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered and the filtrate was concentrated to about 25 mi. A solution of maleic acid (0.5 g) in ethanol (25 mi) was added and after 0.2 hours the solution was diluted with ether (150 ml). Repeated trituration of the resulting gum with dry ether gave a light brown solid which was filtered off and dried to give the title compound (0.68 g) m.p. 1804'C.

Analysis Found: C, 56.3; H, 5.95; N, 11.9%, C12H,5N30C4H404'1/2H20 requires: C, 56.15; H, 5.85; N, 12.25%.

EXAMPLE 20

3-(2-Aminoethyl)-2-methyl- 1H-indole-5-carboxamide, compound with hydrochloric acid and methanol 15 (10.20:0 i) 3-(2-Aminoethyl)-2-methyl-1H-indole-5-carbonitrile, maleate 4-Cyanopheny[hydrazine hydrochloride (3 g) was shaken with sodium hydroxide (2N, 70 mi) and ethyl acetate (100 mW The dried (Na2S04) organic extract was evaporated in vacuo to give an orange solid (2.2 g).

5-Chloropentan-2-one (2 g), methanol (50 mi) and water (4 mi) were added to the solid and the mixture was 20 heated under reflux for 42 hours. The solvent was distilled off and the residue was dissolved in potassium (carbonate) (20%,50 ml) and the solution was extracted with ethyl acetate (2 x 150 mi, 70 mi). The dried (Na2S04) extracts were evaporated in vacuo to give a brown oil (4.1 g) which was converted into the maleate salt to give the title compound (2.65 g) as an off-white crystalline solid m.p. 177.5 - 179"C.

Analysis Found: C, 60.9; H, 5.6; N, 13.4%; C121-113NTC41-1404 requires: C, 50.9; H, 5.4; N, 13.3%.

fl) 3-(2-Aminoethyl)-2-methyl-1H-indole-5-carboxamide, compound with hydrochloric acidandmethanol (10:20:1) 3-(2-Aminoethyl)-2-methyi-1H-indole-5-carbonitrile, maleate (1.2 g) was hydrolysed with Amberlite resin (32 g) as described in Example Wiii)a and gave after conversion into the hydrochloride salt the title compound (0.84 g) as a buff crystalline solid m.p. 208-212'C.

Analysis Found: C, 493; H, 5.9; N, 14.1; C12H15N30.2HCl.0.1MeOH requires: C, 49.6; H, 6.0; N, 14.3; Analysis Found: Cl, 24.0%; C12H15N30.2HCI.O.]MeOH requires: Cl, 24.2%.

EXAMPLE 21

3-(2-Aminoethyl)-2-methyl-1Hindole-5-carboxamide, compoundwith hydrochloric acidandmethanol (10:20:1) A solution of 4-hydrazinobenzamide (0.5 g) and 5-chloropentan-2-one (0.55 g) in methanol (10 mi) and water (1 mi) was refluxed for 13 hours. The solvent was evaporated in vacuo and the residue dissolved in methanol (10 mi) and the insoluble material removed byfiltration through Hyflo. Excess ethereal hydrogen 45 chloride was added to the filtrate and the product precipitated by the addition of ethyl acetate (25 mi) and ether (150 mi). Crystallisation from a mixture of methanol and ethyl acetate gave the title compound as buff crystals (0.3 g) m.p. 207-213'C. T.L.C. Silica, methanol: ammonia (20: 1) Rf 0.4.

EXAMPLE 22

3-(2-Aminoethyl)2-phenyl-1H-indole-5-carboxamide, maleate i) 3-(2-Aminoethyl)-2-phenyl- 1H-indole-5-carbonitrile maleate Following the method described in Example 20, 4-cya no phenyl hyd razine (3.3 g) and y chlorobutyrophenone (4.8 g) gave the title compound (3.23 9) as a cream crystalline solid m.p. 200-202'C.

Analysis Found: C, 67.2; H, 5.0; N, 10.9%; C171-115N3'C41-1404 requires: C, 66.8; H, 5.1; N, 11.1%.

fl) 3-(2-Aminoethyl)-2-phenyl-1H-indole-5-carboxamide, maleate 3-(2-Aminoethyi)-2-phenyl-1H-indole-5-carbonitrile, maleate (2 g) was hydrolysed with Amberlite resin (50 60 g) as described in Example 9(iii)a and gave after conversion into the maleate salt the title compound (0.68 g) as a colourless crystalline solid m.p. 188.5-190.5'C.

Analysis Found: C, 63.6; H, 55; N, 10.4%; C171-117N30C41-140 requires: C, 63.8; H, 5.4; N, 10.6%; 24 GB 2035310 A 24 EXAMPLE 23

3-(2-Aminoethyl)- 1H-indole-5-carboxamicte 3-(2-Aminoethyi-1H-indole-5-carbonitrile (10.0 g) was stirred with Amberlite resin (90 g) in water (155 mi) at refluxfor 17 hours. The resin was filtered off and washed with hotwater and hot ethanol. The ethanolic and aqueous washings were combined and evaporated in vacuo to give a pale yellow solid (5.0g). Crystallisation from watergave the title compound (3. 0 g) as an off-white solid m.p. 173-60C. T.L.C. silica, ethyl a-cetate, 2propanol, water, ammonia (25:15:8:2) Rf 0.33.

EXAMPLE 24 10 3-(2-Aminoethyl)-1H-indole-5-carboxamide, maleate A mixture of 3-(2-aminoethyi)-1H-indole-5-carbonitrile (2g) and finely ground potassium hydroxide (10g) in 2-methy]-2-propanol (50 mi) and dimethyl sulphoxide (2 mi) was stirred and heated under refluxfor 3 days. The mixture was cooled and diluted with water (50 mO and extracted with ethyl acetate (2 x 50 mi). The combined extracts were evaporated to give a yellow oil (2.9 g). Conversion of the oil into its maleate salt in 2-propanol followed by crystallisation from aqueous ethanol gave the title compound (1.9 9) as a buff crystalline solid m.p. 166-8'C. T.L.C. Silica, ethyl acetate, 2-propanol, water, ammonia (25:15:8:2) Rf 0.33.

EXAMPLE 25 3-(2-Aminoethyl)- 1H-indole-5-carboxamide i) 4[[4-(1,3-Dihydro1,3-dioxo-2H-isoindol-2- yl)butylidenelhydrazinolbenzamide A solution of 4-hydrazinobenzamide (0.26 g), in 25% aqueous acetic acid (20 mi) was added to 4-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yll-butanal diethyl acetal (0.5 g). The mixture was heated on a steam bath for 2 hours and then cooled. The mixture was decanted to leave an oil which was triturated with methanol (3 mi). The solid that resulted was washed with water (5 mi) and dried in vacuo at 500C to give the 'title compound (0.55 g) as a yellow crystalline solid m.p. 147-152'C (decomp).

TLC (Silica/ethyl acetate) Rf 0.4 fl) 2-[2-[1,3-Dihydro1,3-dioxo-2H-isoindol-2-yllethyll- 1H-indole-5- carboxamide An intimate mixture of the benzamide prepared as in (i) above (4.5 g), and powdered, fused zinc chloride (2 g) was heated between 1400 and 1650C for 30 min. The resulting glass-like solid was dissolved in boiling acetic acid (200 mi) and the cooled solution was decanted from some residual gum. Hydrogen sulphide gas was bubbled through the solution and the precipitated zinc salts were filtered off. the filtrate was basified with 0.88 ammonia to pH 8-9 to precipitate the product as a yellow solid (2.7 g) which was recrystallised from a mixture of toluene and methanol to give the title carboxamide m.p. 255-260'C(decomp).

T.L.C. (Silica/ethyl acetate: petroleum spirit b.p. 60-80'C) 9: 1) Rf 0.4 (Ifi) 3-[2-Aminoethyll-1H-indole-5-carboxamide compound with creatinine, sulphuric acidandwater Hydrazine hydrate (30 mi) was added to the crude phthalimido carboxamide prepared in (ii) above (1.5 g) in ethanol (60 ml). The mixture was refluxed for 2.5 hours and cooled. The solvent was evaporated off and the residue stirred with 2N sodium carbonate solution (60 mi) and the resulting solution was evaporated to dryness. The residue was extracted with ethanol and the combined extracts were evaporated to give a yellow solid that was dissolved in hot ethanol (45 mi) and treated with a solution of creatinine sulphate (1.6 g) in water (20 mi) and ethanol (10 mi). The solution obtained was diluted with ethanol to 85 m]. The title compound (1.8 g) precipitated as an off-white solid m.p. 205-210'C.

EXAMPLE 26

3-(2-Aminoethyl)- 1indole-5-carboxamide [245-(Am inocarbonyl)-1 W ndol-3-yilethyllcarbamic acid, phenyimethyl ester (0.15 g) in ethanol (20 mO was hydrogenated over palladium oxide on charcoal (10%, 0.2 9; prehydrogenated). Absorption of hydrogen 50 (7 m]) was complete within three minutes.

The catalyst was filtered off and the solvent was evaporated in vacuo to give a colourless oil (0.08 g).

A solution of this oil in ethanol (5 mi) and water (1 mO was heated under reflux and a solution of creatinine sulphate (0.11 g) in water (1 mi) was added. The crystalline solid that precipitated on cooling was filtered off to give the title compound as its hydrated creatinine sulphate salt (0. 115 9) as a colourless crystalline solid 55 m. p. 205-21 O'C.

T.L.C. (Silicalethyl acetate: propan-2-ol:

water:ammonia, 25:15:8:2) Rf 0.35 EXAMPLE 27

3-(2-Aminoethyl)- 1H-Indole-5-carboxamide, maleate, compound with ethanol (2.2: 1) A mixture of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yi) ethyl 1-1 H-i ndole-5-carboxamide (0.3 g), ethanol (2 mO and ethanolic methylamine (33%, 1 m]) was stirred at room temperature for 1.5 hours, and the mixture becoming homogenous after 5 min. The solvent was evaporated in vacuo to leave a yellow oil. The oil was dissolved in ethanol (2 mi) and a solution of maleic acid (0.1 g) in ethanol (1 mi) was added. The solid which 65 1W 1 GB 2035310 A 25 precipitated was filtered off and dried to give the title compound (0.12 g) as a white crystalline solid. T.L.C. Silica, ethyl acetate: 2- propanol:water: ammonia (25:15:8:2) Rf 0.33.

EXAMPLE 28 5 Recrystallisation of 3-(2-aminoethyl)- 1H-indole-5carboxamide, maleate 3-(2-Aminoethyi)-1H-indole-5-carboxamide maleate, compound with ethanol (2:2A) (10 g) was dissolved in hot water (50 mi) to give a clear yellow solution, which was cooled to room temperaturewith stirring. The resulting solid was filtered off and dried at WC in vacua to give the title compound(8.6 g) as a white crystalline solid m.p. 180-183'C. T.L.C. Silica, ethyl acetate:2-propanol:water: ammonia (25:15:8:2) Rf 0.4 Analysis Found: C, 56.47; H, 5.33; N, 13.19%; C111-113N3O'C41-1404 requires: C, 56.4; H, 5.37; N, 13.16%.

EXAMPLE 29

3-(2-Aminoethyl)-1H-indole-5-carboxamide, maleate A solution of 3-(2-Aminoethyi)-1H-indole-5-carbonitrile (2g) and potassium t-butoxide (12 g) in a mixture of t-butanol (50 mi) and dimethyl sulphoxide (3 mi) was stirred under reflux for 72 hours. The mixture was cooled and diluted with water (50 mi). The product was extracted into ethyl acetate (2 x 50 mi) and the dried (Na2S04) extracts were evaporated to leave a yellow oil (3 g). The oil was dissolved in 2-propanol (10 mi) and the resulting solution was added to a hot solution of maleic acid (1.25 9) in 2-propanol (20 mi). The solution 20 was cooled to room temperature and diluted with ethyl acetate (50 mO. The precipitated solid was filtered off and dried at WC to give the title compound (1.6 g) as a white solid m.p. 161-20C T.L.C. Silica, ethyl acetate: 2-propanol:water: ammonia (25:15:8:2) Rf 0.4.

EXAMPLE 30

3-(2-Aminoethyl)-1-butyl-1H-indole-5-carboxamide, compound with creatinine, sulphuric acid and water (8:10:9:16) i) [2-[5-(Aminocarbonyl)1-butyl- 1H-indol-3-yllethyllcarbamic acid, phenyImethyl ester Following the method of Example 16(i),-[2-[5-(aminocarbonyi)-1H-indol-3yi]ethyllcarbamic acid, pheny Imethyl ester (1.5 g), sodium hydride (0.16 g) and 1 -bromobutane (1 mi) gave a pale brown oily solid (1.5 g). 30 Chromatography on a silica column (Kieselgel 60,60 g) eluted with chloroform containing 1% methanol gave the title compound(l.0 g) as a colourless crystalline solid m.p. 138-WC (ethyl acetate).

Analysis Found: C, 70.0; H, 63; N, 10.4%; C23H27N303 requires: C, 70.2; H, 6.9; Nt 10.7%.

fl) 3-(2-Aminoethyl)- lbuty- 1H-indole-5-carboxamide, compound with creatinine, sulphuric acidand water (8:10:9:16) A solution of [2-[5-(aminocarbonyl)-1-butyi-1H-indol-3-yilethyllcarbamic acid, phenyimethyl ester (1 g) in Analar ethyl acetate (60 mi) was hydrogenated at room temperature and pressure over palladium oxide on 40 charcoal (10%; 0.5 g; pre-reduced) until hydrogen uptake ceased. The mixture was filtered through a Hyflo pad and the filtrate evaporated to dryness to give a colourless solid (0. 28 g). This material was purified on a silica column (Kieselgel 60,25 g) eluted with a mixture of ethyl acetate: 2-propanol:water: ammonia (25:15:4:1) to give a colourless oil (0.15 g) which was converted into its creatinine sulphate saitto givethe title compound (0.17 g) as a colourless solid m.p. 143-1480C.

Analysis Found: C, 43.95;H,6.4;N,17.2%; 8C15H2,N30'10C4H7N30.9H2S04'16H20 requires: C,419;1-1,6.7;NJ7.3%.

Claims

CLAIMS so 1. An indole of the general formula (I):

R1 X R3 '\j 11 5 4 Alk-N 55 R 1-11 2 R4 6 N R6 R5 60 wherein R, and R2, which may be the same or different, each represents a hydrogen atom, or an aryl, aralkyl, cycloalkyl, fluoroalkyl or alkyl group, which alkyl group may be unsubstituted or substituted by an alkenyl 65 26 GB 2035310 A group or by a group -OR7 or by a group I-R7 -N-- R8 26-, where R7 and RF3, which may be the same or different, each represents a hydrogen atom, an alkyl, aryl or 5 aralkyl group; or R, and R2 together with the nitrogen atom to which they are attached form a saturated monocyclic 5 to 7 membered ring which may contain a further hetero function (viz oxygen or the group 0 -H or -Me); R3 and R4, which may be the same or different, each represents a hydrogen atom, or an aryi, aralkyl, cycloalkyl, fluoroalkyl or alkyl group, which alkyl group may be unsubstituted or substituted by an alkenyl is group or by a group -OR7 or by a group -N '- R7 ---ffl8 where R7 and R8 are as previously defined; or R3 and R4 may togetherform an aralkylidene group; or R3 and R4 together with the nitrogen atom to which they are attached form a saturated monocyclic 5 to 7 membered ring which may contain a further hetero function (viz oxygen or the group 25, a -NH of -NMe); R5 represents a hydrogen atom or an alkyl or aralkyl group; R6 represents a hydrogen atom or an ary] or Cl-C:3 alkyl group; Alk represents an alkylene group of one to four carbon atoms in chain length, which group may be unsubstituted or substituted at one or more of its carbon atoms by one to three Cl-C3 alkyl groups; and X represents an oxygen or sulphur atom, and physiologically acceptable salts, hydrates and bioprecursors.
2. An indole according to claim 1, wherein R, and R2 both represent hydrogen atoms.
3. An indole according to clam 1 or 2, wherein one or both of R3 and R4 represent hydrogen atoms or Cl-C3 alkyl groups or R3 represents a hydrogen atom and R4 is an aralkyl group.
4. An indole according to any of claims 1 to 3, wherein Rs and R6 both represent hydrogen atoms.
5. An indole according to any of claims 1 to 4, wherein Alk represents a C2-C3 alkylene group.
6. An indole accordi rig to any of claims 1 to 5, wherein X represents an oxygen atom.
7. An indole according to claim 1, wherein R, represents a hydrogen atom; R2 represents a hydrogen atom or an aralky], cycloalkyl or alkyl group which alkyl group may be unsubstituted or substituted by an alkenyl group or by the group -OR7; R3 represents a hydrogen atom or an alkyl group; R4 represents a hydrogen atom or an aralky], fluoroalkyl or an unsubstituted alkyl group or R3 and R4 together form an aralkylidene group ortogether with the nitrogen atom to which they are attached form a 45 saturated monocyclic 5 to 7 membered ring containing a further hetero function; R5 represents a hydrogen atom, an alkyl group or a ben zyl group; R6 represents a hydrogen atom or an alkyl group; and Alk represents an alkylene group containing 2 or 3 carbon atoms.
8. An indole according to claim 1, wherein R, represents a hydrogen atom; R2 represents a hydrogen atom or a methyl or hydroxymethyl group; R3 represents aflydrogen atom or a methyl group; R4 represents a hydrogen atom or a methyl, tri-fluoroethyl or benzyi group orthe group CH3CH(CH2)21Ph (where Ph is an unsubstituted phenyl group); or R3 and R4 together with the nitrogen atom to which they are attached represent a benzylidene or morpholino group; R5 represents a hydrogen atom or a methyl group; R6 represents a hydrogen atom; Alk represents an unsubstituted aikylene group containing 2 or 3 carbon atoms; and X is an oxygen atom.

M 1 is i 27 GB 2035310 A 27.
9. An indole of general formula W:

R1 X R3 11 4 5 N C 5 Alk-N R2 R4 R6 R5 10 wherein R, and R2, which may be the same or different, each represents a hydrogen atom, or a n aryl, aralkyl, cycloalkyl or alkyl group, which alkyl group may be unsubstituted or substituted by an alkenyl group or by a group -OR7 or by a group -N.R7 -- R13 where R7 and R8, which may be the same or different, each represents a hydrogen atom, an alky], aryl or aralkyl group; or R, and R2 together with the nitrogen atom to which they are attached form a saturated monocyclic 5 to 7 membered ring which may contain a further hetero function (viz oxygen or the group -H or Me); R3 and R4, which may the same or different, each has the same meanings as defined for R, and R2 but R3 and R4 are not necessarily the same as R, and R2; R5 and R6 which may be the same or different, each represents a hydrogen atom or a Cl-C3 alkyl group; Alk represents an alkylene group of one to four carbon atoms in chain length, which group maybe 30 unsubstituted or substituted at one or more of its carbon atoms by one to three Cl-C3 alkyl groups; and X represents an oxygen or sulphur atom, and its physiologically acceptable salts, hydrates and bioprecursors.
10. 3-(2-Aminoethyi)-1H-indole-5-carboxamide and its physiologically acceptable salts.
11. A compound selected from 3-[2-[1-methyi-3-phenylpropyi)aminolethyil1H-indole-5-carboxamide; 35 3-[2-(dimethylamino)ethyi]-1H-indole-5-carboxamide; 3-[2-(methylamino)ethyll-lH-indole-5-carboxamide; 3-[2-(4-morpholinyi)ethyil-1H-indole-5-carboxamide; > 3-(2-aminoethyi)-1H-indole-5-carbothioamide; 3-(3-aminopropyl)-1H-indole-5-carboxamide; 3-[2-(2,2,2-trifluoroethyi)aminoethyil-1H-indole-5-carboxamide and their physiologically acceptable salts.
12, A pharmaceutical composition comprising a compound according to any of claims 1 to 11, together with one or more physiologically acceptable carriers or excipients.
13. A pharmaceutical composition according to claim 12 comprising at least one other active ingredient in addition to the compound according to any of claims 1 to 11.
14. A process for the preparation of an indole of general formula (1) as defined in claim 1, which process comprises the step (a) in order to prepare an indole of general formula (1) wherein Xis an oxygen atom, reacting an activated carboxylic acid derivative of general formula (ii):

R3 YOC AR-N R4 55 R6 CU) R5 wherein Alk, R3, R4, R5 and R6 are as defined in claim 1, wherein R3 and/or R4 may optionally be protected 60 by a protecting group or groups and wherein Y is a leaving group with a reagent of general formula R1R2NH in which R, and R2 are as defined in claim 1 and, where necessary, removing the protecting group or groups to yield the desired indole of general formula (1) wherein X is an oxygen atom; or (b) in order to prepare an indole of general formula(]) wherein R, and R2 are both hydrogen atoms, 65 28 GB 2 035 310 A 28 reacting a nitrile of general formula Oll):

NC Alk-N 1.1,R3 N 1 R6 R5 R4 (X) 10. - wherein Alk, R3, R4, Rr, and R6 are as defined in claim 1 and wherein R3 andlor R4 may optionally be protected by a protecting group or groups with a suitable oxygen- or sulphur-containing compound and, where necessary, removing the protecting group or groups to yield the desired indole of general formula (1) wherein R, and R2 are both hydrogen 15 atoms; or (c) in order to prepare an indole of general formula (1) wherein R5 and/or at least one of R3 and R4 is other than a hydrogen atom, by conversion of another indole of general formula (1), selectively alkylating an indole of general formula (1) wherein R5 and/or R3 and R4 are hydrogen atoms and may be protected by a protecting group or groups and, where necessary, removing the protecting group or groups to yield the desired indole 20 of general formula (1) wherein R5 and/or at least one of R3 and R4 is other than hydrogen; or (d) in order to prepare an indole of general formula (1) wherein R3 is a hydrogen atom by conversion of another indole of general formula (1), subjecting an indole of general formula (1) wherein R3 is a benzy] group to reduction in the presence of a suitable catalyst and recovering the desired indole of general formula (1) wherein R3 is a hydrogen atom; or (e) in order to prepare an indole of general formula (1), reducing a compound of general formula (IV): 25 RI R2 NCO W N R6 30 1 (T7) ---5 wherein R,, R2, R5 and R6 are as defined in claim 1 and W represents the group -CHR9CH,-CH2CHR9NO2, -CH=CR9N02 or -COCHR9Z (where R9 is a hydrogen atom or a C,-C3 alkyl group and Z is an azido group -N3 35 or an amino group -NIR3R4) and recovering the desired indole of general formula (1) in which X is an oxygen atom an Alk is a 2-carbon chain with the proviso that except where, in general formula (R), W represents the group -COCHR9Z and Z is an amino group NIR3R4, R3 and R4 in the desired indole of general formula (1) are both hydrogen atoms; or (f) in order to prepare an indole of general formula (1) as defined in claim 1, cyclising a phenylhydrazone of 40 general formula (XIV):

R1R2NCO (MZ) 45 NRSN==CR6CH2AlkO wherein Q is the group -NIR3R4 or a halogen atom and R,, R2, R3, R4, R5 and R6 are as defined in claim 1 and 50 wherein R3 and R4 may be a protecting group or groups and, where necessary, removing the protecting group or groups to yield the desired indole of general formula (1) wherein Alk represents an alkylene chain containing from one to four carbon atoms; or (g) in order to prepare an indole of general formula(]), reacting a 3- haloalkylindole of general formula (XVIO:

so R1 R2 NCO AlkHal 55 N Rr, 1 R5 60 in which R,, R2, R5, R6 and Alk are as defined in claim 1 and Hal represents a halogen atom, with ammonia or an amine of formula R3R4NH (where R3 and R4 are as defined in clam 1) and recovering the desired indole of general formula (1).
15. A process according to claim 14, wherein Xis an oxygen atom, and wherein step (b) of the process 65 z 9 29 GB 2035310 A 29 comprises hydrolysing under controlled conditions the nitrile of general formula (111) with acid or alkali and recovering the desired 5-carboxamide of general formula (1).
16. A process according to claim 14, wherein Xis a sulphur atom, and R3 and R4 maybe protected by a protecting group or groups and wherein step (b) of the process comprises treating the nitrile of general formula (111) with hydrogen sulphide in a solvent and recovering the desired 5-thioamide of general formula 5 (I).
17. A process according to claim 14, wherein step (c) of the process comprises subjecting an indole of general formula (1) wherein X is an oxygen atom and R3 and R4 are both hydrogen atoms to reductive alkylation with an aldehyde or ketone either in the presence of a suitable catalyst or with subsequent reduction of the intermediate thus formed with sodium borohydride or sodium cyanborohydried or with 10 hydrogen in the presence of a metal catalyst and recovering the desired indole of general formula (1) wherein X is an oxygen atom and one of R3 and R4 is a hydrogen atom.
18. A process according to claim 14, wherein step (c) of the process comprises treating an indole of general formula (1) wherein R3 and R4 are both hydrogen atoms with formaldehyde and formic acid and recovering the desired indole of general formula (1) wherein R3 and R4 are both methyl groups.
19. A process according to claim 14, wherein step (c) of the process comprises treating an indole of general formula (1) wherein R3 is a hydrogen atom and R4 is other than hydrogen with formaldehyde and formic acid and recovering the desired indole of general formula (1) wherein R3 and R4 may be the same or different and are other than hydrogen atoms.
20. A process according to claim 14, wherein step (c) of the process comprises treating an indole of general formula (1) wherein R3 and R4 are both hydrogen atoms with a halide in the presence of a solvent, subsequently treating with a base and recovering the desired indole of general formula (1) wherein at least one Of R3 and R4 is other than a hydrogen atom.
21. A process according to claim 14, wherein step (c) of the process comprises treating an indole of general formula (1) wherein R3 and R4 are both hydrogen atoms with an aromatic aldehyde, subsequently 25 treating with an akyl halide and recovering the desired indole of general formula (1) wherein one of R3 and R4 is other than a hydrogen atom.
22. A process according to claim 14, wherein step (c) of the process comprises treating an indole of general formula (1) wherein R3 and R4 are both hydrogen atoms with an a, u)-dihaloalkane or an a,(o-dihalodialkyl ether and recovering the desired indole of general formula (1) in which the moiety -NIR3R4 30 forms a heterocyclic ring.
23. A process according to claim 14, wherein step (c) of the process comprises treating an indole of general formula (1) wherein R5 is a hydrogen atom with an alkyl or aralkyl halide or a dialkyl sulphate and recovering the desired indole of general formula (1) in which REi represents an alkyl or aralkyl group.
24. A process according to claim 14, wherein step (e) of the process comprises subjecting a nitrile of general formula (V):

0 11 40 txl t(21MC CHR9CN ':( Rr, (V) 45 R5 in which IR,, R2, R5, R6 and R9 are as defined in claim 1 and step (e) of claim 14 to catalytic reduction or subjecting a nitro-compound of general formula (Vi):

0 so 11 rltx2NC CH2CHR9NO2 R6 (VF) 55 RS 60 in which R,, R2, R5, R6 and R9 are as just defined, to reduction with Raney nickel and hydrogen, and recovering the desired indole of general formula (1) wherein R3 and R4 are both hydrogen atoms and Alk is a 2- carbon chain which may be unsubstituted or substituted by a C1-3 alkyl group on the carbon atom adjacentto the indole nucleus or the group NIR3R4.
25. A process according to claim 14, wherein step (e) of the process comprises reducing a GB 2035310 A 3-nitrovinylindole of general formula (Vil):

R1 R2 NCO -CRaNOD N R6 (VID i R5 in which IR,, R2, R5, R6 and R9 are as defined in step (e) of claim 14 and recovering the desired 3-(2-aminoethyi)-indole of general formula (1) wherein R3 and R4 are both hydrogen atoms and the carbon atom adjacent to the amino group may be unsubstituted or substituted by a C1-3 alkyl group.
26. A process according to claim 14, wherein step (e) of the process comprises reducing an azidoketone 15 or an aminoacylindole of general formula (Vill):

R1 R2 NCO COCHR9Z R6 (ME) R!5 in which IR,, R2, R5, R6, R9 and Z are as defined in claim 1 and step (e) of claim 14 25 and recovering the desired indole of general formula (1) wherein Alk is a 2-carbon chain which may be unsubstituted or substituted atthe carbon atom adjacent to the amino group by a Cl-C3 alkyl group.
27. A process according to claim 26, wherein the compound of general formula (Vill) is an azidoketone (wherein Z is -N3) and wherein the resulting indole of general formula (1) is a 2-aminoethyl derivative in which R3 and R4 are both hydrogen atoms.
28. A process according to claim 26, wherein the compound of general formula (Vill) is an amino-acylindole (wherein Z is -NIR3R4) and wherein the resulting indole of general formula (1) is a 2-aminoethyl derivative in which one or both of R3 and R4 may be other than hydrogen.
29. A process according to claim 14, wherein instep (b) of the process a compound of general formula (Villa):

NC i N R6 (3zllra) 1 R5 COCHR9NR3R4 in which R3, R4, R5, R6 and R9 are as defined in claims 1 and 14 is reduced to form a nitrile of general formula (111) wherein Alk is a 2- carbon chain which may be unsubstituted or substituted at the carbon atom adjacent to the amino group by a Cl-C3 alkyl group and wherein the resulting nitrile of general formula (111) is reacted with a suitable oxygen- or sulphur-containing compound to yield the desired indole of general formula (1) wherein R, and R2 are both hydrogen atoms.
30. A process according to claim 14, wherein instep (b) of the process a compound of general formula (X1Va):

N C "la (-=a) R5NCR6CH2AlkO wherein R5, R6, Q and Alk are as defined in claims 1 and 14 and wherein, when Q represents -NIR3R4, R3 and R4 may be protected by a protecting group or groups, is cyclised and wherein the resulting nitrile of general formula (111) wherein Alk is an alkylene chain containing from one to four carbon atoms is reacted with a suitable oxygen- or sulphur-containing compound and, where necessary, the protecting group or groups are removed to yield the desired compound of general formula (1) wherein R, and R2 are both hydrogen atoms.

A0
31. A process according to any of claims 14to 30 wherein the indole is recovered in the form of its salt by 65 31 GB 2035310 A 31 treating the free base of general formula ffiwith an equivalent amount of an acid or with creatinine sulphate in a solvent.
32. A process for the preparation of a compound according to claim 1 substantially as herein described with reference to any of the specific Examples.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1AV, from which copies may be obtained.