NZ197998A

NZ197998A - 5-amino(methyl)-1h-indol-3-ylalkaneamines

Info

Publication number: NZ197998A
Application number: NZ197998A
Authority: NZ
Inventors: I H Coates; K Mills; C F Webb; M D Dowle; D E Bays
Original assignee: Glaxo Group Ltd
Priority date: 1980-08-12
Filing date: 1981-08-11
Publication date: 1985-08-16
Also published as: FR2488606A1; DE3131752A1; SE454777B; DK157995C; NL8103764A; IE51493B1; GB2083463B; ES8300699A1; DK357281A; AU7399581A; FR2488606B1; DK157995B; GB2083463A; DE3131752C2; ES504694A0; IT8149085A0; IT1171450B; IE811832L; CH652394A5; ES513934A0

Description

New Zealand Paient Spedficaiion for Paient Number 1 97998 1 97 9 9 £ U Priority Datels): JP: "P. ' P.*?'.

Complete Specification Fifed: .......

Class: Ak'.

PubHcetson Date: ..... ff 6 AUG 19^5.

P.O. Jo'rrnal, No: .? NEW ZEALAND AUG 1981 PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION HETEROCYCLIC COMPOUNDS We, GLAXO GROUP LIMITED, a British company, of Clarges House, 6/12 Clarges Street, London WlY 8DH, England hereby declare the invention for which &/ we pray that a patent may be granted to rife/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - Min & -2- 197998 This invention relates to heterocyclic compounds/ to processes for their preparation, to pharmaceutical compositions containing them and to their medical use.

The present invention provides an -indole of the general formula (I): R1R2N(Cim3)n^ AlkNR4R5 (I) wherein R-^ represents a group CHO, CORg, C02Rg, CONRgR10, CSNR9R1q or SO2NRgR10, where g [ represents an optionally substituted alkyl, a cycloalkyl, n optionally substituted aryl or an optionally substituted R an aralkyl group; Rg represents a hydrogen atom or an alkyl group and R^q represents a hydrogen atom or an alky 1/cycloalkyl, optionally substituted aryl or optionally substituted aralkyl group; R2 , R-j , R4 , Rg and R-,, which may be the same or different, each represents a hydrogen atom or a alkyl group; R^ represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or an optionally substituted aralkyl group or R^ and R,- together form an aralkylidene group or 1 979 and R together with the nitrogen atom to which they are attached form a saturated monocyclic 5- to 7-membered ring; n is zero or 1; and 5 Alk represents an alkylene chain containing two or three carbon atoms which may be un-substituted or substituted by not more than two alkyl groups; with the proviso that, when n is zero and 10 (i) R^ and R,_ both represent alkyl groups, does not represent the group CHO or CORg; and (ii) R^ does not represent the group SC^Nf^; and physiologically acceptable salts, solvates (e.g. hydrates) and bioprecursors thereof. 15 The compounds according to the invention include all optical isomers thereof and their racemic mixtures.

Referring to the general formula (I) the alkyl groups may be straight chain or branched chain alkyl groups and they preferably contain from 1 to 6 carbon atoms unless 2 0 otherwise specified. The alkyl groups represented by Rg may be unsubstituted or substituted by one to three halogen atoms e.g. fluorine. The cycloalkyl groups preferably contain 5 to 7 carbon atoms. The term aryl, used as such or in the term aralkyl, preferably means 2 5 phenyl which may be unsubstituted or substituted by one or more alkyl groups e.g. methyl, ii7 n e. halogen atoms e.g. fluorine, or hydroxy or alkoxy groups e.g. methoxy. The alkyl moiety of the aralkyl groups preferably contains 1 to 4 carbon atoms. The aralkylidene group is preferably an arylmethylidene 5 group. The alkenyl groups preferably contain 3 to 6 carbon atoms.

Suitable physiologically acceptable salts of the indoles of general formula (I) include acid addition salts formed with organic or inorganic acids for example hydro-10 chlorides, hydrobromides, sulphates, fumarates and maleates. Other salts may be useful in the preparation of compounds of formula (I) e.g. creatinine sulphate adducts.

The term "bioprecursors" used herein means compounds which have a structure different from that 15 of the compound of formula (I) but which, upon administration to an animal or human being, are converted in the body to a compound of formula (I).

The compounds of the invention mimic methysergide in contracting the dog, isolated saphenous vein strip 20 (E.Apperley e_t al. , Br. J. Pharmacol., 1980, 6_8, 215 -224) and, like methysergide, they have little effect on blood pressure in the DOCA Hypertensive rat. Methysergide is known to be useful in the treatment of mirgraine and produces a selective increase in carotid 25 vascular resistance in the anaesthetised dog; it has been suggested (P.R. Saxena., Eur. J. Pharmacol, 1974, 27, 99 - 105) that this is the basis of its efficacy. 197 99 8 Those compounds which we have tested show a similar effect in the anaesthetised dog and the compounds according to the invention are thus potentially useful for the treatment of migraine.

Accordingly, the invention also provides a pharmaceutical composition adapted for use in human medicine which comprises at least one compound of general formula (I), a physiologically acceptable salt, solvate (e.g. hydrate) or bioprecursor 10 thereof and formulated for administration by any convenient route. Such compositions may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.

Thus, the compounds according to the invention 15 may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyIcellulose); fillers (e.g. lactose, microcrystalline cellulose or 25 calcium phosphate); lubricants (e.g. magnesium stearate, ( 97 talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for 5 oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means 10 with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and pre-15 servatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. 2 0 The compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterisation techniques or infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose 25 containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions , ^ '--v --T? ^ ;; v v in oily or aqueous vehicles, and may contain form-ulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with 5 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 10 suppository bases such as cocoa butter or other glyceride.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from 15 pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane , trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurised aerosol the dosage unit may be de-20 termined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. 25 A proposed dose of the compounds of the invention for oral, parenteral or buccal administration to man for the treatment of migraine is 0.1 to 100 mg of the active ingredient per unit dose which could be administered, for example 1 to 4 times per day. 5 Aerosol formulations are preferably arranged so that each metered dose or 'puff" of aerosol contains 2O jug - 1000 pg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 jug - 10 mg. Administration may 10 be several times daily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator could be double those with aerosol formulations. 15 A preferred class of compounds represented by the general formula (I) is that wherein Alk represents an unsubstituted alkylene chain containing two carbon atoms. Another preferred class of compounds of general formula (I) is that wherein and R<- each 20 represents a hydrogen atom or a methyl or ethyl group and Rg and R-, each represents a hydrogen atom. It is preferred that the total number of carbon atoms in R^ and R<- together does not exceed two.

A further preferred class of compounds of general t<n Y'g 197998 formula (I) is that wherein represents a hydrogen atom. A yet further "preferred class of compounds represented by the .general formula (I) is that wherein R2 represents a hydrogen atom or a methyl group.

A preferred class of compounds according to the invention is represented by the general formula (la): C02R8a' v^iere ^sa is 311 optionally substituted alkyl group containing 1 to 4 carbon atoms, e.g. a methyl, ethyl or isobutyl group, or a trifluoromethyl group; R0. represents a hydrogen atom or a methyl group; c. ct n is zero or 1; and R^^ and R^Q/ which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group (with the provisos that the total number of carbon atoms in R. and Rr together 4 a 5a ^ does not exceed two and that when R^ represents a group CHO or a group CORr when n is zero, (la) H wherein R-^ represents a qroup CHO, CONIU, COR„ or -10- 197998 then R4a represents a hydrogen atom") , and physiologically acceptable salts, solvates (e.g. hydrates) or bioprecursors thereof.

A particularly preferred class of compounds 5 according to the invention is represented -by the general formula (lb): Rlb*2bN CH2CH2NR4bR5b H (lb) wherein Rlb rePresents a group CHO, CONH2 or C^Rg^ where Rg^ is a methyl, ethyl or isobutyl group; R2b rePresents a hydrogen atom or a methyl group; and and R^' which may be tlie same or different, each represents a hydrogen atom or a methyl or ethyl group (with the provisos that the total number of carbon atoms in R^ and R^ together does not cxceed two and that when R-^ is the group CHO,R4^ represents a hydrogen atom), and physiologically acceptable salts, solvates (e.g. hydrates) and bioprecursors thereof. l\71t 5 197998 A further particularly preferred group of compounds according to"the invention is represented by the general formula (l£): R, R~ NCH~ lc 2 c wherein CH0CH-NR. Rj. 2 2 4c 5c (Ic) H R represents a group CHO or a group COR 8c where R is an optionally substituted alkyl group containing from 8c 1 to 3 carbon atoms, e.g. a methyl group; R2c represents a hydrogen atom or a methyl group; and R, and R.. , which may be the same or different, 4C DC each represents a hydrogen atom or a methyl or ethyl group with the proviso that the total number of carbon atoms in R^c and R^c together does not exceed two, and physiologically acceptable salts, solvates (e.g. hydrates) and bioprecursors thereof.

According to another aspcct of the invention, compounds of general formula (I) and physioloc 197998 acceptable salts, solvates (e.g. hydrates)' or bioprecursors thereof, may be prepared by the general methods outlined below. In the following processes, R^, R2, R^ , R^ , R,- , Rg, R-y / n and Alk are as defined for the general formula (I), unless otherwise specified.

According to one general process (A), a conpound of general formula (I) may bo prepared by reacting a compound of general formula (II): R^NII (CIIR-3) 2 . v 3 n> AlkNR^R5 R, (II) R. or a protected derivative thereof, with a suitable reagent which serves to introduce the group R-^.

Suitable reagents which serve to introduce the group include acids of formula R-^OH or acylating agents corresponding thereto, inorganic 15 cyanates, appropriate organic isocyanates or organic isothiocyanatec.

Acylating agents which may conveniently be employed in the above process include acid halides (for example acid chlorides and sulphamoyl chlorides), u - r) '</ V' ^ alkyl esters (c?.g. the methyl or ethyl ester) , activated esters (for example the 2-(1-methylpyridinyl)ester), symmetrical anhydrides or mixed anhydrides, halo-formates (e.g. ethylchloroformate) or other activated 5 carboxylic acid derivatives such as those conventionally used in peptide synthesis.

The process may be effected in a suitable aqueous or non-aqueous reaction, medium, conveniently at a temperature of from -70 to +150°C. Thus, the 10 process using an activated ester or an anhydride may be effected in a suitable reaction medium such as an amide (e.g. dimethylformamide), an ether (e.g. tctrahydrofuran), a nitrile (e.g. acetonitrile),a haloalkane (e.g. dichloromethane) or a mixture thereof, 15 optionally in the presence of a base, such as pyridine or a tertiary amine such as triethylamine. The reaction is preferably effected at a temperature of from -5 to +2 5 °C.

The reaction using an alkyl ester may be effected 20 in a suitable reaction medium such as an alcohol (e.g. methanol), an amide (e.g. dimethyIformamide), an ether (e.g.tctrahydrofuran) or a mixture thereof and conveniently at a temperature of from O to 100°C. When the reagent is an inorganic cyanate, an organic iso-2 5 cyanate or an organic isothiocyanatc the reaction may _14_ 197999 be carried out in water, an alcohol (e.g. e-thanol) , an amide (e.g. dimethyIformamide ) an ether (e.g. tetrahydro- furan) or a mixture thereof, optionally in the presence of * a base such as pyridine or a tertiary amine such as tri-5 ethylamine and conveniently at a temperature of from 0 to 100°C.

Acids of formula R-^OH may themselves be used in the preparation of compounds of formula (I). The reaction with such an acid is desirably conducted in the presence of a 10 coupling agent, for example N,N'-carbonyldiimidazole or N,N'- dicyclohexylcarbodiimide. The reaction may be carried out in a suitable reaction medium such as a haloalkane (e.g. dichloroir.ethane) , a nitrile (e .g . acetonitr ile) , an amide (e.g.dimethylformamide) or an ether (e.g.tetrahydrofuran) 15 conveniently at a temperature of from -5 to +30°C. The reaction may also be carried out in the absence of a coupling agent in a suitable reaction medium such as a hydrocarbon (e.g. toluene or xylene)conveniently at a temperature of from 50 to 120°C. 2 0 A compound of general formula (I) wherein R-^ rep resents -CHO may be prepared by heating a compound of general formula (II) in formic acid, preferably at reflux.

In a particular embodiment of this process, a compound of formula (I) wherein R-^ represents the group 25 -CONRgR-^g or -CSNRgR-^g, may also be prepared by reaction of a compound of formula (II), or protected derivative thereof, with phosgene or thiophosgene followed by an appropriate amine of formula RaR-,nNI The reaction is conveniently carried out in an organic solvent, such as an aromatic hydrocarbon (e.g. toluene).

Some starting compounds of general formula (II) wherein R2 is hydrogen, may be prepared by reduction of a corresponding compound having an appropriate reducible group as the 5-position substituent such as -CN or CH^-C- , using for example, lithium aluminium u ^ NOH hydride.

According to another general process (B), compounds of general formula (I) may be prepared by cyclisation of a compound of general formula (III): wherein Q is the group NR^R,. (or a protected derivative thereof) or a leaving group such as halogen (e.g. chlorine), acetate, tosylate or mesylate.

Suitable cyclisation methods are referred to in "A Chemistry of Heterocyclic Compounds - Indoles Part I", Chapter II, edited by W.J. Houlihan (1972) (III) NR7N=CRgCH2AlkQ u I 97 9 9 Wiley Intcrscience, New York. Particularly convenient embodiments of the process are described below.

When Q is the group NR^R,- (or a protected derivative thereof) , the process is desirably carried 5 out in an aqueous reaction medium, such as an aqueous alcohol (for example methanol) in the presence of an acid catalyst. (In some cases the acid catalyst may also act as the reaction solvent). Suitable acid catalysts include inorganic acids such as sulphuric 10 or hydrochloric acid or organic carboxylic acids such as acetic acid. Alternatively the cyclisation may be carried out in the presence of a Lewis acid such as zinc chloride in ethanol or boron trifluoride in acetic acid. The reaction may conveniently be carried 15 out at temperatures of from 20 to 200°C, preferably 50 to 12 5 °C.

When Q is a leaving group such as chlorine, the reaction may be effected in an aqueous organic solvent, such as an aqueous alcohol (e.g. methanol, ethanol or 20 isopropanol), in the absence of a mineral acid, conveniently at a temperature of from 20 to 200°C, preferably 50 to 125°C. This process results in the formation of a compound of formula (I-) wherein R^ and R^ are both hydrogen atoms.

According to a particular embodiment of this process compounds of general formula (I) may be prepared directly by the reaction of a compound of general 1 97 M formula (IV): R1R2N(CHR3)n (IV) NR?NH2 or a salt thereof, with a compound of formula (V) R,COCH^AlkQ (V) D ^ wherein Q is as defined above or a salt or protected derivative thereof (such as an acetal or ketal e.g. formed with an appropriate alkyl orthoformate), using the appropriate conditions as described abGve.

Compounds of formula (III) may be isolated as intermediates during the process for the preparation of compounds of general formula (I) wherein a compound of formula (IV), or a salt or protected derivative thereof, is reacted with a compound of formula (V) or a salt or protected derivative thereof, in a suitable solvent, such as an aqueous alcohol (e.g. methanol) and at a temperature of, for example, from 2 0 to 3 0°C. If an acetal or ketal of a compound of formula (V) is used, it may be necessary to carry out the reaction in the presence of an acid (for example, acetic or hydrochloric acid ). ~18~ 197998 As illustrated in the following general processes (C) and (D), the aminoalkyl substituent -AlkNR^R^ may be introduced at the 3-position by a variety of conventional techniques which may, 5 for example, involve modification of a substituent at the 3-position or direct introduction of the aminoalkyl substituent into the 3-position.

Thus a further general method (C) for preparing compounds of general formula (I) involves 10 reacting a compound of formula (VI): R1R2N(CIIR3) . AlkY (VI) R? (wherein Y is a readily displaceable group) or a protected derivative thereof, with an amine of formula R.RrNH. 4 5 The displacement reaction may conveniently be 15 carried out on those compounds of general formula (VI) wherein the substituent group Y is a halogen atom (e.g. chlorine, bromine or iodine) or a group OR where OR is, for example, an acyloxy group, such as acetoxy, chloroacetoxy, _19_ 197 998 dichloroacetoxy, trifluoroacetoxy or £-nitrobenzoyloxy or a sulphonate group (e.g. p-toluene sulphonate).

The above reaction is conveniently effected in an organic solvent (optionally in the 5 presence of water), examples of which include alcohols, e.g. ethanol; ethers, e.g. tetrahydrofuran; esters e.g. ethyl acetate; amides e.g. N,N-dimethyIformamide; and ketones e.g. acetone, at a temperature of from -10 to , +150°C, preferably 20 to 50°C." The compounds of formula (VI) wherein Y is a halogen atom may be prepared by reacting a hydrazine of general formula (IV) with an aldehyde or ketone (or protected derivative thereof) of general formula (V) in which Q is a halogen atom, in an aqueous 15 alkanol (e.g. methanol) containing an acid (e.g. acetic or hydrochloric acid) or by treating a compound of general formula (VI) wherein Y is a hydroxyl group with the appropriate phosphorous trihalide. The intermediate alcohol where Y is a hydroxyl group 2 0 may also be used to prepare compounds of formula (VI) wherein Y is the group OR by acylation or sulphonylation with the appropriate activated species (e.g. an anhydride or sulphonyl chloride) using conventional techniques. The intermediate alcohol may be prepared by cyclisation 2 5 of a compound of formula (III) wherein Q is a hydroxyl <r Compounds of general formula (I) irtay also be prepared by another general process (D) which comprises reducing a compound of general formula (VII): 137^98 R1R2N(CHR3)n (VII) wherein W is a group capable of being reduced to give the required AlkNR^R^ group or a protected. derivative thereof j or a salt or protected derivative thereof; said reduction optionally being carried out in conjunction with an appropriate additional reagent.

The required Alk and NR^R^ groups may be formed by reduction steps which take place separately or together in any appropriate manner.

Groups which may be reduced to the group Alk include corresponding unsaturated grouDs and corresponding groups containing either a hydroxyl group or a carbonyl function.

Groups which may be roduced to the group NR4R5 where R^ and R,. are both hydrogen include nitro, azido, hydroxyimino and nitrile groups. Reduction of a nitrile group yields the group an(^ thus provides a methylene group of the group Alk.

O £ - v- ■/' V, - ! J u J ✓/ The required NR^R,. group wherein R^* and/or Rj. are other than hydrogen may be prepared by reduction of a nitrile (CHR.^) xCHR12CN or an aldehyde (CHRn)x~ CHR^CHO (Where R-^ and R-^ / which may be the same or 5 different, each represents a hydrogen atom or a alkyl group and x is zero or 1) in the presence of an amine, R^R^NH. Alternatively the R^R^NH group may be prepared by reaction of the corresponding compound wherein R^ and/or R^ represent hydrogen with an 10 appropriate aldehyde or ketone in the presence of a suitable reducing agent. In some instances (e.g. for the introduction of the group R^ where R^ is benzyl) the aldehyde (e.g. benzaldehyde) may be condensed with the amine and the intermediate thus formed 15 may subsequently be reduced using a suitable reducing agent.

Examples of groups represented by the substituent group W include the following:-TMC>2 (whore T is Alk or an alkenyl group corresponding 20 to the group Alk); AlkN^; (CHR^)XCI1R12CN; COCHR12Z; (CHR11) xCR-L2=NOH; or CH (OH) CHR12NR4R5 (where R-^, R^2 and x are as previously defined and Z is an azido group N3 or the group NR^R,- or a protected derivative thereof).

It will be appreciated that the choice of reducing agent and reaction conditions will be dependent , <1 ji w-ty y^. ,v'* 1 W V v on the nature of the group W and other groups already present on the molecule.

Suitable reducing agents which may be used in the above process include hydrogen in the presence 5 of a metal catalyst (except wherein R^ is the group CSNRgR-^Q)r an alkali metal borohydride or cyanoborohydride, e.g. sodium borohydride or cyanoborohydride (except wherein VI contains a nitrile or hyciroxyimino group) or a metal hydride, e.g. lithium 10 aluminium hydride (wherein R^■is the group CSNRgR^g and one of , Rg and R1Q is hydrogen).

The metal catalyst may, for example be Raney Nickel or a noble metal catalyst, such as platinum, platinum oxide, palladium or rhodium, which may be 15 supported, for example, on charcoal or kieselguhr.

In the case of Raney nickel, hydrazine may also be used as the source of hydrogen.

Reduction in the presence of hydrogen and a metal catalyst may conveniently be carried out in a 20 solvent such as an alcohol e.g. ethanol, an ether e.g. dioxan or tetrahydrofuran or an ester e.g. ethyl acetate at a temperature of from -10 to +50°C, preferably -5 to +30°C. The alkali metal borohydride or i cyanoborohydride reduction may conveniently be 2 5 carried out in an alcohol such as propanol or ethanol and at a temperature of from 0 to 100°C. 197998 In some instances the borohydride reduction may be carried out in the presence of cobaltous chloride. The metal hydride reduction may be carried out using an ether, e.g. tetrahydrofuran as solvent and conveniently at a temperature of from -10 to +100°C.

Particular embodiments of this process include the reduction of a compound of formula (VII) wherein W is the group CHR-^2CN' CHR-^CHR^2N02' CH=CRi2N02 or CHR^-jCR^2=N0H (where and R^, which may be the same or different, each represents a hydrogen atcra or a C^-3 alkyl group) for example, by catalytic reduction- with hydrogen, e.g. hydrogen in the presence of a catalyst such as palladium, Optionally in the presence of a mineral acid such as hydrochloric or sulphuric acid.

A sccond embodiment of the process involves, for example, the reduction of a compound of formula (Vri) wherein W is the group CHR-^CN (where is a hydrogen atom or a C1_3 alkyl group) in the presence of an amine HNI^R using hydrogen in the presence of a catalyst such as palladium, except that R^ may not be -CSNRgR^g.

Accordinq to a third embodiment, a compound of formula (VII) wherein W is the group CCCHR^Z (where is a hydrogen atcm or a alkyl group) may be reduced, preferably with heating, using for example, sodium borohydride in propanol. Where Z is an azido group, the process results in the formation of a compound of general formula (I) wherein R^ and R^ are both hydrogen atoms.

According to a fourth embodiment, a compound of formula (VII) wherein W is the group AlkN-j or 197$98 CH(OH)CHR12NR4R5 (where. R12 is a hydrogen atom or a C±_3 alkyl group) may be reduced using for example hydrogen in the presence of a catalyst (e.g. palladium)or sodium boroUydride, These reducing agents are also suitable for the reductive alkylation of for example AlkNHR^ in the presence of a suitable aldehyde or ketone.

The starting materials or intermediate compounds of general formula (VII) may be prepared by analogous methods to those described in New Zealand Patent Specification No. 19180 2 and "a Chemistry of Heterocyclic Coinpounds-Indoles Part II", Chapter VI, edited by W.J. Houlihan (1972) Wiley In terseience, New York.

Compounds of formula (VII) wherein W is the group (CHR11)xCHR12CHO (where R±1 and R which may be the same or different, each represents a hydrogen atom or a cl-3 alkyl group and x is zero or 1) may be prepared by oxidation (e.g. with Jones' reagent) of a compound of general formula (VI) wherein Y is a hydroxyl group. A compound of general formula (VII) wherein W is the group (CHR^)^-GR^->-NOH may be prepared by treatment of the corresponding aldehyde with hydroxylamine hydrochloride using standard conditions.

The intermediate compound of general formula (VII) •fc'V wherein W is the group A1 k N ^ may be prepared from a compound of general formula (VI) wherein Y is a halogen a torn using standard procedures.

Standard reducing agents such as sodium borohydride may be used to prepare a compound of general OFF? 197998 . -25- formula (VII) wherein W is the group CH(OH)CHR12NR4R5 from the corresponding rompound of formula (VII) wherein W is the group COCHR12NR4R5 (where R^2 is a hydrogen atom or a alkyl group) .

The following reactions (E), in any appropriate 5 sequence, may if necessary and/or desired, be carried out subsequent to any of the above described processes: (-i) conversion of one compound of general formula (I) or a salt or protected derivative thereof into another compound of general formula (I); 10 (ii) removal of any protecting groups, and (iii) conversion of a compound of general formula (I) or a salt thereof into a physiologically acceptable salt, solvate (e.g. hydrate) or bioprecursor thereof.

Thus, a compound of formula (I) according to the invention may be converted into another compound of the invention using conventional procedures.

For example, a compound of general formula (I) wherein R2, R4, R^ and/or R_, are alkyl groups may be 20 prepared from the corresponding compounds of formula wherein one or more of R2, R4 , and R? represent ^ hydrogen, by reaction with a suitable alkylating agent •/ such as an alkyl halide, alkyl tosylate or dialkyl- - s,=** sulphate. The alkylation reaction is conveniently carried out in an inert organic solvent such as an amide (e.g. dimet.hylformamide) an ether (e.g.

■J g? g9 8 tetrahydrofuran) or an aromatic hydrocarbon (e.g. toluene) preferably in the. presence of a base. Suitable bases include, for example, alkali metal -hydrides, for example sodium hydride, alkali metal amides, such 5 as sodium amide, alkali metal carbonates, such as sodium carbonate or an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or t-butoxide.

A particularly suitable method for preparing a compound of formula (I) wherein and/or is 10 other than hydrogen, is reductive alkylation of the corresponding compound wherein R^ and/or R,- represents hydrogen, with an appropriate aldehyde or a ketone (e.g. benzaldehyde or acetone) in the presence of a suitable reducing agent. Alternatively the aldehyde 15 or ketone may be condensed with the primary amine and the intermediate thus formed may subsequently be reduced using a suitable reducing agent.

It. will be appreciated that the choice of reducing agents and reaction conditions depends upon 20 the nature of the substituent groups already present on the compound of formula (I) which is to be alkylated. Suitable reducing agents which may be employed in this reaction include hydrogen in the presence of a metal catalyst, an alkali metal borohydride.or cyanoboro-25 hydride (e.g. sodium borohydride or cyanoborohydride) using the conditions previously described or formic \ 9799 acid (using the carbonyl compound as reaction solvent, at a temperature of from 0-100°C, conveniently 0 - 50°C.

According to a further embodiment," a compound of general formula (I) where R,. is a hydrogen atom, may 5 be prepared by reduction of a corresponding compound of general formula (I) wherein R^ is a benzyl group, for example with hydrogen in the presence of a catalyst e.g. 10% palladium on carbon.

It should be appreciated that in some of the 10 above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question to avoid any undesirable side reactions. For example, during any of the reaction sequences described above, it may be necessary to 15 protect the group NR^R,., wherein R^ and/or R,. represent hydrogen, with a group easily removable at the end of the reaction sequence. Such groups may include, for example, aralkyl groups, such as benzyl, di-phenylmethyl or triphenylmethyl; or acylvgroups, such 20 as N-benzyloxycarbonyl or t-butoxycarbonyl or phthaloyl.

In some cases, it may also be necessary to protect the indole nitrogen wherein R? is hydrogen.

Subsequent cleavage of' the protecting group may be achieved by conventional procedures. Thus an aralkyl (1 111e -28- 197998 group such as benzyl, may be cleaved by hydrogenolysis in the presence of a catalyst (e.g. palladium on charcoal); an acyl group such as N-benzyloxycarbony1 may be removed by hydrolysis with, for ex-ample, 5 hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation. The phthaloyl group may be removed by hydrazinolysis (e.g. by treatment with hydrazine hydrate) or by treatment with a primary amine (e.g. methylamine') .

' Where it is desired to isolate a compound of the invention as a salt, for example as an acid addition salt, this may be achieved by treating the free base of general formula (I), with an appropriate acid, preferably with an equivalent amount or with creatinine 15 sulphate in a suitable solvent (e.g. aqueous ethanol).

The starting materials or intermediate compounds for the preparation of the compounds according to this invention may be prepared by analogous methods to those described in New Zealand Patent Specification No. 2q 191802.

As well as being employed as the last main step in the preparative sequence, the general methods indicated above for the preparation of tho compounds of the invention may also be used for the introduction of the 25 desired groups at an intermediate stage in the I 9799 the required group at the 5-position may be introduced either before or after cyclisation to form the indole nucleus. It should therefore be appreciated that in such multi-stage processes, the sequence of reactions should be chosen in order that the reaction conditions do not affect groups present in the molecule which are desired in the final product.

The invention is further illustrated by the following Examples. All temperatures are in °C.

V ./ «,v ■ ^ ' t: ,/ /, y ^ Preparation 1 N-[3-(Cyanomethyl)-lH-indol-5-yl]formamide A solution of 5-amino-lH-indole-3-acetonitrile (0.5 g) in methyl formate (20 ml) was stirred at room temperature for 5 24h. The resulting solid precipitate was filtered off, washed with ether (2 x 20 ml) and dried in vacuo to give the title compound (0.41 g) as a white microcrystalline solid m.p. 196 -200° (softens 194°).

Preparation 2 5- (Methylamincj)-lH-indole-3-acetonitrile, quarter hydrate A solution of 5-amino-lH-indole-3-acetonitrile (3.6 g) in triethyl orthoformate (80 ml) containing trifluoroacetic acid (3 drops) was refluxed for 24h. The solvent was evaporated in vacuo and the residue was dissolved in absolute 15 ethanol (50 ml), cooled to 0°C, treated with excess sodium borohydride (4.5 g) and then refluxed for 5h.

The cooled solution was then added to a mixture of 2N hydrochloric acid (400 ml) and ice, washed with ethyl acetate (2 x 100 ml) and the acid solution was then basified (^2^^) 20 and extracted with ethyl acetate (2 x 200 ml). These combined extracts were dried (Na2S0^), filtered, and the solvent was evaporated in vacuo yielding a brown oil. Column chromatography (Kieselgel 60, 250 g) eluting with ether afforded the title compound as a fawn solid (1.5 g) m.p. 25 120-2 °. n 7ns 197998 Preparation 3 2-[2-[5-(Aminomethyl)-lH-indol-3-yl]ethyl]-lH-isoindole-1,3(2H)- "— ■ - ii —— - ~— 11 ■ ■— — ■■ 11 ■- dione, hemisulphate, hydrate A suspension of 3-[2-CI,3-dihydro-l,3-dioxo-2H-isoindol-5 2-y1)ethyl]-lH-indole-5—carbonitrile (4.7 g) in methanol (2 50 ml) and sulphuric acid (1..5 ml) was hydrogenated at room temperature and pressure over 10% palladium on charcoal (.50% aqueous paste; 2.0 g) for 45h. The catalyst was filtered off, and the; filtrate was evaporated to dryness, giving an orange 10 oil, which was dissolved in hot water (70 ml). On cooling, the title comppund crystallised as a cream solid (3.8 g) m.p. 235-8°.

Preparation 4 Phenylmethyl [2-[5-(aminomethyl)-lH-indol-3-yl]ethyl]carbamate i) Phenylmethyl [2-[5-(hydroxymethyl)-lH-indol-3-y1]ethyl]-carbamate A solution of 3-[2-[[(phenylmethoxy)carbonyl]amino]ethyl]-1H-indole-5-carboxylie acid (9 g) and N,N'-carbonyldiimidazole (5.2 g) in dry tetrahydrofuran (THF) 150 ml) was stirred 20 vigorously under nitrogen at room temperature for 5h. A solution of lithium borohydride (1.6 g) in dry THF (70 ml) was added over 70 min and the mixture then stirred for 18h.

Aqueous acetic acid (30%, 25 ml) was added slowly to the ice-cooled mixture and the solution was then partitioned between 25 brine (25%, 300 ml) and ethyl acetate (250 ml). The or I 97998 layer was washed with sulphuric acid (0.4M, saturated with sodium chloride, 3 x 80 ml), brine (100 ml) and potassium carbonate solution (25%, 2 x 100 ml). The dried (MgSO^) solution was evaporated in vacuo, the residue taken 5 up in dichloromethane (150 ml) and insoluble material was filtered off. The filtrate was evaporated in vacuo to leave the alcohol (9 g) as a colourless oil containing some (ca. 45 mole %) ethyl acetate.

T.l.c. Si02/Et20, Rf 0.25. ii) Phenylmethyl [2-[5-(aminomethyl)-lH-indol-3-yl]ethyl]-carbamate A solution of diethyl azodicarboxylate (1.48 g) in dry tetrahydrofuran (THF) (8 ml) was added over 2 min., keeping the temperature at 25°, to a stirred solution of 15 phenylmethyl [2-[5-(-hydroxymethyl)-lH-indol-3-yl]ethyl]- carbamate (2.6 g), triphenylphosphine (2.35 g) and phthalimide (1.75 g) in THF (20 ml). After 4h, the solvent was evaporated in vacuo and the residue was dissolved in a solution of hydrazine hydrate (15 ml) in ethanol (100 ml). 20 After 5 days the mixture was partitioned between sulphuric acid (0.5N, 500 ml) and ethyl acetate (2 x 300 ml). The acid layer was basified with potassium carbonate and the product was extracted into ethyl acetate (200 ml). The dried (Na2S04) extract was evaporated in vacuo to 25 leave the crude amine (0.7 g) as a brown oil which later solidified. Crystallisation from ethyl acetate gave the title compound (0.15 g) as cream coloured crystals m.p. 123. 5 - 126.5°.

Example 1 N— [ [3— (2-Aminoethyl) -lH-indol-5-yl]methyl] acetainide, compound with creatinine, sulphuric acid and water (1:1:1:1) (i) N-[[3[2-(l,3-Dihydro-l,3-dioxo-2H-isoindol-2-yl) ethyl]-lH-indol-5-yl]methyl]acetamide An ice-cold suspension of 2-[2-[5-(aminomethyl)-1H- indol-3-yl]ethyl]-lH-isoindole-1,3(2H)-dione, hemisulphate, hydrate (1.01 g) in pyridine (40 ml) was treated dropwise with acetic anhydride (0.6 ml). The mixture was stirred at room temperature for 1 h, water (15 ml) was added, and after a further 15 min the solution was acidified with hydrochloric acid (2N) and extracted into ethyl acetate (3 x 150 ml). The combined extract was washed with sodium carbonate (2N; 300 ml), dried (MgSO^) and evaporated to dryness, affording a yellow foam. On trituration with ethyl acetate (ca. 10 ml) this afforded the title amide as a pale yellow crystalline solid (0.79 g) m.p. 180-2°. (ii) N-[[3-(2-Aminoethyl)-lH-indol-5-yl]methyl]acetamide. compound with creatinine, sulphuric acid and water (1:1:1:1) A solution of N-[[3-[2-(1,3-dihydro-l,3-dioxo—2H- isoindol-2-yl)ethyl]-lH-indol-5-yl]methyl]acetamide CO.62 g) I 97 99 in ethanol (90 ml) and hydrazine hydrate (0.45 ml) was heated at reflux for 4h. After cooling the solution was evaporated to dryness, and the resulting white solid was partitioned between ethyl acetate (100 ml) and sodium 5 carbonate (2N; 100 ml). The aqueous phase was further extracted with ethyl acetate (3 x 100 ml), and the combined organic phase was dried (MgSO^) and evaporated to dryness, giving a yellow oil. This was dissolved in a hot mixture of ethanol (50 ml) and water (6 ml) and treated with an 10 aqueous solution of creatinine and sulphuric acid (1:1, 2M, 0.85 ml) to give, on cooling, the title compound as a white crystalline solid (0.48 g) m.p. 233-5° (d) Analysis Found: C,43.9; H,6.0; N,17.8; C13H17N30.C4H7N30.H2S04.H20 requires: C,44.3; H,6.1; N,18.2%.

Example 2 Ethyl [3-(2-Aminoethyl)-lH-indol-5-yl]carbamate, compound with creatinine, sulphuric acid and water (2:2:2:1) (i) Ethyl [3-(cyanomethyl)-lH-indol-5-yl]carbamate A solution of 5-amino-lH-indole-3-acetonitrile (1.5 g) in dimethyl-formamide (35 ml) was treated with potassium carbonate (4.2 g) and ethyl chloroformate (0.9 ml) added dropwise over 20 min. After a further 5 min, the 25 reaction mixture was poured into water (150 ml), left for 1 97 v v * min and then extracted with ethyl acetate (3 x 130 ml). The combined ethyl acetate extracts were washed with water ( 2 x 150 ml), 8% sodium bicarbonate solution (2 x 150 ml) and water (2 x 100 ml) and dried (MgSO^) and the solvent 5 was removed under reduced pressure to afford a brown oil.

The oil was crystallised from ethyl acetate and cyclohexane to give the title compound (1.65 g) as a brown crystalline solid, m.p. 119-123°. (ii) Ethyl [ 3- (2-aminoethyl) -ljj-indol-5-yl] carbamate, 10 compound with creatinine, sulphuric acid and water (2;2;2:1) Ethyl [3-(cyanomethyl)-lH-indol-5-yl]carbamate (1.5g) was catalytically hydrogenated over 5% rhodium-on-alumina (0.5g) in a mixture of ethanol (50 ml) and ammonia (0.6 ml) for 40 h at 40° then at 50° for a further 8h. The mixture 15 was filtered through hyflo and evaporated to dryness to afford a brown oil. This oil was purified by column chromatography on silica (25g) using ethyl acetate/ 2-propanol/ water/ammonia (25:15:4:1) as eluant to give a brown oil (0.58g) which was dissolved in ethanol and treated with an aqueous 20 solution of creatinine and sulphuric acid (1:1, 2M, 1 ml) to give an off-white solid which was recrystallised frcm aqueous acetone to give the title compound as a colourless solid (0.65g) m.p. 184.5-187.5° Analysis Found: C,43.4; H,5.9; N,17.65 C13H17N302.C4H7N30.H2S04.0.5H20 requires: C,43.7; H,5.8;N,18.0% p Example 3 N-[[3-(2-Aminoethyl)-lH-indol-5-yl]methyl]formamide, compound with creatinine, sulphuric acid and water (.1:1:1:1) (i) Phenylmethyl [2—[5—[(formylamino)methyl]-ljj-indol-3-yl] 5 ethyl]carbamate A mixture of phenylmethyl [2-[5-(aminomethyl)-lH-indol-3-yl]ethyl]carbamate (0.25g), ethyl formate (5 ml) and ethanol ( 1 ml) was heated under reflux for 9h. The solvent was evaporated in vacuo and the residue was evaporated with 10 ethanol (2x5 ml) to give the title compound (0.27g) as cream crystals m.p. 114-6°. (ii) N-[[3-(2-Aminoethyl)-lH-indol-5-yl]methyl]formamide, compound with creatinine, sulphuric acid and water lH-indol-3-yl]ethyl]carbamate (0.34g) in ethanol (30 ml) was hydrogenated at room temperature and pressure over palladium oxide on charcoal (10%; 0.3g pre-reduced) until uptake of hydrogen ceased. The catalyst was filtered off and the 20 filtrate was evaporated in vacuo. The residual oil was dissolved in a hot mixture of ethanol (8 ml) and water (0.8 ml) and an aqueous solution of creatinine and sulphuric acid (1:1; 2M; 0.8 ml) was added. Filtration of the cooled mixture gave the title compound as a white solid (0.33 g) 25 m.p. 197-200°. (foaming). (1:1:1:1) A solution of phenylmethyl [2-[5-[(formylamino)methyl] 1 ^7 'CP Analysis Found: C,43.2; H,5.8; N,19.0 C12H15N30*C4H7N30*H2S04*H2° recIuires: C,43.05; H,5.85; N,18.85% Example 4 N-[3-(2-Aminoethyl)-lH-indol-5-y1]formamide, compound with 5 creatinine, sulphuric acid and water (1:1:1:1.3) Hydrazine hydrate (30 ml) was added slowly over 3h to a mixture of N-[3-(cyanomethyl)-lH-indol-5-yl]formamide (l.Og) and Raney nickel (2g) in ethanol (100 ml) at reflux under nitrogen. The catalyst was filtered off and the 10 filtrate evaporated to an oil (l.lg) which was dissolved in a hot mixture of ethanol (60 ml) and water (30 ml) and treated with a solution of creatinine sulphate (1.2g) in water (4 ml). Dilution with ethanol (150 ml) precipitated the title compound as a white solid (1.4g) m.p. 175-183°. 15 Analysis Found: C,41.5; H.5.6 N,18.7; C11H13N3O.C4H7N3O.H2SO4.1.3H2O requires: C,41.1; H,5.7; N.19.2% Example 5 N-[3-(2-Aminoethyl)-lH-indol-5-yl]-N-methylformamide, compound with creatinine, sulphuric acid and water (8:10:9:16) i) N-[3-(Cyanomethyl)-lH-indol-5-yl]-N-methylformamide A solution of 5-(methylamino-lH-indole-3-acetonitrile (0.2g) in methyl formate (7 ml) was kept at room temperature for 36h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (10 ml) and hydrochlo-25 ric acid (2N, 10 ml). The organic layer was dried (Na2S04) and evaporated in vacuo yielding the title compound as a fawn solid, (0.13g) m.p. 118-120°C. 97 /J ^ ii) n-[3-(2-Aminoethyl)-lfl-indol-5-yl]-n-methylformamide compound with creatinine, sulphuric acid and water (8;10;9:16) Following the method described in Example 4, N-[3-(cyanomethyl)-lH-indol-5-yl]-N-methylformamide C1.2g) in 5 ethanol (150 ml) was reduced with Raney nickel (0.03g) and hydrazine hydrate (23 ml) over 8h. The title compound (1.4g) was obtained as a buff solid m.p. 208-210° after creatinine sulphate formation.

Analysis Found: C,40.8; H,5.6; N,18.7; C12H15N30.1.2 5C4H7N30.1.125H2S04.2H20 requires: C,40.4; H,6.0; N,18.7% Example 6 Ethyl[3-(2-aminoethyl)-lH-indol-5-yl]methylcarbamate, compound with creatinine sulphuric acid and water (1:1:1:2) 15 i) Ethyl [3-(cyanomethyl)-lH-indol-5-yl]methylcarbamate Ethyl chloroformate (0.21 ml) was added dropwise to a stirred solution of 5-(methylamino)-lH-indole-3-acetonitrile (0.4g) in dimethylformamide (15 ml). After 10 min. the solution was diluted with water (30 ml), stirred 20 for 30 min. and extracted with ethyl acetate (2 x 100 ml).

The combined extracts were washed with 10% brine (2 x 100 ml), 8% sodium bicarbonate (2 x 100 ml) and water (2 x 100 ml), dried (Na2S04) and evaporated in vacuo to yield the crude product as a brown oil. Trituration with ether gave a fawn 25 solid (0.4g). A sample was crystallised from ether to give the title compound as a white solid m.p. 104-106°. ''"v *.• ?-) y / v ^ ii) Ethyl [3-(2-aminoethyl)-lH-indol-5-yl]methylcarbamate, compound with creatinine, sulphuric acid, and water (1;1;1;2) A solution of ethyl [3-(cyanomethyl)-lH-indol-5-yl] methylcarbamate (0.2g) in absolute ethanol (30 ml) 5 containing concentrated hydrochloric acid (8 drops) was hydrogenated at room temperature and pressure over palladium on charcoal (10%, 0.4g) until hydrogen uptake ceased (8h, 23 ml). The catalyst was filtered off, washed with absolute ethanol, and the filtrate evaporated in vacuo 10 yielding a brown oil. The amine was dissolved in a hot solution of ethanol and water (8:1, 18 ml) and treated with an aqueous solution of creatinine and sulphuric acid (1:1, 2M, 0.38 ml). Filtration of the cooled mixture gave the title compound as a white solid m.p. 210-212° (dec.) 15 (0.15g).

Analysis Found: C,42.7; H,5.9; N,16.7; C14H19N3°2 "C4H7N3°*H2S04" 2H2° recJuireS: C,42.5; H,6.3; N,16.5% Example 7 N-[3-(2-Aminoethyl)-lH-indol-5-yl]urea, compound with 20 creatinine, sulphuric acid and water (1:1:1:1) i) N-[3-(Cyanomethyl)-lH-indol-5-yl]urea A solution of sodium cyanate (1.2g) in water (10 ml) was added to a stirred solution of 5-amino-lH-indole-3-aceto-nitrile (1.5g) in glacial acetic acid (5 ml) and water (10 ml).

Stirring was continued until a brown gum precipitated (10 min). The aqueous layer was then decanted off, and C" vv /' vV» ^ V ft 2 extracted with ethyl acetate (2 x 100ml). The combined extracts were washed with sodium carbonate soln. (2N, 2x100ml) , dried (Na2S04) and evaporated in vacuo to yield the crude urea as an off-white solid (0.3g). The brown gum was purified 5 by column chromatography (Kieselgel 60, 25 g) using ethyl acetate as eluant to yield more of the crude urea (O.lg). The crude urea was then crystallised from isopropanol to yield the title compound as a fawn solid (0.3g) m.p. 200-204°. ii) N-[3-(2-Aminoethyl)-lH-indol-5-yl]urea, compound with .10 creatinine, sulphuric acid and water (1;1;1;1): Following the method of Example 4, N-[3-(cyanomethyl)-lH-indol-5-yl]urea (0.2g) in ethanol (30 ml) was reduced with Raney nickel (0.03g) and hydrazine hydrate (6 ml) over 5h. The title compound (0.15g) was obtained as a cream 15 solid m.p. 208-12° after creatinine sulphate formation.

Analysis Found: C,40.1; H,5.6; N , 21.05; C11H14N40*C4H7N3°*H2S04*H20 requires: C,40.3; H,5.6; N.21.9% T.l.c. Silica ethyl acetate/2-propanol/water/0.88 amonia 20 (25:15:8:2) 0.44 Example 8 Methyl[3-(2-aminoethyl)-lH-indol-5-yl]carbamate, compound with creatinine, sulphuric acid and water (1:1:1:1) i) Methyl [ 3- (cyanomethyl) -ljj-indol-5-yl j carbamate 25 Following the method of Example 6(i), 5-amino-lH- indole-3-acetonitrile (0.8g) in dimethylformamide (10 ml) was reacted with methyl chloroformate (0.5ml) to give the title compound (0.44g) as a white solid m.p. 146-8° after column chromatography (Kieselgel 60, 100G) e-luted with ether, ii) Methyl [ 3- ( 2-aminoethyl) -ljj-indol-5-yl] carbamate, 5 compound with creatinine, sulphuric acid, and water (1:1:1:1) Following the method of Example 6 (ii) methyl[3-(cyanomethyl)-lH-indol-5-yl]carbamate (0.7g) was hydrogenated in ethanol (100 ml) over palladium on charcoal (10%, l.Og) 10 for 24 h to give, after creatinine sulphate formation, the title compound (0.5g) as a white solid m.p. 197-200°. Analysis Found: C,41.4; H,5.7; N,18.1; C12H15N3°2"C4H7N3°,H2S04 *H2° requires: C,41.55; H,5.7; N.18.2% Example 9 N-[3-[2-(Methylamino)ethyl]-lH-indol-5-yl]formamide, compound with creatinine, sulphuric acid and water (10:12:11:20) A solution of N-[3-(cyanomethyl)-lH-indol-5-yl]formamide (0.3g) in absolute ethanol (30 ml) containing methylamine, 20 (33% in ethanol, 2 ml) was hydrogenated at room temperature and pressure over palladium oxide on charcoal (10%, 0.5g) for 24h until hydrogen uptake ceased (90 ml). The catalyst was filtered off, washed with absolute ethanol, and the filtrate was evaporated in vacuo yielding a brown oil. 25 The amine was dissolved in a hot mixture of ethanol and water (8:1, 18 ml) and an aqueous solution of creatinine and sulphuric acid (1:1, 2M, 0.6 ml) was added. Filtration of the cooled mixture gave the title compound as an off-white solid (0.35g) m.p. 205-207 °.

Analysis Found: C,40.6: H,5.5: N,18.8; C12H15N3°"1* 2C4H7N3°-1•1H2S04.2H20 requires: C,40.7; H,5.8; N.18.6% Example 10 N-[[3-(2-Aminoethyl)-lH-indol-5-yl]methyl]-N'-methylurea, 10 compound with creatinine, sulphuric acid and water (2:2:2:3) i) a N- [ [ 3- [ 2- (1, 3-Dihydro-l, 3-dioxo-2£L-isoindol-2-yl ] ethyl]-lH-indol-5-y1]methyl]-N'-methylurea, hemihydrate A suspension of 2-[2-[5-(aminomethyl)-lH-indol-3-yl] ethyl]-lH-isoindole-1,3(2H)-dione, hemisulphate, hydrate (1.53g) in pyridine (50 ml) was cooled in an ice bath and treated dropwise with methylisocyanate (2.5 ml). The mixture was stirred at room temperature for 4h, and water (15 ml) was added to the resulting white suspension. After 10 min. the yellow solution was acidified with hydrochloric 20 acid (2N), and extracted into ethyl acetate (3 x 100 ml). The combined organic extract was washed with sodium carbonate solution (2N; 100 ml), dried (magnesium sulphate and evaporated to dryness, giving a pale yellow solid. On trituration with ether, this afforded the pure title 25 material as a cream crystalline solid (1.22g) m.p. 210-212°.

The following compounds were similarly prepared from 2[2-[5-(aminomethyl)-lH-indol-3-yl]ethyl]-lH-isoindole-1,3(2H)-dione, hemisulphate, hemihydrate and the appropriate isocyanate or isothiocyanate as detailed in Table I.

Table I Example No.

Wt. of starting ma^ejrial Reagent Vol. of Reagent (ml) Reaction time (h) Vol. of pyridine (ml) Wt. of product (g) Mol. formula m.p. ( °C) (i) b 1.4 j^N^NCO 0.8 4.75 50 0. 23 C26N28N4°3* ^H2° 219 - 21 (i) c 2.0 PhNCO 0. 8 4 65 0. 8 C26H22N4°3'^H2° 218 - 1 (i) d 1.1 MeNCS 1.2 2 I ! 0. 4 C21H20N4°2S" 0.4 C4H802 126 - 8 2 1. Crystallised from methanol 2.

Purified by column chromatography (Kieselgel 60, ether then recrystallised from ethyl acetate. 20g) eluted with Example 10 (Cont.) ii)a N-[[3-(2-Aminoethyl)-lH-indol-5-yl]methyl]-N'-methylurea, compound with creatinine, sulphuric acid and.water (2:2:2:3) Following the method described in Example I(ii), a 5 solution of N-[[3-[2-(1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl) ethyl]-lH-indol-5-yl]methyl]-N'-methylurea, hemihydrate (0.81g) in ethanol (80 ml) was deprotected with hydrazine hydrate (0.8 ml) to give, after creatinine sulphate formation, the title compound (0.32g) as a white solid m.p. 205-7° (dec.) 10 Analysis Found: C,42.5; H,5.9; N.20.0; C13H18N40,C4H7N30,H2S04" 1^H2° rec2uireS: C,42.1? H,6.2; N,20.2% The following compounds were similarly prepared by deprotection of the appropriate starting material as detailed in Table II.

TABLE II Ex. No.

Ex. No.

Wt. of Vol.EtOH Vol.

Wt. of s of prod. of R1 starting (ml) N2H4'H2° prod.

Mol. formula starting material (g) material (g) (ml) 3 (ii) b (i) b ^^-NHCO- 0.73 75 1 0.56 C18H26N4°"C4H7N3°*H2S04 *H2° (ii) c (i) c PhNHCO- 0.57 100 1 o • 00 ^18^20^4^* 4^7^3^" ^2^^4 " ^2^ (ii) d (i) d ! MeNHCS- 0.32 0. 4 0.17 C13H18N4S,C4H7N30,H2S04*H2° Table II Cont.

Analysis Ex. No. m.p.

Found Required of prod.

( °C) C H N C H N (ii) b 220 - 222 (dec) 48.8 6.6 17.85 48.6 6.9 18.0 (ii) c 196 - 9 (dec) 48.9 .8 18.15 49.15 .8 18.2 (ii) d 204 - 6 41.7 .8 19.7 41. 6 . 95 19. 9 J 97998 -4 7- Example 11 i)a N-[[3-[2-(1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl) ethyl] -l|j-indol-5-yl]methyl] benzamide Benzoyl chloride (0.9 ml) was added to a stirred 5 suspension of 2-[2-[5-(aminomethyl)-lH-indol-3-yl]ethyl]-lH-isoindole-1,3(2H)-dione, hemisulphate hydrate (l.Og) in dry pyridine (40 ml). The mixture was stirred at room temperature for 2.7 5h and then water (10 ml) was added. The resultant solution was stirred for 0.5h and acidified with 10 with 2N hydrochloric acid. The precipitate solid was filtered off, washed with water (30 ml) and dried (1.04g). Recrystallisation from aqueous dimethylformamide gave the title amide as yellow crystals (0.77g) m.p. 227.5°-229°.

The following compounds were similarly prepared 15 from 2-[2-[5-(aminomethyl)-lH-indol-3-yl]ethyl]-1H- isoindole-1,3(2H)-dione, hemisulphate, hydrate and the appropriate chloro compound (R-^-Cl) as detailed in Table III. ii) Following the method described in Example 10 ii)a the following compounds were similarly prepared by deprotection of the appropriate starting material as detailed in Table IV.

TABLE III Ex. No.

Wt. of starting material (g) Rj-Cl Quantity R, -CI (ml) Reaction time (h) Wt. of product (g) Mol. formula m.p. 11(i) b 1.0 coci 1.2 0. 62 C25H27N3°3 198-198.5° 1 11(i) c 1. 4 PhCH2C0Cl 4.8 6. 25 0. 85 C27H23N3°3* ^H2° 202.5-203.5° 2 11(1) d 1.14 EtOCOCl 0. 5 1 0. 92 C22H21N3°4* ^H2° 158-9 ° 11(1) e 1.15 MeOCOCl 0. 7 7 1.05 C21H19N3°4 150-1° 1. Recrystallised from ethyl acetate 2. Recrystallised from chloroform/ether * 4/ $ d Example 12 (i) [3-[2-(1,3-Dihydro-l,3-dioxo-2H-isoindol-2-yl)ethyl]-1.H-indol-5-yl]methylurea A solution of 2-[2-[5-(aminomethyl)-lH-indol-3-yl] 5 ethyl]-lH-isoindole-1,3-(2H)-dione, hemisulphate, hydrate (l.Olg) in hot water (27 ml) was treated with a solution of sodium cyanate (0.25g) in water (9 ml) and heated on a steam bath for 1.5h. The reaction mixture was cooled and filtered, affording the title urea as a white crystalline 10 solid (0.82g) m.p. 230-2°. (ii) Following the procedure as described in Example 10 ii)a, the above product was deprotected as detailed in Table IV.

TABLE IV N.

Ex. NO. ^ of prod. v-<- Ex. No. of starting material R1 Wt. of starting material (g) Vol.EtOH (ml) Vol.

N2H4.H2O (ml) Wt. Of prod. (g) Mol. formation „ (ii) a 11 (i) PhCO- 0.51 60 0.3 0.24 C18H19N3°*C4H4°4 2 (ii) b 11(i) b i o u 6 0. 61 0.35 0. 35 C18H25N3°-C4H4°4 (ii) c 11 (i) c PhCH2CO- 0. 68 50 0. 53 0.54 C19H21N3°*C4H7N3°*H2S04,H20 (ii) d 11 (i) d Et02C- 0.49 60 0.32 0.50 C14H19N302*C4H7N3°"H2S04*^H20 (ii) e 11 (i) e Me02C- 0. 52 60 0. 70 0. 52 c, ,h, _Nt0o .c.h-jN-jo.h-so. .ho0 13 17 32 473 2 4 2 (ii) f 12 (i) h2nco- 0. 56 80 0. 4 0. 3 C12H16N4°*C4H7N30-H2S04*H20 Table IV Cont.

I 0 in 1 Ex. NO. of prod. in • p • ( °C) Analysis Found Required C H N C H N (ii) a 167 - 71 64.1 .6 9.9 64. 5 .7 . 3 (ii) b 147 - 9 63.6 7.0 9.8 63. 6 7.0 . 1 (ii) c 230-231.5 51.3 .85 .4 51.5 6.0 .7 (ii) d 213 - 5 (dec) 44.1 6.1 17 .6 44. 5 6.1 17.3 (ii) e 216 - 8 (dec) 42. 9 .9 17.4 42. 85 .9 17. 6 (ii) f 208 - 10 (d^£) 41.8 m .8 1 .7 41.6 .9 ■ 21.2 m .

TABLE IV Cont Converted into a maleate salt with maleic acid in methanol/ether Recrystallised from methanol/ethyl acetate.

Converted into a maleate salt with maleic acid in methanol/ether Recrystallised from isopropanol/ethyl acetate. '• ; <■' Example 13 N-[3-(2-Aminoethyl)-lH-indol-5-yl]acetamide, compound with creatinine, sulphuric acid and water (2:3:2.: 5) i) N-[3-(Cyanomethyl)-lH-indol-5-yl]acetamide Acetyl chloride (0.21 ml) was added dropwise to a stirred solution of 5-amino-lH-indole-3-acetonitrile (0.5g) and pyridine (0.24 ml) in dry acetonitrile (10 ml) at 0-2° under nitrogen. When the addition was complete the solution was stirred at 00 for 30 minutes., poured 10 into water (50 ml) and extracted with ethyl acetate (3 x 25 ml). The combined, extracts were dried (MGSO^), filtered and evaporated under reduced pressure to a brown solid (0.5g) which was recrystallised from an ethanol-cyclohexane mixture to give the title compound (0.43g) as off-white 15 needles, m.p. 171.5-175°. ii) N-[3(2-Aminoethyl)-lH-indol-5-yl]acetamide, compound with creatinine, sulphuric acid and water (2:3:2:5) Following the method described in Example 4, N-[3-(cyanomethyl)-lH-indol-5-yl]acetamide (0.3g) in ethanol (15 ml) was reduced with Raney nickel (0.06g) and hydrazine hydrate (6.2 ml) over 6h. The title compound was obtained as a white crystalline solid m.p. 177-182° (dec).

Analysis Found: C,40.6; H,5.7; N,20.1; C12H15N30.1.5C4H7N30.H2S04.2.5H.O: C,40.8; H,6.2; N,19.8% (6) V & Example 14 N-[3-(2-Aminoethyl)-lH-indol-5-yl]-2-methylpropanamide, compound with hydrogen chloride and water (4:4:3) (ii) A solution of N-[3-(cyanomethyl)-lH-indol-5-yl]~ ^ 2-methylpropanamide (0.4g) in absolute ethanol (50 ml) containing concentrated hydrochloric acid (10 drops) was hydrogenated at room temperature and pressure over palladium on charcoal (10%. 1.5g) for 16h, before the catalyst was replaced (10%, lg). After a further 4h, 10 when hydrogen uptake (75 ml) had ceased, the catalyst was filtered off, washed with absolute ethanol, and the filtrate was evaporated in vacuo yielding a brown solid. The crude hydrochloric was crystallised from a mixture of methanol and ethyl acetate, to give the title 15 compound as a light brown solid (0.2 g) m.p. 274-276°. Analysis Found: C,56.7; H,7.4; N,13.7; C14H19N30'HC1*0,75H2° re<3uires: C,56.95; H,7.3; N,14.2% Example 15 N-[3-(2-Aminoethyl)-lH-indol-5-yl]trifluoroacetamide, 20 compound with creatinine, sulphuric acid and water (1:1:1:2) (ii) N-[3-(Cyanomethyl)-lH-indol-5-yl]trifluoroacetamide (1.3g) in ethanol (50 ml) and ammonia (0.6 ml) was hydrogenated at room temperature and pressue over rhodium-on-alumina (0.5g) for 48h. The mixture was filtered through hyflo and evaporated to dryness under reduced pressure to C- " (> id \ ^ V V afford a brown oil. The brown oil was purified by column chromatography (Kieselgel 60, 25g) using a mixture of ethyl acetate, 2-propanol, water and ammonia (25:15:4:1) as eluent. The resulting solid was dissolved in hot ethanol and treated with an aqueous solution of creatinine and sulphuric acid (2M, 1:1, 1 ml) and the resulting solid was recrystallised from aqueous acetone to give the title compound as a pinkish solid m.p. 186-215° (dec).

Analysis Found: C,37.2; H,5.05; N,16.2; C12H12F3N30*C4H7N3°"H2S042H20 rec3uires: C,37.1; H,4.9; N,16.2% The following compounds were prepared according to the method described in Example 13(i) from 5-amino-lH- indole-3-acetonitrile and the appropriate acid chloride or acid anhydride as detailed in Table V. table v Ex. No.

Wt. of starting material (g) Reagent Vol. of Reagent (ml) Vol. of pyridine (ml) Vol. of ch-.cn (ml) Wt. of product (g) Recrystallisation solvent Mol. formula in • p • ( °C) 14(i) 2.8 Pr^OCl 1.8 2 50 1.8 * C14H15N3° 138-140 (i) 2.0 (cf3co) 2o 2.45 1 40 1.46 Ethyl acetate/ cydohexane C12H8F3N3° 165-6 * Purified by column chromatography on Kieselgel 60 (150g) eluted with ethyl acetate Example 16 N-[3-(2-Aminoethyl)-lH-indol-5-yl]-N1-methylthiourea, compound with creatinine, sulphuric acid and water (1:L:1:1) i) N-[3-(Cyanomethyl)-lH-indol-5-yl]-N'-methylthiourea, 5 compound with ethanol (2:1) Methyl isothiocyanate (0.40 ml) was added to a stirred solution of 5-amino-lH-indole-3-acetonitrile (lg) in dry acetonitrile (20 ml). The solution was stirred at room temperature for 3 days. A further quantity of methyl isothio-10 cyanate (0.05 ml) was added and the mixture was heated at 50° for 5h. The solution was evaporated in vacuo to a viscous oil which solidified on trituration with an ethanol-ether mixture. The resulting solid was filtered off and dried in vacuo to give the title compound (1.17g) as an off-15 white crystalline solid, m.p. 103-110°. ii) N-[3-(2-Aminoethyl)-lH-indol-5-yl]-N'-methylthiourea, compound with creatinine, sulphuric acid and water (1:1:1:1) Lithium aluminium hydride (0.19g) was added in small portions at 18-20° to a stirred suspension of N-[3-(cyano-20 methyl)-lH-indol-5-yl]-N'-methylthiourea (0.4g) in dry tetrahydrofuran (10 ml) under nitrogen. When the addition was complete the yellow suspension was heated at reflux for 2h. The suspension was cooled to room temperature and the excess lithium aluminium hydride was destroyed by the careful 25 addition of a water-ethanol mixture (1:1) (30 ml). 1 97 Th e resulting suspension was filtered off and the filtrate was evaporated under reduced pressure to a yellow semi-solid. Ethanol (50 ml) and water (.10 ml) were added and the solution was filtered to remove a small quantity of insoluble material. 5 The filtrate was heated to reflux and treated with a hot solution of creatinine sulphate (0.6g) in water (2 ml). On cooling, the title compound was obtained as a buff-coloured solid m.p. 226-9° (dec).

Analysis Found: C,40.3; H,5.5; N,20.1; C12H16N4S'C4H7N3°'H2S04'H2° re<3uires: C,40.2; H,5.7; N,20.5% Example 17 N-[3-(2-Aminoethyl)-lH-indol-5-yl]thiourea, fumarate, hemihydrate i) Ethyl[[[3-(cyanomethyl)-lH-indol-5-ylJ amino]thio-carbonyl]carbamate Ethoxycarbonyl isothiocyanate (1.2 ml) was added dropwise to a stirred solution of 5-amino-lH-indole-3-acetonitrile (1.7 g) in dry acetonitrile (50 ml). After 10 min. the resulting suspension was diluted with water (40 ml) and stirred for 20 min.

The precipitate was filtered off, washed with dry acetonitrile, and dried in vacuo to give the title compound as a cream solid (1.5g) m.p. 201-202°C. ii) N-[3-(Cyanomethyl)-lH-indol-5-yl]thiourea A solution of ethyl [[[3-(cyanomethyl)-lH-indol-5-yl] 25 amino]thiocarbonyl]carbamate (0.5g) in 2N sodium hydroxide -ss- cs ml) and ethanol (10 ml) was stirred at 40°C for 2h. The resulting precipitate was filtered off, triturated with water (40 ml), washed with ethanol (ca. 30 ml) and dried in vacuo to give the title compound as a white 5 solid (0.25g) m.p. 212-214°C. iii) N-[3-(2-Aminoethyl)-l&-indol-5-yl]thiourea, fumarate, hemihydrate Lithium aluminium hydride (0.5g) was added portion-wise, under nitrogen, to a stirred suspension of N-[3-10 (cyanomethyl)-lH-indol-5-y1]thiourea (0.6g) in THF (150 ml). When the addition was complete aluminium chloride (1.74g) was added, and the resulting grey suspension was stirred at reflux for lh.

The mixture was cooled in ice and excess reagent 15 decomposed by cautious addition of 10% water in THF.

Brine (100 ml) and ethyl acetate (100 ml) were added, insoluble material filtered off, and the aqueous layer extracted with ethyl acetate (100 ml).

The combined organic solutions were washed with brine 20 (100 ml), dried (Na2S04) and evaporated in vacuo to yield a pale yellow oil. The oil was dissolved in a solution of fumaric acid (0.3g) in methanol (5 ml) and the fumarate precipitate by the addition of ethyl acetate (250 ml). The salt was crystallised from isopropanol and recrystallised 25 from a mixture of methanol and ethyl acetate to give the I 97 99 title compound as a cream solid (0.15g) m.p. 147-150°. Analysis Found: C,50.1; H,5.4; N,15.8; C11H14N4S*C4H404"°"5H20 re<3uires: C,50.1; H,5.3; N,15.6% Example 18 N-[1-[3-(2-Aminoethyl)-lH-indol-5-yl]ethyl]acetamide, compound with creatinine, sulphuric acid and water (1:1:1:2) i) 2-[2-(5-Acetyl-lH-indol-3-yl)ethyl]-lH-isoindole-1, 3(2H)-dione A suspension of 5-acetyl-lH-indole-3-ethanamine 10 (l.Og), phthalic anhydride (0.83g) and sodium acetate (l.Og) in acetic acid (15 ml) was heated at reflux for 3h. On cooling the title compound was deposited as an off-white crystalline solid (1.5g) m.p. 234-5°. ii) 2-[5-[1-(Hydroxyimino)ethyl]-lH-indol-3-yl]-lH-iso-15 indole-1,3(2H)-dione A suspension of 2-[2-(5-acetyl-lH-indol-3-yl)ethyl]-lH-isoindole-1,3(2H)-dione (l.Og) in ethanol (20 ml) was treated with a solution of hydroxylamine acetate [generated from a solution of hydroxylamine hydrochloride (0.5g) and 20 sodium acetate (0.5g) in water (5 ml) diluted with ethanol (75 ml) to deposit sodium chloride]. The reaction mixture was heated at a reflux for 2.5h. On cooling the title compound crystallised out as a yellow solid (l.Og) m.p. 220-223°. 1 97 9 9 iii) N-[1-[3-[2-(1,3-Dihydro-l,3-dioxo-2H-isoindol-2-yl) ethyl]-lH-indol-5-yl]ethyl]acetamide A suspension of 2-[5-[1-(hydroxyimino)ethyl]-1H-• indol-3-yl]-lH-isoindole-1,3(2H)-dione (0.8g) in methanol (150 ml) and concentrated sulphuric acid (0.8 ml) was hydrogenated over pre-reduced palladium on charcoal (0.8g) at room temperature and pressure until hydrogen uptake ceased (4h, 120 ml). The catalyst was filtered off, washed with methanol, and dimethylformamide (10 ml) was added to the filtrate before evaporating off the methanol under reduced pressure. The resulting brown solution was cooled in an ice-bath and treated successively with pyridine (10 ml) and acetic anhydride (0.8 ml). The reaction mixture was allowed to warm to room temperature overnight then partitioned between ethyl acetate (250 ml) and dilute hydrochloric acid (2N, 500 ml). The organic phase was washed with water ( 5 x 100 ml), dried (NaSO^) and evaporated to dryness to give a brown gum which was purified on a silica column (Kieselgel 60, 70 g) eluted with ethyl acetate to give the title compound as a yellow crystalline solid (0.45g) m.p. 224-6°. iv) N-[1-[3-(2-Aminoethyl)-lH-indol-5-yl]ethyl]acetamide, compound with creatinine, sulphuric acid and water (1:1:1:2) Following the method described in Example l(ii), a <5 y -61" solution of N-[1-[3-[2-(1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)ethyl]-lH-indol-5-yl]ethyl]acetamide (0.38g) in ethanol (50 ml) was deprotected with hydrazine hydrate (0.25 ml) to give, after creatinine sulphate formation the title compound as a white crystalline solid (0.35g) m.p. 205-12° (dec).

Analysis Found: C ,43.4; H,6.15;,N,17.65; C14H19^3°'C4H7^3°"H2S04* 2H2° re<3uires : C,43.9; H,6.5; N,17.1% Example 19 N-[[3-(2-Aminoethyl)-l-methyl-lH-indol-5-yl]methyl]formamide, compound with creatinine, sulphuric acid and water (10:12:11:10) i) N- [ [ 3- [ 2- (1,3-Dihydro-l, 3-dioxo-2_H-isoindol-2-yl) ethyl]-lH-indol-5-ylj methyl]formamide 15 Formic acetic anhydride (5 ml) was added over 1 min. to an ice-cooled, stirred solution of 2-[2-[5-(aminomethyl)-lH-indol-3-yl]ethyl]-lH-isoindole-1,3(2H)-dione, hemisulphate, hydrate (0.65g) in dry pyridine (25 ml).

After 10 min. the mixture was removed from the ice bath and 20 stirred at room temperature for 0.5h.

The mixture was then cooled in ice and water (10 ml) added. After 10 min., the mixture was slowly diluted with water to 400 ml, with scratching. Filtration gave pale yellow needles (0.53g) m.p. 174-6° (partial melting at 145°). 25 As sample (0.14g) was recrystallised from ethyl 19799® acetate to give the title compound (O.llg) as a yellow powder m.p. 176-8°. ii) N-[[3-[2-(1,3-Dihydro-l,3-dioxo-2H-isoindol-2-yl)ethyl] -l-methyl-lH-indol-5-yl]methyl]formamide, hemihydrate Sodium hydride in oil (80%, 0.045g) was added under nitrogen to a stirred solution of N-[[3-[2-(1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)ethyl]-lH-indol-5-yl]methyl]formamide (0.5g) in dimethylformamide (20 ml) and stirring continued for 30 min. The solution was then treated with methyl 10 iodide (0.2 ml). After 3h, the solution was diluted with ethyl acetate (150 ml) washed with brine (10%, 3 x 50 ml), dried (sodium sulphate), filtered and evaporated to dryness giving a yellow solid which was crystallised from ethyl acetate to give the title compound (0.2g) as an off-white 15 solid m.p. 189-191°. iii) N- [ [3- (2-Aminoethyl) -l-methyl-ljj-indol-5-yl]methyl] formamide compound with creatinine, sulphuric acid and water (10; 12 :11:10) A solution of N-[[3-[2-(1,3-dihydro-l,3-dioxo-2H-20 isoindol-2-yl)ethyl]-l-methyl-lH-indol-5-yl]methyl]formamide (0.3g) in ethanolic methylamine (33%, 10 ml) was kept at room temperature for 2h. The solvent was evaporated in vacuo and the residue re-evaporated with ethanol (3 x 50 ml). The residue was dissolved in a hot mixture of ethanol 25 (50 ml) and water (1 ml) and an aqueous solution of 7 97998 creatinine and sulphuric acid (1:1, 2M, 0.4 ml) added. Filtration of the cooled mixture gave the title compound (0.26g) as an off-white solid m.p. 204-208°.

Analysis Found: c,43.8; h,6.1; n,19.3% c13h17n3o.i.2c4h7n3o.i.ih2so4.h2o requires: C,43.4; H,6.1; N,18.8% Example 20 N-[[3-(3-Aminopropyl)-lH-indol-5-yl]methyl]formamide, compound with creatinine, sulphuric acid and water 10 (1:1:1:2) i) 2-[3-[5-(Aminomethyl)-lH-indol-3-yl]propyl]-lfl-isoindole-1,3(2H)-dione, sulphate A suspension of 3-[3-(1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)propyl]-lH-indole-5-carbonitrile (2.0g) and palladium 15 on carbon catalyst (aqueous paste 50%, 0.85g) in absolute methanol (100 ml) containing sulphuric acid (0.64 ml) was stirred under a hydrogen atmosphere for 25h. The catalyst was filtered off and the filtrate was evaporated in vacuo. The resulting yellow solid was washed with ether (2 x 50 ml), 20 crystallised from water (10 ml) and dried in vacuo to afford the title compound as a pale yellow-green solid (1.77g) m.p. 176-180° (dec). ii) N-[[3-[3-(1,3-Dihydro-l,3-dioxo-2H-isoindol-2-yl) propyl]-lH-indol-5-yl]methyl]formamide Following the method described in Example 19(i), a solution of 2-[3-[5-(aminomethyl)-lH-indol-3-yl]propyl]-1H-5 isoindole-1,3(2H)-dione, sulphate (0.75g) was reacted with formic acetic anhydride (15 ml) in pyridine (27.5 ml) to give the title compound as a yellow solid (0.49g) m.p. 150-152° after crystallisation from ethyl acetate. iii) N-[[3-(3-Aminopropyl)-lH-indol-5-yl]methyl]formamide, 10 compound with creatinine, sulphuric acid and water (1;1;1;2) A solution of N-[[3-[3-(1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)propyl]-lH-indol-5-yl]methyl]formamide (0.2g) in efehanolic methylamine (33%, 5 ml) was stirred at room temperature for 2.5h, then evaporated to dryness 15 in vacuo below 5°. The resulting off-white solid was dissolved in cold ethanol (25 ml), filtered, diluted with hot ethanol (25 ml) and water (10 ml) before treating with an aqueous solution of creatinine and sulphuric acid (1:1, 2M, 0.25 ml) to give, after recrystallisation from aqueous 20 acetone, the title compound as an off-white solid (O.llg) m.p. 175-8°.

Analysis Found: C,42.45; H,5.8; N,17.6 C13H17N3°"C4H7N3°*H2S04* 2H2° re<3uire: C,42.7; H,6.3; N,17.6% ' V,'' > Example 21 II- [ [ 3~ ( 2-Aminoethyl) -1H- indol- 5-y 1 ]me thyl ] ace tamide i) N-f(L-HydrazinophenylImethyl lacetamide, hydrochloride A solution of sodium nitrite (0.2g) in water (2 ml) was added, over 1 /2h, to a stirred suspension of N-[ (4-aminophenyl)methyl]acetamide hydrochloride (0.5g) in water (1.5 ml) cone, hydrochloric acid (2 ml) keeping the temperature below 0°. The solution was stirred with ice cooling for 40njin and then added, over Jmixi, to an ice-cooled, stirred solution of sodium acetate (2.3g) and sodium sulphite (1.3g) in water (14 ml). After 1/2h, the ice bath was removed and the mixture left at room temperature overnight.

The mixture was acidified with conc. hydrochloric acid then warmed to 85° for 15min. The solvent was evaporated in vacuo and the residue re-evaporated with ethanol (2 x 20 nil). The residue was extracted with ethanol (2 x 25 e?.) and the filtered extracts evaporated in vacuo to leave a brown gum, which crystallised on the addition of ethanol (ca 3 ml). Filtration gave a cream crystalline solid (0.21g) m.p. 205-10°, which was recrystallized from ethanol to give the title compound as a beige crystalline solid (O.lg) m.p. 212-4° ii) N-[[3-(2-Aminoethyl)-lH-indol-5-yl]methyl]acetamide A solution of N-[(4-hydrazinophenyl)methyl]acetamide hydrochloride (0.05g), 4-chlorobutanal diethyl acetal (0.05 ml) and sodium acetate (0.02g) in a mixture of methanol (1.5 e!)» acetic acid (0.3 ml) and water (10 drops) was refluxed for 7h.

TLC Silica, ethyl acetate/2-propanol/water/0.86 ammonia (25:15iSs2) showed the title compound as the major basic product, Rf 0.3* ;e Q, t / C' // & Example 22 N-[ [ ;>-[2-( Me thyl amino) ethyl ]-lH-indol-5-yl jmethyl Jacetamide, hydrochloride i) 5~(Aminomethyl)-N-me thyl-N-(phenylme thyl)-1H-indole-J-ethanamine A solution of 3-[2-[methyl(phenylmethyl)amino]ethyl]-lB-indole-5-carbonitrile (log) in dry tetrahydrofuran (100 ml) under nitrogen was treated with lithium aluminium hydride (l.Og) and heated at reflux for 3h. Excess lithium aluminium hydride was destroyed with wet tetrahydrofuran, the reaction mixture diluted with ethyl acetate (200 ml), filtered and the filtrate evaporated to dryness to give a pale yellow oil which slowly crystallised to give the title compound as a cream solid (1.2g) m.p. 84-5°. i i) N-[[3-[2-[Me thyl(phenylme thyl) amino]e thyl]-1H- indo1-5~yl]methyl] acetamide, compound with creatinine, sulphuric acid and water (2:2:2:3)• An ice-cold solution of 5-(a^iinoinethyl)-N-iiiethyl-N-(phenylmethyl)-lH-indole-3-ethanamine (1.3g) in pyridine (5 ™1) was treated dropwise with acetic anhydride (0.9 ml) over lOmin. The solution was stirred at room temperature for lh and then evaporated to dryness to give a brown oil which was purified on a silica column (kieselgel 60, 50g) eluted with ethyl acetate/methanol (5:1) to give the free base of the title compound as a pale brown oil (l.Og). A sample of this oil (lOOmg) was dissolved in a hot mixture of ethanol (3 ml) and water (1 ml) and treated with an aqueous solution of creatinine and sulphuric acid (2M, 1:1, O.l^nil). Cooling ana scratching deposited the title compound as a gummy off-white solid m.p. 150-165° (starts foaming at approx 120°). 1 g y </ t; J i fo) O iii) N-[[3-[2-(Methylaiaino)ethyl]-lH-indol-5-yl]methyl]acetamide, hydrochloride A solution of N-[[3-[2-[methyl(phenylmethyl)amino]ethyl]-lH-indol-5-yl] methyl]acetamide (0. 9g) in absolute ethanol (100- ml) vas hydrogenated over palladium on charcoal (10%, 5^c aqueous paste, 0.2g) at room temperature and pressure until hydrogen uptake ceased (4h, 70 ml). The catalyst was filtered off, washed with ethanol and the filtrate evaporated to small volume and treated with ethereal hydrogen chloride then ether to deposit the title compound as a white crystalline solid (0.24g) m.p. 240-2420 (darkens at 220°) after recrystallisation from ethanol.

Analysis Found: C, 59-6; H, 7.1; N, 14.75; C±4HL9N30.HC1 requires: C, 59-7; H, 7-15» N, 14.9%.

Example _2i N-[ [j-[2-( Cyclopentylamino)ethyl ]-lH-indol-5-yl ]methyl ]f ormainl de, compound with creatinine, sulphuric acid and water (4:6:5;6) A solution of N-[[3~(2-aminoethyl)-lH-indol-5~yl]methyl]formamide (0. 3g) and cyclopentanone (l ml) in absolute ethanol (40 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on carbon (50% aq. paste; pre-reduced; 0.3g) until hydrogen uptake ceased.

The catalyst was filtered off, washed with ethanol (20 ml) and the filtrate evaporated in vacuo. The residual pale yellow oil was partitioned between ethyl acetate (20 ml) and 2N hydrochloric acid (l x 20 ml; 2 x 10 ml). The aqueous layer was basified with solid sodium carbonate, saturated with sodium chloride and extracted with ethyl acetate (l x 20 ml; 8 x 10 ml). The combined organic extracts were dried (Na2S04) and evaporated to dryness.

The residual white gum (0.22g) was dissolved in a hot mixture of acetone (15 ml) and water (2 ml) and an aqueous solution of creatinine and'sulphuric acid (2M; . 1:1;. 0.35 ml) was added. On cooling and scratching the title compound crystallised as a pale yellow solid (0.25g) m.p. 196 - 198° (shrinks 190°) Analysis Found: " "G-j 45.4; H, 6.7; N, 17.2; C17H23N30.1.5C4H7N30.1.25H2S04.1.5H20 requires: C, 45.7; H, 6.5; N, 17.4% y «-T - e' " :-g ;J L v Example 24 2-Methylpropyl [3-(2-aminoethyl)-lH-indol-5-yl]carbamate, hydrochloride i) 2-Methylpropyl [3-(cyanomethyl-lH-indol-5-yl]carbamate, quarter hydrate Isobutyl chloroformate (1.5 nil) was added dropwise to a stirred solution of 5-amino-lH-indole-3-acetonitrile (1.7g) in dry DMF (20 ml). After lOmin the solution was diluted with water (150 ml) arid stirring continued for JOmin. The resulting solution was extracted with ethyl acetate (2 x 100 ml) and the combined extracts washed with brine (10%, 100 ml), water (100 ml), dried (Na2S04) and evaporated in vacuo to yield the crude product as a brown oil. This was purified by column chromatography (Kieselgel 60, lOOg) using ether as the eluent, to give the title compound as a colourless gum (1.08g) which darkened to a brown gum on storage. This material failed to crystallise from common organic solvents.

Analysis Found: C, 65-8> H, 6.4> N, 14*7» 5Hj_7N502 .0.25 H20 requires: C, 65-3> H, 6-4> N, 15-2%. ii) 2-Methylpropyl [j-(2-aminoethyl)-lH-indol-5-ylJcarbamate, hydrochloride A solution of 2-methylpropyl [3-(cyanomethyl)-lH-indol-5~ylJcarbamate, .quarter hydrate (0.5g) in absolute ethanol (30 ml) containing concentrated hydrochloric acid (8 drops) was hydrogenated at room temperature and pressure over palladium on charcoal (10%, lg) for 24h before the catalyst was replaced (10%, 0>5g). After a further 4h when hydrogen uptake ceased (90 ml) the catalyst was filtered off, washed with absolute ethanol, and the filtrate evaporated in vacuo giving a pink solid. The crude hydrochloride was crystallised from a mixture of methanol and ethyl acetate, to give the title compound as a white solid (0.15g) m.p. 258-260° Analysis Found: C, 57-7; H, 7.0; N, 13•1? 5H21N302.HC1 requires: C, 57.8; H, 7•15 N, 13-5%- Example ?5 1 97 ^ N-[[3~[2-(Phenylmethylideneamino)ethyl]-lE-indol-5~yl]methyl]formamide, compound with toluene and water (6:2;5) A solution of N-[[3-(2-aminoethyl)-lH-indol-5-yl]methyl]foxjnamide, (0.3g) in absolute ethanol (1 ml) was added dropwise to a "stirred solution of benzaldehyde (0.15g) in dry toluene (15 ml). The mixture was stirred for 5min and then evaporated to dryness lander reduced pressure. Toluene (15 ml) was added and the mixture re-evaporated to give the title compound as a dark brown oil. (0.35g)« Analysis Pound: C, 73.9; H, 6«5» N, 12.0 C19HL9N30.1/3C7H8.:1/2H20 requires: C, 74*2;' E, 6.6; N, 12.2 t (EMSO) 1.7 (15,S) N=CHPh Example 26 N-[3-(2-Aminoethyl)-lH-indol-5-yl]-Nl ,N'-dimethylsulphamide, maleate . i) N-[3-(Cyanomethyl)-lH-indol-5-yl]-N',N'-dimethylsulphamide Dimethyl sulphamoyl chloride (1.2 ml) was added dropwise to a stirred solution 5-aiJii:no-13-indole-3-acetonitrile (1.7g) in dry dimethyl-formamide. (50 ml) containing triethylamine (2.8 ml). After 3h> the resulting suspension was diluted with water (20 ml) and stirred for 30 min. The resulting solution was poured into water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water (100ml) and brine (2 x 100 ml), dried (Na2S04) and evaporated in vacuo, to give a dark brown oil which was purified by column chromatography (kieselgel 60, lOOg) eluted with ether/ethyl acetate, (9:1) to give the title compound as a white solid (0.75g) m.p. 147-150°. ii) N-[3~(2-Aminoethyl)-15-indol~5-yl]-N' methylsulphamide, maleate A solution of N-[3-(cyanomethyl)-lH-indol-5-yl]-Nt ,N'-dimethylsulphajni.de (0.;g) in absolute ethanol (50 ml) containing concentrated hydrochloric acid (6 drops) was hydrogenated at room temperature and pressure over palladium on charcoal (10^, 0.2g) for 24h before the catalyst was replaced (lfr/, 0.5g). After a further Ah, when hydrogen uptake ceased (60 ml) the catalyst was filtered off, washed with ethanol, and the filtrate evaporated in vacuo to give a brown oil. The oil was then partitioned between ethyl acetate (2 x 20 ml) and 2N sodium carbonate (10 ml), the combined organic extracts dried (Na2S04) and evaporated in vacuo to give a fawn foam. The foam was dissolved in a soltion of maleic acid (0.16g) in methanol (4 ml) and the maleate precipitated by the addition of ethyl acetate (100 ml) and ether (150 ml). The salt was crystallised from a mixture of methanol and ethyl acetate to give the title compound (0.06g) as a fawn solid m.p. 138-142°.

Analysis Found: C, 48.3; H, 5-5* N, 13*8; ci 2Hi6N4°2S-04H404 requires: C, 48.2; H, 5*6; N, 14«l?c.

A f- C N~[[3-(2-Aminoethyl)-lH-indol-5-yl]methyl]-U',N*-dimethylsulphamide compound with creatinine, sulphuric acid and water (1:1:1:1) i) N-[[3-[2-(l,3-Dihydro-l,3-d.ioxo-2H-isoindol-2-yl)ethyl]-lH-indol-5~ yl]methyl]-N',N'-dimethylsulphamide hemihydrate. .

An ice-cold suspension of 2-[2-[5~(aminomethyl)-lH-indol~3~yl]ethyl]-lH-isoindole-1,3(2H)-dione, hemisulphate, hydrate (2.0g) in pyridine (40 ml) was treated dropwise with dime thyl sulphamoyl chloride (0.75g) over five minutes. The solution was then allowed to warm to room temperature. After 16h the orange solution was poured into water (100 ml) and extracted with ethyl acetate (3 x 70 ml). Hie combined organic extracts were washed with saturated copper sulphate (7 x 50 ml), sodium carbonate (2N, 2x40 ml), dried and concentrated under vacuum to afford an orange oil (1.3g). Column chromatography (Kieselgel 60, 50g) with chloroform as eluent afforded the title compound (0.62g) as a pale yellow solid, m.p. 174~176°C. ii) N-[ [ 3-(2-Aminoethyl) -lH-indol-5-yl ]methyl ]-N' ,N' -dime thyl sulphamide compound with creatinine, sulphuric acid and water (1:1:1:1) A solution of N-[[3~[2-(l,3-dihydro-l,3~dioxo-2H-isoindol-2-yl)ethyl] -lg-indol-5-yl ]methyl]-N' Slime thyl sulphamide, hemihydrate (0.45g) and hydrazine hydrate (0.2 ml) in ethanol (20 ml) was heated at reflux for two hours. The filtrate was concentrated under vacuum to afford a cream solid which was partitioned between ethyl acetate (30 ml) and sodium carbonate (2N, 25 ml) and the aqueous phase re-extracted with ethyl acetate (1 x 25 ml; 2x 15 ml). The combined organic extracts were washed with water (3 x 25 ml), dried and concentrated under vacuum to afford the amine as a pale yellow oil, which gave, after creatinine sulphate formation the title compound (0.3g) as a white crystalline solid m.p. 220-222°.

Exaaple 27 Analysis Found: C, 38.9; H, 5*8; Nj 18-4% Cx 3H20N,.02S.C4H7K30.H2S04.H~0 requires: C, 38.9; H, 6.0; N, 18.7%.

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

A. Direct Compression mg/tablet Active ingredient 10.0 Microcrys'talline Cellulose B.P.C. 89.5 Magnesium Stearate 0.5 100.0 The active ingredient is sieved through a 250 pm 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 punches to suit.

B. Wet Granulation mg/tablet Active ingredient 10.0 Lactose B.P. 74.5 Starch B.P. 10.0 Pregelatinised Maize Starch B.P. 5.0 Magnesium Stearate B.P. 0.5 Compression Weight 100.0 1 The active ingredient is sieved through a 250 jim 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 formulae.

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

Capsules mg/capsule Active ingredient 10.0 *Starch 1500 89.5 Magnesium Stearate B.P. 0.5 Fill Weight 100.0 * A form of directly compressible starch supplied by Coloron Ltd., Orpington, Kent.

The active ingredient is sieved through a 250 pm sieve and blended with the other materials. 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. t 1 97 v S 2s syrup mg/5 ml dose Active ingredient .0 Sucrose B.P 2750.-0 Glycerine B.P 500.0 Buffer Flavour as required Colour Preservative Distilled Water .00 ml 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.

Suppositories Active ingredient 10.0 mg * Witepsol H15 to 1.0 g * A proprietary grade of Adeps Solidus ph. Eur.

A suspension of the active ingredient in the matter Witepsol H15 is prepared and filled using a suitable machine into lg size suppository moulds. 1 9/ Injection for Intravenous Administration % w/v Active ingredient 0.20 Water for injections B.P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the active ingredient using dilute acid or alkali or by the addition of suitable buffer salts. 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 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.

Claims

1 97 9 9 -77- INHALATION CARTRIDGES mq/cartridge Active ingredient micronised 1.00 Lactose B.P. 39.0 5 The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into No. 3 hard gelatin capsules on a suitable encapsulating machine. The contents of the 10 cartridges are administered using a powder inhaler (e.g. Glaxo Rotahaler). METERED DOSE PRESSURISED AEROSOL mg/metered dose Per can Active ingredient micronised 0.500 120 mg 15 Oleic Acid B.P. 0.050 12 mg Trichlorofluoromethane B.P. 22.25 5.34 g Dichlorodifluoromethane B.P. 60.90 14.62 g The active ingredient is micronised in a fluid energy mill to a fine particle size range. The Oleic Acid is mixed with 20 the Trichlorofluoromethane at a temperature of 10-15°C and the micronised drug is mixed into this solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves, delivering a metered dose of 85 mg of suspension are crimped onto the 25 cans and the Dichlorodifluoromethane is pressure filled into the cans through valves. 197S98 WHAT +/V/E CLAIM IS : -78- efcjtTM5~

1. A compound of the general formula (I): wherein represents a group CHO, CORg, C02Rg, CONRgR-^Q ,

* CSNRgR1Qor S02NR9R1Q, where;Rg represents an optionally substituted alkyl, a cycloalkyl, an optionally substituted aryl or an optionally substituted aralkyl group,;Rg represents a hydrogen atom or an alkyl group, and represents a hydrogen atom or an alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl group;;R2, R^, R^, Rg and R?, which may be the same or different, each represents a hydrogen atom or a C^_3 alkyl group;;Rt- represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or an optionally substituted aralkyl group or and R^. together form an aralkylidene group or R^ and R^ together with the nitrogen atom to which they are attached form a saturated monocyclic 5-to 7-membered ring;;n is zero or 1; and;197898;Alk represents an alkylene chain containing two or three carbon atoms which may be unsubstituted or substituted by not more than two alkyl groups;;with the provisos that, when n is zero and (i) and R^ both represent alkyl groups, R^ does not represent the group CHO or CORg; and (ii) R^ does not represent the group SO2NH2;;and physiologically acceptable salts (as hereinbefore .defined) and solvates thereof.;2. A compound according to claim 1, wherein Alk represents an unsubstituted alkylene chain containing two carbon atoms.;

3. A compound according to claim 1, wherein R^ and;R^, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group and R, and o;R^ each represents a hydrogen atom.;

4. A compound according to claim 1, wherein R^ represents a hydrogen atom.;

5. A compound according to claim 1, wherein R2 represents a hydrogen atom or a methyl group.;

6. A compound according to claim 1, having the general formula (la):;197998;-80-;wherein;R;, represents a group CHO, CONH-, C0Ro or xa » z oa;C0_Ro , where ^ oa;Rga is an optionally substituted alkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group;;R2a represents a hydrogen atom or a methyl group;;n is zero or 1; and;R. and Rr , which may be the same or different, 4 a 5 a J;: each represents a hydrogen atom or a methyl or ethyl group with the provisos that the total number of carbon atoms in R. and R_ together;4a 5a ^;does not exceed two and that when R^a represents a group CHO or a group COR„ when n is zero, then;O cl;R^a represents a hydrogen atom,;and physiologically acceptable salts (as hereinbefore defined) and solvates thereof.;

7. A compound according to claim 1 having the general formula (lb):;RlbR2bN;wherein;CH2CH2NR4bR5b;(lb);Rlb rePresents a group CHO, CONH2 or CO^g^ where;R;8b is a methyl, ethyl or isobutyl group;;R;2b represents a hydrogen atom or a methyl group; and R^k and which may be the same or different, each;I;-81-;19799s represents a hydrogen atom or a methyl or ethyl group with the provisos that the total number of carbon atoms in R * and R-, toaether does not 4b 5b exceed two and that when R^ is the .group CHO, R^k represents a hydrogen atom, and physiologically acceptable salts (as hereinbefore defined) and solvates, thereof.

8. A compound according to claim 1 having the general formula (Ic): Rlc represents a group CHO or a group CORgc where Rgc is an optionally substituted alkyl group containing from 1 to 3 carbon atoms; R^c and Rgc/ which may be the same or different each represents a hydrogen atom or a methyl or ethyl group with the proviso that the total number of carbon atoms in R^c and R^c together does not exceed (ic) h wherein represents a hydrogen atom or a methyl group; and two and physiologically acceptable salts (as hereinbefore defined) and solvates thereof. -82- 19799S

9. Ethyl[3-(2-aminoethyl)-lH-indol-5-yl] carbamate, 2-methylpropyl[3-(2-aminoethyl)-1H-indol-5-yl]carbamate and N-[[3-(2-aminoethyl)-lH-indol-5-yl] methyl] acetamide and tjieir physiologically acceptable salts (as hereinbefore defined) and solvates.

10. A compound according to claim 1, wherein the physiologically acceptable salt is a hydrochloride, hydrobromide, sulphate, fumarate or maleate.

11. A-pharmaceutical composition comprising at least one compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt (as hereinbefore defined) or solvate thereof together with one or more physiologically acceptable carriers or excipients.

12. A process for the preparation of a compound of -83- 197998 general formula (I) as defined in claim 1 or a physiologically acceptable salt (as hereinbefore defined) or solvate thereof which process comprises: (A) reacting a compound of general formula (II): r2nh(chr3) AlkNR,Rc 4 5 (II) ; wherein R2, R^, R^, Rg, Rg, R^, n and Alk are as defined for general formula (I), or a protected derivative thereof, with a suitable reagent which serves to introduce the group R^; or (B) cyclising a compound of general formula (III) : r1r2n(chr3)n- (III) NR7N=CRgCH2AlkQ "84" 19 799S wherein Q is the group NR^Rg or a protected derivative thereof or a leaving group and R^, R2, R^r R4, R5, Rg, R7, Alk and n are as defined for general formula (I); or (C) reacting a compound of general formula (VI): r1r2n(chr3)it AlkY (VI) w;herein Rn , R„, R_, R,, , R_, Alk and n are as defined for 1 Z J D / — general formula (I) and Y is a readily displace-able group, or a protected derivative thereof, with a compound of formula R.R-.NH, where R„ and Rc are as defined 4 5 4 5 for general formula (I); or (D) reducing a compound of general formula (VII): R^^'n (VII) v Ql A ^ >// R E G irms 197988 -85- wherein W is a group capable of being reduced to give the required AlkNR^R,. group or a protected derivative thereof and R^, R^r R^, R^/ R , R , Alk and n are as defined for general 6 7 — formula (I), or a salt or protected derivative thereof^ said reduction optionally being carried out in conjunction with an appropriate additional reagent; and, if necessary and/or desired, subjecting the compound thus obtained to one or more further reactions comprising: (E) (i) converfinq the resulting compound of general formula (I) or a salt (as hereinbefore defined) or protected derivative thereof into another compound of general formula (I); and/or (ii) removing any protecting group or groups; and/or (iii) converting a-compound of general formula (I) or a salt (as hereinbefore defined) thereof into a physiologically acceptable salt (as hereinbefore defined) or solvate thereof. , .

13. A process according to claim 12, wherein the reaction (A) comprises (i) reacting the compound of general formula (II) with an acid of formula R^OH, where R^ is as defined for general formula (I) in the presence of a ^ coupling agent at a temperature of from -5 to +30°C 197908 -86- or, in order to prepare a compound of general formula (I) wherein represents -CHO, with formic acid at reflux; or (ii) reacting the compound of gaieral formula (II) with an acylating agent corresponding to an acid of formula R^OH, where R^ is as defined for . general formula (I), at a temperature of from -70 to +150 °C> or (iii) in order to prepare a compound of general formula (I) wherein R-^ represents the group -CONR^R^q or -CSNRgR^Q, reacting the compound of general formula (II) with phosgene or thio-phosgene and an appropriate amine of formula R9R10NH' where Rg and R^g are as defined for general formula (I) , or a salt (as hereinbefore defined) thereof.

14. A process according to claim 12 , wherein the cyclisation reaction (B) comprises reacting a compound of general formula (IV): (IV) wherein R^, R2, R^, Rj and n are as defined for general 197998 -87- formila (I), or a salt (as hereinbefore defined) thereof, with a compound of formula (V): Rg and Alk are as defined for general formula (I) and 0 is as defined in claim 12 or a salt (as hereinbefore defined) or protected derivative thereof.

15. A process according to claim 12 or 14, wherein the cyclisation reaction (B) is effected at a temperature of from 20 to 200°C and wherein, when Q is the group NR^Rj. or a protected derivative thereof, the reaction is effected in an aqueous reaction medium in the presence of an acid catalyst and wherein, when Q is a leaving group, the reaction is effected . in an aqueous organic solvent in the absence of a mineral acid.

16. A process according to claim 12, wherein, in reaction (C), Y represents a halogen atom or a group OR where OR is an ac.yloxy group or a sulphonate group and the reaction (C) is effected in an inert organic solvent at a temperature of from -10 to +150°C.

17. a process according to claim 12, wherein the reaction (D) comprises: (i) reducing a compound of formula (VII), R,C0CHoAlkQ O C (V) wherein wherein W is the group CHR^CN, CHR^CHR^NO 1 97 9 -88- CH=CR12N02 or CHR11CR12=NOH/ by catalytic reduction with hydrogen; or (ii) reducing a compound of formula (VII), wherein W is the group CHR^CN, in the presence of an amine of formula HNR^R^ using hydrogen in the presence of a catalyst; or (iii) reducing a compound of formula (VII) wherein W is the group COCHR^Z with heating using an alkali metal borohydride in a solvent; or (iv) reducing a compound of formula (VII) , wherein W is the group AlkN^ or CH (OH) CHR^NR^R^ using hydrogen in the presence of a catalyst; wherein R^^ and Rj2/ which may be the same or different, each represents a hydrogen atom or a alkyl group, Z is an azido qroup or the group NR^R,- or a protected derivative thereof and R., R_ and Alk are as defined 4 b for general formula (I).

18. A process according to claim 12, wherein the reaction (E(i)) comprises preparing a compound of general formula (I) wherein R^ and/or R,- is other than hydrogen by reductive alkylation of the corresponding compound of general formula (I) wherein R^ and/or R^ represents hydrogen using an appropriate aldehyde or ketone and a suitable reducing agent. - 89 - 197998

19. A compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt (as hereinbefore defined) or solvate thereof for use in the treatment of"migraine. DATED THIS 53 ^DAY OF 19^ A. J. PARK & SON PER cx - ( AGENTS FOR THE APPLICANTS