GB2185020A - Indole derivatives - Google Patents

Description

GB2185020A 1

SPECIFICATION

Chemical compounds This invention relates to indole derivatives, to processes for their preparation, to pharmaceutical 5 compositions containing them and to their medical use, in particular to compounds and compo sitions of use in the treatment of migraine.

The pain of migraine is associated with excessive dilatation of the cranial vasculature, and known treatments for migraine include the administration of compounds having vasoconstrictor properties, such as ergotamine. However, ergotamine is a non-selective vasoconstrictor which 10 constricts blood vessels throughout the body and has undesirable and dangerous side effects.

Migraine may also be treated by administering an analgesic, usually in combination with an antiemetic, but such treatments are of limited value.

There is thus a need for a safe and effective drug for the treatment of migraine, which can be used either prophylactically or to alleviate an established headache, and a compound having a 15 selective vasoconstrictor activity would fulfil such a role.

We have now found a group of indole derivatives having potent and selective vasoconstrictor activity.

The present invention provides an indole of the general formula fl):

20 R1 ty (C H 2) j.-A- N (C H 2) n (CH 2) 2NR 4R 5 25 Nf 1 (1) - R3 wherein 30 R, represents a halogen atom, a C1-3 alkoxy group, a group R^NCO(C1-12)p-, a group R6CONH(C1-12)p-, a group R^NS02(C1-12)p-, or a group IR,S02NH(C1-12),_ (where R6 and R7, which may be the same or different, each represents a hydrogen atom or a C1-3 alkyl group, R, represents a C1-3 alkyl group and p is zero or 1); R2 represents a hydrogen atom or a C,3 alkyl group; R3 represents a hydrogen atom or a C1-3 35 alkyl group; R, and R, which may be the same or different, each represents a hydrogen atom, a C,_3 alkyl group or a 2-propenyl group; A represents -CO- or -S02_; n represents an integer from 2 to 5; and m represents zero or an integer from 1 to 4; and 40 physiologically acceptable salts and solvates (e.g. hydrates) thereof.

The invention includes within its scope all optical isomers of compounds of formula (1) and their mixtures, including the racemic mixtures thereof.

In the compounds of general formula (1) it will be appreciated that the substituent R, may be in the ortho, meta or para positions. 45 Referring to the general formula (1), the alkyl groups may be straight chain or branched chain alkyl groups, such as methyl, ethyl or isopropyl groups. A C,, alkoxy group may be for example methoxy, and a halogen substituent may be for example fluorine, chlorine or bromine.

The substituent R, in compounds of formula (1) may be for example a chlorine atom or a group such as methoxy, H,NCO-, H2NCOCH,-, CH,Ni1C0-, CH3NHCOCH2-, (CH3)2NCO-, (CH,)N2COCH2-, 50 CH,CONI-1-, CH,CONI-ICH2-, H2NS02-, H2NSO2CH2-, CH,NHS02-1 CH,NHS02CH2-, (CHINSO2CH2-, CH3S02NI-1-, or CH3SOMCH,-.

In one general preference, R, is a chlorine atom or a methoxy group.

In another general preference R, is a H2NCOCH2-, CH,NI-ICOCI-12(CHI)2NCOCH2-, CH3CONI-1-, CH3CONHCH2-, H2NS02-, CH3S02NI-1- or CH,S02NI-ICH2- group. 55 m may be zero or an integer 2, 3 or 4, but in general is preferably an integer 1.

n may be an ineger 3, 4 or 5, but in general is preferably an integer 2.

The group A may be -S02-, but is preferably -CO-.

A preferred class of compounds represented by the general-formula (1) is that wherein R2 represents a hydrogen atom. A further preferred class of compounds is that in which R, 60 represents a hydrogen atom.

A still further preferred class of compounds is that in which R, and R, which may be the same or different each represents a hydrogen atom or a methyl or ethyl group. It is preferred that the total number of carbon atoms in R, and R, does not exceed two.

A particularly useful group of compounds according to the invention has the formula (1a) 65 2 GB2185020A 2 Rl CH2CONH(CH2)2 02)2N(CH3)2 (1 a) 5 Ni 1 H in which 10 R, is a chorine atom or a methoxy group or is a, H,NCOCH2-, CH3NHCOCH2-, (CH3)2NCOCH2-, CH3CONH-,CH3CONHCH2-,H2NS02-, CH3S02NI-1- or CH,SOfflCH2- group; and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

Particularly important compounds of this type are those in which R, is a H2NCOCH2-, CH,NHCOCH2-, CH,S02NI-ICI-12-, or H,NS02-group, or, especially, a CH3CONH- or CH3S02NI-1- 15 group.

A preferred compound according to the invention is:

4-(acetylamino)-N-[2-[3-[2-(dimethylamino)ethyil-1H-indol-5-yilethyllbenzen eacetamide and its phy siologically acceptable salts and solvates (e.g. hydrates).

Suitable physiologically acceptable salts of the indoles of general formula (1) include acid 20 addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobrom ides, sulphates, nitrates, phosphates, oxalates, tartrates, citrates, fumarates, maleates, succi nates, and sulphonates e.g. mesylates. Other salts may be useful in the preparation of com pounds of formula (1) e.g. creatinine sulphate adducts.

It will be appreciated that the invention extends to other physiologically acceptable equivalents 25 of the compounds according to the invention, i.e. physiologically acceptable compounds which are converted in vivo into the parent compound. Examples of such equivalents include physiolog ically acceptable, metabolically labile, N-acyl derivatives.

Compounds of the invention potently and selectively constrict the carotid arterial bed of the anaesthetised dog, whilst having a negligible effect on blood pressure. This potent and selective 30 vasoconstrictor action has been demonstrated in vitro.

Compounds of the invention are useful in treating pain resulting from dilatation of the carotid vascular bed, in particular migraine and cluster headache.

Accordingly, the invention also provides a pharmaceutical composition adapted for use in human medicine which comprises at least one compound of formula (1) or a physiologically 35 acceptable salt or solvate (e.g. hydrate) thereof and formulated for administration by any conve nient 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 may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. 40 For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutical ly acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch 45 glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for 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 with pharmaceutically acceptable additives such as suspending 50 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 preservatives (e.g. methyl or propyl-phydroxybenzoates or sorbic acid).

For buccal administration the compositions may take the form of tablets or lozenges formu lated in conventional manner. 55 The compounds of the invention may be formulated for parenteral administration by injection.

Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi dose containers, with an added preservative.

The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or 60 dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. 65 GB2185020A 3 For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules 5 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.

A proposed dose of the compounds of the invention for oral, parenteral, buccal or rectal administration to man (of average bodyweight e.g. about 70kg) for the treatment of migraine is 10 0.03 to 10Orng preferably 0.03 to 30rng of the active ingredient per unit dose which could be administered, for example 1 to 4 tinies per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated.

For oral administration a unit dose will preferably contain from 0.3 to 30rng of the active 15 ingredient. A unit dose for parenteral administration will preferably contain 0. 1 to 5mg of the active ingredient.

Aerosol formulations are preferably arranged so that each metered dose or 'puff' delivered from a pressurised aerosol contains 0.1 to 2mg of a compound of the invention and each dose administered via capsules or cartridges in an inhaler or insufflator contains 0.2 to 1Orng. The 20 overall daily dose by inhalation will be within the range 0.3mg to 30rng. Administration may be several times daily, for example from 2 to 8 times, giving for example 1, 2 or 3 doses each time.

The compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents, such as analgesics, anti-inflammatory agents and anti-nauseants. 25 According to another aspect of the invention, compounds of formula (1), and physiologically acceptable salts or solvates (e.g. hydrates) thereof, may be prepared by the general methods outlined below. In the following processes, R, R21 R3, R, R, A, m and n are as defined for the general formula (1) unless otherwise specified.

According to one general process (A), a compound of general formula (1) may be prepared by 30 reacting a compound of general formula (]I):

R 2NH (C H2)n CH2) 2N R4 R5 35 R3 40 or a salt thereof (for example, an organic or inorganic acid addition salt such as the hydrochlo ride, hydrobromide, maleate, sulphate or creatinine sulphate adduct) or an N-silyl derivative thereof or a protected derivative thereof with a reagent serving to introduce the group R 45 - (CH2)MA-.

Suitable reagents which serve to introduce the group 50 R 1"-(CH'2)M-Ainclude acids of the general formula 55 R 1"(CH2)M-A-OH 60 or acylating agents corresponding thereto. Acylating agents which may conveniently be used in the above process include acid halides (for example carboxylic acid chlorides and sulphonyl chlorides), alkyl esters, (for example the methyl or ethyl ester), activated esters (for example the 65 4 GB2185020A 4 2-(1-methylpyridinyi)ester), symmetrical anhydrides, mixed anhydrides or other activated carboxy lic acid derivatives such as those conveniently used in peptide synthesis.

The process may be effected in a suitable aqueous or non-aqueous reaction medium, conveni ently at a temperature of from -70 to +150'C. Thus the process using an acid halide, an activated ester or an anhydride may be effected in a suitable reaction medium such as an amide 5 (e.g. N,N-dimethyiformarnide) or hexa methyl phosphoramide, an ether (e.g. tetra hydrofu ran), a nitrile (e.g. acetonitrile), a haloalkane (e.g. dichloromethane) or mixtures thereof, optionally in the presence of an organic base, for example a tertiary amine such as triethylamine or pyridine, or an inorganic base such as potassium carbonate or sodium bicarbonate. The organic base may also serve as a reaction solvent. The reaction is preferably effected at a temperature of from 10 -15 to +25'C, for example -5 to +25'C.

The reaction using an alkyl ester may be effected in a suitable reaction medium such as an alcohol (e.g. methanol), an amide (e.g. dimethylformamide), an ether (e.g. tetra hydrofuran) or mixtures thereof and conveniently at a temperature of from 0 to 100'C.

Where A represents -CO- carboxylic acids of formula 15 R CH2)mCOOH 20 may also be used in the preparation of compounds of formula (1). The reaction is desirably conducted in the presence of a coupling agent for example N,N'-carbonyidiimidazole or a carbodiimide such as N,N'dicyclohexylcarbodiimide. The reaction may be carried out in a suitable reaction medium such as a haloalkane (e.g. dichloro methane), a nitrile (e.g. acetonitrile), an amide 25 (e.g. dimethylformamide) or an ether (e.g. tetra hyd rofura n) or mixtures thereof conveniently at a temperature of from -50 to +50'C, preferably -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.

Compounds of general formula (11) are novel and comprise a further feature of the invention. 30 Compounds of general formula (11) wherein R2 is a hydrogen atom may be prepared for example by reduction of a corresponding compound having an appropriate reducible group as the 5- position substituent, such as -(CHA,-,CK The reduction may be effected by catalytic hydro genation, or using a reducing agent such as lithium aluminum hydride.

Such nitrile compounds are novel and constitute a further feature of the invention. They may 35 be prepared for example by cyclisation of the appropriate hydrazone, in an analogous manner to general process (B), described hereinafter.

Compounds of general formula (11) wherein R, is an alkyl group may be prepared for example by reduction of a corresponding nitrile in the presence of an amine R2NH2, or by reacting a compound of formula (11) wherein R2 is a hydrogen atom with a suitable alkylating agent. 40 According to another general process (B), compounds of formula (1) may be prepared by the cyclisation of a compound of general formula (ill):

R R2 1 " 1 45 (CH2)m-A-N (CH2)n NR3 NCH(CH2)3a 50 wherein Q is the group NR4R, (or a protected derivative thereof) or a leaving atom or group such as a halogen atom (e.g. chlorine or bromine) or an acyloxy group, (e.g. a carboxylic or sulphonic acyloxy group such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitroben zoyfoxy, p-toluenesulphonyloxy or methanesulphonyloxy group).

The reaction may conveniently be effected in aqueous or non-aqueous reaction media, and at 55 temperatures of from 20 to 200'C, preferably 50 to 125'C.

Particularly convenient embodiments of the process are described below.

When Q is the group NR^ (or a protected derivative thereof) the process is desirably carried out in the presence of polyphosphate ester in a reaction medium which may comprise one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichlorometh- 60 ane, dichloroethane, dichlorodifluoromethane, or mixtures thereof. Polyphosphate ester is a mix ture of esters which may be prepared from phosphorus pentoxide, diethylether and chloroform according to the method described in 'Reagents for Organic Synthesis', (Fieser and Fieser, John Wiley and Sons 1967).

Alternatively the cyclisation may be carried out in an aqueous or nonaqueous reaction me- 65 GB2185020A 5 dium, in the presence of an acid catalyst. When an aqueous medium is employed this may be an aqueous organic solvent such as an aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous ether (e.g. dioxan or tetra hydrofura n) as well as mixtures of such solvents. The acid catalyst may be for example an inorganic acid such as concentrated hydrochloric or sul phuric acid or an organic acid such as acetic acid. (in some cases the acid catalyst may also act 5 as the reaction solvent). In an anhydrous reaction medium, which may comprise for example one or more ethers (e.g. as previously described) or esters (e.g. ethyl acetate), the acid catalyst will generally be a Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride.

When Q is a leaving atom or group such as a chlorine or bromine atom the reaction may be effected in an aqueous organic solvent, such as an aqueous alcohol (e.g. methanol, ethanol or 10 isopropanol) in the absence of an acid catalyst, 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 (1) wherein R, and R, are both hydrogen atoms.

According to a particular embodiment of this process compounds of formula (1) may be prepared directly by the reaction of a compound of general formula (IV): 15 R, R2 \---/--(CH2)m-A N(CH2), 20 (where T is a group N%NJ-12) or a salt thereof, 25 with a compound of formula (V):

OHC(CH2)IQ (V) (wherein Q is as defined above) or a salt or protected derivative thereof (such as an acetal or 30 ketal e.g. formed with an appropriate alkyl orthoformate or diol, or protected as a bisulphite addition complex) using the appropriate conditions as described above for the cyclisation of compounds of general formula (111). It will be appreciated that in this embodiment of the cyclisa tion process (B) a compound of general formula (111) is formed as an intermediate, and may be reacted in situ to form the desired compound of general formula (1). 35 Compounds of general formula (111) may, if desired, be isolated as intermediates during the process for the preparation of compounds of formula (1) 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 water or in a suitable aqueous alcohol (e.g. methanol) at a temperature of, for example, 20 to 30'C. If an acetal or ketal of a compound of formula (V) is 40 used, it may be necessary to carry out the reaction in the presence of an acid (for example, acetic or hydrochloric acid).

Compounds of general formula (IV) may be prepared for example from the corresponding nitro compounds (i.e. in which T is N02), using conventional procedures.

A further general process (C) for preparing compounds of general formula (1) involves reacting 45 a compound of general formula (Vi):

R2 1 50 CY(CH2)m-A-N\ (CH2)n (CH2) 2Y (V 1) 55 R 3 (wherein Y is a readily displaceable atom or group) or a protected derivative thereof, with an amine of formula R4R,Ni-1.

The displacement reaction may conveniently be carried out on those compounds of formula 60 (V1) wherein Y is a halogen atom (e.g. chlorine, bromine or iodine) or a group OR, where OR, is, for example, an acyloxy group which may be derived from a carboxylic or sulphonic acid, such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, pnitrobenzoyfoxy, p-toluenesulpho nyloxy or methanesulphonyloxy group.

The displacement reaction may be conveniently effected in an inert organic solvent (optionally 65 6 GB2185020A 6 in the presence of water), examples of which include alcohols, e.g. ethanol; cyclic ethers, e.g.

dioxan or tetrahydrofuran; acyclic ethers e.g. diethylether, esters, e.g. ethyl acetate; amides, e.g.

N,N-dimethy[formarnide; and ketones e.g. acetone or methylethyl ketone, at a temperature of from - 10 to + 1 WC, preferably 20 to WC.

The compounds of general formula (V1) wherein Y is a halogen atom may be prepared by 5 reacting a hydrazine of general formula (IV) with an aldehyde or ketone (or a protected derivative thereof) of formula (V) in which Q is a halogen atom, in an aqueous alcohol (e.g. methanol) containing an acid (e.g. acetic or hydrochloric acid). Compounds of formula (V1) wherein Y is the group OR, may be prepared from the corresponding compound wherein Y is a hydroxyl group by acylation with the appropriate activated species (e.g. anhydride or sulphonyl chloride) using 10 conventional techniques. The intermediate alcohol may be prepared by cyclisation of a compound of formula (111) wherein Q is a hydroxyl group (or a protected derivative- thereof) under standard conditions.

Compounds of formula (1) may also be prepared by another general process (D) involving reduction of a compound of general formula (Vil): 15 R2 1 W (C H 2)m -A _N - 9 (V11) 20 Nm 1 H3 25 (wherein W is a group capable of being reduced to give the required - (CH2)2NR,R, group or to give a protected derivative of -(CH2)2NR,R,; and B represents the group - (CH2),as herein defined or a group capable of being reduced to -(CHAA or a salt or protected derivative thereof.

The required -(CH2)2- and -NR^ groups at the 3- position may be formed by reduction 30 steps which take place separately or together in any appropriate manner.

Groups B which may be reduced to give the required group -(CHA,_ include corresponding unsaturated groups, such as C2-, alkenyl or alkynyl groups.

Examples of groups represented by the substituent W include -(CH2)2NO2; CH=CHN02; -(CH2)2N3; -CH2CN; -CH2CHO; -COCH2Z; -CH2CH=NOH; -CH(OH)CH,NR,R5; - (CH2)2NR,COR',; 35 -COCONR^ and -CH2COZ (wherein Z is an azido group or the group -NR^ or a protected derivative thereof and R', is a hydrogen atom or a methyl or ethyl group or R', represents the group OR,, where R,o is an alkyl or aralkyl group).

Groups which may be reduced to the -(CH2)2- moiety at the 3-position include the corre- sponding unsaturated group and corresponding groups containing one or more hydroxyl groups 40 or carbonyl functions.

Groups which may be reduced to the group -NR,R, where R4 and R, are both hydrogen include nitro, azido, hydroxyimino and nitrile groups. In the latter case, reduction yields the group -CH2NH2 and thus provides a methylene group of the -(CH,),- moiety.

A compound of general formula (1) where R, is a hydrogen atom may also be prepared by 45 reduction of a corresponding compound wherein R, is a benzy] group, e.g. with hydrogen in the presence of a catalyst, e.g. 10% palladium on charcoal.

The required -NR^ group wherein R, and/or R, are other than hydrogen may be prepared by reduction of a nitrile -CH,CN or an aldehyde -CH2CHO in the presence of an amine, R4R, NH.

A particularly suitable method for preparing a compound of formula (1) wherein R, and/or R, is 50 other than hydrogen is reductive alkylation of the corresponding compound wherein R, and/or R, represent hydrogen with an appropriate aldehyde or ketone (e.g. acetaldehyde or acetone) in the presence of a suitable reducing agent. Suitable reducing agents for use in this process include hydrogen in the presence of a metal catalyst, or an alkali metal borohydride or cyanoborohydride (for example, sodium borohydride or cyanoborohydride) using the conditions described below for 55 the reduction of compounds of formula (VII). In some instances (e.g. for the introduction of the group R, where R, is ethyl) the aldehyde (e.g. acetaidehyde) may be condensed with the amine and the intermediate thus formed may subsequently be reduced using a suitable reducing agent.

The required -NR^ group wherein R, and/or R, are other than hydrogen may also be prepared by reduction of a corresponding acylamino group, e.g. of the formula -(CHI)2NR,COR'5 60 where R', is as previously defined).

It will be appreciated that the choice of reducing agent and reaction conditions will be dependent on the nature of the groups W, B and other groups already present on the molecule.

It will also be appreciated that when A represents -CO- the group W will not contain an amide function. 65 7 GB2185020A 7 Suitable reducing agents which may be used in the above process for the reduction of compounds of formula (VII) wherein W represents, for example, the groups - (CH2)2NO2; -CH=CHN02, -(CH2)2N3, -CH2CN, -CH2CH=NO1-1 and -CH(OH)CH2NR,R, include hydrogen in the presence of a metal catalyst, for example Raney Nickel or a noble metal catalyst such as platinum, platinum oxide, palladium, palladium oxide-or rhodium, which may be supported, for 5 example on charcoal, kieselguhr or alumina. In the case of Raney Nickel hydrazine may also be used as the source of hydrogen. This process may conveniently be carried out in a solvent such as an alcohol e.g. ethanol, an ether, e.g. dioxan or tetrahydrofuran, an amide, e.g. dimethylfor mamide or an ester e.g. ethyl acetate, and at a temperature of from - 10 to + 500C, preferably -5 to +300C. - 10 The reduction process may also be effected on compounds of formula (VII) wherein W represents, for example, the groups -(CH,),N02, -CH=CHNO, -(CH, ),N,, -CH(OH)CH,NR,R, or -COCH2Z (where Z is as previously defined), using an alkali metal or alkaline earth metal borohydride or cyanoborohydride e.g. sodium or calcium borohydride or cyanoborohydride which process may conveniently be carried out in an alcohol such as propanol or ethanol or a nitrile 15 such as acetonitrile, and at a temperature of from 10 to 1OWC, preferably 50 to 1OWC. In some instances the reduction using a borohydride may be carried out iry the presence of cobaltous chloride. When A represents a group -S02-, reduction of compounds of formula (VII) wherein W represents, for example, -(CH2)2NO2;, CH=CHN02, -(CH2)2N3, (CH2)2NR,COR'5; -CH2CH=NO1-1, 20 -CH(OH)CH 2 2NR^; -COCONFl,R, -CH2COZ and -COCH Z (wherein R', and Z are as previously defined) may also be carried out using a metal hydride such as lithium aluminium hydride. This process may be carried out in a solvent, for example, an ether such as tetrahydrofuran, and conveniently at a temperature of from -10 to +1OWC, preferably 50 to 1000C.

A particular embodiment of general process (D) includes the reduction of a compound of 25 formula (VII) wherein W is the group -CH2CN for example, by catalytic reduction with hydrogen in the presence of a catalyst such as palladium on charcoal or rhodium on alumina, optionally in the presence of an amine MR4R5.

Suitable reducing agents which may be used in the reduction of the group B include hydrogen in the presence of a metal catalyst. Appropriate metal catalysts and conditions for the reduction 30 process are as described for the reduction of the group W.

The starting materials or intermediate compounds of formula (VII) may be prepared by analo gous methods to those described in UK Published Patent Application No. 2035310, and 'A Chemistry of Heterocyclic Compounds-Indoles Part W, Chapter V], edited by W J Houlihan (1972) Wiley Interscience, New York. 35 Compounds of formula (V11), wherein W is the group -CH,CHO may be prepared by oxidation (e.g. with Jones' reagent) of a compound of formula (V1) wherein Y is a hydroxyl group. A compound of formula (VII) wherein W is the group -CH2CH=NO1-1 may be prepared by treatment of the corresponding aldehyde with hydroxylamine hydrochloride using standard conditions.

The intermediate compound of formula (V11) wherein W is the group (CH2)2N, may be 40 prepared from a compound of formula (V1) wherein Y is a halogen atom using standard proce dures.

Standard reducing agents such as sodium borohydride may---be used to prepare a compound of formula (VII) wherein W is the group -CH(OH)CH2NR,R,, from the corresponding compound of formula (VII) wherein W is the group -COCH2NR,R,,. 45 A compound of formula (VII) wherein W isthe group -(CH20R4COR', may be prepared by acylation of the corresponding unsubstituted amine using conventional procedures.

The intermediate compounds of formula (VII) wherein B represents a C2-, alkenyl group may be prepared by reacting a compound of general formula (Vill) 50 OHC (CH2)n W (V111) R 3 (wherein W is as defined for general formula (VII) and n is zero -or an integer of from 1 to 3).

with for example an appropriate phosphonium salt, using standard conditions. 60 According to a further general process (E) a compound of formula (1) according to the invention, or a salt or protected derivative thereof, may be converted into another compound of formula (1) using conventional procedures.

For example, a compound of general formula (1) wherein one or more of R3, R, and/or R5 are alkyl groups may be prepared from the corresponding compounds of formula (1) wherein one or 65 8 GB2185020A 8 more of R3, R4 and R. represent hydrogen atoms, by reaction with a suitable alkylating agent such as a compound of formula R.,L, (where R, represents the desired R3, R4 or Rr' group and L represents a leaving atom or group such as a halogen atom or a tosylate group) or a sulphate (RIS04. Thus, the alkylating agent may be for example an alkyl halide (e. g. methyl or ethyl iodide), alkyl tosylate (e.g. methyl tosylate) or dialkylsulphate (e.g. dimethyisulphate). 5 The alkylation reaction may conveniently be carried out in an inert organic solvent such as an amide (e.g. dimethylformamide), an ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g.

toluene preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides such as sodium or potassium hydride, alkali metal amides such as sodium amide, alkali metal carbonates such as sodium carbonate or alkali metal alkoxide such as sodium or potas- 10 sium methoxide, ethoxide or t-butoxide; or tetrabutylammonium fluoride. When an alkyl halide is employed as the alkylating agent the reaction may also be carried out in the presence of an acid scavenging -agent such as propylene or ethylene oxide. The reaction may be conveniently effected at a temperature of from -20' to 1000C.

Compounds of formula (1) wherein one or both of R3 and R, represents propenyl may be 15 prepared similarly, using an appropriate compound of formula R.'I_ or (R1S01.

- According to another general process (F), a compound of general formula (1) according to the invention, or a salt thereof may be prepared by subjecting a protected derivative of general formula (1) or a salt thereof to reaction to remove the protecting group or groups.

Thus, at an earlier stage in the reaction sequence for the preparation of a compound of 20 general formula (1) or a salt thereof it may have been necessary or desirable to protect one or more sensitive groups in the molecule to avoid undesirable side reactions. For example it may be necessary to protect the group NR,11, wherein R4 and/or R, represents hydrogen, by protonation or with a group easily removable at the end of the reaction sequence. Such groups may include, for example, aralkyl groups, such as benzyi, diphenyimethyl or triphenyimethyi; or acyl groups 25 such as N-benzyloxycarbonyl or t-butoxycarbonyl or phthaloyl.

In some cases, it may also be desirable to protect the indole nitogen with, for example, an aralkyl group such as benzyi.

Subsequent cleavage of the protecting or groups may be achieved by conventional procedures.

Thus an araikyl group such as benzyi, may be cleaved by hydrogenolysis in the presence of a 30 catalyst (e.g. palladium on charcoal) or sodium and liquid ammonia; an acyl group such as N benzyloxycarbonyl may be removed by hydrolysis with, for example, 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). 35 As will be appreciated, in some of the general processes (A) to (E) described previously it may be necessary or desirable to protect any sensitive groups in the molecule as just described.

Thus, a reaction step involving deprotection of a protected derivative of general formula (1) or a salt thereof may be carried out subsequent to any of the previously described processes (A) to (E). 40 Thus, according to a further aspect of the invention, the following reactions may if necessary and/or desired be carried out in any appropriate sequence subsequent to any of the processes (A) to (E).

(i) removal of any protecting groups; and (ii) conversion of a -compound of general formula (1) or a salt thereof into a physiologically 45 acceptable salt or solvate (e.g. hydrate) thereof.

- 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 (1), with an appropriate acid, preferably with an equivalent amount or with creatinine sulphate in a suitable solvent (e.g. aqueous ethanol). 50 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 UK Published Patent Application No. 2035310.

As well as being employed as the last main step in the preparative sequence, the general methods indicated above for the preparation of the compounds of the invention may also be 55 used for the introduction of the desired groups at an intermediate--- stagein the preparation f the required compound. Thus, for example, the required group at the 5position may be introduced 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 60 product.

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

Chromatography was carried out either in the conventional manner using silica gel (Merck, Kieselgel 60, Art. 7734) or by flash chromatography (W. C. Still, M. Kahn and A. Mitra, J. Org.

Chem. 2933, 43, 1978) on silica gel (Merck Keisolgel 60, Art. 9385) and thin layer chromato- 65 9 GB2185020A 9 graphy (t.l.c.) on silica (Macherly-Nagel, Polygram) except where otherwise stated. The following abbreviations define the eluants used for chromatography and t.l.c.: (A)---(H)=CH,CI,-ethanol-0.88 ammonia in the following ratios (A)-89:10:1, (B)-78:20:2, (C)-50:8:1, (D)-83.5:15:1.5, (E)-75:8:1, (F)-25:8:1, (G)-50:10:1, (H)-100:8:1; (1) ethyl acetate- methanoltriethylamine-80:20: 1. 5 The following abbreviations are used: THIF-tetrahydrofuran; ER-ether; EA- ethyl acetate.

Intermediates were routinely checked for purity by t.l.c. employing u.v. light for detection and spray reagents such as potassium permanganate (KMnO,). In addition indolic intermediates were detected by spraying with aqueous ceric sulphate (CeIV) and tryptamines by spraying with a solutoin of iodoplatinic acid (IPA) or ceric sulphate. 10 Proton ('H) nuclear magnetic resonance (n.m.r.) spectra were obtained either at 90MHz using a Varian EM 390 instrument or at 250MHz using a Bruker AM or WM 250 ihstrument. s=singlet, d=doublet, t=triplet, m=multiplet and q=quartet.

Intermediate 1 15 4-Hydrazinobenzeneacetonitrile hydrochloride A solution of sodium nitrite (4.09) in water (34m]) was added dropwise at -5' to -20 to a suspension of 4-aminobenzeneacetonitrile (7.6g) in concentrated hydrochloric acid (80mi), and stirring was continued at -2' for 20min. The mixture was filtered and the filtrate added dropwise at 0' to 5' to a solution of tin (11) chloride dihydrate (65g) in concentrated hydrochloric 20 acid (130mi). The mixture was allowed to warm to room temperature overnight (17h), and the precipitate was filtered off, washed with concentrated hydrochloric acid, cold absolute ethanol, and dry ER, and dried to give the title salt as a powder (6.05g). m.p. 207-210' (foams).

salt as a powder (6.05g). m.p. 207-210' (foams).

25 Intermediate 2 4-[2-[4-(Dimethylamino)butylidenelhydrazinolbenzeneacetonitrile 4,4-Diethoxy-N, N-di methyl buta na m in e (9.45g) was added to a stirred suspension of Intermediate 1 (9.29) in deionized H20 (200mi) at room temperature under nitrogen, 2N hydrochloric acid (22mi) was added (pH2), and stirring was continued at room temperature for 5h. The clear 30 solution was basified with 8% aqueous Nal-ICO,, (200mi) and extracted with CHCI, (3x200mi).

The organic layers were dried (MgSOJ and evaporated to give the title compound as an oil (15.6g). T.I.c. (Silica, A) Rf 0.35 detection uv/IPA.

Intermediate 3 35 5-(Cyanomethyl)-N,N-dimethyl- 114-indole-3-ethanamine oxalate Intermediate 2 (15.4g) was heated under reflux with polyphosphate ester (108g) in CHCI, (200m1) with stirring under nitrogen for 8 min. The mixture was poured onto ice, 8% aqueous NaHC03 (500m1) was added, and after 20 min stirring the layers were separated and the aqueous layer extracted with CI-IC13 (3x400mi). The aqueous layer was further basified to pH 9 40 with 2N Na2C03 (200mi), solid NaCI was added, and the mixture was extracted with CHC13 (3x400mi). The combined organic layers were dried (M9S04) and evaporated to give an oil (40.29). The oil was partitioned between EA (200m1) and 2N hydrochloric acid (4x40m1); the aqueous layers were basified (200mi 2N and 20mi 5N NaOH) and extracted with EA (4 x 1 00mi).

The latter organic layers were washed with brine, dried (M9S04) and evaporated to give an oil 45 (9.3g). Purification by flash chromatography (A and D) gave a first crop (1.91g) as an oil and a second crop (4.09) also as oil. The second crop oil was dissolved in hot methanol (10mi), and oxalic acid (1.599) in hot methanol was added. On cooling, crystals were deposited and after cooling in ice, the crystals were filtered off, washed with methanol and dried to give the title compound (4.09) m.p. 183.5-187'. The pure first crop was converted similarly to the oxalate 50 salt (2.159).

Intermediate 4 N3,N3-Dimethyl- 1H-indole-3,5-diethanamine dioxalate Intermediate 3 (3.179) was partitioned between 8% aqueous NaHC03 (100m1) and CH,Cl, 55 (3x80mi) and the organic layers dried (MgSOJ and evaporated to give the free base as an oil (2.419). The oil was hydrogenated at 45' and 70psi over 5% rhodium on alumina (1.09) in 7% w/w ethanolic ammonia (200m1) for 15.5h. The catalyst was filtered off and the solvent evaporated to give the title compound, free base as an oil (2.589). A portion (1.379) of the oil was dissolved in methanol (6mi), and oxalic acid (1.129) was added in methanol (2mi). Addition 60 of dry ER (80mi) gave a gum, which was triturated with dry ER to afford the title compound as a solid (1.79g) m.p. 160-170' (foams).

Intermediate 5 4-(Aminocarbonyl)benzeneacetic acid 65 GB2185020A 10 A mixture of ethyl 4-cyanobenzeneacetate (1.99) and freshly ground KOH (2. 8g) in 2-methylpro- pan-2-ol (20mi) was heated under gentle reflux for 20 min. The resulting mixture was cooled, diluted with 50% saturated NaCI solution (50mi), washed with CHC13 (4x50mi), and acidified with 2M hydrochloric acid (25m1) to precipitate the title compound (1.65g) as a fine white solid m.p. 226-227'. 5 Intermediate 6 Phenyl 4-[(methylsulphonyl)aminolbenzenemethaneseulphonate Methanesulphonyl chloride (1.12m1) was added to a cooled stirred solution of phenyl 4-amino benzenemethaneseulphonate, hydrochloride (3.0g) in pyridine (9mi). The resulting mixture was 10 allowed to warm up to 20' and then stirred for 20h. The reaction mixture was diluted with EA (150mi) and washed with 8% NaHCO, (400m1), H20 (250mi) and brine R50mi). The organic extract was dried (MgSOJ and evaporated to leave a brown gum which was crystallised from toluene (100mi) to give the crude title compound (as an off-white solid which was recrystallised from toluene (100mi) to give the title compound (1.25g) as a white solid m.p. 128-129'. 15 Intermediate 7 4-[2-(Methylamino)-2-oxoethyllbenzeneacetic acid A mixture of N,N'-carbonyidiimidazole (4.869) and 1,4-phenylenediacetic acid (5.8g) in dry dis tilled THF (250m1) was stirred under nitrogen at reflux for 2h. The reaction mixture was cooled 20 to 20' and methylamine gas (about 6g) was bubbled through. The mixture was then refluxed for 3h, cooled overnight, filted and the filtrate evaporated to leave a light yellow solid. The solid was partitioned between 2M Na,CO, (1 50mi) and EA (3 X 150mi) and the alkaline aqueous layer was then acidified (to pH1) with 2M hydrochloric acid and extracted with EA (3x300mi). The latter extracts were combined, dried (MgSOJ and evaporated to leave an off-white solid which 25 on trituration with ER gave the title compound (0.3g) as a white solid m. p. 102-104' Intermediate 8 4-[2-(Dimethylamino)-2-oxoethyllbenzeneacetic acid N,N'-Carbonyidiimidazole (1 1.4g) was added to a stirred solution of 1,4phenylenediacetic acid 30 (1 1.4g) in dry dimethylformamide (300mi) under an atmosphere of nitrogen. The mixture was stirred at 20' for 2h as dimethylamine gas (about 10g) was bubbled through. The reaction mixture was then stirred at 20' for 3h and evaporated in vacuo to leave a brown oil which was diluted with saturated K2C01 solution (50m1). The resulting mixture was evaporated in vacuo to leave an off-white solid which was triturated with EA (2x200mi). The organic phase was 35 discarded and the aqueous phase was acidified (pHl) with 5M hydrochloric acid to precipitate an off-white solid which was triturated with absolute ethanol (25mi) and filtered to give the title compound (1.1g) as a fine white solid m.p. 163-165' (softening at 160') Intermediate 9 40 4-[[(methylsulphonyl)aminolmethyllbenzeneacetic acid A solution of ethyl 4-[[(methyisulphonyi)aminolmethyllbenzeneacetate (3. 1g) and 1M KOH (22mi) in ethanol (50mi) was stirred at room temperature for 3h and evaporated in vacuo to leave an off-white solid. This solid was dissolved in water (50mi) and washed with EA (2 x 50mi). The organic extract was discarded and the aqueous layer was acidified (pHl) with 5M hydrochloric 45 acid (about 10mi) to precipitate the title compound (2.549) as a white solid m.p. 167-169'.

Intermediate 10 Methyl 4-[(2-propynylamino)carbonyllbenzoate Terephthalic acid mono methyl ester (0.7759) was dissolved in dry pyridine (10mi) in a N2 50 atmosphere. The solution was cooled in an ice-water bath, and thionyl chloride (0.44mi) was added dropwise. The mixture was warmed to room temperature and was stirred for 1h to give a pale brown suspension. The mixture was re-cooled in an ice-water bath, and a suspension of propargylamine hydrochloride (413m9) in pyridine was added rapidly. The mixture was warmed to room temperature and was stirred for 18h to give a dark solution. The solvent was evapo- 55 rated in vacuo to give a dark brown gum, which was dissolved in EA/ hexa ne /acetic acid (1:1:1% v/v) and flash chromatographed using the same solvent system to give a yellow sludge, which was triturated with ER to give the title compound as a white solid, (0.5449), m.p.

151.5-1530.

60 Intermediate 11 Methyl 4[[3-[3-[2(dimethylamino)ethyll-1H-indol-5-yll-2propynyllaminolcarbonyllbe nzoate Intermediate 10 (1.09), 3-[2[N,N-di methyla min o) ethyl[-5-iod o- 1 HA n dole (0.359) and bis(tripheny] phosphine)palladium dichloride (1 25m9) were suspended in diethylamine (11 Orni). Copper (1) iodide (67mg) was added, and the mixture was stirred at room temperature for 24h. The solvent65 GB2185020A 11 was evaporated in vacuo to give a brown oil, which was slurried in CH2C12/ethanol/aqueous NH, (120:8A) and flash chromatographed using the same solvent system to give a brown oil, which was triturated with ER to give a pale brown solid. The supernatant was treated with excess ER to give a pale brown solid. On cooling, the supernatant from the second crop gave a cream coloured solid, which was dried in vacuo at 60' for 18h, to yield the title compound (67mg) 5 m.p. 154.5-15T.

Intermediate 12 Methyl 4-[[3-[2-(dimethylamino)ethyll-1H-indol-5-yllpropyllaminolcarbonyllbenzoate oxalate Intermediate 12 (1.25g) was dissolved in methanol (100mi) and activated charcoal (1g) was 10 added. The mixture was heated at reflux for 2h. filtered and the filtrate added to a pre-reduced suspension of 10% palladium oxide-on-carbon (50% aqueous paste, 50Orng) in ethanol (20mi).

The resulting mixture was hydrogenated at 1 atmosphere hydrogen for 4h then filtered and the filtrate was evaporated in vacuo to give a pale green oil. This oil was dissolved in (H) and flash chromatographed using the same solvent system to give the free base of the title compound as 15 a white foam (590rng). The white foam (99mg) was dissolved in methanol (l mi) and a solution of oxalic acid (21.5mg) in methanol (0.5m[) was added. The resulting solution was treated with ER (25mi) to give a gummy precipitate. The mixture was stirred at room temperature for 4h to give the title compound as a white solid, (75mg), m.p. 98-102' (becomes gummy), 138-142' (clear oil). 20 Intermediate 13 4-[(Methylsulphonyl)aminolbenzenebutanoic acid Methanesulphonyl chloride (2.26mi) in CHCI, (30mi) was added to a cooled (5') solution of 4 aminobenzenebutanoic acid (3.5g) in pyridine (35mi) over a period of 30 min. After 1h the 25 solution was allowed to warm to room temperature and stirring continued overnight. The resulting solution was evaporated to a red oil. 2N hydrochloric acid (100mi) was added and the resulting precipitate filtered off. The filtrate was extracted with EA (2x50mi). The combined organic extracts and solid from filtration were evaporated to dryness in vacuo. Purification by flash chromatography [eluant ER] gave the title compound as a white solid (39) m.p. 108'-1090. 30 Intermediate 14 2-[3-[2-(Dimethylamino)ethyll- 1H-indol-5-yll-N-methylethanamine, di-ptoluoyl-tartrate Intermediate 3 (3.0g) was suspended in EA (150mi) and saturated aqueous K, CO, solution (100m1) was added. Ethanol (50mi) was added and the layers were separated. The aqueous 35 layer was extracted with ethanol (100mi) and the combined organic layers were evaporated in vacuo to give an aqueous sludge which was co-evaporated with toluene to give a dark brown oil. This oil was dissolved in a solution of methylamine in ethanol (33% w/w) (200mi) and the solution was added to a pre-reduced suspension of 10% palladium oxide-on- carbon (50% aque ous paste, 3.0g) in ethanol (75m]). The mixture was hydrogenated at 1 atmosphere hydrogen for 40 72h. The catalyst was removed by filtration through 'hyflo' and the filtrate was evaporated in vacuo to give a pale gum. This gum was dissolved in (C) and flash chromatographed using (C) grading to (25:8: 1) to give the free base of the title compound (1.43g) as a clear gum. A sample (90m9) was dissolved in methanol (3mi) and a solution of di-ptoluoyl-Ltartaric acid monohydrate (148rng) in methanol (lmi) was added. ER (45m[) was added and the mixture was 45 stirred at room temperature for 6h to give the title compound (20mg) as a white solid, m.p.

157-1600.

Intermediate 15 4-Methoxy-N-[2-(4-nitrophenyl)ethyllbenzeneacetamide 50 A solution of 4-methoxybenzeneacetic acid (8.39) in dry THF (250mi) was treated with triethy lamine (6.9mi) and cooled in a salt/ice-bath with stirring under a nitrogen atmosphere. Pivaloyl chloride (6.1mi) was added and stirring continued for 1h. A further aliquot of triethylamine (6.9mi) was added followed by p-nitrophenethylamine hydrochloride (109). The resultant suspen sion was warmed to room temperature and stirred for 19.5h (overnight). The reaction mixture 55 was acidified to pHl using hydrochloric acid solution (2N; 30mi) and the resultant solution was extracted with EA (1 x 250mi, 1 x 1 00mi). The combined organic extracts were washed with 8% NaHCO, solution (200mi), dried (MgSOJ and evaporated under reduced pressure to give a brown oil. Purification by 'flash' chromatography, ER:CH2C11 (4: 1) gave the title compound as a pale yellow solid (7.4g) m.p. 109- 11 W. 60 Intermediate 16 N-[2-(4-aminophenyl)ethyll-4-methoxybenzeneacetamide A suspension of 10% PdO/C (500mg of a 50% paste with H20) in absolute ethanol (50mi) was stirred under one atmosphere of hydrogen at room temperature for 1h. A solution of Intermedi- 65 12 GB2185020A 12 ate 15 (1.59) in absolute ethanol (50mi) was added and the mixture stirred for 2.5h. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure to give the title compound (1.39) as a white crystalline solid. A portion of the title compound was dried under vacuum at room temperature overnight to give a sample m.p. 112-113. 5'.

5 Intermediate 17 N-[2-(4-Hydrazinophenyl)ethyll-4-methoxybenzeneacetamide hydrochloride Sodium nitrite (0.122g) in water (0.5mi) was added to a stirred, cold (W) suspension of Intermediate 16 (0.59) in a mixture of water (2m1) and concentrated hydrochloric acid (6.5mi). A further portion of water (4m1) was added, the solution was filtered and the filtrate was poured 10 into a stirred, cold (salt/ice bath) solution of tin (11) chloride dihydrate (1.99g) in concentrated hydrochloric acid (5ml). The resultant yellow suspension was filtered, the solid was collected and covered with ER and methanol (20mi) added. The resultant homogeneous solution was evaporated under reduced pressure to give the title compound as a pale yellow foam (422mg). T.I.c.

(EA), Rf 0. 14 15 Intermediate 18 N[2-[4-[2-(3-Cyanopropylidene)hydrazinolphenyllethyll-4methoxybenzeneaceta mide A suspension of Intermediate 17 (5.93g) and 3-cyanopropionaldehyde diethyl acetal (3.23mi) in water (100mi) was treated with hydrochloric acid solution (2N; 2mi) and stirred for 17h at room 20 temperature. The resultant white solid was filtered off, washed with water (50mi) followed by ER (20mi) then dried under vacuum at room temperature to give the title compound as a white powder. T.I.c. (EA) Rf 0.34.

Intermediate 19 25 N-[2-[3-(Cyanomethyl)1H-indol-5-yllethyll-4-methoxybenzeneacetamide A solution of Intermediate 18 (5.73g) in polyphosphoric acid ethyl ester (57g) and CHQ, (100mi) was heated at reflux for 15 min and then poured onto ice (100g). The resultant suspension was stirred for 20 min then the organic layer was separated and the aqueous layer was extracted with CHCl, (2 x 1 00mi). The combined organic solutions were washed with NaHCO, solution (8%; 30 80mi) and water (80mi) then dried (MgSOJ and evaporated in vacuo in the presence of silica gel. The impregnated silica was applied as a plug to a silica gel column (Merck Art 9385; 5cm diam). Elution with EA-ER (1: 1) followed by EA-ER-ethanol (9:9:2) gave the title compound as a pale yellow solid (60mg) m.p. 155-156'.

35 Intermediate 20 4-(Acetylamino)-N-[2-[3-[2-(1,3-dihydro1,3-dioxo-2H-isoindol-2-yl)- ethyll- 1H-indol-5-yllethyllben zeneacetamide Triethylamine (222mg) was added to a solution of 4(acetylamino)benzeneacetic acid (386rng) in dry THF (12mi) at 5' (ice bath) under nitrogen. Pivaloyl chloride (265m9) was then added. The 40 mixture was stirred in an ice bath for 1 h. Solid 2-[2-[5-(2-aminoethyl)1 H-indol-3-yllethyll- 1 H isoindole-1,3-(2H)-dione, hydrochloride (615rng) was added to the resultant white suspension, followed immediately by triethylamine (222mg). The mixture was stirred at 21' for 4h then partitioned between 2N hydrochloric acid (20mi) and EA (30m1). The organic phase was sepa rated, washed with 2N hydrochloric acid (20m1), water (20m1), 8 % NaHCO, solution (2 x 1 Orni), 45 water (20mi) and saturated brine (20mi), dried (Na,SO,) and evaporated to give an oil. The oil was chromatographed using initially EA and then a mixture of EA and methanol (100:1) to give the title compound (275m9) as a yellow foam. Solidification gave a yellow powder (m.p.

191-195% 50 In the following Examples, Intermediate 4 was used as the free base.

Example 1

N-[2-[3-[2-(Dimethylamino)ethyll- 1H-indol-5-yllethyll-4methoxybenzeneacetamide oxalate N,N'-carbonyidiimidazole (195m9) was added to a stirred solution of 4- methoxyphenylacetic acid 55 (166rng) in dry CH,CI, (10mi) at room temperature under nitrogen, and stirring was continued for 1h. Intermediate 4, (231mg) was added in CH,Cl, (10mi), and stirring was continued for 1h. The reaction mixture was combined with a similarly-prepared mixture, washed with 8% aqueous NaHCO, (20mi) and water (2x20mi), dried (M9SOJ and evaporated to give an oil (0.723g).

Purification by flash chromatography (B) gave an oil (214mg; first crop) and slightly impure 60 material (1 19m9; second crop). The first crop was dissolved in methanol (2mi), and oxalic acid (56mg) in methanol (lmi) was added. Addition of dry ER gave a precipitate which was filtered off, washed with dry ER and dried to give the title salt as a solid (0. 274g) m.p. ca 96-103' (foams).

N.m.r. (5(DMSO) includes 2.68 (6H,s,NMe,); 3.25-3.36 (4H,m,CONHCHCH, and COCHAr); 3.73 65 GB2185020A 13 (3H, s, OCH3); 8.10 (1H, t, CONM; and 10.9 (1H,brs, indole, Nm.

Example 2

4-(Acetylamino)-N-[2-[3-[2-(dimethylamino)ethyll- 1H-indol-5yllethyllbenzeneacetamide oxalate A mixture of N,N'-carbonyidiimidazole (0.819) and 4-(acetylamino)- benzeneacetic acid (0.979) in 5 dry THF (75m]) was stirred under nitrogen at reflux for 1.5h and then Intermediate 4 (1.2g) was added. Refluxing was continued for 5h and the mixture was allowed to cool to room tempera ture and concentrated in vacuo to leave a gum (ca. 3g) which was purified by flash chromato graphy (C) and appropriate fractions were combined and evaporated. The resulting gum (0.7g) was dissolved in absolute ethanol (70mi) and treated with ethereal hydrogen chloride until the 10 solution was acidic. The resulting solution was diluted with dry ER (120mi) to precipitate a solid which was triturated with fresh dry ER (l20mlx2) to give the title compound, hydrochloride salt (0.4g) as a white solid. The salt was converted to the title compound, free base on a column of silica (C). The free base obtained (0.33g) was dissolved in absolute ethanol (35mi) and treated with a solution of oxalic acid (0.07g) in ethanol (15m]). The resulting solution was diluted with 15 dry ER (120mi) to precipitate the title compound (0.339) as a solid, m.p. (softens) 75-80', (foams) 115-120'.

N.m.r. (5 (DMSO) includes 2.05 (3H,s,COCH3); 23-2.85 (8H,m,NMe2 and ArCH2CH2MC0); 8.13 (1H,t,CONHCH2); 10.0 (1H,s,NHCOCH,) and 10.95 (1H,brs,indole NM.

20 Example 3

N-[2-[3-[2-(Dimethylamino)ethyll-1H-indol-5-yllethyll-1,4-benzene diacetamide dl-tartrate A mixture of N,N'-carbonyidiimidazole (0.379) and 4-(ami noca rbonyimethyl) benzene acetic acid (0.45g) in dry distilled THF (150mi) was stirred under nitrogen at reflux for 1.5h and then Intermediate 4, (0.54g) was added. Refluxing was continued for 3h and the mixture was allowed 25 to cool to room temperature. The cooled mixture was evaporated in vacuo to leave a gum (ca 2g) which was adsorbed onto silica and purified by flash chromatography (C). Appropriate fractions were combined and evaporated to leave a solid (0.439) which was adsorbed onto alumina (Merck 1077) and chromatographed on alumina (E) to effect further purification. Appro priate fractions were combined and evaporated to leave a solid (0.28g) which was dissolved in 30 hot absolute ethanol (3m]) and treated with a hot solution of tartaric acid (0. 1 g). The resulting solution was diluted with dry ER (50m1) to precipitate a solid which was stirred under ER at 20' for 24h and filtered to give the title compound (0.38g) as a solid m.p. (shrinks) 68-72' (foams) 80-820.

N.m.r. 6(DMSO) includes 2.65-2.75 (8H,m,NMe2 and ArCH2NHCO); 3.28-3.40 (6H,m,Ar- 35 CH2CONH2 and ArCH2CONI-ICH2); 8.15 (1H,t,CONHCH2) and 10.88 (1H,d,indole NM.

Example 4

4Chloro-N-[2-[3-[2-(dimethylamino)ethyll-1H-indol-5-yllethyllbenzeneacetam ide hydrochloride A mixture of N,N'-carbonyidiimidazole (0.58g) and 4-chlorobenzene acetic acid (0.619) in dry THF 40 (75mi) was stirred under nitrogen at reflux for 2h and then Intermediate 4 (0.79) was added.

Refluxing was continued for 3h and the mixture was allowed to cool to room temperature. The cooled mixture was evaporated in vacuo to leave asemi-solid (20g) which was purified by flash chromatography (C). Appropriate fractions were combined and evaporated to leave a solid (0.9g) which was partitioned between CH2C11 (3 x 1 00mi) and H,0 (1 00mi). The organic extracts were 45 combined, washed with H20 (100mi), dried (Na2SOJ and evaporated. The resulting gum (0.79) was dissolved in absolute ethanol (15mi) and treated with ethereal hydrogen chloride (2mi) to give a cloudy solution whch was diluted with dry ER (50mi) to precipitate a solid. The superna tent liquid was decanted and the solid triturated with fresh ER (100m1) to give the title com pound (0.63g) as a solid m.p. (softens) 65-70', (melts) 95-100'. N.m.r. 6 (DMSO) includes 50 23-2.85 (8H,m,NMe2 and ArCH2CH2WC0); 3.3-3.5 (4H,m,ArCH2CONHCH2); 8.27 (1H,t,CONHCH2) and 10.95 (1H,brd, indole NM.

Example 5

4-(Aminocarbonyl)-N-[2-[3-[2-(dimethylamino)ethyll- 1H-indol-5-yllethyllbenzeneacetamide, hydro- 55 chloride A suspension of N,N'-Carbonyidiimidazole (0.589) and Intermediate 5 (0. 59g) in dry THF (20mi) under nitrogen was refluxed for 2h and then Intermediate 4 (0.79) was added. Refluxing was continued for a further 17h and the cooled mixture evaporated in vacuo to give a brown gum which was purified by flash chromatography (F). The second fraction (100mi) (first=300mi) was 60 collected and evaporated to leave a light brown gum which was crystallised from a mixture of ethanol (20m1) and ER (20m1) to give a white solid which was dissolved in warm ethanol (30m1) and treated with ethereal hydrogen chloride (2m]). The resulting solution was stirred under nitrogen for 0.5h, then diluted with ER (100mi) to precipitate a white solid. The supernatant was decanted and the solid triturated with ER (100mi) to give the title compound (0.269) as a white 65 14 GB2185020A 14 solid m.p. (softens) 65-70' (melts) 120-124'.

Example 6 N-[2-[3-[2-(Dimethylamino)ethyll-1H-indol-5-yllethyll-4[(methylsulphonyl)am inoj benzenemethanesul- phonamide hydrochloride 5 A solution of Intermediate 6 (0.689) and Intermediate 4 (1.4g) in pyridine (6mi) was heated at 100' for 2h. The resulting mixture was evaporated to leave a brown gum which was adsorbed on silica and purified by flash chromatography (C) collecting 50m] fractions. Fractions 28-32 were combined and evaporated to leave a pale brown foam which was dissolved in absolute ethanol (26mi) and treated with ethereal hydrogen chloride and ER (30mi) to precipitate the title 10 compound (0.24g) as an off-white solid m.p. (shrinks) 120-125', (foams) 135-140'.

Example 7 N-[2-[3-[2-(Dimethylamino)ethyll- 1H-indol-5-yllethyll-4[(methytsulphonyl)amino benzeneacetamide oxalate 15 A mixture of N,N'-carbonyidiimidazole (1.62g) and 4-[(methyisulphonyi) amino]benzeneacetic acid (2.3g) in dry distilled THF (100mi) was stirred under nitrogen at reflux for 2.5h and then Intermediate 4 (1.2g) was added. Refluxing was continued for 4h and the mixture allowed to cool to 20' overnight. The cooled mixture was evaporated in vacuo to leave a brown gum which was partitioned between EA (3 x 1 00mi) and 2M hydrochloric acid (1 00mi). The acidic aqueous 20 layer was basified (to pH 8) with K,CO, and extracted with EA (3 x 150mi). The EA extracts were combined and washed with brine (3 x 150mi), dried (Na,SOJ and evaporated to leave a brown gum, which was purified by flash chromatography (C) collecting 25mi fractions. Fractions 26-32 were combined and evaporated to leave a white foam which was dissolved in hot ethanol (150mi) and treated with a hot solution of oxalic acid (0.25g) in ethanol (65mi) to 25 precipitate on cooling (0% the title compound (1.17g) as white solid m.p. 165-166'.

Example 8

4-(Acetylamino)-N-[2-[3-[2-(dimethylamino)ethyll- IH-indol-5yllethyllbenzeneacetamide oxalate Oxalyl chloride (1. '1 mi) was added dropwise to a cold (0') stirred suspension of 4(acetylamino)benzeneacetic acid (1.6g) in dry CH2C12 (80mi) under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for 3h, a further quantity of oxalyl chloride (1. '1 mi) was added and the mixture stirred at 20' for a further 3h. The mixture was then evaporated in vacuo below 30' to leave a yellow solid which was dissolved in dry THF (80mi) and added to a stirred solution of triethylamine (2.5mi) and Intermediate 4 (1.27g) in dry THF 35 (80mi). The resulting yellow mixture was stirred at 20' for about 19h, diluted with methanol (20mi) and evaporated in vacuo to leave a brown solid (about 3.09). This was purified by flash chromatography (G) to give a brown gum which was further purified by column chromatography eluting with methanol:ammonia (100:1) to give the title compound, free base as a colourless foam. Part of the foam (0.219) was dissolved in warm ethanol (5mi) and treated with oxalic acid 40 (47m9) in ethanol (2mi) to precipitate the title compound (0.18g) as a white solid m.p.

201-202' (foams).

Example 9

4-(Acetylamino)-N-[2-[3-[2-(dimethylamino)ethyll-1H-indol-5yllethyllbenzene acetamide oxalate 45 A suspension of 4-(acetylamino)benzeneacetic acid (0.0839) in dry CH2C12 (20m1) was treated with trimethylacetyl chloride (0.06m1) followed by triethylamine (0.12mi). The reaction mixture was stirred at 20' for 2h to give a clear solution to which a solution of Intermediate 4 (0.1 g) in dry CH2C12 (20mi) was added. The resulting mixture was stirred at 20' for 20h and evaporated in vacuo to leave a brown gum which was purified by column chromatography (1) to give an off- 50 white foam which was dissolved in absolute ethanol (5m[) to precipitate the title compound (80m9) as a white solid m.p. 201-202' (foams).

Example 10

4-(Acetylamino)-N-[2-[3-[2-(dimethylamino)ethyll-1H-indol-5yllethyllbenzene acetamide oxalate 55 A suspension of 4-(acetylamino)benzeneacetic acid (0.083g) and Intermediate 5 (0.19) in dry CH2C12 (40mi) at 5' was treated with triethylamine (0.12mi) followed by diphenylphosphorylazide (0.185mi). The resultant suspension was stirred at room temperature for 21h and evaporated in vacuo to leave a yellow gum which was partitioned between EA (3 x 35mi) and 0.2M hydro- chloric acid (35mi). The organic phase was discarded and the acidic aqueous phase was basified 60 (pH 8) with K2CO, and extracted with EA (3x35mi). This organic extract was dried (Na2SOJ and evaporated to leave an off-white foam which was purified by column chromatography (1) to give a white foam which was dissolved in absolute ethanol (5mi) and treated with oxalic acid (27mg) in ethanol (5mi) to precipitate the title compound (80mg) as a white solid m.p. 200.5-202' (foams.) 65 GB2185020A 15 Example 11

N-[2-[3-[2-(Dimethylamino)ethyll- 1H-indol-5-yllethyll-4[[(methyisulphonyl)aminolmethyllbenzeneace- tamide oxalate A suspension of Intermediate 9 (0.739) and Intermediate 4 (0.79) in dry CH2C12 (240mi) under 5 nitrogen at 5' was treated with triethylamine (0.9mi) followed by diphenylphosphorylazide (1.29mi). The resultant suspension was stirred at room temperature for 21h and quenched with 1 M hydrochloric acid (2x75mi). The two phases were separated, the organic phase was dis carded and the acidic aqueous layer was further washed with EA (75mi). The acidic aqueous layer was basified (pH8) with K2C03 and extracted with a mixture of EAAsopropanol (20A, 10 3 x 1 00mi). These organic extracts were combined, washed with brine (1 00mi), dried (Na2SOJ and evaporated to leave a white foam which was purified by flash chromatography (1) to give a white foam which was dissolved in absolute ethanol (70mi) and treated with oxalic acid (0.1389) in ethanol (5m]) to precipitate the title compound (0.58g) as a white solid m.p. 168-169'.

15 Example 12

N-[3-[3-[2-(dimethylamino)ethyll-1H-indol5-yllpropyllamino-1,4benzeneaceta mide oxalate Intermediate 12 (476m9) was dissolved in methanolic ammonia (3.1M, 30mi) and further ammo nia was bubbled through the solution for about 5 min. The mixture was heated at 110' for 72h.

The solvent was evaporated in vacuo to give a pale brown foam, which was dissolved in 20 CH2C]2/ethanol/NH,(aqueous) and flash chromatographed using the same solvent system to give the free base of the title compound as a white solid (38 1 mg). The free base (369rng) was dissolved in methanol (3mi) and a solution of oxalic acid (84mg) in methanol (lmi) was added.

ER (75mi) was added, and the mixture was stirred at room temperature for 6h, resulting in the formation of a white precipitate. The title compound was isolated by filtration, (435m9), m.p. 25 105-1550.

Example 13

4-(Aminosulphonyl)-N-[2-13-[2-(dimethylamino)ethyll- 1H-indol-5-yllethyllbenzeneacetamide oxalate A mixture of 4-(aminosulphonyi)benzeneacetic acid (0.58g) and Intermediate 4 (0.569) in dry 30 CH2C12 (150mi) under nitrogen at 5' was treated with triethylamine (0. 7mi) followed by diphenyl phosphorylazide (l mi). The resultant suspension was stirred at room temperature for 24h and quenched with 1 M hydrochloric acid (2 x 60mi). The organic phase was discarded and the aqueous layer was washed with EA (60mi), then basified (pH8) with K2CO, and extracted with a mixture of EAAsopropanol (20A, 3 x 1 00mi). The organic extracts were combined, washed with 35 brine (100mi), dried (Na2SOJ and evaporated to leave an off-white foam, which was purified by column chromatography (1) to give a white foam which was dissolved in hot ethanol (25mi) and treated with oxalic acid (0.14g) in ethanol (10mi). The resulting solution was cooled to about 20' and diluted with dry EA (about 100mi) to precipitate the title compound (0.569) as an off- white solid m.p. (shrinks) 123-125'. 40 Example 14

4-[(Acetylamino)methyll-N-[2-[3-[2-(dimethylamino)ethyll-1H-indol-5yllethyl lbenzeneacetamide dj tartrate A suspension of 4-[(acetylamino)methyl]benzene acetic acid (0.62g) and Intermediate 4 (0.7g) in 45 dry CH,Cl, (240mi) under nitrogen at 5' was treated with triethylamine (0. 9mi) followed by d i phenyl phos phorylazide (1.29mi). The resultant suspension was stirred at room temperature for 64h and quenched with 1M hydrochloric acid (2x75mi). The two phases were separated, the organic phase discarded, and the aqueous layer was washed with EA (75m1). The EA extract was discarded and the acidic aqueous layer was basified (pH8) with K2CO, and extracted with a 50 mixture of EA:isopropanol (20A, 3 x 1 00mi). The organic extracts were combined, washed with brine (100mi), dried (Na2SOJ and evaporated to leave a brown gum which was purified by column chromatography (1) to leave a pale brown foam which was dissolved in absolute ethanol (15mi) and treated with oxalic acid (90m9) in ethanol (10mi). The resulting solution was diluted with dry ER (about 100mi) to precipitate an off-white solid which formed a gum on filtration. 55 This gum was dissolved in water (20mi) and dilute hydrochloric acid (2M, 2mi) and the aqueous solution was washed with EA (2x20mi). The organic washings were discarded and the aqueous layer was basified with K2CO, and extracted with a mixture of EA and isopropanol (20A, 3x50mi). The organic extracts were combined, dried (Na2SOJ and evaporated in vacuo to leave a pale brown gum (0.359) which was dissolved in absolute ethanol (20m1) and treated with a 60 hot solution of d,l-tartaric acid (125m9) in ethanol (10mi). The resulting solution was diluted with dry ER to precipitate an off-white solid. This solid was filtered and dried to give the title compound (0.299) as a pale brown solid m.p. (shrinks) 90-93' (foams) 95- 100'.

Example 15 65

16 GB2185020A 16 N-[2-[3-[2-(Dimethylamino)ethyll-1H-indol-5-yllethy]-NI,Nl-dimethyl-1,4benz enediacetamide, di-tar trate A suspension of 4-[2(dimethylamino)-2-oxoethyllbenzeneacetic acid (0.749) and Intermediate 4 (0.7g) in dry CH,C12 (300mi) under nitrogen at 5' was treated with triethylamine (lmi) followed by diphenylphosphorylazide (1.29m1). The resultant suspension was stirred at room temperature 5 for 60h and quenched with 1M hydrochloric acid (2x75mi). The two phases were separated, the organic phase was discarded and the acidic aqueous layer was further washed with EA (75mi). The organic extract was discarded and the aqueous fraction was basified (pH8) with K2CO, and extracted with a mixture of EA:isopropanol (20A, 3 x 1 00mi). The organic extracts were combined, washed with brine (100mi), dried (Na2SOJ and evaporated to leave a white 10 foam which was purified by column chromatography (1) to give a white foam which was dissolved in hot absolute ethanol (65m1) and treated with tartaric acid (215mg) in ethanol (15mi).

The resulting solution was cooled to 20' and diluted with dry EA (about 200mi) to precipitate the title compound (0.659) as a white solid m.p. (shrinks) 85-90' (foams) 100-110'.

15 Example 16 (a) N-[2-[3-[2-(Dimethylamino)ethyll-1H-indol-5-yll-4-methoxybenzene propanamide oxalate Diphenylphosphorylazide (1.5mi) was added to a solution of Intermediate 4 (0.8g) and 3-(4 methoxyphenyl)propanoic acid (0.62g) in THF (100mi) and triethylamine (0. 96mi) and stirred at 5' for 1.5h. The solution was allowed to warm up to room temperature and stirred for an extra 20 16h. The resulting solution was added to saturated NI-1,Cl (100m1) and extracted with EA (3x50mi). The combined organic extracts were dried (Na2S04) and evaporated in vacuo to give the crude product as a clear oil. Purification by flash chromatography (H) gave pure title corn poundfree base as a clear oil (1.0g). The free base was dissolved in hot ethanol (10mi) and oxalic acid (0.259) in ethanol (2mi) was added, the solution was evaporated to dryness and the 25 resulting. solid recrystallised from CHCI, (20m1) and ethanol (3mi) to give the title compound as a white solid (0.6g) m.p. 112'-1 W.

The following compounds were prepared in a similar manner:

(b) N-[2-[3-[2-(Dimethylamino)ethyll-1H-indol-5-yllethy]13-[4[(methylsulphonyl) aminolbenzene pro panamide oxalate, (0.369) m.p. 83-85', from Intermediate 4 (0.8g) and 4- [(methyisulphonyl)amino]-benzenepropanoic acid (0.729).

(c) 4-(Acetylamino)-N-[2-[3-[2-(dimethylamino)ethyll-1H-indol-5-yllethyllbenzen epropanamide oxa late, (0.35g) m.p. 161-162', from Intermediate 4 (0.8g) and 4- (acetylamino)benzenepropanoic acid (0.72g).

(d) N-[2-[3-[2-(Dimethylamino)ethyll-1H-indol-5-yllethyll-4[(methylsolphonyl)a minolbenzenebuta- 35 namide oxalate, (19) m.p. 70-75' from Intermediate 4 (0.8g) and Intermediate 13 (0.8g).

Example 17

N-[2-[3-[2-(Dimethylamino)ethyll- 1 H-indol-5-yllethyll-N' methyl- 1, 4benzenediacetamide dl tartrate A suspension of Intermediate 7 (0.21g) and Intermediate 4 (0.239) in dry CH,Cl, (80mi) under 40 nitrogen at 5' was treated with triethylamine (0.3m]) followed by di phenyl p hosp ho rylazide (0.43mi). The resultant suspension was stirred at room temperature for 23h and extracted into 1M hydrochloric acid (2x320m1). The acidic aqueous layers were combined and washed with EA (40m1), basified (pH8) with K,CO, and extracted with EA:isopropanol (20A, 3x30mi). The organic extracts were combined, washed with brine (30mi), dried (Na2S04) and evaporated to 45 leave a brown gum which was purified by flash chromatography (1) to give a white foam which was dissolved in hot absolute ethanol (20mi) and treated with d,l tartaric acid (0.0689) in hot ethanol (5mi). The resulting solution was cooled (20') and diluted with dry EA (about 150mi) to precipitate the title compound (0.2g) as an off-white solid m.p. 85-90' (foams).

50 Example 18

4-(Acetylamino)-N-[2-13-[2-(dimethylamino)ethylll-H-indol-5-yllethylJ benzenebutanamide succinate Diphenylphosphoryl azide (1.5mi) was added to a cooled (ice bath) solution of Intermediate 4 (0.89) and 4-(acetylamino)benzenebutanoic acid (0.769) in THF (100m1) and triethylamine (lmi).

After 1h the solution was allowed to warm to room temperature and stirring continued over- 55 night. Saturated K,CO, (100mi) was added and the solution extracted with ethanol (2x50mi).

The combined organic extracts were evaporated to dryness in vacuo to give a brown oil which was purified by chromatography (C) to give the title compound, free base as a brown oil (0.6g).

The free base (0.6g) was dissolved in hot CI-ICI,/ethanoi (10:1) (20mi) and succinic acid (0.17g) in ethanol (2mi) was added and on cooling the title compound crystallised out as a light brown 60 solid (0.39) m.p. W-70'.

Example 19

N-(Acetylamino)-N-[[2-[3-[2-(dimethylamino)ethyll- 1H-indol-5yllethyllmethylaminolbenzeneacetam ide oxalate 65 17 GB2185020A 17 4-(Acetylamino)benzeneacetic acid (696m9) was dissolved in dry dimethy[formamide (30mi) con taining triethylamine (0.56mi) in a nitrogen atmosphere. The solution was cooled in an ice-bath and pivaloyl chloride (0.50mi) was added. The mixture was stirred in the ice-bath for 1h to give a white precipitate, and a solution of Intermediate 14, free base (868m9) in dimethylformamide (20mi) was added dropwise. The resulting suspension was stirred at room temperature for 72h. 5 The solvent was evaporated in vacuo to give an oil which was suspended in (C) and flash chromatographed (C) to give the free base of the title compound (1. 119) as a clear gum.

A sample (892m9) was dissolved in methanol (3mi) and oxalic acid (182rng) was added. The resulting solution was treated with ER (80mi) and the mixture was stirred for 6h to give the title compound (1.019) as a white solid, m.p. (foams) 100-110'. 10 Example 20

N-[2-[3-(2-Aminoethyl)- 1H-indol-5-yllethyll-4-methoxybenzeneacetamide oxalate A mixture of Intermediate 17 (500mg), Na,HPO, (21mg) and 4-chlorobutanal sodium bisulphite addition complex (89% w/w; 156m9) in water (25mi) and ethanol (50mi) was heated at reflux 15 under a nitrogen atmosphere for 26h. Solid K,CO, was added to the solution until 2 layers were observed. The organic layer was separated and the aqueous layer extracted with ethanol (20mi).

The combined organic solutions were evaporated in vacuo to give a solid which was purified by flash chromatography (C) to give the free base of the title compound (175mg). A solution of oxalic acid (42.9mg) in ethanol (0.5mi) was added to a solution of the free base (172mg) in 20 ethanol (2ml). The resultant gum was stirred with ER until a fine solid was formed, which was filtered off and dried under vacuum at room temperature for 2h, to afford the title compound as a salmon pink solid (190rng) m.p. 43-45' (foams).

Example 21 25 (a) N-12-[3-[2-(Methylamino)ethyll-1H-indol-5-yllethyll-4methoxybenzeneacetamid e oxalate Intermediate 19 (80Orng) in ethanolic methylamine (33% w/w; 50mi) was hydrogenated over pre-reduced 10% PdO/C (lg of a 50% paste with water) in absolute ethanol (20mi) under one atmosphere of hydrogen at room temperature for 68h. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give a pale yellow foam. Purification by 'flash' chromato- 30 graphy (C) gave the free base of the title compound (672m9). A solution of oxalic acid (157rng) in ethanol (lmi) was added to a solution of the free base (637rng) in ethanol (3mi). The supernatant liquid was decanted from the resultant gum and replaced with ER (50mi). After stirring with ER for 2h the gum solidified. The solid was filtered off and dried under vacuum at room temperature for 26h to afford the title compound as a white, crystalline solid (676m9) 35 m.p. 157-159'.

(b) N-[2-[3-[2-(Ethylamino)ethyll-1H-indol-5-yllethyll-4methoxybenzeneacetamide oxalate (753rng) m.p. 88-90' (glass) was prepared in a similar manner from Intermediate 19 (80Orng) in ethanolic ethylamine (33% w/w; 50mi).

40 Example 22

4-(Acetylamino)-N-[2-[3-(2-aminoethyl)- 1H-indol-5yllethyllbenzeneacetamide hemi-succinate A solution of Intermediate 20 (787rng) and hydrazine hydrate (1.Olmi) in absolute ethanol (60mi) was stirred and heated at reflux for 4h; cooled and evaporated. The residue was partitioned between EA (60m1) and 2N Na2C03 (40mi). The aqueous phase was separated and extracted 45 with EA (3x50mi). The combined organics were dried (Na,SOJ and evaporated to give a gum which was chromatographed using CH2C12, ethanol and ammonia (20:8A) as the eluent, to give the title compound, free base as a colourless gum. The gum was dissolved in a hot mixture of EA (10mi) and ethanol (20mi). A solution of succinic acid (15Orng) in hot ethanol (lml) was added. A white powder was immediately deposited. The mixture was left at 0' overnight, then 50 filtered. The solid residue was dried in vacuo to give the title compound (307rng) as a white powder, m.p. 212-214'.

Examples 23-30 These illustrate the preparation of 4-(acetylamino)-N-[2-[3-[2- (dimethylamino)ethyll-1H-indol-5-yllethyllbenzeneacetamide, (referred to as the title product). In each instance where the presence of the compound was determined by h.p.l.c. analysis this was carried out against an authentic sample with a 5p-OlDS 1 column eluting with CH,W(68):1-1,0 (20):0.05M sodium acetate adjusted to pH5 with 6% acetic acid (12); flow 3m1/min. Yields quoted are % of theory.

60 Example 23

A solution of triphenylphosphite (1.6g) and triethylamine (0.72mi), in dry dimethylformamide (40mi) was stirred at 20' for 5min. A solution of 4acetylaminobenzeneacetic acid (19) in dry dimethylformamide (10mi) was added and the stirring continued for 15min. The resulting mixture was treated with a suspension of Intermediate 4 (1.329), and triethylamine (1.2mi) in dry 65 18 GB2185020A 18 dimethylformamide (20mi) and the solution was stirred at 40', under nitrogen, for 20h to yield the title compound (h.p.l.c.-68%).

Example 24

A solution of 1,3-dicyclohexyi-carbodiimide (1.34g) in CH2C11 (10M1) was treated with a solution 5 of 4-acetylaminobenzeneacetic acid (1.25g) in dimethylformamide (5mi) and dichloromethane (5mi) over 5min at 0-5'. The resulting suspension was stirred for 10min at 0' and treated with a suspension of Intermediate 4 (1.32g) and triethylamine (1.25mi) in dry dimethylformamide (15mi) over 5min at 0-5'. The solution was allowed to warm to room temperature and stirred under nitrogen for 18h to yield the title product (h.p.l.c.-62%). 10 Example 25 -

A solution of oxaly] chloride (0.471mi) in CH2C12 (10mi) was added to a mixture of dimethylfor mamide (1 Omi) and CH2C11 (1 Omi) at - 10 to - 15'. After stirring for a further 20min at - 6 to - 10', a solution of 4-acetylaminobenzeneacetic acid (958rng) in dimethylformamide (1 Omi) was 15 added while maintaining the reaction mixture below -2'. The resulting suspension was stirred at 0' for 30min, cooled to - 15' and then treated with a solution of Intermediate 4 (1.29) and triethylamine (2.23m]) in dry dimethy[formamide (10mi) over 5min. The mixture was then slowly allowed to warm to 20' and stirred for 1h to yield the title product (h.p. i.c.-71%).

20 Example 26

A solution of 4-acetylaminobenzeneacetic acid (1.009) Intermediate 4 (1. 32g), tri phenyl phosphine (2.02g) and triethylamine (3.29m1) in a mixture of dry dimethylformamide (32mi) and CHIC12 (22mi) was treated dropwise at O'-5'C with a solution of CCI,(7.26m]) in CH2C12 (10M1) over about 20min. The resulting mixture was stirred at room temperature under nitrogen for 20h to 25 yield the title product (h.p.l.c.-59.6%).

Example 27

A stirred solution of the compound of Example 22 (175m9) in methanol (2mi) was treated portionwise with 0.05mi aliquots of (a) 0.35mi 40% HCHO in 0.35m1 methanol and (b) 0.1g 30 NaBH, in 1m] H20. The additions were carried out at 5-10' (ice bath), with (a) being added before (b). The reaction mixture was monitored by t.i.c. following each addition of (a) and (b).

When all the starting material had been consumed, the reaction mixture was warmed to 21' over 1h then evaporated to give a gum. The material was chromatographed using a mixture of CH2C12, ethanol and ammonia (40:8A) as the eluent, to give the title product (101m9) as a white 35 foam. T.I.c. (C) Rf 0.25.

Example 28

A suspension of 4-(acetylamino)benzeneacetic acid (1.00g) in dry CH2C12 (50mi) was treated with trimethylacetyl chloride (0.72mi) followed by triethylamine (1.44mi), and the mixture was stirred 40 at room temperature under nitrogen for 2.3h, when an amber solution was obtained. A solution of Intermediate 4 (1.329), and triethylamine (1.20mi) in dry dimethylformamide (50mi) was added, and the solution was stirred at room temperature under nitrogen for 20.7h to yield the title product (h.p.l.c.-43.7%).

45 Example 29 (a) 4-(Acetylamino)benzene N-[2-(4-nitrophenyl)ethyllacetamide 4-(Acetylamino)benzeneacetic acid (3.429) was dissolved in tetrahydrofuran (150mi) and the solution was cooled in an ice bath. Triethylamine (2.71mi) was added, followed by pivaloyl chloride (2.4mi). The mixture was stirred in the ice bath for 1h to give a white precipitate. 50 Further triethylamine (2.71mi) was added, followed by the solid 4- nitrophenethylamine hydrochlo ride (3.59g) and the mixture was stirred at room temperature for 20h. The reaction mixture was poured into saturated aqueous NaHCO, solution (200mi) and the aqueous layer was extracted with EA (2 X 200mi). The combined organic layers were dried MgSO, and evaporated in vacuo to give an orange solid which was suspended in CH,Cl,/ethanol /aqueous NH., (200:8: 1) and flash 55 chromatographed using the same solvent system, grading to (C) to give the title compound which was recrystallised from ethanol as pale orange needles (1.06g), m.p. 197-200'.

(b) 4-Acetylamino N-[2-(4-aminophenyl)ethyllbenzeneacetamide, dihydrochloride The compound of Section (a) (0.881g) was dissolved in ethanol (150m1) and saturated ethanolic hydrogen chloride (15mi). The resulting solution was added to a pre- reduced suspension of 10% 60 palladium oxide-on-carbon (0.5g, dry) in ethanol (50mi). The mixture was hydrogenated at 1 atmosphere hydrogen for 2h (hydrogen uptake ceased). The catalyst was removed by filtration through 'hyflo' and the filtrate was evaporated in vacuo to give a brownish gum which was triturated with ER (2x200mi) and flash chromatographed (C) to give the free base of the title compound as a pale gum. This gum was dissolved in saturated ethanolic hydrogen chloride and 65 19 GB2185020A 19 the solution was evaporated in vacuo to give a gummy solid which was triturated with ER to give the title compound as an off-white solid m.p. 181-1850.

(c) 4-Acetylamino N-[2-(4-Hydrazinophenyl)ethyll-benzeneacetamide hydrochloride The compound of Section (b) (6.259) was suspended in a mixture of water (1 7mi) and concen trated hydrochloric acid (8.5mi). The mixture was cooled in an ice bath and a solution of sodium 5 nitrite (1.399) in water (8.5mi) was added dropwise. The reaction mixture was stirred in the ice bath for 10 min to give a yellow solution with a fine suspension. The suspension was removed by filtration and the filtrate was collected in a cool receiver. The fitrate was poured into a solution of tin (11) chloride (20.6g) in concentrated hydrochloric acid (8.5mi) to give a yellow gum, which was removed and dissolved in ethanol (100mi). The ethanol solution was evapo- 10 rated in vacuo and re-evaporation with toluene gave a yellow gum. This gum was triturated with ER (250mi) to give the title compound (9.36g) as a pale yellow solid.

(d) The compound of Section (c) (252rng) was dissolved in aqueous 25% acetic acid (4mi) Dimethylaminobutanal diethylacetal (131mg) was added and the mixture was heated at 80' for 2.5h. The cooled reaction mixture was poured into EA (10mi) and 2N NaOH solution (10mi). The 15 aqueous layer was saturated with K,C03 and the layers were separated. The organic layer was discarded and the aqueous layer was extracted with ethanol (15mi). The ethanolic extract was evaporated in vacuo to give an orange gum, which was suspended in (C) and flash chromato graphed (C) to give the title product (40rng) as a pale orange gum. T.I.c. (C), Rf 0.13.

20 Example 30 (a) 4-(Acetylamino)-N-[2-[3-(cyanomethyl)- 1H-indol-5yllethyllbenzeneacetamide The compound of Example 29 Section (c) (1.5g) was suspended in aqueous 25% acetic acid (10mi) and 3-cyanopropanal diethyl acetal (0.237g) was added. The mixture was heated at 80' for 2.5h. The cooled reaction mixture was poured into NaOH solution (2N, 15mi) and EA (15mi) cooled in an ice-bath. K2C03 (2g) was added portionwise and the layers were separated. The aqueous layer was washed with EA (25mi) and thecombined organic extracts were dried (MgSO,) and evaporated in vacuo to give a yellow oil. The oil was dissolved in CH2C12/ethanol/a queous NH, (200:8A) and flash chromatographed using the same solvent system to give the title compound (33mg) as a white solid, m.p. 187.5-189'. 30 (b) The compound of Section (a) (23m9) was dissolved in dimethylamine in ethanol solution (33% w/w, 10mi), and the resulting solution was added to a pre-reduced suspension of 10% PdO/C (50% aqueous paste, 40rng) in ethanol (10mi). The mixture was hydrogenated at 1 atmosphere. hydrogen for 18h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give the title product (25mg) as a clear gum. T.I. c. (C), Rf 0.15. 35 Example 31

N-[2-[3-[2-(dimethylamino)ethyll- 1H-indol-5-yllethyll-4methoxybenzeneacetamide (a) N-[2-[3-(2-Hydroxyethyl)1H-indol-5-yllethyll-4- methoxybenzeneacetamide Intermediate 17 (366rng) was stirred at room temperature under nitrogen with 2,3-dihydrofuran 40 (0.09mi) in ethanol:water (5:1) (12mi) for 2h. Hydrochloric acid (2N; 10 drops) was added and the solution was heated at reflux for 22h. The solution was basified to pH 8 using NaHCO, (8% solution; 3mi) and the ethanol was removed under reduced pressure. The resultant aqueous suspension was extracted with EA (2x20mi) then the combined extracts were washed with saturated NaCI solution (20mi), and evaporated in vacuo to give a foam. Purification by 'flash' 45 column chromatography, eluent ethyl acetate, gave the title compound as a foam (170rng). T.I.c.

(EA), Rf 0.25.

(b) N-[2-[3-(2-Bromoethyl)- IH-indol-5-yllethyll-4methoxybenzeneacetamide Triphenylphosphine (149m9) in dry CH2C12 (0.5mi) was added dropwise at - 10 to -5' under nitrogen to a stirred solution of the compound of section (a) (155mg) and CBr, (139rng) in dry 50 CH2C11 (10mi). After stirring at room temperarture for 20h (overnight) the solution was evapo rated in the presence of silica gel and the resultant fine powder was chromatographed [elution with Ekhexane (1: l)] to give the title compound as a pale yellow viscous oil (1 17mg). T.I.c. EA, Rf 0.51 (major).

(c) A solution of the product of Section (b) (117mg) in ethanolic dimethylamine (33% w/w; 55 10mi) was stirred at room temperature for 19h. The solvent was removed in vacuo and the residue purified by 'flash' chromatography (C) to give the title compound of the invention as a colourless oil (96mg). T.I.c. (C), Rf 0.27.

Example 32 60

N-[2-[3-[2-(Dimethylamino)ethyll- 1H-indol-5-yllethyll-4methoxybenzeneacetamide To a stirred solution of the compound of Example 20 (37mg) in methanol (2mi) solutions of NaBH, (19m9) in water (0.5m1) and HCHO (0.07mI of a 37-40% aqueous solution) in methanol (0.5mi) were added dropwise simultaneously maintaining the temperature of 9-10'. After stirring for 1.5h solid K,CO, was added to the solution until 2 layers were observed. The methanolic 65 GB2185020A 20 layer was separated and concentrated (to about 1 mi) in vacuo, then chromatography (H) grading to (C) gave the title compound as a colourless oil (25mg). T.I.c. (C) (50:8A), Rf 0.27.

Example 33

N-[2-[3-[2-(Dimethylamino)ethyll- 1H-indol-5-yllethyll-4methoxybenzeneacetamide 5 A solution of Intermediate 19 (37mg) in ethanolic dimethylamine (10mi, 33%w/w) was hydrogenated over pre-reduced dry 10% PdO/C (40rng) in absolute ethanol (7m]) at room temperature and atmospheric pressure for 120h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by chromatography (C) to give the title compound (14m9) as a colourless oil. T.I.c. (C), Rf 0.29. 10 NJ The following N.M.R. data was obtained for the compounds shown: Spectra were run in deuterated dimethylsulphoxide R, 2 % -(CH 2) m AN-(CH2)n\ /11314 N H 6(ppm) includes Compound of Example R1 (CH2)m R2 (CH 2)n R 3tif No.

7.33,7.98;8.0,brs,1H 3.5,s,2H 8.22,brt,1H 2.8,m 2.26,s,6H,2.82,d 6 3.03,s 4.1,s,2H 3-3.3 2.72,s,6H 7 2.98,s,3H 3.38's 8.16,t,1H M-3.4,m;2.75-2.85,m 2.8,s 11 2.88,s,3H;4.13,d,2H; 3.4,s,2H 8.18,t,1H 2.8,m;3.3,m 2.82,s 7.57,t,1H 12 7.53+8.12(2xbrs,2x1H) 8.77,t,1H 1.9l,m,2H;2.73,t;3.34,m 2.81,s G) 13 3.51,s,2H 8.31,brt,1H 2.80,m;3.34,m 2.85,s ca A 00 M 14 1.88,s,3H;4.2l,d,2H; 3.38,s 8.13,t,1H 3.30^2H;2.70,t,2H 2.68,s,6H 0 NJ N) bi Compound of Example R1 (CH2)m R2 (CH2)n R R-4 No.

16a 3.72,s,3H 2.36,t,2H;2.76,m 7.96,t,1H 3.3,m;2.76,m 2.82,s 16b 2.96,s,3H;9.63;brs, 2.37,t,2H;2.77,m 7.98,t,1H 2.77,m;3.3,m 2.83,s 1H 16c 2.03,s,3H;9.9l,s,1H 2.37,t,2H;2.77,m 7.79,t,1H 3.3,m;2.76,m 2.85,s,6H 16d 2.97,s 2.08,t,2H;2.50,t; 7.92,t,1H 2.79,t,2H;3.31,m 2.70,s,6H 1.76,m,2H 17 2.79,d;3.38,s,2H; 3.37,s 8.15,brt,1H 2.85,m;3.3,m 2.72,s 7.98,brq,1H 18 2.05,s;9.85,s,1H 2.07,m;2.48,m; 7.91,brt,1H 2.8,t;3.31,%2H 2.45,s 1.76^2H 19 2.0-2.1,2xs,3H(rotamers) 3.22,s 2.97+2.91,2xs 3.55,m;2.82,m 2.77+2.79, 2xs,6H 3.73,s,3H 3.32,s 8.09,brt,1H 2.79,t;3.3^2H 21a 3.72,s,3H 3.32's 8.11,brt,1H 3.32,m;2.78,t,2H R 2.59,s,3H 21b 3.72,s,3H 4 3 33,s 8.11,brt,1H 3 32,m;2.78,t,2H R4 2.96,9,1.19,t,3H 22 2.11,s,3H 3:4,s 3:46,t;2.83,t G) The analytical data below was obtained for the compounds prepared according to the Examples shown:

Example No. Analysis Found c H N % c H N % 1 64.1 6.7 8.7 C 23H 29N 30 2 -C 2H204 requires 63.95 6.65 8.95 2 62.2 6.8 11.1 C 24H 3 ON 40 VC 2H 204 requires 61.6 6.7 10.8 3 58.3 6.5 9.4 C 24H 3 ON 40 2.C4H60 6.0.9H P requires 58.6 6.8 9.6 4 61.5 6.4 9.8 C22H26N3O.HCl.0.5H20 requires 61.5 6.5 9.8 59.0 6.6 11.8 C 23H28N1,02.1.25HCl.1.5H20.0.2C2H50H requires 59.2 6.9 11. 8 6 51.3 6.5 10.6 C 22H30,0 S VHCL0.2C 2H 50H requires 51.3 6.2 10.7 7 55.8 5.8 10.2 C 23H 3 ON 40 3S C 2HP If 0. 3BH 20 requires 55.7 6.1 10. 4 8 58.9 6.4 12.5 C24H3ON402'CP204 requires 62.9 6.5 11.3 9 61.8 6.4 10.9 C 24H 3 ON 40 2. C 2H 20 4.0.17C 2H 50H.0.1 1 H 20 requires 62.5 6.6 11.1 61.9 6.5 10.8 C 24H3 ON 402'C2H204.0.17C 2H50H.0.1 H 20 requires 62.5 6.6 11.1 11 56.2 5.9 9.8 C24H32NIP3S.1.1C2H2(3&f.0.14H2(3 requires 56.4 6.2 10.0 12 61.0 6.4 11.3 C23H28N402'C2H204'0.7H20 requires 60.7 6.4 11.3 13 54.5 6.0 10.6 C22H28N403S.C2H2(34.0.41H20.0.17 ethyl acetate requires 54.8 6.0 10.4 14 57.3 6.6 8. C25H32N402.1.35C4H604-0.521t20 requires 57.7 6.6 8.9 60.3 6.9 9.3 C26H39N402'C4H606'0.57H20 requires 60.6 7.0 9.4 16a 64.7 6.9 8.6 C24H31N302.CP204 requires 64.6 6.9 8.7 16b 55.8 6.3 9.7 C24H32N403S.C2H204'0.5H20 requires 56.2 6.3 10.1 16c 59.9 6.5 9.8 G) C25H32N402.1.6C2H204.0.2H20 requires 59.6 6.3 9.9 W 17 P0 58.6 6.9 8.9 C2SH32N402'1.2C4H606.0.3 ethyl acetate.

OD M 0.58H20 requires 58.4 6.8 8.8 0 r-i 18 64.9 7.7 10.2 0 C26H30402X4H604 requires 65.2 7.3 10.1 > N) -P- Example No. Analysis Found c H N % c H N % 19 63.1 7.0 10.5 C 25H 32NfO 2. C 2H 20 4.0.6C 2H 60 requires 62.9 7.0 10. 4 61.1 6.5 8.6 C21H25N3OV1.1c2H204'0.26H20'0"C4H,00 requires 61.3 6.3 9.0 21a 63.1 6.5 9.1 C22H27N302-C2HP4 requires 63.3 6.4 9.2 21b 64.0 6.7 9.0 C23H20302'C2H204 requires 64.0 6.7 9.0 22 65.5 6.7 12.7 C22H26N402.0.5C4H604.0.15H2() requires 65.5 6.7 12.7 m P.

-j -1.1 GB2185020A 25 The following examples illustrate pharmaceutical formulations according to the invention containing 4-(acetylamino)-N-[2-[3-[2-(dimethylamino)ethyll-1H-indol-5-yilethyllbenzen eacetamide oxalate as the active ingredient. Other compounds of the invention may be formulated in a very similar manner.

5 TABLETS FOR ORAL -ADMINISTRATION DIRECT COMPRESSION mgltablet 10

Active ingredient 2.4 Calcium hydrogen phosphate 95.10 B.P.

Croscarmellose sodium USP 2.00 Magnesium stearate, 13.P. 0.50 15 Compression weight 100M9 of a grade suitable for direct compression The active ingredient is sieved before use. The calcium hydrogen phosphate, croscarmellose 20 sodium and active ingredient are weighed into a clean polythene bag. The powders are mixed by vigorous shaking then the magnesium stearate is weighed and added to the mix which is blended further. The mix is then compressed using a Manesty F3 tablet machine fitted with 5.5mm flat bevelled edge punches, into tablets with target compression weight of 10Orng.

Tablets may also be prepared by other conventional methods such as wet granulation. 25 Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit.

The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellu lose, using standard techniques. Alteratively the tablets may be sugar coated.

30 INJECTION FOR INTRAVENOUS ADMINISTRATION Mg1M1 Active ingredient 0.6mg Sodium Chloride BP as required 35 Water for Injection BP to 1.0M1 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or to facilitate solution of the active ingredient. Alternatively suitable buffer salts may be used. 40 The solution is prepared, clarified and filled into appropriate size 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 or other suitable gas. 45

Claims (12)

1. Compound of the general formula fl):

R1 R2 50 1 (CH2),i-A-N (CH2) n (CH 2) 2NR 4R 5 N 55 R3 wherein 60 R, represents a halogen atom, a C,-3 alkoxy group, a group R^NCO(CHAP-, a group R6CONH(C1-12),-, a group R^NSOACH2)p-, or a group R,S02NH(CHAp(where R6 and IFI, which may be the same or different, each represents a hydrogen atom or a C,3 alkyl group R.

represents a C,-3 alkyl group and p is zero or 1); R2 represents a hydrogen atom or a C1-3 alkyl group; 65 26 GB2185020A 26 R, represents a hydrogen atom or a C,3 alkyl group; R4 and R5 which may be the same or different each represents a hydrogen atom, a Cl-3alkyl group or a 2-propenyl group; A represents -CO- or -S02_; n represents an integer from 2 to 5; and m represents zero or an integer from 1 to 4; and 5 physiologically acceptable salts and solvates thereof.

2. Compounds according to claim 1, wherein, in the general formula (1), R, is a chlorine atom or a methoxy group.

3. Compounds according to claim 1, wherein, in the general formula (1), R, is a H2NCOCH2, CH3MCOCH27, (CHINCOCH27, CH3COW-, CH3CONI-ICI-12-, H2NS02-, CH3S02NH- or 10 CH3S02NHCH27 group.

4. Compounds according to any of claims 1 to 3, wherein, in the general formula (1), m represents the integer 1 and n represents the integer 2.

5. Compounds according to any of claims 1 to 4, wherein, in the general formula (1), R, and R3 each represents a hydrogen atom. 15

6. Compounds according to any of claims 1 to 5, wherein, in the general formula (1), R4 and R, which may be the same or different each represents a hydrogen atom or a methyl or ethyl group.

7. Compounds according to the general formula (1a):

20 RI -0- CH2CONH (CH2) 2 "N 1 (CH2)2N(CH3)2 (1 a) 25 in which R, is a chlorine atom or a methoxy, H2NCOCH2-, CH,NHCOCH2-, (CH3)2NCOCH2-, CH,CONI-1-, 30 CH3CONI-ICH2, H2NS02-, CH3S02NH- or CH,S021MI-ICI-12group; and physiologically acceptable salts and solvates thereof.

8. Compounds according to claim 7, wherein, in the general formula ([a), R, is a H2NCOCH2-, CH3NHCOCH,-, CH.S02NI-ICH2-1 or H2NS02- group.

9. 4-(Acetylamino)-N-[2-[3-[2-(dimethylamino)ethyi-1H-indol-5yilethyllbenzenea cetamide and its 35 physiologically acceptable salts and solvates.

10. A pharmaceutical composition which comprises at least one compound of formula (1) as defined in claim 1 or a physiologically acceptable salt or solvate thereof together with one or more physiologically acceptable carriers or excipients.

11. A process for the preparation of a compound of general formula (1) as defined in claim 1, 40 or a physiologically acceptable salt or solvate thereof which comprises:

(A) reacting a compound of general formula (]I):

R 2NH (C H 2)n (CH 2) 2N R 4 R 5 45 N 1 R3 50 (wherein R, R, IR, R, and n are as defined in claim 1) or a salt thereof, or an N-silyl derivative thereof or a protected derivative thereof, with a reagent capable of introducing the group 55 R' (C H 2)m A- 60 (wherein R' and A are as defined in claim 1); or (B) cyclising a compound of general formual (ill):

27 GB2185020A 27 R R2 1 (CH2)m-A-N(CH2)n 5 ""GNR3N=CH(CH2)3Q (wherein R,, R2, R,3, A, m and n are as defined in claim 1 and Q is the group W,R5, where R4 10 and R, are as defined in claim 1, or a protected derivative thereof, or a leaving atom or group; or (C) reacting a compound of general formula (Vi):

15 R2 1 (CH2)m-A-N\ (CH2)n (C H 2) 2Y (V fl 20 R 3 (wherein R,, R2, IR, m, n and A are as defined in claim 1 and Y is a readily displaceable atom 25 or group) or a protected derivative thereof, with an amine of formula R^NH (where R, and R, are as defined in claim 1); or (D) reducing a compound of general formula (Vil):

RI R2 30 1 W (CH2)m-A-N-B (VIT) li 35 R3 (wherein R, R2, R3, m and A are as defined in claim 1 and W is a group capable of being reduced to give the required (-CH2)2NR4R, group or to give a protected derivative of 40 -(CH2)2NR,R,, where R, and R, are as defined in claim 1, and B represents the group -(CH2),- or a group capable of being reduced to -(CH2)n- where n is as defined in claim 1) or a salt or protected derivative thereof; or (E) in order to prepare a compound of general formula (1) subjecting another compound of general formula (1) to an interconversion reaction, or 45 (F) subjecting a protected derivative of a compound of general formula (1) or a salt thereof to reaction to remove one or more protecting groups; and if necessary or desired subjecting the compound resulting from any of steps (A) to (E) to one or two further reactions comprising (G) (i) removing any protecting groups.; and 50 (ii) converting a compound of general formula (1) or a salt thereof into a physiologically acceptable salt or solvate thereof.

12. Compounds of the general formula (if):

55 R 2NH (C H2)n (CH2) 2M R4 R5 1 (11) 60 R3 wherein R2, R, IR, R, and n are as defined in claim 1. 65 28 GB2185020A 28 Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 8991685, 1987. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.