AU597324B2 - Indole derivatives, processes for their preparation and pharmaceutical compositions containing them - Google Patents

Description

CO0M MON W E A-LTH OF A US T RALIIA PATENT ACT V~)52 COMPLETE SPECIFICATION (original)59 3 FOR OFFICE USE class Int. Class Application Number: Lodged: 67 96 Complete Specification Lodged,- Accepted: rublished: Priority: Related Art: 4 1 I II

I

4*1416 4 4 6 4*4 4 #000 *0 0 *0# 0* 0 0 1 000* 00 0 o 04* o 00 o 0 0 o *o F.'hisdournntcontai-nst WThiHdIdments inade unc *Section 49 arnd 'Is ccic, Vi, ~prit~ffg.

Naime of Applicant: Address Df Applicant; GLAXO GROUP LIMITED Clarges House, 6-12 Clarges Street, London W1Y 8DH

ENGLAND

Keith MILLS David Edmund BAYS Michael Dennis DOWLE :~oActual Inventor(s)- *Address for Service: Ian Harold COATES Colin Frederick WEBB DAVIES COLLISON, Patent A~ttorneys, 1 Little Collins Street, Mlbourne, 3000, Complete Specification for the invention entitled: "INDOLE DERIVATIVES, PROCESSES FOR THEIR PREPARATION ANDll PHARMACEUTICAL COMPO,(ITIONS CONTAINING THEM"1.

Thu, Z-,14owing statement is a full description of this invention, including the best method of performing it known to us

A

xTpl -la- "INDOLE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM".

This invention relates to indole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use, in particular to compounds and compositions 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 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 ef,"ctive drug for the treatment of migraine, which can be used either prophylactically or to t"" 1 5 alleviate an established headache, and a compound having a selective vasoconstrictor activity would fulfil such a role.

We have now found a group of indole derivatives having potent and 0 0 selective vasoconstrictor activity.

The present invention provides an indole of the general formula 2 0

R

R1-A-N(CH 2

(CH

2 2

NR

4 "I II II R3 wherein RI represents a hydrogen atom, a C1- 6 alkyl or C3.

7 cycloalkyl group, or a phenyl or phenyl (Ci-4) alkyl group;

R

2 represents a hydrogen atom or a C 1 3 alkyl group;

R

3 represents a hydrogen atom or a C 1 -3 alkyl group; 2

R

4 and R 5 which may be the same or different each represents a hydrogen atom, a C1-3 alkyl group or a 2-propenyl group; A represents -CO- or -SO 2 and n represents an integer from 2 to 5; (with the proviso that R 1 does not represent hydrogen when A represents -S02-) and physiologically acceptable salts and sol\ates hydrates) thereof.

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

Referring to the general formula the alkyl groups may be straight chain or branched chain alkyl groups, such as methyl, ethyl or isopropyl groups. The cycloalkyl group may be for example a cyclopentyl or cyclohexyl group.

The alkyl moiety of a phenyl (C1- 4 alkyl group may be for example i ,o 5 a methyl or ethyl moiety.

In one class of compounds of formula the group R 1 may be a

C

1 -6 alkyl, phenyl or phenyl(Ci- 4 )alkyl group.

In general, the group RI is preferably a methyl or phenyl group.

n in the compounds of formula may be an integer 3,4 or 5, but is preferably an integer 2.

S ,A preferred class of compounds represented by the general formula 0 a is that wherein R 2 represents a hydrogen atom. A further preferred o IU class of compounds is that in which R 3 represents a hydrogen atom.

A still further preferred class of compounds is that in which R 4 and R5 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 4 and Rg does not exceed two.

U o A particularly important compound according to the invention is N-[2-[3-[2-(methylamino)ethyl]-1 -indol-5-yl] ethyl] ethanesulphonamide and its physiologically acceptable salts and solvates hydrates).

Suitable physiologically acceptable salts of the indoles of general formula include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphetes, nitrates, phosphates, oxalates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates. Other salts may 'T 7 -3 be useful in the preparation of compounds of formula e.g.

creatinine sulphate adducts.

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

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

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

o o Accordingly, the invention also provides a pharmaceutical a a composition adapted for use in human medicine which comprises at least one compound of formula or a physiologically acceptable salt or solvate hydrate) thereof and formulated for administration by 0 any convenient route. Such compositions may be formulated in S0'. conventional manner using one or more pharmaceutically acceptable carriers or excipients.

Thus the compounds according to the invention may be formulated 0 0 for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation.

a o: For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers lactose, microcrystalline 4cellulose or calcium phosphate); lubricants magnesium stearate, talc or silica); disintegrants potato starch or sodium starch glycollate); or wetting agents 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 agents sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents lecithin or acacia); non-aqueous vehicles almond oil, oily esters or ethyl alcohol); and preservatives methyl or propyl-p-hydroxybenzoates or sorbic acid).

fi: For buccal administration the compositions may take the form of 15 tablets or lozenges formulated in conventional manner.

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 00 Soo containers, with an added preservative.

0 o o20 The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory 0 "o'g agents such as suspending, stabilising and/or dispersing agents.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, o os 0 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.

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 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 0.1 to 100mg of the active ingredient per unit dose which could be administered, ror example, 1 to 4 times 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 a- well as the severity of the condition to be treated.

For oral administration a unit dose will preferably contain from 2 to 50mg of the active ingredient. A unit dose for parenteral administration will preferably contain 0.2 to 5mg of the active ingredient.

Aerosol formulations are preferably arranged so that each metered dose or 'puff' delivered from a pressurised aerosol contains 0.2 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 The overall daily dose by inhalation will be within the range 1mg to 100mg. 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.

According to another aspect of the invention, compounds of formula and physiologically acceptable salts or solvates hydrates) thereof, may be prepared by the general methods outlined below. In the 30 following processes, R, R 2

R

3

R

4

R

5 A and n are as defined for the i general formula unless otherwise specified, According to one general process a compound of general formula may be prepared by reacting a compound of general formula

(II):

-6

R

2

NH(CH

2 (CH2 2R4R5

(II)

N

S

3 or a salt thereof (for example, an organic or inorganic acid addition salt such as the hydrochloride, 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 RIA.

Suitable reagents which serve to introduce the group RiA include acids of the general formula R 1 AOH 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 2-(1-methylpyridinyl)ester), a symmetrical anhydrides, mixed anhydrides or other activated carboxylic 4 o, acid derivatives such as those conveniently used in peptide synthesis.

The process may be effected in a suitable aqueous or non-aqueous .zo reaction medium, conveniently at a temperature of from -70 to +150 0

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 o amide N,N-dimethylformamide) or hexamethylphosphoramide, an ether tetrahydrofuran), an ester ethyl acetate) a nitrile (e.g.

acetonitrile), a haloalkane 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 -5 to +25 0

C.

The reaction using an alkyl ester may be effected in a suitable reaction medium such as an alcohol methanol), an amide (e.g.

.RI 7 -7 4 4 4 o 0 00 dimethylformamide), an ether tetrahydrofuran) or mixtures thereof and conveniently at a temperature of from 0 to 100 0

C.

When A represents -CO- carboxylic acids of formula RICOOH may also be used in the preparation of compounds of formula The reaction is desirably conducted in the presence of a coupling agent for example N,K'-carbonyldiimidazole or a carbodiimide such as N,N'-dicyclchexylcarbodiimide. The reaction may be carried out in a suitable reaction medium such as a haloalkane dichloromethane), a nitrile (e.g.

ecetonitrile), an amide dimethylformamide) or an ether (e.g.

tetrahydrofuran) conveniently at c temperature of from -50 to +50 0

C,

preferably -5 to +30 0 C. The reaction may also be carried out in the absence of a coupling agent in a suitable reaction medium such as a hydrocarbon toluene or xylene) conveniently at a temperature of from 50 to 120 0

C.

115 A compound of general formula wherein R 1 A represents -CHO may be prepared by heating a comprund of general formula (II) with ethyl as fornate optionally in the presence of a solvent e.g. ethanol.

o4 Compounds of genec-al formula (II) are novel and comprise a further feature of the invention.

Compounds of general formula (II) wherein R 2 is a hydrogen atom o may be prepared for example by reduction of a corresponding compound oo having an appropriate reducible group as the 5- position substituent, such as -(CH 2 )n-1CN or a corresponding cyano-substituted alkenyl group. The reduction may be effected by catalytic hydrogenation, or 25 with a reducing agent such as lithium aluminium hydride.

Such nitrile compounds are novel and constitute a further feature of the invention. These compounds may b( prepared for example by cyclisation of an appropriate hydrazone, in an analogous manner to general process described hereinafter. Alternatively, intermediates with a 5-(cynoalkenyl) substituent may be prepared by reacting an appropriate indole-5-carboxaldehyde with a cyanoalkyl phosphonate.

Compounds of goneral foamula (II) wherein R 2 is an alkyl group may be prepared for example by reduction of a corresponding nitrile in the presence of an amnne R 2

NH

2 or by reacting a compound of formula (II) wherein R 2 is a hydrogen atom with a suitable alkylating agent.

0 0 00( rO S iI 0-

I

I

8 According to another general process; compounds of formula (I) may be prepared by the cyclisation of a compound of general formula

(III):

R -A-R 2

N(CH

2

(III)

NR

3

N=CH(CH

2 3 wherein Q is the group NR 4

R

5 (or a protected derivative thereof) or a leaving atom or group such as a halogen atom chlorine or bromine) or an acyloxy group a carboxylic or sulphonic acyloxy group such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulphonyloxy or methanesulphonyloxy group).

The reaction may conveniently be effected in aqueous or non-aqueous reaction media, and at temperatures of from 20 to 200 0

C,

preferably 50 to 125 0

C.

a I Particularly convenient embodiments of the process are described below.

When Q is the group NR4R 5 (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 halogenaced hydrocarbons such as chloroform, dichloromethane, dichloiethani, dichlorodifluoromethane, or mixtures thereof.

'25 Polyphosphate ester is a mixture of ester;r which may be prepared from phosphorus pentoxide, diethylether and chloroform according to the Smethod 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 non-aqueous reaction medium, in the presence of an acid catalyst. When j an aqueous medium is employed this may be an aqueous organic solvent such as an aqueous alcohol methanol, ethanol or isopropanol) or an aqueous ether dioxan or tetrahydrofuran) as well as mixtures of such solvents. The acid catalyst may be for example an inorganic acid such as concentrated hydrochloric or sulphuric acid or an o'ganic _11 Y 6 9 acid such as acetic acid. (In some cases the acid catalyst may also act as the reaction solvent). In an anhydrous reacti -n medium, which may comprise for example one or moie ethers ar previously described) or esters 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 orgaric solvent, such as an aqueous alcohol methanol, ethanol or isopropanol) in the absence of anf'acid catalyst, conveniently at a temperature of from to 2000C, preferably 50 to 125 0 C. This process results in the formation of a compound of formula wherein R4 and R 5 are both hydrogen atoms.

According to a particular embodiment of this process compounds of formula may be prepared directly by the reaction of a compound of general formula (IV): R A-R 2

N(CH

2 o (IV) o I I 0 T 0 09 (where T is'a group -NR 3

NH

2 or a salt thereof, 25 o' with a compound of formula 0 0

OHC(CH

2 3 (V) 0 0 o (wherein Q is as defined above) or a salt or protected derivative 3C thereof (such as an acetal or 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 (III). It will be appreciated that in this embodiment of the cyclisation process a compound of general formula (III) is be formed as an intermediate, and 10 may be reacted in situ to form the desired compound of general formula Compoiuds of general formula (III) may, if desired, be isolated as intermediates during the process for the preparation of compounds of formula wherein a compound of formula or a salt or protected derivative thereof, is reacted with a compound of formula or a salt or protected derivative thereof, weter or in a suitable solvent, such as an aqueous alcohol methanol) at a temperature of, for example, 20 to 30 0 C. If an acetal or ketal of a compound of formula is 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 where T is NO 2 compounds, using conventional procedures.

A further general process for preparing compound of general formula involves reacting a compound of general formula (VT):

V-

4 44 4s 440 4rc 44 44 4 414 R I-A-R CH2)\ (CH2) 2Y

N

R

3 (vI) o (wherein Y is a readily displaceable atom or group) or a protected derivative thereof, with an amine of formula R4R 5

NH.

Thu displacement reaction may conveniently be carried out on those compound of formula (VI) wherein Y is a halogen atom chlorine, 4ao. bromine or iodine) or a group OR 6 where OR 6 is, for example, an acyloxy group which may be derived from a carboxylic or sulphonic acid, such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesuphonyloxy or metharesulphonyloxy group.

The displacement reaction may be conveniently effected in an inert organic solvent (optionally in the presence of water), examples of which include alcohols, e.g. ethanol; cyclic ethers, e.g. dioxan or tetrahydrofuran; acylic ethers e.g. diethylether, esters, e.g. ethyl acetate; amides, e.g. NN-dimethylformamide; and ketones e.g. acetone

A

r p" 11 or methylethyl ketone, at a temperature of from -10 to +1500C, preferably 20 to 50 0

C.

The compounds of general formula (VI) wherein Y is a halogen atom may be prepared by reacting a hydrazine of general formula (IV) with an aldehyde or ketone (or a protected derivative thereof) of formula (V) in which Q is a halogen atom, in an aqueous alcohol methanol) containing an acid acetic or hydrochloric acid). Compounds of formula (VI) wherein Y is the group OR 6 may be prepared from the corresponding compound wherein Y is a hydroxyl group by acylation with the appropriate activated species anhydride or sulphonyl chloride) using conventional techniques. The intermediate alcohol may be prepared by cyclisation of a compound of formula (III) wherein Q is a hydroxyl group (or a protected derivative thereof) under standard conditions.

Compounds of formula may also be prepared by another general process involving reduction of a compound of general formula S0.. (VII):

SR-A-R

2 W 0 0 o99 20 II II (VII) A1

N

R

3 (wherein W is a group capable of being reduced to give the required .o 25 -(CH 2 2 NR4R 5 group or to give a protected derivative of -(CH 2 )2NR 4

R

5 and B represents the group -(CH 2 )n as herein defined or a group 0 0H capable of being reduced to or a salt or protected derivative thereof.

o"oo *The required -(CH 2 and -NR4R 5 groups at the 3- position may be formed by reduction steps which take place separately or together in any appropriate manner.

Groups B which may be reduced to give the required group

-(CH

2 include corresponding unsaturated gr-upos such as alkenyl or alkynyl groups.

Examples of groups represented by the substituant W include -(CH2) 2 NO2; -CHNCHNO 2

-(CH

2 2 3

-CH

2 CN H -CH2CO1 0 -CCZ CHeaNGH1 j. ,1 12

-CH(OH)CH

2 NR4R 5

-(CH

2 2

NR

4

COR'

5

-COCONR

4

R

5 and -CH 2 COZ (wherein Z is an azido group or the group -NR 4

R

5 or a protected derivative thereof and R' 5 is a hydrogen atom or a methyl or ethyl group or R' represents the group OR 7 where R 7 is an alkyl or aralkyl group).

Groups which may be reduced to the -(CH 2 2 moiety include the corresponding unsaturated group and corresponding groups containing one or more hydroxyl groups or carbonyl functions.

Groups which may be reduced to the group -NR4R 5 where R4 and R are both hydrogen include nitro, azido, hydroxyimino and nitrile groups.

rn the latter case, reduction yields the group -CH2NH 2 and thus provides a methylene group of the -(CH 2 moiety.

A compound of general formula where R 5 is a hydrogen atom may also be prepared by reduction of a jrresponding compound wherein Rg is S f a benzyl group, e.g. with hydrogen in the presence of a catalyst, e.g.

0'1% palladium on charcoal.

The required -NR4R5 group wherein R 4 and/or Rg are other than hydrogen may be prepared by reduction of a nitrile -CH 2 CN or an aldehyde -CH 2 CHO in the presence of an amine, R4R 5

NH.

o0 20 A particularly suitable method for preparing a compound of formula 0 0 ooo whereinR 4 and/or Rg is other than hydrogen is reductive alkylation of the corresponding Pompound wnerein R4 and/or R 5 represent hydrogen "o aith an appropriate aldehyde or ketone acetaldehyde or acetone) S"n 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 the reduction of compounds of formula (VII). In some instances for the introduction of the group R5 where Rs is ethyl) the aldehyde acetaldehyde) may be condensed with the amine and the intermediate thus formed may subsequently be reduced using a suitable reducing agent.

The required -NR 4

R

5 group wherein R 4 and/or R 5 are other than hydrogen may also be prepared by reduction of a corresponding amide group, e.g. of the formula -(CH 2 2

NR

4

COR'

5 where R'5 is as previously defined).

2 13 o oa 0 0 o 0 00 o 0 0 0 0( soo04 4 O a 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.

Suitable reducing agents which may be used in the above process for th reduction of compounds of formula (VII) wherein W represents, for example, the groups -(CH 2 2 N0 2 -CH=CHN0 2

-(CH

2 2

N

3

-CH

2

CN,

-C,H

2 CH=NOH and -CH(OH)CH2NR4R 5 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 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 15 such as an alcohol e.g. ethanol, an ether, e.g. dioxan or S tetrahydrofuran, an amide, e.g. dimethylf(; namide or an ester e;gethyl acetate, and at a temperature of from -10 to +50 0 C, preferably to +300C.

The reduction process may also be effected on compounds of formula (VII) wherein W represents, for example, the groups -(CH 2 2 N0 2 -CH=CHN0 2

-(CH

2 2

N

3

-CH(OH)CH

2

NR

4

R

5 or -COCH 2 Z (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 25 alcohol such as propanol or ethfnol or a nitrile such as acetonitrile, and at a temperature of from 10 to 100 0 C, preferably 50 to 100 0 C. In some instances the reduction using a borohydride may be carried out in the presence of cobaltous chloride.

When A represents -S02-, reduction of compounds of formula (VII) wherein W represents, for example, -(CH 2 2 N0 2 -CH=CHN0 2

-(CH

2 2

N

3

-(CH

2 2 NR4COR'5 -CH 2 CH2NOH, -CH(OH)CH 2

NRR

5 -COCONR4R 5

-CH

2 COZ and

-COCH

2 Z (wherein R' 5 and Z are as previously defined) may also be carried out using a metal hydride such as lithium aluminium hydride.

Thks process may be carried out in a solvent, for example, an ether suoh as tetrahydrofuran, and conveniently at a temperature of from to +1000C, preferably 50 to 103 0

C.

I

14 A particular embodiment of general process includes the reduction of a compound of formula (VII) wherein W is the group -CH 2

CN

for eyample, 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 HNR4R 5 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 process are as described for the reduction of the group W.

The starting materials or intermediate compounds of formula (VII) may be prepared by analogous methods to those described in UK Published Patent Application No.2035310, and 'A Chemistry of Heterocyclic Compounds Indoles Part II', Chapter VI, edited by W 3 Houlihan (1972) Wiley Interscience, New York.

Compounds of formula (VII), wherein W is the group -CH 2 CHO may be prepared by oxidation with 3ones' reagent) of a compound of formula (VI) wherein Y is a hydroxyl group. A compound of formula (VII) wherein W is the group -CH 2 CH=NOH may be prepared by treatment of the corresponding aldehyde with hydroxylamine hydrochloride using 20 standard conditions.

The intermediate compound of formula (VII) wherein W is the group -(C2)2NA may be prepared from a compound of formula (VI) wherein Y is a halogen atom using standard procedures.

O, Standard reducing agents such as sodium borohydride may be used to prepare a compound of formula (VII) wherein W is group

-CH(OH)CH

2

NRIR

5 from the corresponding compound of formula (VII) wherein W is the group -COCH 2 NR4R 5 A compound of formula (VII) wherein W is the group

-(CH

2 2 NRwCOR' 5 may be prepared by acylation of the corresponding 30 un-ubstituted amine using conventional procedures.

SThe intermediate compounds of formula (VII) wherein B represents a C2- 5 alkenyl group may be prepared by reacting a compound of general formula (VIII)

-L

15

OHC(CH

2 n\

N

A3

(VIII)

9 00 0 000 0$ a .60 S 08 0*0a (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.

According to a further general process a compound of formula according to the invention, or a salt or protected derivative thereof, may be converted into another compound of formula using conventional procedures.

For example, a compound of general formula wherein one or more of R 3

R

4 and/or R 5 are alkyl groups may be prepared from the o corresponding compounds of formula wherein one or more of R 3

R

4 and Rg represent hydrogen atoms, by reaction with a suitable S alkylating agent such as a compound of formula RxL, (where Rx represents the desired R 3

R

4 or R 5 group and L represents a leaving atom or group such as a halogen atom or a tosylate group) or a sulphate (Rx) 2 S0 4 Thus, the alkylating agent may be for example an alkyl halide methyl. or ethyl iodide), alkyl tosylate methyl tosylate) or dialkylsulphate dimethylsulphate).

The alkylation reaction may conveniently be carried out in an S inert organic solvent such as an amide dimethylformamide), an ether tetrahydrofuran) or an aromatic hydro.carbon 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 potassium methoxide, ethoxide or t-butoxide or tetrabutylammonium 30 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 0 to 100 0

C.

44 00 o *t 0 OI 41

AZP

ii 16 Compounds of formula wherein one or both of R 3 and R4 represents propenyl may be prepared similarly, using an appropriate compound of formula RxL or (RX) 2 S0 4 According to another general process a compound of general formula according to the invention, or a salt thereof may be prepared by subjecting a protected derivative of general formula 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 general formula 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 NR4R 5 wherein Rq and/or R 5 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 benzyl, diphenylmethyl or triphenylmethyl; or acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl or phthaloyl.

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

,20 Subsequent cleavage of the protecting group or groups may be achieved by conventional procedures. Thus an aralkyl group such as o benzyl, may be cleaved by hydrogenolysis in the presence of a catalyst palladium on charcoal) or sodiur and liquid ammonia; an acyl o group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for examplj, hydrogen bromide in acetic acid or by reduction, for S* example by catalytic hydrogenation. The phthaloyl group may be removed by hydrazinolysis by treatment with hydrazine hydrate) or by treatment with a primary amine methylamine).

As will be appreciated, in some of the general processes to iL- 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 or a salt thereof may be carried out subsequent to any of the previously described processes to

-I

r 17 Thui, according to a further aspect of the invention, the following reactions in any appropriate sequpce may if necessary and/or desired be carried out subsequent to any of the processes to removal of any protecting groups; and (ii) conversion of a compound of general formula or a salt thereof into a physiologically 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 with an appropriate acid, preferably with an equivalent amount or with creatinine sulphate in a suitable solvent aqueous ethanol).

The starting materials or intermediate compounds for the preparation of the compounds according to this invention may be l""15 prepared by analogous methods to those described in UK Published Patent Application No. 2035310.

S -oo As well as being employed as the last main step in the preparative 0o sequence, the general methods indicated above for the preparation of the compounds of the invention may also be used for the introduction of oo 20 the desired groups at an intermediate stage in the preparation of the required compound., Thus, for example, the required group at the o position may be introduced before or after cyclisation to form the indole nucleus. It should therefore be appreciated that in such oo multi-stage processes, the sequence of reactions should be chosen in order that the reaction conditions do not affect groups present in the molecule which are desired in the final product.

The invention is further illustrated by the following Examples.

All temperatures are in °C.

Chromatography was carried out either in the conventional manner using silica q i1 (Merck, Kieselgel 60, Art. 7734) or by flash chromatogrephy C. Still, M. Kahn and A. Mitra, 3. Org. Chem. 2933, 43, 1978) on silica (Merck 9385) and thin layer chromatography on silica (Macherly-Ngel, Polygram) except where otherwise stated.

The following abbreviations define the eluants used for chromatography and t.l.c: Ethyl acetate-2-propanol-water-0.88 ammonia 25:15:8:2,

CH

2 C12-ethanol-0.88 ammonia 89:10:1, Ethyl acetate, (D) 8 01884 888 08 08 4, 0 00 8 440 0 (>01.0 43 o (~o #444 8 448 *84348 43 #4 1.8- Cl1 2

CI

2 -ethanol-0.88 ammonia B3:5:15:1.5, Ethyl acetate:cyclohexane 1:1, Ether-methanol 9:1, Ethyl acetate-methanol 9:1, Ether, Ethyl acetate-2-propanol-water-0.88 ammonia 200:15:8:2, WJ Ethyl acetate-2-propanol-water-0.88 ammonia 100:15:8:2, (K) Ethyl acetate-2-propanol-water-0.88 ammonia 50:15:8:2, CH 2 Cl 2 ethanol-0.88 ammonia 87:12:1.2, CHPC 2 -ethanol-0.88 ammonia 95:5,:0.5, CH 2 Cl 2 -ethanol-0.88 ammonia 91:8:0.8.

Intermediates were routinely checked for purity by t.l.c. enploying u.v. light for detection and spray reagents such as potassium permanganate (KMnO4Q. In addition indolic intermediates were detected by spraying with aqueous ceric sulphate (CeIV) and tryptanines by spraying with a solution of iodoplatinic acid (IPA) or ceric sulphate.

Proton OHI~) nuclear magnetic resonarice spectra were obtained either at 90MHz using a Varian FM 390 instrument or at 250MHz using a Bruker AM or WM 250 instrument. s singlet, d doublet, t triplet, mr= multiplet and q =quartet.

Intermediate 1 4-Hydrazinbenzeneacetnitrile, hydrochloride #20 A solution of sodium nitrite (4.0g) in water (34m1) was added dropwise at -50to -2-0 to a suspension of 4-aminobenzeneacetonitrile (7.6g) in concentrated hydrcohloric acid (80m1), and stirring was continued at -20 for 20mmn. The mixture Was filtered and the filt. ,kte added dropwise at 00 to 50 to a solution of tin (II) chloride dihydrate in concentrated hydrochloric acid (130m1). The mixture was allowed to 4 warm to room temperature overnight (1 7h) and the precipitate was filtered off, washed with concentrated hydrochloric acid, cold absolute ethanol, and dry ether, and dried to give the title salt as a powder (6.05g), m.p. 207-2100 (foams).

Intermediate 2 3-[2-0 (13-Dihydro-l ,3-dioxo-2H-isoindol-2.-yl)ethyl]-1 nitrile A mixture of Intermediate 1 (3.15g) and 4-(1 ,3-dihydro-1,3-dioxo- 2H-isoindo l-2-yl) butanal diethyl acetal (4.95g) in aqueous acetic acid (25%,p 150m1) was heztad at reflux for 2h, cooled, and the t -19 precipitate filtered off, washed with water (2 x 20ml) ,then ether (lO0mI) The crude product was triturated with ethyl acetate to give the title compound as a solid (3.2g) m.p. 185-1860.

Intermediate~ 3 2-[24[5- (2-AminoethXi) -1 H- indol-3-yl] ethyl]1-1 H-isoindole-1 dione, sulphate A suspen~sion of Intermediate 2 (0.96g) in methanol containing concentrated sulphuric acid (Q;58g) was hydrogenated over PdO on charcoal (50% Fqueous paste, 0.96g) at room temperature and p.s.i. for 24h, The catalyst was filtered uff, washed with methan'l and the filtrate evaporated to dryness to give the title compound as an oil (1.4g).

Intermediate 4 2412- (2-Aminoethyl) )-H-indol-3-yll ethyl]1-1 H-isoindole-1 (2H)dione hydrochloride A solution of Intermediate 2 (1.5g) in methanol (400m1) 8:4, containing concentrated hycirochlofic acid (0.6m1) was hydrogenated over PdO on charcoal (50',1 aqueous paste, 3.0g) at room temperature and presure fo 24h. The catalyst was' filtered off, washed with mcrthanol and the filtrate evaporated to dryness to give the title compound as a foam T,l-c. Rf 0.6.

Intermediate 3- (1 3--4)ihydro-1 ,3-dioxo-2H- isoindol-2-yl )ethyl 1-1 H- carboxaldehyde, quarter hydrate Raney nickel (about 2g) was added to a stirred solution of 3[2- (1 ,3-dihydro-1 ,3-d.1oxo-2H-isoindol-2-yl) ethylJ1-1 H-indol carbonitrile (4.98g) and sodim hy'pophosph~te (10.06g) in pyridine (lO0ml), water (50fnl) and acetic acid (50m1). The mixture was heated at about50 0 for 6h, periodically adding further Raney nickel (5 x about 2g). Af ter cooling,, the mixture was filtered, and the filtrate was diluted with water (1250m1) kind extrai'ted with ethyl acetate (3 x 500ml),~ The combined orgeAic extract w~s washed with hydrochloric acid (2N; 2 x 5fJ0ml), dried evaporated in vacucp. and azeotroped 20 with toluene (2 x 100ml), affording the title aldehyde as a solid A sample (0.53g) was purified by chromatography affording the pure title aldehyde as a solid (0.49g), m.p. 202-2030.

Intermediate 6 ,3-Dihydro-1 3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol- 5-yl]-2-propenenitrile A solutioh of diethyl cyanomethylphosphonate (1.6ml) in dry tetrahydrofuran (THF; 40ml) was added slowly to a stirred suspension of NaH 0.30g) in THF (40ml) under nitrogen. After 10 min a solution of Intermediate 5 (1.70g) in THF (40ml) was added to the resulting clear solution and the mixture was stirred at room temperature for 19h.

The solution was then partitioned between hydrochloric acid (1N; 200ml) containing NaC1 (50g) and ethyl acetate (3 x 150ml). The combined 15 organic extract was dried (MgS04), and evaporated to dryness to give a .solid (1.53g) which was purified by chromatography affording the title compound as a crystalline solid (1.13g) m.p. 232-2340.

SIntermediate 7 (Dimthylamino)butylidene]hydrazino]benzeneacetonitrile /i 4,4-Diethoxy-N,N-dimethylbutanamine (9.45g) was added to a stirred S It suspension of Intermediate 1 (9.2g) in deionized water (200ml) at room S temperature under nitrogen, 2N hydrochloric acid (22ml) was added (pH Ii and stirring was continued at room temperature for 5h. The clear f ?5 solution was basified with 8% aqueous NaHCO 3 (200ml) and extracted with 'i CHC13 (3 x 200ml). The organic layers were dried (MgS04) and evaporated to give the titla compound as an oil (15.6g).

(Silica, B) Rf 0.35.

Intermediate 8 ,N-dimethyl-l H-indole-3-ethanamine oxalate Intermediate 7 (15.4g) was heated under reflux with polyphosphate ester (108g) in CHC13 (200mY) with stirring under nitrogen for 8 min.

The mixture was poured onto ice, 8% aqueous NaHCO 3 (500m) was added, and after 20 min stirring the layers were separated and the aqueous _1 21 layer extracted with CHC1 3 (3x400mA). The aqueous layer was further basified to pH 9 with 2N Na 2

CO

3 (200ml), solid NaCI was added, and the mixture was extracted with CHC13 (3x400mA). The combined organic layers were dried (MgSO 4 and evaporated to give an oil (40.2g). The oil was partitioned between ethyl acetate (200m and 2N hydrochloric a*'id (4x40mi); the aqueous layers were basified (200mA 2N and 20mA NaOH) and extracted with ethyl acetate (4x100mA). The latter organic layers were washed with brine, dried (MgSO 4 and evaporated to give an oil Purification by flosh chroriatography (B and D) gave a first crop (1.91g) as an oil and a second crop (4.0g) also as oil. The second crop oil was dissolved in hot methanol (10ml), and oxalic acid (1.59g) 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 (4.0g) m.p. 183.5-187 0 Intermediate 9

N

3

,N

3 -dimethyl-lH-indole-3 ,5-diethanamine dioxalate Intermediate 8 (3.17g) was partitioned between 8% aqueous NaHC03 (100mz) and CH 2 C1 2 (3x8OmA) and the organic layers were dried (MgSO 4 S"2 and evaporated to give the free base as an oil (2.41g). The oil was oS" hydrogenated at 450 and 70psi over 5% rhodium on alumina (1.0g) in 7% w/w ethanolic ammonia (200mA) for 15.5h. The catalyst was filtered off 0 and the solvent evaporated to give an oil (2.58g). A portion (1.37g) of the oiJ was dissolved in methanol (6mA), and oxalic acid (1.12g) was S0°o25 added in methanol (2mA). Addition of dry rther (80mA) gave a gum, which was triturated with dry ether to afford the title compound as a solid (1.79g) m.p, 160-170 0 (foams).

Intermediate '.3b N 3

,N

3 -Dimethyl-IH-indole-3,5-diethanamine dihydrochloride i Intermediate 8 (2.40g) was hydrogenated at 55psi over 10% palladium on Scharcoal (50% paste with water; 1.2g initially; a further 2.4g added t 4 after 25h and 1.2g after 70h) in ethanol (240mA) containing concentrated hydrochloric acid (2.4mR) for 138h. The catalyst was filtered off and the solvent evaporated to give a foam (2.81g), a -22sample (about 0.7g) of which was partitioned between saturated aqueous N8 2

CO

3 and butanone (3x7Om.Z). The organic layers were washed with brine, dried (MgSO 4 and evaporated to give an oil (0.57g), A sample (169mg) of the oil was puL-ified by flash chromatograproy to give an oil (46mg) T.l.c. Rf 0.35.

Example 1 N- (2-Aminoethyl H-indol-5-yl ]ethyllmethanesulphonamide, compound with creatinine, sulphuric acid and water ,3-Dihydro-1 ,3-dioxo--2H-isoindol-2-yl )ethyl]-1 Hethyl] methanesulphonamide A solution of Intermediate 3 (1.4g) in pyridine (10m1) at 50 was treated with methanesulphonyl chloride (0.46m1). After 24h at room K 0 temperature the mixture was poured onto concentrated hydrochloric acid 0 0 0*15 (20nil) and ice (100g). The resulting so'lid was collected and purified by chromatography to give the title compound, as a foam (0.45g).

T,1.c. Rf 0.2 (ii N-2[-(-mioty)lH-.,l5yl ty]mtanslhnmb compound with creatinirie, sulphuric acid -and water (1:1:1:1) A solution of the product of stage Wi (0.29g) in ethanol (5m1) ~and tetrahydrofuran (2m1l) was treated with hydrazine hydrate (0.2m1) and heated at reflux for lbh. After ctooling the solution was evaporated to dryness, and the resulting solid wes partitioned between ethyl acetate (50m1) and a saturated solution of K 2 C0 3 (l0ml). The aqueous layer was extracted with ethiyl acetate (3 x 50m1), and the organic layer was dried (MgSO4) and evaporated, giving an uil. This ,*was dissolved in a hot mc.xture of ethanol/water (9:1t 20m1) and treated with an aqueous solution of creatinine and sulphuric acid 2M, 0.3m1). On cooling the title compound crystallised (0.16g) m.p.

209-21 00.

N.rmr. 6 0D 2 0) includes 2.8-3.5 (14H,m$-CY2HCHHSO 2 Me and ?L H_2H 2 anid creatinine N-Me); 7,.2 (1Hjdd, indole and 7.5-7.7 (2Htm, indole -4 and indole ~422 Example 2 (Methylamino) ethyl H-indol- 5-ylehl ]methane sulphonamidcn, compound with creatinine, sulphuric acid and water (2:2:2:1) forinamide, quarter hydrate A solution of' the product of Example 1 as the free base (0.98g) in ethyl formate (5Uml) and ethanol (5Oml) was refluxed for 48h. The solvent was evaporated in vacuo and the residue partitioned between sulphuric acid (1N, 25m1) and ethyl acetate (50m1). The aqueous layer was extracted with ethyl acetate (25m1) and the combined organic extracts washed with brine (25ml), dried (Na 2

SO

4 and evaporated in vacuo to give an oil. Purification by column chromatography (C and F) gave a foam, Trituration with ethyl acetate gave the title compound as a solid (0.159,) m~p. 89-910.

sul phonamide, cornpound with creatinine, sulphuric acid, and water a 040(2:2:2:1) ~o A solution of the product of Stage (0.6g) in dry tetrahydrofuran (TF) (20m1) was added dropwise under nitrogen, to a stirred suspension of LiAlI-H(O.7g) in dry THF (15m1). The mixture was refluxed for 5h, cooled in ice, and excess reagent decomposed by cautious addition of 10% water in THF. Brine (50m1) and ethyl acetate (lO0rni) .025 were added, insoluble material filtered off, and the aqueous layer 0 C extracted with ethyl acetate (lO0ml). The combined organic extracts were washed with brine (50m1), dried (Na 2

SO

4 and evaporated in vacuo to give an oil. The oil was dissolved in A hot mixture of ethanol 0(24m1) and water (3m1) and an aqueous solution of creatinine and 0 030 sulphuric acid (1 :11 2M, O.5m1) added. Filtration of the cooled mixture gave the title compound as a solid (0.379) m,p. 222-2Z40.

N.m.r. 6 (D 2 0) includes 2.6-3.6 (17H, m, LIL4H*Me andC Hjj*SO M and creatinine N-Me).

24 Example 3 N-E-[3-(2-Anminoethyl 1)-1 H-indol-5-yl pr'o yLmethaneslphnamide," compound-with creatinine, sulphuric acid and water 2-C2-[5-(3-Aminiopropyl)- H.-inidol-3-yllethlll-1 H-istdndole-1 ?3- (2H)-dione, hemisuiphate A solution of Intermediate 6 (0.95g) in methanol (550m1) a.id sulphuric acid (1.0m1) was hydrogenated at room temperature and2 pressure over, pre- reduced 10% palladimn on charcoal (50% aqueous paste; 2.08g) for 0.5h until hydrogen uptake (201l) had ceased.

Catalyst was filtered off', and the filtrate evaporated in vacuo to give ;n oil T.l~c. Rf 0.3 (ii) (1 3-Dihydro-1 ,3-dioxo-2H-isoindol-2-yl) ethyLL- H- Imethanesulphonamide A mixture of the product of Stage methanes ul phonyl1 t chloride (1.Oml) NaHC0 3 solution 300m1) and ethyl acetate was stirred vigorously at room temperature for 24h,, adding further methank~sulphonyl chloride (1 .Oml) after 17h. The mixture (which contai~ied an insoluble solid) was separated, and the aqueouti phase was '2A) further extracted with ethyl acetate (2 x 200m1). The combined o~rganic extract was 'washed with hydrochloric acid (2N;j 200ml), dri~ed (MgS0O) I4) and evaporated, affording an oil (0.49g), which was purified by chromatography on a silica columin On allowing appropriate fractions to stand briefly, title compound crystallAsed as a solid compound with creatinine, sulphuric acid and~ water(1::) A solution of the product of Stage (ii) (0.48g) in ethanol o (1O0mI) was treated with hydrazine hydrate (1 O0ml) and heated at reflux for lh 20mmn. After cooling, the soluition was evaporated in vacua, and azeotroped with ethanol (2 x 5Oinl) to give a solid, which 7 4 was partitioned between Na 2

CO

3 solution lO0nd) and ethyl acetate (3 x lO0mI). The combined organic extract was dried and evaporated to dryness, giving an oil which was dissolved in a hot mixture or ethanol (64m1) and water (8m1) and on aqueous soluton~ of creatinine and sulphuric acid 2M, O.56m1) added. On cooling, the title salt crystallised (0.43g) m.p. 2 12 2 14 N.m.r. 8 (DMSO-d 6 includes 2.6-3.2(14H,m,CH 2

CHCH

9 NHSO9Me,

CHCH

9 2NH 2 and creatinine N-Me' 6.8-7.5 (4Hym,aromatics); and 10.9 (1H,dindole-1).

Example 4 N-[2-[3-(2-Aminoethyl)-iH-indol-5- A ~.ethyl] acetamide compound with creatinin sulphuric acid and watvor (10:12:11:20) ,3-Dihydro-1 ,3-dioxo-2H-isoindol-2-yl)ethyl]-1 H-indolquarter hydrate A solution of Intermediate 4 (0.3g) in pyridine (10m1) was cooled in an ice bath, and treated dropwise with stirring with acetic anhydride (O.3m1). The solution Was stirred at room temperature for lh, diluted with water (15m1) and stirred for 15 min. The resulting solution was poured into hydrochloric acid (2N, 50r1) and extracted with ethyl acetate, (2 x 50 ml). The combined extracts were washed with 2N hydrochloric acid (50m1), 2N Na 2

CO

3 (50m1), dried (Na 2 S04) and evaporated in vacua to give a foam which was purified by chromatography to give the title compound as a solid (0.125g) m.p. 165-1680, (ii) N-[2-[3-(2-Aminoethyl)-lH-.indol-5,-yllethyllacetamide, compound with creatinine, sulphuric acid and water (10:12:11 A solution of the product of Stage (0.5g) in ethanol (100m1) containing hydrazine hydrate (j.Oml) was heated at reflux for 3hf oaoled, evaporated in vacua, and re-evaporated with ethanol (2 x Z2rl). The resulting solid wao partitioned between Na 2

CO

3 solution (2N, lO0ml) and ethyl acetate (2 x lO0ml). The combined organic extraco Were dried (Na 2 SO.) and evaporated in vacua, to give an oil which was dissolved in a hot mixture of ethanol (16m1) and wate- (2m1) and treated with an aqueous solution of oreatinine and sulphuric acid (1:10 2M, 0.5mni), On cooling# the title salt crystallised (0.3g) m.p. 211-2140.

N.m.r. 60D 2 0) includes 2.95 (31ipI~aNHC0Me); and 2.7-3.6 (11H-ImQ1 9 CH9 HCO, Dj9CH NH 2 and creatinine N-Me), Th~ 4 4 *1 4 4 g 26 N4[24-4A2-(Dimethitlamino) ethyl I-1H-indol-5-yl IethyI acetamide, oxalate Intermediate 10 (0.4g) was added at room temperature to a stirred 5 solution of triethylamine (0.55m1) in dry tetrahydrofuran (15m1), under nitrogen, and stirring was continued at room temperature for rpin. The mixture was coo].~d to 00, acetic, anhydride (0.15m1) was added, and sti.pring was continued for 4h between 00 and 100. The mixture was partitioned between saturated N8 2

CO

3 solution (65ml) and butanone (3 x 5Oml); the organic layers were washed with brine, dried (MgS04) and evaporated to give an oil (C.64g). Purificaticn by flash chromatography (B3 anti D) gave an oil (139mg) which was dissolved in methanol (2m1) and com~bined with a further sample (57mg) which had been similarly prepared, Oxalic acid (77mg) in methanol (0.5m1) was added.

Addition of dry ether gave a precipitate which was filtered off, washed with dry ether and dried to give the title compound as a solid (205mg), m.p. 85-930 (foems).

N.m.r. 6(DMSO) includes 1.81 (3H,s,NHCOMe); 2.7-3.0 (8H,m,NMe2 2 and tCONHCI 9 CI-b); 3.08 2H~t.,CHICHONMe 2 7.98 (lHtt,C0NH) and 10.9 (1H,d tindole-1 o Example 6 N-(2 (D imethylaminoethy I I H-indol-5 -yl Ieth yl IMethanesulphonamiae, oxeate 25 Intermediate 10 (0.905g) was added to a stirred solution of triethylamine (1.26m1) in dry CH2Cl 2 (50ml) at room temperature under nitrogen, and stirring was continued at room temperature for 5 min.

Methanei.phonyl chloride m)was added with cooling to 00, and the mixture was allowed to wai,g to room temperature with stirring for 5h. The mixture was poured into 2N Na 4

CQ

3 solution (60m1) and extracted with CH 2

CI

2 (3 x 50ml);j the organic layers were dried (MgSO4) and evaporated to give a gum (0.85g). Puri fic ation by short path chromatography (6,DI,J and,,) gave an oil. (65mg), whioh was dissnlved in methanol (1ln). Oxalic acid (25mg) in methanol (0.5m1) vwati added.

Addition of dry ether gave a precipitate wilch was washed with dry -27ether and dried to give the title salt as a solid (38mg), m.p.

1 5 9 1 6 5 0 (foams).

N.m.r. 6 (DMSO) includes 2.9-3.0 (11H,m,NMe) and MeS0 2

NHCH

9

CH

9 3.0-3.4 (6H,m,CH2CH2NMe 2 and S0 2 ,NHCH.); 7.15 (1H,t,SO 2 NH) and 1L.93 (1H,d, findole-1) Example, 7 N- 3 (Dimethylamino) ethyl-1 H- indol.5 -yl Iethyl benzamidC oxalate Benzoyl bhloride (0.53m1) was added to a sti'red solution of Intermedi~ate 9 as the free brise (0.95g) and triethylaminu (0.7nil) in dry CH 2 Cl 2 (40m1.) at room temperature under nitrogen, and stirring was continved at room temperature for 1h 40 min. The mixture was washed with 8% aqueous NaHC0 3 (2Orcl) and water (2 x 20mI), dried (MgSO 4 and the solvent evaporated. The resulting oil (1.47g) was combined with another portion prepared similarly, and purified by flash chromatography (B and L) to give a foam whcih was dissolved in methanol 44 (2m1) and a solution of oxalic acid (230mg) in methanol (lml) was added. Addition of dry ether (80m1) gave a precipitate which was washed with dry ether and dried to give the title salt as a solid (0 .873g) m.p. 158-1600.

N.m.r. 6 (DMSO) includes 2.80 (AH,s,N Me 2 2.95 (2H,ttC0NHCH9CHj 2 3.0M6 (2H,m,CH2CH 2 NMe 2 3.55 (2H,q,CONHCIH 2 74-7.6 (4H,m,phenyl 0 .00(m and p) and indole-4); 8.63 (1HtCONH) and 10.95 (1Hdjindole-1).

Example-8 N-[2-[3-[2-(Dimethylamino)ethyl1-1 H- irol-5-yl IethX1 benzenes ulphonamide oxalate Benzenesulphonyl chloride (0.6lrnl) was added to a stirred solution of Intermediate 9, as the free base (0.98g) and triethylanine (0.72m1) in dry CH 2 Cl 2 (40m1) at room temperature under nitrogen, and stirring was continued at room tem~perature For lh 40 min. The mixture was washed with 0' aqueous NaHC0j (20m1) slid water (2 x 20m1), dried

(MS

4 and evaporated to give a foam (0.90g). This was combined wit' similarly-prepared material and the combined samples purified by chromatography (M and The resulting foam (0.607g) was dissolved in methanol (2ml) and oxalic acid (1 54mg) in methanol (imI) was added.

28.- Addition of dry ether (80m1) gave a precipitate which was washed by decantation with dry ether, filtered off, and dried to .3ive the title salt as a solid (0.702g) m.p. about 80-900 (foams).

N.m.r 6(DMSO) includes 2.7-2.85 (BH'mN e 2 and S0 2 NHCHgCH 2 2.95-3.1

(GH,M,SO

2

NHCH

2

CH

2 and C Hj'Me 2 7.37 (1H,brs,SO 2 NH); 7.55-7.7 (4H,m,Ph (m and P) and indole-4); and 10.9 (1Hs,indole-1).

Example 9 ,3-Dihydro-1 ,3-dioxo-2H- isoindol-2-yl) ethyl] -1 Hindol-5-yll ethyl] benzamide, comnpound with ethyl acetate (2:1) A solution of thionyl chloride (1 in dry tetrahydrofuran (20m1) was added dropwise under nitrogen to a stirred, ice-cooled solution of benzoic acid (1.41g) in a mixture of triethylamine (8.00ml) and dry tetrshydrofuran (80m1). The solution was stirred in ice for 1h, and Intermediate 4 (2.13g) was added and stirring IIcontinued for 0.75h. The resulting suspension was partitioned between 2N Na 2

CO

3 (250m1) and ethyl acetate (2 x 250m1). The combined organic extracts were washed with water (2 x 250m1) and 2N Na 2

CO

3 (250m1), dried (Na 2 SO4) and concentrated in vacuo. The residual oil (3.1g) was ?0 chromatographed The required fractions were combinod. and concentrated in vacuo to give the title compound as a fj-.m (0.92g) m.p.

75-820.

.4q(ii) N-[2-[3-(2-Aminoethyl)-lH-indol-5-yl othyllbenzamide, compound with creatinine, sulphuric acid and water (1:1:1:1) A solution of hydrazine hydrate (0.9Ornl) and the product of stage (0.67g) in ethanol (25m1) was stirred at reflux for 3.5h and then left to cool. The resultant suspension was concentrated in vacuo and the residual solid was part.ltioned between 2N Na 2

CO

3 (50m1) and ethyl 00".*30 acetate (3 x 50m1). The combined organic extracts were then dried (Na 2 SO4) and concenfrated in vacuo. The residual gun (0.47g) was dissolved in a hot mixture of ethanol (4Or~il) and water (5m1) and an i 4aqueous solution of cicatin 'ine and suli'turic acid 2M; 0.76m1) was added. The jolid that crystallised on cooling was filtered off, washed successively with a mixture of ethanol and water 27mlt) and -49 29 ethanol (10mI) and dried at 600 for 8h to give the title compound as a solid (0.60g) m.p. 228'-229.5'.

N.m.r. 6

(D

2 0) includes 3.0-3.25 (9H,m,CONHCHpCH.,, 2j2LjH 2 and creatinine NMe; 3.68 (2H,t,CHZCH2NHCO); and 7.4-7.64 (7H,m,phenyl, indole-4 and indole-7).

Eamle- Wi 13-Dihydro-1 13-dioxo-2H-isoindol-2--yl) ethyl 1-1 Hethyl] benzenesulphonamide A solution of benzenesulphonyl chloride (1 .38m1) in dry dimethylformamide (25m1) was added dropwise under nitrogen to a stirred, ice-cooled suspension of Intermediate 4 (2.0g) in a mixture of triethylamine (3.Om1), dry tetrahydrofuran (50m1) and dry 0 AO dimethylformamide (25m1) and stirring was continued for 2.75h. The suspension was then left at room temperature overnight, and partitioned between 2N Na 2 C0 3 (500m1) and ethyl acetate (2 x 500m1).

0 The comr A.red organic extracts were washed with water (2 x 500m1) and 2N Na 2

CO

3 (!M0ml), dried (Na 2 SOit) and concentrated in vacuo. The residual foam (2.41g) was chromatographed The required fractions were combined anid concentrated in vacuo to give the title compound as a sol,;d (0.73d) mp. 183-1840.

compound with creatinine, sulphuric acid, and water suspension of the product of Stage (0.60g) and hydrazine hydrate (0.75m1) in ethanol (30m1) was stirred Lunder reflux for 4.25h.

The resultant suspension was evaporated in vacuo and the residual solid 00 06 '5was partitioned between 2N Na 2

CO

3 (25m1) and ethyl acetate (3 x 25m1).

The combined organic extracts were then dried (Na 2

SO

4 and concentrated in vacuo. The residual gum (0.46g) was dissolved in a hot mixtZure of ethanol (36m1) and 'water (4.5m1)s and an aqueous solution of creatinine and sulphuric acid 2M, 0.68m1) was added. The solid which crystallised on cooling was filtered off, washed with a mixturoe of ethanol and water (8:1 2 x 5m1) and ethanol (2 x 5m1) and then driedi in vacup at 600 for 6h to give the title compound as a solid (0.48g) m.p. 216-7-17.50.

N~m.r. 6(DMSO) includes 2.78 (2HltpSG 2 NHCHZH2); 2.85-3.2 2 NH .CH H CHNH and crestlinine N-Me); 7.2-7.4 (3H,m,indole-2, indole-7 and SOLN); 7.5-8.0 6H,m~phenyl and indole-4) and 10.9 (1H,8, indole-1).

The following e,,ample5 illustratepharmec utual aformulations according to the invention coontainingA* E J i. I J~Jl12 .L.1 liL~ as the active Ingredient. Other compounds of' the invention may be formulated in a very similar manner.

TABLETS FOR ORAL ADMINISTRATION D!RECT COMPRESSION m/tablet a44Active ingredient 2.4 Calcium hydrogen phosphate 95.10 411Iegnesium etearae, BP 01,50 Copeso wegh'.0m *of a grade suitable for direct compression The active ingredient is sieved before use. The calcium hydrogen phoophate, crosoarmellose sodium, and active ingredient are weighed into a clean polythene beg. The powders are mixed by Yigorous shaking then the magnesiumn stearste is weighed and added to the -mix Which is 0~ blended further. The mix is then compressed using a "lanesty F3 tablet machine fitted with 5.5mm flat bevelled edge punohe4:, into tablets with target compression weight of 100mg.

Tablets may also be prepared by other conventional methods such as wet granulation, Tablets or' other strengths may be prepar~ed by altering the rat),o of active ingredient to lactose or the compression weight and using puniches to suit.

Th, tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulosep using standard techniques.

~Z~~jJ Alternatively thie tablets may be sugar coated.

-31- INJECTION FOR INTRAVENOUS ADMINISTRATION Active ingredient 0.6mg Sodium Chlor~ide SP as required Water for Injection BP to lOml Sodium chloride may be added to adjust the tonicity of the solution and the p,4 may be adjusted, using aoid or alkali, to that of optimum stability and/or to facilitate solution of the active ingredient, Alternatively suitable buffer salts may be used.

The solution I1s prepared, clarified and filled into appropriate size It ampoules sealed by fusion of the glass. The injection is sterilised by heating In ani at,toclave using one of the acceptable cycles.

Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution maly be 04 packed under an inert atmosphere of nitrogen or other suitable gas.

000 00 a coo 0 00 00 00 0 d 0 0 0 0 040

Claims (10)

1. Compounds of the general formula I1 (CH 2NR R R 1 -A-N(CH n (CH 2 )R I /I n (I) N N 3 wherein R 1 represents a hydrogen atom, a C 1 6 alkyl or C3- 7 cycloalkyl group; or a phenyl or phenyl (C1_ 4 alkyl group; R 2 represents a hydrogen atom or a C1-3 alkyl group; R 3 represents a hydrogen atom or a C 1 3 alkyl group; R4 and R 5 which may be the same or different each represents a hydrogen atom, a C 1 3 alkyl group or a 2-propenyl group; A represents -CO- or -S02-; and n represents an integer f m 2 to 5; (with the proviso that R 1 goes not spresent hydrogen when A represents -S0 and physiologically acceptable salts and solvates thereof.

2. Compounds according to Claim 1, wherein, in the general formula R 1 represents a Cl 6 alkyl, phenyl or phenyl (C 1 4 alkyl group.

3. Compounds according to Claim 2, wherein, in the general formula R 1 represents a methyl or phenyl group.

4. Compounds according to any of Claims 1 to 3, wherein, in the general formula n represents the integer 2. -33- Compounds in the general atom.

6. Compounds in the general atom.

7. Compounds in the general according to any of Claims 1 to 4, wherein, formula R2 re,,rn-5ents a hydrogen according to any of Claims 1 to 5, wherein, formula R 3 represents a hydrogen according to any of Claims 1 to 6, wherein, formula R, and which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group.

8. N-C2-[3-[2-(Methylamino)ethyl]-lH-indol-5-yl]ethyl] mnethanesulphonamide and its physiologically acceptable salts and solvates.

9. A pharmaceutical composition comprising at least one compound of general formula or a physiologically acceptable salt or solvate thereof together with one or more physiologically acceptable carriers or excipients. A process for the preparation of a compound of general formula as defined in Claim 1 or a physiologi- cally acceptable salt or solvato thereof which comprises: reacting a compound of general formula (II): 4 S* 4 a 0 41 a 4 4 a 44 R2NH(CH 2) n (CH 2) 2 NR4 R I I 3 (11) (wherein R 2 R 3 .R 4 R 5 and n are as defined in Claim 1) salt thereof, or an N-silyl derivative thereof protected derivative thereof, with a reagent serving or a or a PP-- -S -34- to introduce the group R 1 A (where R 1 and A are as defined in Claim or cyclising a compound of general formula (III): R 1 -A-R 2 N(CH 2 I (III) NR 3 N=CH(CH 2 3 (wherein Rl, R 2 R 3 A and n are as defined in Claim 1 and Q is the group NR4R 5 (where R 4 and R 5 are as defined in Claim 1) or a protected derivative thereof, or a leaving atom or group; or reacting a compound of general formula (VI): N R -A-R CH2)n\ /(CH2) 2Y I I II (YT) (wherein RI, R 2 R 3 Y and n are as defined :s in Claim 1 and Y is a readily displaceable atom o or group) or a protected derivative thereof, with an amine of formula R 4 R -NH (where R 4 and R 5 are as ao..i -lefined in Claim or reducing a compound of general formula (VII): St': R12-A- /NBw V I (VII) N 4 R 3 (wherein R R, R 3 and A are as defined in Claim 1 and W is a group capable of being reduced to r -3 give the required -(CH 2 2 NR 4 R 5 group, where R 4 and R 5 are as defined in Claim 1, or to give a protected derivative of -(CH 2 2 NR 4 R 5 and B represents the group -(CH 2 )n where n is as defined in Claim 1, or a group capable of being reduced to -(CH 2 or a salt or protected derivative thereof; or in order to prepare one compound of general formula as defined in Claim 1, or a physiologically acceptable salt or solvate thereof, subjecting another compound of general formula or a salt or solvate thereof to an interconversion reaction; or subjecting a protected derivative of general formula or a salt thereof to reaction to remove the protecting group or groups; and if necessary and/or desired subjecting the compound resulting from any of processes to to one or two further reactions comprising: removing any protecting groups; and a (ii) converting a compound of general formula or a salt tlereof into a physiologically acceptable salt or solvate thereof. a s

11. Compounds of general formula (II): SR2NH(CH2) (CH 2 2 I ii '4 wherein R 2 represents a hydrogen atom or a C 3 alkyl group; R 3 represents a hydrogen atom or a C1-3 alkyl group; R 4 and Rg, which may be the same or different, each represents a hydrogen atom, a C 3 alkyl group or a 2-propenyl group; and -36- n represents an integer from 2 to and salts thereof.

12. Compounds of the general formula I according to claim 1, pharmaceutical compositions comprising said compounds, or processes for the preparation thereof, substantially as hereinbefore described with reference to the Examples. to or indicated in the specification alms of this application, indiv or collectively, and any and all SDated this 8th day of January 1987 I GLAXO GROUP LIMITED By its Pat&nt Attorneys SDavies Collison o