WO1995007887A1 - Indole derivatives as antagonists of excitatory amino acids - Google Patents

Abstract

Compounds of general formula (I) or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO2R2 or COR2 wherein R2 represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; A represents an optionally substituted ethenyl, in the trans configuration; R1 represents an optionally substituted fused bicyclic carbocyclic group, having NMDA antagonist activity and methods for their preparation.

Description

INDOLE DERIVATIVES AS ANTAGONISTS OF EXCITATORY AMINO ACIDS.

This invention relates to novel indole derivatives to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. In particular it relates to indole derivatives which are potent and specific antagonists of excitatory amino acids.

U.S. Patent No. 4960786 discloses that certain known 2-carboxylic indole derivatives are antagonists of excitatory amino acids. EP-A 0396124 also teaches certain 2-carboxylic indole derivatives as being therapeutical ly effective in the treatment of CNS disorders resulting from neurotoxic damage or neurodegenerative diseases. Further 3-substituted-2-carboxyindole derivatives which are useful in the treatment of neurodegenerative diseases including cerebrovasular disorders are disclosed in W092/16205.

We have now found a novel group of 3-substituted-2-carboxyindole derivatives that have a specific antagonist activity at the strychnine insensitive glycine binding site located on the N-methyl-D-aspartate (NMDA) receptor complex.

Accordingly the present invention provides a compound of formula (I)

or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, triflu omethyl, trifluoromethoxy, nitro, cyano, Sθ2R2^^>r COR2 wherein R₂ represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; A represents an optionally substituted ethenyl, in the trans configuaration; R., represents an optionally substituted fused bicyclic carbocyclic group. The term trans configuration refers to the relative configuration of the 3-indolyl group and the group CONHR-, attached to the ethenyl group A.

For use in medicine the salts of the compounds of formula (I) will be physiologically acceptable thereof. Other salts however may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore unless otherwise stated references to salts includes both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).

Suitable physiologically acceptable salts of compounds of the invention include base addition salts and where appropriate acid addition salts. Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline metal salts such as sodium, potassium,, calcium, and magnesium, and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases ( e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).

The compounds of formula (I) and or salts thereof may form solvates (e.g. hydrates) and the invention includes ail such solvates.

It will be appreciated that the compound of formula (I) may be produced in vivo by metabolism of a suitable prodrug. Such prodrugs may be for example physiologically acceptable metabolically labile esters of compounds of the general formula (I). These may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with where appropriate prior protection of any other reactive groups present in the molecule followed by deprotection if required. Examples of such metabolically labile esters include Cι_ alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N,N- diethylamino) ethyl, or 2-(4-morpholino)ethyl esters or acyloxyalkyl esters such as, acyloxymethyl or 1 -acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1- acetoxyethyl, 1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1- benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1 -isopropoxycarbonyioxyethyl, cyclohexylcarbonyioxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyioxymethyl, 1 -cyclohexyloxycarbonyloxyethyl, 1 -(4- tetrahydropyranyloxy)carbonyloxyethyl or 1 -(4- tetrahydropyranyl)carbonyloxyethyl.

Preferred metabolically labile esters of compounds of formula (I) include C-_|_ 4alkyl esters more particular methyl or ethyl, aminoalkyl esters more particular 2-(4'-morpholino)ethyl, or acyloxyalkyl esters e.g. acetoxymethyl, pivaloyloxymethyl, 1 -cyclohexyloxycarbonyloxyethyl or 1-(4- tetrahydropyranyloxycarbonyloxy)ethyl.

The group R may be at any of the four possible positions on the fused benzene ring and when m is 2 the two R groups may be the same or different.

The term alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term optionally substituted ethenyl means an ethenyl group optionally substituted by 1 or 2 alkyl groups e.g. methyl groups. Examples of such groups include ethenyl, 1-methylethenyl, 2-methylethenyl and/or 1 ,2-dimethylethenyl.

The term optionally fused bicylic carbocyclic group preferably refers to a 5,66,5 or 6,6 bicyclic carbocyclic ring system containing 9 or 10 carbon atoms which may be saturated or unsaturated and which may be substituted by 1 to 3 groups selected from halogen, alkyl, alkoxy, amino, alkylamine, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, S0₂R₂ or COR₂ wherein R₂ represents hydroxy, methoxy, amino, alkylamino or dialkylamino.

Examples of suitable R., groups include optionally substituted naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl or indanyl.

SUBSTITUTE SHEET (RULE 26; A preferred class of compounds of formula (I) are those wherein m is 1 or 2 and within this class those wherein R is at the 4 and/or 6 position are particularly preferred.

The group R is preferably a chlorine atom.

When A is a subsituted ethenyl group the substituent is preferably in the α- position, with respect to the group CONHR-,. e.g 1 -methylethenyl .

Compounds of formula (I) wherein A is an unsubstituted ethenyl group or α- substituted ethenyl group e.g. 1 -methylethenyl represent a preferred class of compounds according to the invention, of which those wherein A is unsubstituted ethenyl group are particulalry preferred.

Compounds of formula (I) wherein R., is naphthyl e.g. 1-naphthyl, or tetrahydronaphthyl, e.g. 1-1 ,2,3,4,-tetrahydronaphthyl or 1-5,6,7,8 tetrahydronaphthyl represents a further preferred class of compounds according to the invention. Of this class of compounds those wherein R*ι is naphthyl e.g. 1-naphthyl are particularly preferred.

A preferred group of compounds of formula (I) are those wherein m is 2, R is chlorine in the 4 and 6 positions and R-| is 1-naphthyl.

A particularly preferred compound according to the invention is: (E)-3-[2'-(1"- naphthyl carbamoyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid and physiologically acceptable salts thereof e.g. sodium or potassium salts or metabolically labile esters thereof.

The compounds of formula (I) and or physiologically acceptable salts thereof are excitatory amino acid antagonists. More particularly they are potent antagonists at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. As such they are potent antagonists of the NMDA receptor complex. Moreover the compounds of the invention exhibit an advantageous profile of activity including good bioavailibility. These compounds are therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus the compounds are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasc-^am, hypoglycemia, anaesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest. The compounds are useful in the treatment of chronic neurodegenerative diseases such as; Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodengeration , (e.g. AIDS, encephalopaties), Down syndrome, epilepsy, schizophrenia, depression, anxiety, pain, neurogenic bladder, irritative bladder disturbances, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine, benzodiazepine, and emesis.

The potent and sei action of the compound of the invention at the strychnine- insensitive . ycine binding site present on the NMDA receptor complex may be readily determined using conventional test procedures. Thus the ability to bind at the strychnine insensitive glycine binding site was determined using the procedure of Kishimoto H et al. J Neurochem 1981 , 37

1015-1024. The selectivity of the action of compounds of the invention for the strychnine insensitive glycine site was confirmed in studies at other ionotropic known excitatory amino acid receptors. Thus compound of the invention were found to show little or no affinity for the kainic acid (kainate) receptor, a-amino-

3-hydroxy-5-methyl-4-isoxazole-prophonic acid (AMPA) receptor or at the

NMDA binding site.

Compounds of the invention have also been found to inhibit NMDA induced convulsions in mice using the procedure Chiamulera C et al. Psychopharmacology (1990) 102, 551-552.

The invention therefore provides for the use of a compound of formula (I) and or physiologically acceptable salt or metabolically labile ester thereof for use in therapy and in particular use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex. The invention also provides for the use of a compound of formula (I) and/or a physiologically acceptable salt or metabolically labile ester thereof for the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.

According to a further aspect the invention also provides for a method for antagonising the effects of excitatory amino acids upon the NMDA receptor complex, comprising administering to a patient in need thereof an antagonistic amount of a compound of formula (I) and/or a physiologically acceptable salt or metabolically labile ester thereof.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.

It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 800mg per day, dependent upon the route of administration.

Thus for parenteral administration a daily dose will typically be in the range 20- 100mg preferably 60-80mg per day. For oral administration a daily dose will typically be within the range 200-800mg e.g. 400-600mg per day.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or metabilcially labile ester thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflation, implant, or rectal administration. Parenteral administration is preferred.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or εrdium starch glycollate, or wetting agents such as sodium lauryl sulphate. The icDlets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p- hydroxybenzoates or ascorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form 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 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.

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, such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, 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.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable carrier such as lactose or starch. The powder composition may be presented in unit dosage form in for example capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The compositions according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30- 95% for tablets and capsules and 3- 50% for liquid preparations.

Compounds of general formula (I) and salts thereof may be prepared by the general methods outlined hereinafter. In the following description, the groups R₁ , R₂ and X are as defined for the compounds of formula (I) unless otherwise stated.

Compounds of formula (I) wherein the groups R, R^ A and m have the meanings defined above may be prepared by reaction of an activated derivative of the carboxylic acid (II)

wherein R, m, and A have the meanings defined above, R3 is a carboxyl protecting group and R₈ represents hydrogen or a nitrogen protecting group with the amine

HzNR! (Ill)

where R-| , have the meanings defined above, followed where necessary by subsequent removal of the carboxyl protecting group R3 and any nitrogen protecting group R₈.

Suitable activated derivatives of the carboxyl group include the corresponding acyl halide, mixed anhydride, activated ester such as a thioester or the derivative formed between the carboxylic acid group and a coupling agent such as that used in peptide chemistry, for example carbonyl diimidazole or a diimidide such as dicyclohexylcarbodiimide.

The reaction is preferably carried out in an aprotic solvent such as a hydrocarbon, a halohydrocarbon, such as dichloromethane or an ether such as tetrahydrofuran.

Suitable carboxyl protecting groups R3 for use in these reactions include allyl, alkyl, trichloroalkyl, t alkylsilylalkyl or arylmethyl groups such as benzyl, nitrobenzyl or trityl.

Suitable nitrogen protecting groups R₈ include alkoxycarbonyl e.g. t- butoxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2- trimethylsilylethoxymethyl.

The activated derivatives of the carboxylic acid (II) may be prepared by conventional means. A particularly suitable activated derivative for use in this reaction is thioester such as that derived from pyridine-2-thiol. These esters may conveniently be prepared by treating the carboxylic acid (II) with 2,2'- dithiopyridine and triphenylphosphine in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, a halohydrocarbon e.g. dichloromethane, an amide e.g. N,N-dimethylformamide or acetonitrile.

Compounds of formula (I) may also be prepared from compound (IV) in which R and m have the means given above, R3 is a carboxyl protecting group, R4 is a hydrogen atom or a C-|_4alkyl group, and R₈ is hydrogen or a nitrogen protecting group.

by reaction with an appropriate phosphorus reagent capable of converting the group CR4O into the group ACONR1 wherein R-| has the meanings defined above for formula (I) followed where necessary or desired by removal of the carboxyl and/or nitrogen protecting group.

When R₈ is a nitrogen protecting examples of suitable groups include alkoxycarbonyl e.g. t-butoxycarbonyl or 2-trimethylsiiylethoxymethyl or arylsulphonyl e.g. phenylsulphonyl.

Suitable carboxyl protecting groups include allyl, alkyl, trichloroalkyl, trialkylsilylalkyl or arylmethyl groups such as benzyl, nitrobenzyl or trityl.

In one embodiment of this process the reaction may be carried using a phosphorus ylide of formula (V)

( 5)3P=CHCONHR-| (V)

wherein R5 is an alkyl or phenyl group, and R-| has the meanings defined above, as the appropriate reagent for converting the group CR₄0 into the group ACONR.,.

The reaction is carried out in aprotic solvent such as acetonitrile or an ether such as 1 ,4-dioxane and preferably with heating e.g. 40-120°. In a further embodiment of the process the reaction is carried out using a phosphonate of formula (VI)

(R₇O)₂OPCH(R₆)CONHR₁ (VI)

wherein R5 represents hydrogen or C-|_4alkyl;

Ryrepresents C-_j^alkyl and R., has the meaning defined above.

The reaction is carried out in an aprotic solvent such as tetrahydrofuran and optionally with heating.

In any of the above reactions the carboxyl protecting group R3 may be removed by conventional procedures known for removing such groups. Thus compounds when R3 is an alkyl group, this may be removed by hydrolysis using an alkali metal hydroxide e.g. lithium hydroxide or sodium hydroxide in a solvent such as an alkanol e.g. ethanol or isopropanol, followed where desired or necessary by that addition of a suitable acid e.g. hydrochloric acid to give the corresponding free carboxylic acid.

In any of the above reactions the nitrogen protecting group may be removed by conventional procedures known for removing such groups, for example by acid or base hydrolysis. Thus when R₈ is alkoxycarbonyl e.g. t-butoxycarbonyl may be removed by alkaline hydrolysis using for example lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol e.g. isopropanol.

Physiologically acceptable salts of compounds of formula (I) may be prepared by treating the corresponding acid with an appropriate base in a suitable solvent. For example alkali and alkaline metal salts may be prepared from an alkali or alkaline metal hydroxide, or the corresponding carbonate or bicarbonate thereof. Alternatively alkali or alkaline metal salts may be prepared by direct hydrolysis of carboxyl protected derivative of compound of formula (I) with the appropriate alkali or alkaline metal hydroxide.

Metabolically labile esters of compounds of formula (I) may be prepared by esterification of the carboxylic acid group or a salt thereof or by trans esterfication using conventional procedures. Thus for example acyloxyalkyl esters may be prepared by reacting the free carboxylic acid or a salt thereof with the appropriate acyloxylalkyl halide in a suitable solvent such as dimethylformamide. For the esterifcation of the free carboxyl group this reaction is preferably carried out in the presence of a quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride.

Aminoalkyl esters may be prepared by transesterfication of a corresponding alkyl ester e.g. methyl or ethyl ester by reaction with the corresponding aminoalkanol at an elevated temperature e.g. 50-150°.

Compounds of formula (II) are either known compounds or may be prepared by analogous methods to those described for known compounds. Thus compounds of formula (II) may be prepared from cpmpound of formula (IV) and a phosphorus ylide (R5)3P=CH 0026^ or phosphonate (RjO^OP-CH (R6)Cθ2Bu^t using similar reaction conditions for those described above for the reaction of (IV) with the compounds of formula (V) or (VI) followed by removal of the t-butyl protecting group.

Compounds of formula (IV) wherein R3 is a carboxyl protecting group, and R₄ is hydrogen may be prepared by treating the corresponding indole (VII).

(vπ)

wherein R, R₃, R₈ and m are as defined above with N- methylformanilide and phosphorous oxychloride in a solvent such as 1 ,2-dichloroethane.

Compounds of formula (IV) wherein R3 is a carboxyl protecting group, R4 is alkyl may be prepared by treating the indole (VII) with the amide (CH3)2NCOR4 and phosphorous oxychloride in a suitable solvent.

The indoles of formula (VII) are either known compounds or may be prepared by analogous methods to these described for the known compounds.

The compounds of formula (V) or (VI) are either known or may be prepared using methods described for analogous compounds.

In order that the invention may be more fully understood the following examples are given by way of illustration only.

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus and are uncorrected .All temperature refers to °C. Infrared spectra were mesured on a FT-IR instrument. Proton Magnetic Resonance (¹ H-NMR) spectra were recorded at 300 MHz, chemical shifts are reported in ppm downfield (d) from Mβ4Si, used as internal standard , and are assigned as singlets (s), doublets (d), doublets of doublets (dd), triplets (t), quartets (q) or multiplets (m). Colum chromathography was carrier out over silica gel (Merck AG Darmstaadt, Germany). The following abbrevietions are used in text: EA = ethyl acetate, CH = cyclohexane, DCM = dichloromethane. Tic refers to thin layer chromatography on silica plates. Solution were dried over anhydrous sodium sulphate.

Intermediate 1

Ethyl 4.6-dichloroindole-2-carboxylate To a solution of ethyl pyruvate (2.05 ml), in absolute ethanol (38 ml), concentrated sulphuric acid (0.5 ml) was added slowly under vigorous stirring. The resulting mixture was stirred at 30° for 10 minutes, then 3,5- dichlorophenylhydrazine hydrochloride (4g) was added portionwise. The mixture was heated to reflux for 4 hours, cooled to 23°, poured into cold water (500 ml) and extracted with diethyl ether (3 X 300 ml). The organic layers were separated and dried. The solvent was evaporated under reduced pressure to give the 2-(3,5-dichlorophenylhydrazone)propionic acid ethyl ester as yellow solid (5g; tic DCM, Rf=0.79, 0.47) in E and Z isomers mixture. The solid was added to polyphosphoric acid (20 g) under stirring and the mixture was heated at 45° for 20 minutes to give a brown product which was crystallized by 95% ethanol (300 ml) to obtain the title compound as a yellow-brown solid (3.3 g;m.p.180°; Tic DCM, Rf=0.54). IR(CDCI₃) Vmax(crτr¹ )3440(NH), 1772- 1709(C=O). ¹ H-NMR(CDCI₃) 9.00(s), 7.28(d), 4.42(q), 1.42(t).

Intermediate 2

Ethyl 3-formyl-4.6-dichloroindole-2-carboxylate

A solution of N-methyl formanilide (5.19 g) and phosporous oxychloride (5.53g) was stirred at 23° for 15 minutes. 1 ,2- Dichloroethane (60ml) and intermediate 1

(6g) were added and the resulting suspension was stirred at 80° for 6 hours. The reaction mixture was poured into a 50% aqueous solution of sodium acetate (300 ml) to give , by filtration, the title compound as a yellow solid (4.1 g; tic EA/CH:4/6, Rf=0.4).

IR(Nujol) Vmax(cm-¹ ) 1726 (C=0), 1663 (C=0), 1556 (C=C), 2725-2669 (CH). H-NMR(DMSO) 13.15(s), 10.60 (s), 7.54(d), 7.40(d), 4.43(q), 1.36 (t). ]nt -mediate 3

(E__ thyl 3-r2-(tertbutoxycarbonyl)ethenyll-4.6-dichloroindole-2-carboxyl ate

A solution of tertbutoxycarbonylmethyltriphenylphosphorane (5.33g) and intermediate 2 (3g) in dioxan/acetonitrile (1 ;1 ;60ml) was stirred at 60° for 7 hours. The solvent was evaported under reduced pressure and the residual oil was purified by chromatography, eluting with cyclohexane and ethyl acetate 7/3, to obtain the title compound (2,73g) tic EA/CH: 3/7; Rf = 0.35. IRWujol) Vmax (cm"¹ ) 3240-3128 (OH,NH), 1699-1670(C=O). ¹ H~NMR(DMSO) 12.6(s), 8.28(d), 7.51(d), 7.32(d), 6.44(d), 4.37(q), 1.35(t).

Intermediate 4

(E) Ethyl 3-r2-carboxyethenvn-4.6-dichloroindole-2-carboxylate Intermediate 3 (0.5g) was dissolved in 100% formic acid (60ml) and the suspension was left at 23° for 2 hours. The solvent was evaporated under reduced pressure to give the title compound as a white solid (0.408g; tic EA/CH: 45/55; Rf = 0.18).

IR(Nujol) Vmax (cm"¹ ) 3246-3128 (O^' MH), 1699-1670(C=O), 1634 (C=C). ¹ H-NMR(DMSO) 12.6(s), 8.28(d), 7.51 (d), 7.32(d), 6.44(d), 4.37(q), 1.35(t).

Example 1

(E) Ethyl 3-r2'-(1"-naphthyl aminocarbonvπethenyll-.4.6-dichlorindole-2- carboxylate

To a solution of intermediate 4 (280mg), in do/ THF (18ml) 2,2'-dithiopyridine

(267mg), and triphenyl phosphine (317mg), were added. The solution was stirred under nitrogen at room temperature for 3 hours, then 1- aminonaphthalene (380mg) was added. The resulting solution was refluxed for

20 hours and the resultant precipitate was filtered to give the title compound

C-95mg). m.p. >256°C.

-R (Cm-¹); 3306 (N-H), 1676 (C=0), 1620(C=C). H-NMR; 12.64(bs), 10.19(s), 8.29(d), 8.12(d), 7.96(m), 7.89(d), 7.78(d), 7.62-

7.48(m), 7.35(d), 7.03(d), 4.41 (q), 1.39(t).

Example 2

(E Ethyl 3-r2V5 6^>\7'\8^* etrahvdronaphthyl-1^"-amiπocarbonyl)-ethenylV 4.6-dichloroιndole-2-carboxylate 2,2^'-Dithiopyridine (291 mg) and triphenylphosphine (347 mg) were added to a solution of intermediate 4 ( 310 mg) in acetonithle (20 ml). The mixture was stirred at room temperature for 1.5 hours, then 1-amino-5,6,7,8- tetrahydronaphtalene (166 mg) was added.The resulting solution was heated at 60° for 1 hour and then kept at room temperature overnight. The following day it was refluxed for 5 hours and the precipitate formed was filtered to give the title compound (264 mg).as an off-white solid. IR(Nujol)V_max(crτr¹): 3440-3300(NH), 1674(C=0)

¹ H-NMR(DMSO): 12.6(s), 9.34(s), 8.18(d), 7.497(d), 7.307(d), 7.30(b_m), 7.06(t), 6.90(d), 6.82(d), 4.37(q), 2.72(t), 2.60(t), 1.70(m).

Example 3

(E) Ethyl 3-f2V1" .2" .3" .4" -tetrahvdronaphthyl-1"-aminocarbonvnethenvn-

4,6-dichloroindole-2-carboxylate 2,2^'-Dithiopyridine (291 mg) and triphenylphosphine (347 mg) were added to a solution of intermediate 4 (310 mg) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 1.5 hours, then a suspension of 1 ,2,3,4- tetrahydro-1-naphtylamine hydrochloride (208 mg), dry triethylamine (0.158 ml) and tetrahydrofuran (3 ml), prestirred for 1 hour, was added. The reaction was kept at room temperature for 17 hours and then refluxed for 5 hours. The precipitate formed was filtered .washed with water and then crystallized from tetrahydrofuran, giving the title compound (152 mg, m.p.>250°C,tlc EA/CH:6/4, Rf=0.37) as white solid. IR(Nujol)V_max(ατr¹ ): 3302(NH), 1676(C=0), 1618(C=0) I H-NMR(DMSO): 12.52(b_s), 8.53(d), 8.14(d), 7.49(d), 7.29(d), 7.16(m), 6.58(d), 5.13(m), 4.35(q), 2.75(m), 1.93(m), 1.75(m), 1.33(t).

Example 4 3-r2'-(1"-naphthylaminocarbonyl)ethenyl)-4.6-dichloroindole-2-carboxylic acid sodium salt

To a solution of Example 1 (295mg), in isopropyl alcohol (20ml) sodium hydroxide (20mg) was added in two portions. The solution was heated at 60° for 11 hours and then poured into water (30ml). The aqueous solution was evaporated under reduced pressure and the resultant precipitate was filtered and washed with water to give the title compound (246mg). mp. >256°. IR (Cm-¹); 3362 (N-H), 1649 (C=0 broad), 1670(C=C).

¹H-NMR; 11.8(bs), 9.98(bs), 8.64(d), 8.11(m), 7.91 (m), 7.84 - 7.7(d+d), 7.58 -

7.57(m), 7.41(d), 7.30(d), 7.11(d).

Example 5

dichloroindole-2-carboxylic acid sodium salt

Example 2 (264 mg) was suspended in isopropyl alcohol (20 ml), sodium hydroxide (92.3 mg) was added and the mixture was heated to 60° for 6 hours. The solvent was removed and the residue was suspended in water and filtered to give the title compound (250 mg, ).

IR(Nujol)V_max(crτr¹ ): 3439-3190(NH), 1639(C=0), 1603(C=O,C=C). ¹ H-NMR(DMSO): 11.8(b_s), 9.16(b_s), 8.56(d), 7.41(d), 7.28(d), 7.17(d), 7.10(d), 7.05(t), 6.88(d), 2.73(m), 2.63(m), 1.71(m).

Using the same general procedure the following compound was prepared:

Example 6

E) 3-f2^{^}-(r\2'\3".4"-tetrahvdrrnaphthyl-r -aminocarbonyl)ethenvn-4.6- dichloroindole-2-carboxylic acid sodium salt

Starting from example 3 (152 mg) and sodium hydroxide (53.2 mg), the title compound was obtained (110 mg,) as white solid.

IR(nujol)V_max(crτr¹): 1607 (C=0)

¹H-NMR(DMSO): 11.6(b_s), 8.47(d), 8.26(d), 7.36(d), 7.05(d), 7.22-7.04(m), 6.93(d), 5.09(m), 2.72(m), 1.90(m), 1.72(m).

Pharmacy Examples A. Capsules/ Tablets

Active ingredient 200.0mg

Starch 1500 32.5mg

Microcrystalline Cellulose 60.0mg

Croscarmellose Sodium 6.0mg

Magnesium Stearate 1.5mg The active ingredient is blended with the other excipients. The blend can be used to fill gelatine capsules or compressed to form tablets using appropriate punches. The tablets can be coated using conventional technqiues and coatings.

B. Tablet

Active ingredient 200.0mg

Lactose lOO.Omg

Microcrystalline Cellulose 28.5mg

Povidone 25.0mg

Croscarmellose Sodium 6.0mg

Magnesium Stearate 1.5mg

The active ingredient is blended with lactose, microcrystalline cellulose and part of the croscarmellose sodium. The blend is granulated with povidone after dispersing in a suitable solvent (i.e. water). The granule, after drying and comminution is blended with the remaining excipients. The blend can be compressed using appropriate punches and the tablets coated using conventional techniques and coatings.

C. Injection Formulation

Active ingredient 0.1 - 7.00mg/ml Sodium phosphate 1.0 - 50.00mg/ml

NaOH qs desidered pH (range 3-10) water for injection qs to 1 ml

The formulation may be packed in glass (ampoules) with a rubber stopper (vials, syringes) and a plastic/metal overseal (vials only).

P. Dry Powder for constitution with a suitable vehicle

Active ingredient: 0.1 - lOO.OOmg Mannitol qs to 0.02 - 5.00mg

packed in glass vials or syringes, with a rubber stopper and (vials only) a plastic metal overseal.

E. Inhalation Cartridges mg/cartridge Active ingredient (micronised) 5.00

Lactose to 25.00

The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into a proper unit dose container as blister or capsule for use in a suitable inhalation or insufflation device.

The affinity of the compound of the invention for strychnine insensitvie glycine binding site was determined using the procedure of Kishimoto H. et al J. Neurochem 1981 , 37,1015-1024. The pKi values obtained with respresentative compounds of the invention are given in the following table. Example No. pKi

4 7.4

5 7.1

6 6.7

The ability of compounds of the invention to inhibit NMDA induced convulsions in the mouse was determined using the procedure of Chiamulera C et al. Psychopharmacology 1990, 102, 551 -552. In this test the ability of the compound to inhibit the generalized seizures induced by an intracerebroventricular injection of NMDA in mice was examined at a number of dose levels. From these results the dose required to protect 50% of the animals from the convulsive action of the NMDA was calculated. This expressed as mg/kg is referred to as the ED₅₀ value. Thus in this test the compound of

Example 4 had an EDso of 0.4mg/kg when administered by i.v and 7.0mg/kg when given orally.

The compounds of the invention are essentially non toxic at therapeutical ly useful doses.

Claims

(1) A compound of formula (I)

or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, S02R2or COR2 wherein R₂ represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2;

A represents an optionally substituted ethenyl, in the trans configuration; R₁ represents an optionally substituted fused bicyclic carbocyclic group.

(2) A compound as claimed in Claim 1 wherein m is 2 and R is chlorine in the 4 and 6 positions.

(3) A compound as claimed in Claim 1 or Claim 2 wherein A is an unsubstituted ethenyl, or an α-substituted ethenyl group.

(4) A compound as claimed in any of Claims 1 to 3 wherein Ri is a 1- naphthyl group.

(5) (E)-3-[2'-(1 '-naphthyl carbamoyl)ethenyl]-4,6-dichloroindole-2- carboxyiic acid and physiologically acceptable salts or metabolically labile esters thereof.

(6) Compounds as claimed in any of Claims 1 to 5 for use in therapy.

(7) The use of a compound as claimed in any of Claims 1 to 5 in the manufacture of a therapeutic agent for antagonising the effects of excitatory amino acids on the NMDA receptor complex.

(8) A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 5 in admixture with one or more physiologically acceptable carrier or excipients.

(9) A method of treatment of a mammal including man for conditions where antagonising the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit comprising administration of an effective amount of a compound as claimed in any of Claims 1 to 8.

(10) A process for preparing the compounds as defined in Claim 1 which comprises:

(a) reacting an activated derivative of the carbocyclic acid (II) wherein R, m and A have the meanings defined in formula (I), R₃ is a carboxyl protecting group and R₈ is hydrogen or a nitrogen protecting group.

with the amine R-i NH₂, wherein R-i has the meanings defined in formula (I) followed where necessary by the subsequent removal of the carboxyl protecting group R₃ and or the nitrogen protecting group R₈.

(b) reacting the indole (IV) wherein R and m have the meanings defined in formula (I), R₃ is a carboxyl protecting group, R₈ is a hydrogen or a nitrogen protecting group and R₄ is hydrogen or C^alkyl,

with an appropriate phosphorous reagent capable of converting the group CR₄O into the group A CONHR, wherein A and R-* have the meanings defined above followed where necessary or desired by removal of the carboxyl and or nitrogen protecting group.