IE84467B1 - Therapeutic heterocyclic compounds - Google Patents

Description

Therapeutic Heterogycllc Comgounds The present invention is concerned with new chemical compounds, their preparation. pharmaceutical formulations containing them and their use in medicine, particularly the prophylaxis and treatment of migraine.

Receptors which mediate the actions of 5-hydroxytryptamine (5-HT) have been identified in mammals in both the periphery and the brain. According to. the classification and nomenclature proposed in a recent article (Bradley gt gt, Neurophannac.. gs, 563 (1986), these receptors may be classified into three main types, fig. "5-HT,-like", 5-HT, and 5-HT,. Various classes of compounds have been proposed as 5-HT agonists or antagonists for therapeutic use, but these have not always been specific to a particular type of 5-HT receptor. European Patent Specification 0313397 describes a class of 5-HT agonists which are specific to a particular type of "5-HT,-like" receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated. For example, the receptor in question mediates vasooonstriction in the carotid vascular bed and thereby modifies blood flow therein. The compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein vasoconstriction in the mrotid vascular bed is indicated, for example, migraine, a condition associated with excessive dilation of the carotid vasculature. However, it is within the scope of the earlier application that the target tissue may be any tissue wherein action is mediated by "5-HT,-like‘ receptors of the type referred to above.

EP-A-354777 describes a class of compounds having an indole ring structure substituted at the 3-position by a piperidine group and at the 5-position by a 2- sulfonylaminoethyl group Le. a sulphonamate group. These indole derivatives exhibit 5-HT,-like receptor agonism.

A broader class of indole derivative is described in EP-A-303506. These compounds are substituted at the 3-position of the indole ring by a piperidine or 1,2.3.6-tetrahydro- 4-pyridinyl group and at the 5-position by a sulphonamide or carboxamide group. They are also said to exhibit 5—HT,-like receptor agonism.

GB-A-2186874 describes indole derivatives substituted at the 3—posltion by an aminoalkyl group and at. the 5-position by a sulphonamide or carboxamide group.

These compounds are said to have selective vasoconstrictor activity.

We have now found a further class of compounds having exceptional "5-HT1-like" receptor agonism and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as "migraine".

According to the first aspect of the present invention, therefore. there is provided a compound N,N-dimethyl[5-(2-oxo-1 .3-oxazolidinyl-methyl)-V1 H-indol yl)ethylamine in either its (3) or (R) form or as a mixture thereof in any proportions. or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof The salts and solvates of these compounds, for example. the hydrate maleates, are particularly preferred.

According to a second aspect of the present invention, there is provided a compound of the invention as hereinbefore defined or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof for use as a therapeutic agent, specifically as a "5~HT,-like" receptor agonist. for example, as a carotid vasoconstrictor in the prophylaxis and treatment of migraine. As indicated, however. target organs for the present compounds other than the carotid vasculature are within the scope of the present invention.

The amount of a compound of the invention as hereinbefore defined, or a salt or solvate thereof, which is required to achieve the desired biological effect will depend on a number of factors such as the specific compound. the use for which it is intended, the means of administration, and the recipient. A typical daily dose for the treatment of migraine may be expected to lie in the range 0.01 to 5mg per kilogram body weight. Unit doses may contain from 1 to 100mg of a compound of the invention as hereinbefore defined, for example, ampoules for injection may contain from 1 to 10mg and orally administrable unit dose formulations such as tablets or capsules may contain from 1 to 100mg. Such unit doses may be administered one or more times a day, separately or in multiples thereof. An intravenous dose may be expected to lie in the range 0.01 to 0.15mg/kg and would typically be administered as an infusion of from 0.0003 to O.15mg per kilogram per minute. infusion solutions suitable for this purpose may contain from 0.01 to 10mg/ml.

When the active compound is a salt or solvate of a compound of the invention, the dose is based on the cation (for salts) or the unsolvated compound.

Hereinafter references to 'compound(s) of the invention’ will be understood to include compounds of the invention as hereinbefore defined, physiologically acceptable salts and solvates thereof According to a third aspect of the present invention, therefore, there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of the invention and/or a pharrnacologically acceptable salt or solvate thereof together with at least one pharmaceutical carrier or excipient. These pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a "5-HT,-like" receptor agonist is indicated, for example, migraine. The carrier must be phamiaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or liquid and is preferably formulated with at least one compound of the invention as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.

Possible fonnulations include those suitable for oral, sublingual, buccal, parenteral (for example. subcutaneous. intramuscular, or Intravenous). rectal, topical and intranasal administration. The most suitable means of administration for a particular patient will depend on the nature and severity of the condition being treated and on the nature of the active compound, but, where possible, oral administration is preferred.

Formulations suitable for oral administration may be provided as discrete units. such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.

Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically. a flavoured base, such as sugar and acacia or tragacanth, and pastilles comprising the active compound in an inert base. such as gelatin and glycerin or sucrose and acacia.

Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.

Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers fonning the suppository base, for example, cocoa butter.

Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes. gels, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly. lanolin, polyethylene glycols, alcohols. and combinations thereof. The active ingredient is typically present in such formulations at a concentration of from 0.1 to 15% wlw.

The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately adrnixlng the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.

For example, a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.

Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in suflicient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.

Thus, according to a fourth aspect of the present invention. there is provided the use of a compound of the invention in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which a "5-HT,-like" receptor agonist is indicated. for example, migraine.

According to a fifth aspect of the invention, compounds of the invention may be prepared by reacting a compound of formula (ll) (isolated or in situ -infra).

NEENH2 w\ » (H) (CH2),, ‘ ' wherein n is 1 and W is a group H ‘ N O \% and the chiral centre * is in its (8) or (R) form or is a mixture thereof in any proportions, with a compound of formula (III) L. '0. (H1) or a carbonyl-protected form thereof, such as the dimethyl or diethyl acetal, wherein L is a suitable leaving group, such as chlorine. or a protected amino group, either of which may be converted into an amino group or a dimethylamino group, or is - NR'R’ where R‘ and R’ are each methyl or hydrogen. The reaction is typically carried out by refluxing the compounds in a polar solvent system, for example, ethanol/water, dilute acetic acid, or water in the presence of an acidic ion exchange resin, for example, 'Amberlyst 15'.

Standard N-alkylation methods may be used to convert compounds wherein R‘ and R2 are hydrogen to corresponding compounds of the invention wherein R‘ and R’ are each methyl.

Compounds of the invention may be prepared from the corresponding compound wherein R‘ = R’ = H by methods of N,N-dialkylation well known to those skilled in the art, for example, by treatment with the appropriate aldehyde in the presence of a reducing system. for example, sodium cyanoborohydride/acetic acid, in a polar solvent, such as methanol.

Hydrazines of formula (ll) may be prepared from the corresponding aniline of formula (IV) \ (CH2), (IV) wherein n and W are as hereinbefore defined, by diazotisation followed by reduction. Diazotisation is typically carried out using sodium nitrite/c. HCl and the resulting diazo product reduced i_r1 fl using, for example, tin(ll) chloride/c.HC|. The Anilines of formula (IV) may be prepared by reduction of the corresponding Q-nitro compound of fonnula (V) N 02 W . : ‘ .

\ (V) (CH2)n wherein n and W are as hereinbefore defined. typically by catalytic hydrogenation using, for example, Pd/C in a polar solvent system, such as an acidified mixture of ethanol, water and ethyl acetate.

Anilines of formula (IV) wherein Wis as hereinbefore defined may also be prepared by cycllsing a compound of formula (XXXIII) NH2 H(R4)N ‘ H\/K(CH2)n wherein n is 1 and X is oxygen and R‘ is -COZR5 where R‘ is CH alkyl, typically by heating in the presence of a base. such as sodium methoxide.

(XXXIII) Compounds of formula (X)(Xlll) may be prepared by reducing a corresponding C14 alkyl ester using, for example, sodium borohydride. in a polar solvent system, such as ethanol/water, at 0°C. The ester may be prepared by esterifying the corresponding carboxylic acid using, for example, the appropriate alcohol and HCI or by reducing the corresponding Q-nitro compound. for example, by catalytic hydrogenation. Both the acid and the Q-nitro compound may be prepared from the corresponding Q-nitroaminoacid, the acid by N-alkoxycarbonylation using, for example, R‘ OCOCI where R5 is as hereinbefore defined, followed by reduction of the nitro group, for example, by catalytic hydrogenation, or by reduction of the nitro group followed by N- alkoxycarbonylation, and the Q-nitro compound by N- alkoxycarbonylation (as for the acid) followed by esterification using. for example, the appropriate alcohol and HCI, or by esterification followed by N- alkoxycarbonylation. The Q-nitroaminoacid may be obtained commercially or prepared from readily available starting materials by methods known to those skilled in the art or obtainable from the chemical literature, for example, by Q-nitration of the corresponding amino acid using. for example, c.H,SO,/c.HNO, at 0°C.

Q-Nitro compounds of formula (V) may be prepared by reacting a compound of fomiula (Vi) N02 H(R)N (VT) (CH2),, wherein n and X are as hereinbefore defined and R is hydrogen. with a compound of formula (Vll) L Y;".‘_'C/l \ (VII) wherein Y is oxygen and L and L‘. which may be the same or different, are suitable leaving groups, for example. chlorine, ethoxy, trichloromethyl, trichloromethoxy, or imidazoyl, for example, in the case where L = L‘ = chlorine, in a non-polar solvent, such as toluene, in the presence of a base, for example, potassium hydroxide.

Compounds of formula (VI) may be prepared by ring-opening a compound of formula (V) wherein n and W are as hereinbefore defined, for example. by refluxing in ZN aqu. KOH.

Compounds of formula (VI) may be prepared by esterification of the corresponding carboxylic acid, typically by treatment with thionyl chloride and an appropriate alcohol at -10°C. followed by reduction of the ester using, for example, sodium borohydride, in a polar solvent system, such as ethanol/water, at 0°C. The acid may be obtained commercially or prepared from readily available starting materials by methods known to those skilled in the art or obtainable from the chemical literature, for example, by ;;-nitration of the corresponding amino acid using, for example. c.H2SO,Ic.HNO, at 0°C.

Compounds of fonnula (Ill) and (VII) may be obtained commercially or prepared from readily available starting materials by methods known to those skilled in the art or obtainable from the chemical literature.

Q-Nitro compounds of formula (V) may also be prepared by Q-nitration of a compound of formula (XXXVI) w (XXXVI) X .(CH2)n wherein n and W are as hereinbefore defined, using, for example, c.H2S0.Ic.HNO3 at 0°C.

Compounds of fonriula (XXXVI) may be prepared by reacting a compound of formula (XXXVII) E[(R) N (XXXVII) ax . ((3111),, wherein n. R and X are as hereinbefore defined, with a compound of formula (VII) wherein Y. L and L‘ are as hereinbefore defined. typically in the presence of a base, for example, potassium hydroxide, in a non-polar solvent. such as toluene.

Compounds of fonnula (XXXVII) may be prepared by reducing the corresponding nitro compounds, typically by catalytic hydrogenation using. for example, Pd/C in a polar solvent, such as ethanol. The nitro compound corresponding to the compound of formula (XXXVII) may be prepared by reacting a compound of formula (XXl\./) :»: , (XXIV) . \<‘-’"z>.n+1 wherein n is as hereinbefore defined. with parafonnaldehyde in a polar aprotic solvent. such as DMF. in the presence of a base, for example, sodium methoxide. at 0°C, or by esterification of the corresponding carboxylic acid. typically by treatment with thionyl chloride and an appropriate alcohol at -10°C, followed by reduction of the ester group using, for example, sodium borohydride, in a polar solvent system. such as ethanollwater at 0°C .

The compound of formula (XXIV) and the acid may be obtained commercially or prepared from readily available starting materials by methods known to those skilled in the art or obtainable from the chemical literature.

Compounds of the invention may also be prepared by reacting a compound of formula (XV) wherein n, R and X are as hereinbefore defined and Z is a group -CH2CHzNR‘R’ wherein R‘ and R’ are each methyl with a compound of formula (Vll) wherein Y, L and L‘ are as hereinbefore defined. for example, in the case where L = L‘ = ethoxy, 1 0 by heating in the presence of a base, for example, potassium carbonate.

Compounds of formula (XV) may be prepared by esterification of the corresponding carboxylic acid. typically by treatment with thionyl chloride and an appropriate alcohol at -10°C, followed by reduction of the ester using, for example. sodium borohydride. in a polar solvent system, such as ethanovwater, at OoC. The acid 1 5 may be prepared by ring-opening a compound of formula (XVI) wherein n. R and Z are as hereinbefore defined and R‘ is hydrogen or benzyl. typically by refluxing in water in the presence of a base, for example, barium hydroxide.

Compounds of formula (XVI) may be prepared by reducing a compound of formula (XVII) R N 2 5 N CH (XVII) Y A \(cH / 2)::-1 R N z wherein n, R, R‘ and Z are as hereinbefore defined typically by catalytic hydrogenation using, for example, Pd/C in a polar solvent system, such as ethanol/water. Alternatively. an enantioselective reducing agent, such as Rh(cod)(dipamp)‘ BF4 '(JCS, Chem. Comm. 275 (1991)), may be used to reduce the double bond and thereby introduce a chiral centre at the 4-position of the dioxoimldazole ring.

Compounds of formula (XVII) may be prepared by reacting a compound of formula (XVIII) OHC / ‘xvm’ % (CH2)n-I ’ wherein n and Z are as hereinbefore defined, with, in the case where R‘ is to be hydrogen, a compound of formula (X) /< N H (X) wherein R is as hereinbefore defined. typically by heating in glac. acetic acid in the presence of ammonium acetate.

Compounds of formula (XVIII) may be prepared by the reduction/hydrolysis of the corresponding nitrile, typically using Raney nickel and sodium hypophosphite in a mixture of water, acetic acid and pyridine.

Compounds of formula (XVI) wherein R‘ is benzyl and Z is as hereinbefore defined may be prepared by reacting a compound of formula (XXXV) >——NR /‘/N (xxxw (032),, wherein n and R are as herelnbefore defined, with a compound of formula (III) wherein L is as hereinbefore defined, typically using the reaction conditions described above for the reaction of (II) with (III).

Hydrazines of formula (XXXV) may be prepared from the corresponding aniline. typically using the reaction conditions described above for the conversion of (IV) to (II). The aniline may be prepared by reducing the corresponding Q-l1itl’0 compound. typically using the reaction conditions described above for the conversion of (V) to (IV). The Q-nitro compound may be prepared by reacting the corresponding Q nitroaminoacid with benzyl lsocyanate in the presence of base. for example, potassium hydroxide, In a polar solvent. such as water. The Q-nitroaminoacid may be obtained commercially or prepared from readily available starting materials by methods known to those skilled in the art or obtainable from the chemical literature, for example, by Q-nitration of the corresponding amino acid using, for example, c.H2S0,,/c.HN03 at 0°C.

Compounds of formula (XV) may be prepared by reducing a compound of fonnula (XX) wherein n, X and Z are as hereinbefore defined, typically by catalytic hydrogenation using, for example, Pd/C in a polar solvent. such as ethanol.

Compounds of formula (XX) may be prepared by reacting a compound of (XXI) o N l b 2 (CH2)n+l wherein n and Z are as hereinbefore defined, with paraformaldehyde in a polar aprotic solvent, such as DMF , in the presence of a base, for example, sodium methoxide, at 09C.

Compounds of formula (XXI) may be prepared from a compound of formula (XXXIX) N\ CH 4 CM \(Cfi2) / ""° n-1 wherein n and Z are as hereinbefore defined, using for example, sodium borohydride and 40% WN aqu. NaOH in a polar aprotic solvent, such as acetonitrile at 0°C. Compounds of formula (XXXIX) may be prepared from a compound of formula (XVIII) wherein n and Z are as hereinbefore defined by treating with nitromethane in the presence of ammonium acetate.

Compounds of the invention may also be prepared from a compound of formula (XXXI) ‘ (C"2)n wherein n and W are as hereinbefore defined, by methods known to those skilled in the art or obtainable from the chemical literature, for example, by treatment with (COL),, where L is a suitable leaving group, for example, chlorine, to-give the corresponding 3-COCOL compound which may then be treated with HNR‘ R’ , where R‘ and R’ are as hereinbefore defined, and reduced using, for example, lithium aluminium hydride. Alternatively, the compound of formula (XXXI) may be treated with CH,OlKCN to give the corresponding 3-cyanomethyl compound which may then be catalytically hydrogenated over Raney nickel in the presence of HNR‘ R’ as hereinbefore defined.

The aforementioned 3-cyanomethyl compound may also be prepared by cyclising a compound of formula (XXXX) NHN-_:: CH(CH_-,_)2CN (XXXX) W \,, wherein n and W are as hereinbefore defined. ti/Dically by refluxing in an aprotic solvent, such as chloroform, in the presence of polyphosphate ester.

Compounds of formula (XXXX) may be prepared by reacting a compound of formula (II) wherein n and W are as hereinbefore defined with 3-cyanopropanal, or a carbonyl- protected form thereof, such as the diethyl acetal, typically in an aqueous acid, for example, dil. HCI.

Compounds of formula (X)0(l) may be prepared by reducing a compound of formula (XXXII) / (KXXH) SP1: wherein n and Ware as hereinbefore defined, typically by heating with Raney nickel in a polar solvent. such as IPA.

Compounds of formula (XXXII) may be prepared by reacting a hydrazine of formula (II) wherein n and Ware as hereinbefore defined with phenylthioacetaldehyde. or a carbony|—protected form thereof, for example, the diethyl acetal. in a polar solvent. such as acidified ethanol.

For a better understanding of the invention, the following Examples are given by way of illustration.

SYNTHETIC EXAMPLES Synthetic Example 1 Preparation of (S1[5-(Z—oxo-1,3-oxazolidinylmethyl)-1H-indolyllethylamine lS);Meth3d 4~nitrophen3dalanate hydrochloride (S)Amino( 4-nltrophenyllproggnol The product from step (a) (21.29) was dissolved in ethanollwater (190m|, 100/90 vlv) and the solution added dropwise at 0°C to a stirred solution of sodium borohydride (13.0g) in ethanol/water (190ml, 100/90 vlv). The resulting mixture was refluxed for 2.5 hours. cooled and the precipitate filtered off. The ethanol was partially removed from the filtrate in ya the resulting precipitate filtered off and dried to give the desired product as a pale yellow solid (7.5g).

(S)(4-Nitrobenzvll-1 .3-oxazolidinone The product from step (b) (4.9g) was suspended in toluene. the suspension cooled to 0°C and a solution of potassium hydroxide (7.09) in water (56ml) added dropwlse. A solution of phosgene (62.5ml of a 12% w/v solution in toluene) was added dropwise to the resulting solution over 30 minutes and stirring continued for I hour. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried and evaporated in i/a_ciig to give a yellow oil. Crystallisation from ethyl acetate gave the desired product as pale yellow crystals (2.39).

A suspension of the product from step (c) (0.799) and 10% palladium on carbon (0.269) in a mixture of ethanol (15ml), water (11ml), ethyl acetate (2.0ml) and aqu. 2N HCl (2.3ml) was stirred under I atmos. pressure of hydrogen until uptake ceased. The mixture was filtered through Hyflo and the filtrate evaporated i_n £9 to give the desired product as a pale yellow foam (0.799).

(S)—4-(4-Hydrazinobenzyl)-1,3—oxazolidinone hydrochloride The product from step (d) (0.79g) was suspended in water (4.8m|) and c.HCl (8.1 ml) added dropwise. The resulting mixture was cooled to -5°C and a solution of sodium ‘nitrite (0.249) in water (2.4ml) added dropwise to the stirred mixture over 15 minutes followed by 30 minutes’ stirring at -5 to 0°C.

The solution was then added at 0°C over 15 minutes to a stirred solution of tin (ll) chloride (3.8g) in c.HCl (6.9ml), followed by 3 hours’ stirring at room temperature. The solution was evaporated in vacuo and the residue triturated with ether to give the desired product as a pale yellow solid (0.969).

(S)[5-(2-Oxo-1. 3-oxazolidin-4wylmethyl)-1H-indolvllethyl-amine The product from step (e) (0.849) was dissolved in ethanol/water (125ml, :1) and the solution treated with 4—chlorobutanal dimethylacetal (JACS 1365 (1951), 0.529). The mixture was refluxed for 2 hours, the solvent removed in yagug and the residue eluted through a silica column using DCM/EtOH/Nl-l,,OH (30321) as eluant. The desired product was obtained as a colourless oil (0.21 g).

Salt of gmthetic Example 1 Maleate Ethanolic rnaleic acid (1.0 equiv.) was added dropwise to the free base (O.2|g) and the ethanol evaporated in vacuo. The resulting gum was freeze-dried from water to give the desired product as a white lyopholate (0.229). [a 2‘ -5.92° (c = 0.3, MeOH).

‘H NMR (DMSO-da, 5): 2.7-3.5 (6H, m, 052), 3.35 (2H, s, NH2), 4.05 (2H, m, CH1), 4.25 (1 H, m, CI_-l_). 6.05 (2H, s. maleic acid). 6.98 (1H, d, Ar), 7.2 (1H, s, Ar). 7.3 (1H, d. Ar), 7.4 (1H, s, Ar), 7.75 (1H, s, Nj) and 10.9 (1H, s, NH) Microanalysis: C 55.03 (54.96), H 5.54 (5.35), N 10.30 (10.68) Smthetic Example 2 Preparation of (StN,N-dimethyl-2;|5-(2-oxo-1,3-oxazolidinylmethylt1H-indol yllethylamine 0.9 isogognolate 0.5 hydrate A solution of formaldehyde (0.039) in methanol (1.8ml) was added to a solution of the free base from step (f) of Synthetic Example 1 (0.12g) and sodium cyanoborohydride (0.049) in a mixture of methanol (5.5m|) and glac. acetic acid (0.149) and the resulting mixture stirred overnight at room temperature. The pH was adjusted to 8.0 using aqu. KZCO3 and the mixture extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated to give a colourless oil (0.14g) which crystallised from isopropanol to give the desired product as a white crystalline solid (0.109). mp 139-141°C .

‘H NMR (DMSO-d... 3): 2.2 (6H, s, NM_e2), 2.5 (2H, m, Cfi,Ar), 2.7-3.0 (4H, m, Cl-_-I2), 4.1 (2H, m, C520), 4.3 (1H, m, Cfl), 6.9 (1H, 01, Ar), 7.1 (1H, s, Ar), 7.3 (1H, d. Ar), 7.4 (1H, s, Ar), 7.? (1H, s, NflCO) and 10.7 (1H, s, Nfi).

Microanalysis: C 64.26 (64.11), H 8.28 (8.34), N 12.02 (12.00) [OJDZ2 -5.79" (C = 0.5. MeOH) Salts of Synthetic Example 2 Maleate A solution of maleic acid (0.179) in ethanol (5ml) was added to a solution of the free base (0.59) in ethanol (5ml). The mixture was evaporated i_n Q1 and the resulting oil triturated with ether and methanol to give the maleate salt as a white solid which was recrystallised fnom ethanol (0.459), mp 151-152°C.

Hydrochloride Ethereal HCI (1.1 equivs.) was added dropwise to a stirred solution of the free base (0.359) in methanol (1ml) at 0°C. The hydrochloride salt precipitated as an oil. The mixture was evaporated in yagug and the resulting foam crystallised from isopropanol to give the desired product as a white solid (0.369), mp 118-120°C, [OJDZ3 -9.35 (c = 0.31, water).

Succinate A solution of succinic acid (0.369) in ethanol (10ml) was added to a solution of the free base (1.09) in ethanol (10ml). The mixture was evaporated in vacuo and the resulting foam triturated with isopropanol to give the suocinate salt as a white solid (1.09). mp 122-123°c.

Benzoate A solution of benzoic acid (0.379) in ethanol (10m|) was added to a solution of the free base (1.0g) in ethanol (10ml). The mixture was evaporated i_n \@u_o and the resulting foam crystallised from ethyl acetate to give the benzoate salt as a white solid (0.749), mp 90-92°C.

Synthetic Example 3 Alternative preparation of (S)-N.N—dimethyl[5-(2-oxo-1.3-oxazolidinvi-metlmk 1H-indolyl|ethylamine 0.9 isogroganolate 0.5 hydrate as a white crystalline solid (3.59), mp 138-140°C. ‘H NMR, microanalysis and [0,_],, as for product of Synthetic Example 2.

Synthetic Example 4 Preparation 0f(*_t-_)-3 1-meth I-4 i ridl indole -oxo-1 3-oxazolidin I-meth l 1H- (a) 3-( 1-Methyl-1 ,2,3,6-tetrahxdropyrigyl E1 H-indolecarbo-nltrile -Cyanoindole (Aldrich. 20.09) was added to a solution of KOH (22.49) in methanol (200ml). N-Methylpiperidone (Aldrich, 40.4g) was then added dropwise and the resulting mixture refluxed for 4 hours, then cooled and poured into water. The resulting precipitate was filtered off and dried to give the desired product as a pale pink crystalline solid (32.69). (b) 3- 1-Math I-1 2 36-tetrah dro ' I 1H-indolecarbaldeh de Raney nickel (Q 10g) was added to a solution of the product from step (a) (5.0g) and sodium hypophosphite (6.0g) in a mixture of water (25ml), glac. acetic acid (25ml) and pyridine (50ml) at 45°C. The resulting mixture was stirred at 45°C for 1 hour, cooled and basified to pH 9 with 0.88 NH.OH.

The mixture was filtered through Hyflo and the filtrate extracted with chloroform. The combined extracts were dried and evaporated i_n va_cu_g to give the desired product as an off-white solid which was recrystallised from ethanol (2.49). - 1-Meth I-12 36-tetrah dro ri imidazolidinedione I -1H-lndol lmeth lens -2 4- A mixture of the product from step (b) (2.49), hydantoin (Aldrich, 0.989) and ammonium acetate (0.749) in glac. acetic acid (2.4ml) was heated at 120°C for 4 hours. The mixture was cooled and the resulting precipitate filtered off and dried to give the desired product as a yellow solid (2.49). (1)(2.5—Dioxoimldazolidinylmethyl)(1-methylpiperidyl)-1 H-indole The product from step (c) (2.4g) was suspended in a mixture of water (100mI) and ethanol (200ml) and 10% w/w Pd/C (0.259) added. The mixture was stirred under 1 atmos. pressure of hydrogen for 17 hours when uptake was complete. The mixture was filtered through Ryllo and the filtrate evaporated lg \fi<:u_o to give the desired product as a colourless solid (2.4g). (1)- 1-Meth l i eri l 1H-indol Ianine A solution of the product from step (d) (2.49) and barium hydroxide hydrate (8.49) in water (50m|) was refluxed for 72 hours. then cooled and evaporated m EM. The residue was taken up in hot methanol and filtered to remove barium salts. The filtrate was evaporated E going, the residue dissolved in water and dry ice added to precipitate barium carbonate. The latter was filtered off and the filtrate evaporated ig vacuo to give the desired product as a yellow foam (1.39). (1)-Methyl 3-[3-(1-methyl-4»p‘iQeridyl)-1H-indolyllalanate A solution of the product from step (e) (6.29) in methanol (40ml) was added dropvvise to a solution of thionyl chloride (2.9ml) in methanol (35ml) at -10°C.

The resulting mixture was stirred overnight at room temperature, then evaporated i3 1 and the residue eluted through a silica column using DCMIEtOH/NH,,OH (30:8: 1) as eluant. The eluate was evaporated i_n vac_ug to give the desired product as a yellow foam (4.89). (1)3Meth l i eri I 1H-indol Iamino-1 anol A solution of the product from step (f) (4.89) in water (20ml) and ethanol (20ml) was added dropwise to a suspension of sodium borohydride (0.619) in a mixture of water (20ml) and ethanol (20ml) at 0°C. The resulting mixture was refluxed for 3 hours, then evaporated ig vacuo and the residue eluted through a silica column using DCM/El0HJNH.OH (30:8:1) as eluant. The eluate was evaporated m vacuo to give the desired product as a colourless foam (1.69). (:)-3 1-Meth i i I 5 2-oxooxazolidin lmeth 1H-indole A mixture of the product from step (g) (1.69), diethyi carbonate (0.73m|) and potassium carbonate (0.089) was heated at 130°C for 5 hours. The mixture was cooled, taken up in methanol and the insoluble potassium carbonate filtered off. The filtrate was evaporated i_n E and the residue eluted through a silica column using DCM/Et0HJNH..OH (30:8:1) as eluant. The eluate was evaporated i_n ya_cu_g and the residue recrystallised from isopropanol/ether to give the desired product as a colourless crystaliine solid (1.19). mp 191-192° ‘H NMR (DMSO-d., 5): 1.6-1.8 (2H, 2 X CflNMe), 1.8-2.1 (4H, 2 x Cflz), 2.2 (3H, s. NMQ). 2.6-3.0 (2H, 2 X CflNMe: 1H, Cfl; 2H, CLl2Ar). 3.9-4.1 (2H, m.

Ct|_20), 4.2-4.4 (1H, m, CflN), 6.9 (1 H, (1, Ar), 7.1 (1H, d, Ar), 7.3 (1H, d, Ar), 7.4 (1H, s, Ar), 7.8 (1H, s. NflC0) and 10.7 (1 H. s, N1-l_).

Salt of Synthetic Example 4 Hydrochloride c.HCl (1.0 equiv. ) was added dropwise to a stirred solution of the free base (1.1 g) in ethanol (5ml) at 5°C. The addition of ether to the resulting mixture precipitated the desired product as a white solid (1.19). mp 235-236°C (dec).

Synthetic Example 5 Preparation Of (R)[5-(2-oxo-1.3~oxazolidinylmethyl)-1H-indolyllethylamine (R)-4;(4-nitrobengyl)-1 .3-oxazolidinone A solution of Dnitrophenylalanine (Fluka, 539) in dimethoxyethane (250ml) was warmed to 67°C and BF; .Et, 0 (Aldrich, 37ml) added over 1 hour. The resulting solution was stirred at 67°C for I hour, then heated to 80°C and BH3 .Me,S (Aldrich, 40ml) added over 1 hour at 80-85°C. The resulting solution was heated at 85°C for 4 hours, then cooled and methanol ( 40ml) added. The solution was heated to 85°C and the solvents removed by distillation to 1/3 of the original bulk. 6N aqu. NaOH (136ml) was added to the hot solution which was then heated at 85°C for 1/2 hour, cooled and DCM (100ml) added. The solution was cooled to -15 to -20°C and a solution of trichloromethyl ohloroformate (Aldrich. 18.2ml) in DCM (23ml) added at below -10°C. The pH was maintained at 9-11 by periodic additions of6N aqu.

NaOH. The resulting solution was stirred at room temperature for 1 hour, then diluted with water and extracted with DCM. The combined extracts were washed with water and brine. dried and evaporated i_n y_a_cgg to give the desired product as a pale brown solid which was recrystallised from ethyl acetate to give a pale yellow solid (359). mp 113-115°, [a]D2‘+46.47° (c = 0.56. MeOH).

(R)-4—(4~Aminobenzyl)-1.3-oxazolidinone hydrochloride The product from step (a) (10.09) was suspended in a mixture of water (120ml), ethanol (60ml) and 2N aqu. HCI (22.5ml) and 10% wlw Pd/C (1 .0g) added. The mixture was stirred under 1 atmos. pressure of hydrogen for 8 hours when uptake was complete. The mixture was filtered through Hyflo and the filtrate evaporated i_n v_a_cgg to give the desired product as a colourless gas (10.39).

(R)(4-Hydrazinobenzyl)-1.3-oxazolidinone hydrochloride The product from step (b) (10.39) was suspended in water (53m|) and c.HCl (106ml) added dropwise. The resulting mixture was cooled to -5°C and a solution of sodium nitrite (3.29) in water (30ml) added dropwise to the stirred mixture over 15 minutes followed by 30 minutes‘ stirring at -5 toV0°C. The solution was then added at 0°C over 15 minutes to a stirred solution of tin (ll) chloride ( 51g) in c.HC| (91 ml), followed by 3 hours‘ stirring at room temperature. The solution was evaporated in va_c_gg and the residue triturated with ether to give the desired product as a pale yellow solid (1lg). (d) lRt2-|fi2-Oxa-1,3-oxazolidinylmethyl)-1H-indolvfl-ethvlamine The product from step (c) (8.39) was dissolved in ethanollwater (500ml, 5:l vlv) and the solution treated with 4~chlorobutanal dimethylacetal (J.Arner.Chem.Soc. 1365 (1951). 5.59). The mixture was refluxed for 2 hours, the solvent removed in vacuo and the residue eluted through a silica column using DCMIEt0H/NH.OH (30:8:1 v/vlv) as eluant. The desired product was obtained as a pale yellow oil (0.609).

Salt of Synthetic Example 6 Hydrochloride c.HCl (0.06ml) was added dropwise to a stirred solution of the free base (0.169) in ethanol (2ml) at 0°C. The hydrochloride salt was precipitated as a fawn solid. mp 269-271°C, [(,]D" +5.88° (c = 0.27, MeOH).

Synthetic Example 6 Preparation of (R)-N.N-dimethvl—2-(5-(2-oxo-1.3-oxazolidinvl-methvl)—1H-indol—3- yllethylamine A solution of 35% w/v aqu. formaldehyde (0.3ml) in methanol (2.0m|) was added to a solution of the product from step (d) of Synthetic Example 6 (0.449) and sodium cyanoborohydride (0.139) in a mixture of methanol (8.5mI) and glac. acetic acid (0.51 g) at 10°C and the resulting mixture stirred at room temperature for 2.5 hours. 2N aqu. NaOH (1 .3ml) was added, then sodium borohydride (0.199) followed by 2N aqu. HCI (1.3ml). The methanol was evaporated i_n y_a_c_:u_o_ and the remaining solution diluted with water. taken to pH 7 with solid potassium carbonate and washed with ethyl acetate. Further) potassium carbonate was added to pH 11 and the solution extracted with ethyl acetate. The combined extracts were evaporated i_n @u_o to give the desired product as a white foam (0.459).

Salt of Synthetic Example 6 Hydrochloride c.HCl (0.16m|) was added dropwise to a stirred solution of the free base (0.459) in ethanol (4.5ml) at 0°C. The mixture was evaporated in yaym and the resulting foam triturated with ethyl acetate to give the desired product as a white solid, mp 130°C,[a],,Z‘ +5.15° (c=0.77,MeOH).

Synthetic Example 7 Preparation of (S)-N,N—dimethylI5-(2-oxo-1,3-oxazolidinylmethyl)-1H-indoI yllethylamine (a) S -5 4-Nitroben I 1 3-imidazolidin-2 4-dione Benzyl isocyanate (Aldrich. 3.29) was added to a solution of L nitrophenylalanine (Aldrich, 4.29) and potassium hydroxide (1.3g) in water (40ml) at 0°C. The mixture was heated at 60-70°C for 2 hours, filtered and the filtrate acidified with c.HCl to give and off-white solid which was filtered off, suspended in 2N aqu. HCI (20m|) and refluxed for 2 hours. The cooled mixture was diluted with water and filtered to give the desired product as a white solid (5.69). (b) S-N,N-Dimethyl|5-(2-oxo-1,3-oxazolidinylmethylflH-indol yllethylamine By steps identical to steps ( d) to (f) of Synthetic Example 1 and Synthetic Example 2 or steps (d) and (e) of Synthetic Example 1 and Synthetic Example 3 and steps (e) to (h) of Synthetic Example 4. the product from step (a) was converted to (S)-N,N-dimethyl[5-(2-oxo-1,3-oxazolidin ylmethyl)-1H-indoly|]ethylamine.

Synthetic Example 8 yl|ethylamine (a) 1 S 1lg-H)grazinoben_;yl)-1 ,3-oxazolidinone hydrochloride By steps analogous to steps (a) to (c) of Synthetic Example 6, L nitrophenylalanine was converted to (S)( 4-hydrazinobenzyl)-1,3- oxazolidlnone hydrochloride (b) HyanopropyIidene)hvdrazino|benzyl}-1.3-oxazolidinone M aqu. HCI (4.0ml) was added to a solution of the product from step (a) (2.49) in water (35ml). 3-Cyanopropanal diethylaoetal (Aldrich, 1.79) was added at room temperature and the mixture stirred for 2 hours. Further acetal (0.209) was added and the mixture stirred for another 20 minutes.

The aqueous phase was decanted from the resulting gum and extracted with ethyl acetate. The extracts were combined with the gum and evaporated i_n_ @3__l.2 to give the desired product (2.59). ( c) (S );3-Qyanomethgd(2-oxo-1 ,3-oxazolidin-4—ylmeth;d );1H-indole A solution of the product from step (b) (2.5g) and polyphosphate ester (20.09) in chloroform ( 40ml) was refluxed for 20 minutes. Ice was added to the cooled mixture and the chloroform evaporated in awe remaining aqueous phase was extracted with ethyl acetate and the combined extracts evaporated in vacuo to give the desired product as a pale yellow oil (1.89).

A suspension of the product from step ( c) ( 1.3 g) and 10% wlw Pd/C (1 .0g) in 30% w/w ethanolic dimethylamine (25ml) was hydrogenated for 24 hours and filtered through Hyflo. Fresh Pd/C (0.7g) and ethanolic dimethylamine (5ml) were added to the filtrate and hydrogenation continued for a further 16 hours. The mixture was filtered through a silica column using DCM/Et0H/NH.OH (40:8:1) as eluant to give the desired product as a colourless foam (0.39). Elemental analysis and ‘H NMR were consistent with the proposed structure.

PHARMACEUTICAL FORMULATION EXAMPLES In the following Examples, the "active ingredient‘ may be any compound of the invention and/or a physiologically acceptable salt. solvate, or physiologically functional derivative thereof (1) Tablet fonnulations (i) _0_ra| Mgfiablet A E 9 Active ingredient 25 25 25 Avicel 13 - 7 Lactose 78 47 - Starch (maize) Starch (pregelatinised, NFl5) - - 32 Sodium starch glycollate 5 - - Povidone 3 3 ' Magnesium stearate 1 1 1 125 85 85 (ii) Sublingual M9/t_ab|_e! Q E Active Ingredient 25 25 Avicel 10 - Lactose - 36 Mannitol 51 57 Sucrose . - 8 Acacia - 3 Povidone 3 - Magnesium stearate 1 1 90 125 Formulations A to E may be prepared by wet granulation of the first six ingredients with the povidone, followed by addition of the magnesium stearate and compression. (iii) Buccal Mg/_tab|et Active ingredient Hydroxypropylmeth cellulose (HPMC) 25 Polycarbophil 39 Magnesium stearate 1 The formulation may be prepared by direct compression of the admixed ingredients. (2) Cagule formulations (i) Powder Mglcapsule E 9.

Active ingredient 25 25 1 5 Avicel 45 - Lactose 153 - Starch (1500 NF) - 117 Sodium starch glycollate - 6 2 0 Magnesium stearate 2 2 225 150 Formulations F and G may be prepared by admixing the ingredients and filling two- part hard gelatin capsules with the resulting mixture. (ii) Liguid fill Mg/capsule H l Active ingredient 25 25 Macrogol 4000 BP 200 - Lecithin - 100 Arachis oil - 100 Formulation H may be prepared by melting the Macrogol 4000 BP, dispersing the " active ingredient in the melt and filling tvvo-part hard gelatin capsules therewith.

Formulation I may be prepared by dispersing the active ingredient in the lecithin and arachis oil and filling soft, elastic gelatin capsules with the dispersion. (iii) Controlled release Mgcagsule Active ingredient 25 Avicel 123 Lactose 62 Triethylcitrate 3 Ethyl cellulose 12 The fonnulation may be prepared by mixing and extruding the first four ingredients and spheronising and drying the extrudate. The dried pellets are coated with ethyl cellulose as a release controlling membrane and filled into two-part, hard gelatin capsules. (3) Intravenous injection formulation % by weight Active ingredient 2°/o Hydrochloric acid ) q.s. to pH 7 Citrate buffer ) Water for Injections to 100% The active ingredient is taken up in the citrate buffer and sufficient hydrochloric acid added to affect solution and adjust the pH to 7. The resulting solution is made up to volume and filtered through a micropore filter into sterile glass vials which are sealed and oversealed. lntranasal formulation % by weight Active ingredient 0.5% Hydrochloric acid ) Citrate buffer ) q.s. to pH 7 Methyl hydroxybenzoate 0.2% Propyl hydroxybenzoate 0.02% Water for injections to 100% The active ingredient is taken up in a mixture of the hydroxybenzoates and citrate buffer and sufficient hydrochloric acid added to affect solution and adjust the pH to 7. The resulting solution is made up to volume and filtered through a micro pore filter lnto sterile glass vials which are sealed and oversealed. (5) intramuscular iniection formulation Active ingredient 0.059 Benzyl alcohol 0.10 g Glycofurol 75 1.45 g Water for Injections q.s. to 3.00 ml The active ingredient is dissolved in the glycofurol. The benzyl alcohol is added and dissolved and water added to 3 mi. The mixture is filtered through a micropore filter into sterile glass vials which are sealed and oversealed. (6) Syrup formulation Active ingredient 0.05 g Sorbltol solution 1.50 g Glycerol 1.00 g Sodium benzoate 0.005 g Flavour 0.0125 ml Purified water q.s. to 5.0 ml The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and made up to the required volume with purified water. (7) Sugmsitory formulation * The active ingredient is used as a powder wherein at least 90% of the particles are of 63pm diameter or less.

One-fiflh of the Wilepsol H15 is melted in a steam-jacketed pan at 45°C maximum.

The active ingredient is sifted through a 200pm sieve and mixed with the molten base using a Silverson mixer fitted with a cutting head until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mix. The entire suspension is then passed through a 250um stainless steel screen and, with continuous stirring. allowed to cool to 40°C. At a temperature of 38-40°C, 2.0g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature. (8) PessaI_'y formulation M ssa Active ingredient (63"m) 50 Anhydrous dextrose 470 Potato starch 473 Magnesium stearate 533 The above ingredients are mixed directly and pessaries prepared by compression of the resulting mixture.

BIOLOGICAL ASSAY The compounds prepared in Synthetic Examples 2/3 were tested for their activity as agonists for the "5~HT,-like" receptor mediating smooth muscle contraction by the following method.

Right and left lateral saphenous veins were obtained from male New Zealand White rabbits (2.4-2.7 kg) which had been killed by intravenous injection of pentobarbltone sodium (60 mg/kg). Ring segments (3-5 mm wide) prepared from each vessel were suspended between two wire hooks and immersed in 20 ml organ baths containing Krebs‘ solution (pH 7.4) of the following composition (mM): NaCl 118.41. NaHC03 .00. KCI 4.75, KH,PO. 1.19. MgSO,, 1.19, glucose 11.10 and CaCI, 2.50.

Cocaine (301 M) was present in the Krebs’ solution throughout the experiment to prevent the uptake of amines by sympathetic neurons. The Krebs‘ solution was maintained at 37°C and continually gassed with 95% oxygen/5% carbon dioxide.

Increases in tissue isometric force were measured using Grass FT03C force displacement transducers and recorded on a Gould BD-212 pen recorder.

A force of 1.09 was applied to each preparation and re-established twice during a subsequent period of 30 minutes. During this period. tissues were exposed to pargyline (5001 M) to irreversibly inhibit monoamine oxidase and to phenoxybenzamine (O.1lM) to inactivate apadrenoceptors. At the end of the 30 minutes. the inhibitors were removed by several changes of the organ bath Krebs’ solution.

Agonist activity was assessed by cumulative additions of the test compound, its concentration being increased in 0.5 log", unit increments until further additions caused no further change in tissue force. In each experiment, the activity of the test compound was compared to the activity of 5-HT. Activity was expressed in terms of the p[A5,,] (-|og,,,[M], where M is the molar concentration of agonist required to produce half the maximum effect). The results obtained for the compounds of Synthetic Examples 2/3 are shown in Table I.

Table 1 TOXICITY DATA The hydrochloride salt of the compound of Synthetic Examples 2/3 were administered orally by gavage to Wistar rats as a solution in distilled water at dosages of 25, 100 and 200mg/kg base and to Beagle dogs at dosages of 0.25, 0.50, 1.0 and 2.0 mg/kg base once a day for 14 days. In a separate dog study over days, the dosage of the free base was increased from 2mg/kg on Day 1 to 100 mg/kg on Day 30. The free base was also administered orally to cynomolgus monkeys at a dosage of 50 mg/kg once a day for 15 days.

No evidence of toxicity was observed in any of the aforementioned studies at any of the dosages used.

Claims (2)

1.CLAIMS The compound N,N-dimethyl[5—(2-oxo-1,3-oxazoIidinylmethyl)-1H- indolyl]ethylamine in either its (S) or (R) form or as a mixture thereof in any proportions, or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof. The compound of formula (I) as claimed in Claim 1, which is (S)-N,N- dimethyl[5-(2-oxo-1.3-oxazolidinylmethyl)-1H-lndolyljethylamine or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof. A compound as claimed in Claim 1 or Claim 2. or a physiologically acceptable salt. solvate. or physiologically functional derivative thereof for use as a therapeutic agent. A compound as claimed in Claim 1 or Claim

2. or a physiologically acceptable salt, solvate or physiologically functional derivative thereof. for use in the prophylaxis or treatment of a clinical condition for which a "5-HT,- like" receptor agonist is indicated. A compound as claimed in Claim 1 or Claim 2, or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof, for use in the prophylaxis or treatment of migraine. Use of a compound as claimed in Claim 1 or Claim 2, or a physiologically acceptable salt. solvate. or physiologically functional derivative thereof, in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a "5-HT,-like‘ receptor agonist is indicated. Use of a compound as claimed in Claim 1 or Claim 2, or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof, in the manufacture of a medicament for the prophylaxis or treatment of migraine. A medicament comprising a compound as claimed in Claim 1 or Claim 2 or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof. a pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents. A medicament as claimed in Claim 8 which is in the form of a tablet or capsule. A process for the preparation of the compound N,N-dimethyl(5oxo-1 ,3-oxazolidinylmethyl)-1H-indolyl]ethylamine in either its (S) or (R) form or as a mixture thereof in any proportions; which comprises reacting a compound of formula (II) NHNH2 W (11) \ (CH2),, wherein n is 1 and W is a group and the chiral centre’ is in its.(S) or (R) form or is a mixture thereof in any proportions with a compound of'formu|a (Ill) or a carbonyl-protected form thereof, wherein L is a suitable leaving group or protected amino group which I may be converted into a dimethyl amino group or is -NR R wherein R and R are each methyl. A method of preparing a medicament which comprises a) preparing the compound N,N-dimethyl[5-(2-oxa-1,3-oxazolidin yl methyl)-1H-indolyl]ethylamine in either its (S) or (R) form or as a mixture thereof in any proportions, or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof by a process as claimed in Claim 10: and b) admixing the product from step a) with a pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents. A method‘ as claimed in Claim 11 which comprises an additional step c) wherein the admixture from step b) is formed into a tablet or capsule.