IE83785B1 - Indole derivatives as 5-HT1 like agonists - Google Patents

Description

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. is indicated. For example, the receptor in question mediates vasoconstriction 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 carotid 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.

.I‘‘ 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 of formula (I) wherein R is hydrogen or CH alkyi, X is , , -NH-, or —CH2-, Y is oxygen or sulphur and the chiral centre " in fonnula (i) or (ii) is in its (8) or ( R) form or is a mixture thereof in any proportions; and Z is a group of fonnula (iv), (v) or (vi) wherein R‘ and R’ are independently selected from hydrogen and C14 alkyl and R3 is hydrogen or 0,. alkyl; and salts. solvates and physiologically functional derivatives thereof provided that said compound is not N.N—dimethyl{5(2-oxo-1,3-oxazolidin- 4—ylmethy|)-1H-lndclyllethylamine.

Compounds of formula (I) having particularly desirable properties for the treatment and prophylaxis of migraine include those wherein n is ‘l, W is a group of formula (i) and Z is a group of formula (iv) or (vi). Of these. compounds of formula (I) wherein n is 1, W is a group of fonnula (i) wherein R is hydrogen, X is and Y is oxygen and Z is a group of formula (iv) or (vi) wherein R = R’ = hydrogen or methyl are particularly preferred.

A compound of formula (I) having exceptional properties for the treatment and is 3- (1-methylpiperidyl)(2-oxo-1.3—oxazolidin-4—ylmethyl)-1H-indole in either its (S) or (R) fonn or as a mixture thereof in any proportions. The salts and solvates of this compound. for example, the hydrate maleates, are particularly preferred.

Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, Lg. basic, compounds. Such salts must clearly have a physiologically acceptable anion.

’ - Suitable physiologically acceptable salts of the compounds of the present invention include those derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic. fumaric, citric, sulphuric, lactic, or tartaric acid. The succinate and chloride salts are particularly preferred for medical purposes. Salts having a non- physiologically acceptable anion are within the scope of the invention as useful intennediates for the preparation of physiologically acceptable salts andlor for use in no n-therapeutic, for example. i_r1 vitro, situations.

According to a second aspect of the present invention, there is provided a compound of fonnula (l) 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 fonnula (l) 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 formula (I). 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 O.15mglkg and would typically be administered as an infusion of from 0.0003 to 0.15mg 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 formula (I). the dose is based on the cation (for salts) or the unsolvated compound.

Hereinafter references to "compound(s) formula (I)'' will be understood to include 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 formula (I) andlor a phamiacologically acceptable salt or solvate thereof together with at least one phannaceutical carrier or excipient. These phamtaceutical compositions may be used in the prophylaxis or3 treatment of clinical conditions for which a "5-HT,-like" receptor agonist is indicated, for example. migraine. The carrier must be pharmaceutically 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 fonnulated with at least one compound of fonnula (I) 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 phannaceutical compositions of the invention.

Possible formulations 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.

Fomrulations 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 forming the suppository base, for example, cocoa butter.

Fonnulations suitable for topical or irrtranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable carriers for such fonnulations 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 admixing 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 sufficient 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 formula (I) in the preparation of a medicament for the prophylaxis or treatment or a clinical ‘condition for which a "5-HT.-like‘ receptor agonlst is indicated. for example, migraine.

According to a fifth aspect. there is provided a method for the prophylaxis or treatment of a clinical condition in a mammal. for example. a human. for which a '5- HT.-like‘ receptor agonlst is indicated, for example. migraine. which comprises the administration to said mammal of a therapeutically effective amount of a compund of formula (I) or a physiologically acceptable salt. solvate. or physiologically functional derivative thereof. ' According to a sixth aspect of the invention. compounds of formula (I) wherein Z is a group of formula (iv) may be prepared by reacting a compound of fonnula (ll) (isolated or in situ - infra).

Nmrnz W\ (6112).. wherein n and W are as hereinbefore defined. with a Compound of the fonnula (ill) (111) 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 beconverted i_r_r fl into an amino group or is - NR‘R’ where R‘ and R’ are as hereinbefore defined. The reaction is typically carried out by refluxing the compounds in a polar solvent system. for example. ethanollwater, dilute acetic acid. or water in the presence of an acidic ion exchange resin, for example. 'Amberlyst '. '1 0 Standard N-alkylation methods may be used to convert compounds of formula (I) wherein Z is a group of formula (iv) and R andlor R are hydrogen to comesponding compounds wherein R‘ andlor R2 are C14 alkyl.

Compounds of fonnula (I) wherein Z = (iv) and R‘ or R‘ = C... alkyl may be prepared from the corresponding compound wherein R‘ = R2 = 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.

Compounds of fonnula (I) wherein Z = (iv) and R’ or R’ = C... aikyl may be prepared from the corresponding compound wherein R‘ = R’ = H by N=benzylation using benzaldehyde and a suitable reducing agent. for example. sodium borohydride, in.a polar solvent. such as ethanol, following by N-alkylation using a suitable agent. such as the appropriate dialkyl sulphate. typically in the presence of a base. for example. anhy. potassium carbonate, in a polar aprotic solvent. such as DMF. and finally N- debenzylation. typically by catalytic hydrogenation using. for example. PdlC in a polar solvent. such as ethanol.

Hydrazines of formula (II) may be prepared from the corresponding aniline of formula (IV) ' W \.. ‘ wherein n and W are as hereinbefore defined. by diazotisation -followed by reduction. Diazotisation is typically carried out using sodium nitritelc. HCl and the resulting diazo product reduced in sitg using, for example, tin(ll) chloridelcgHCl. The resulting hydrazine may be isolated or converted to a compound of fonnula (I) lg situ.

Anilines of formula (IV) may be prepared by reduction of the corresponding Q-nitro compound of formula (V) ' - N02 ‘ W \(CH2),, wherein n and W are as hereinbefore defined, typically by catalytic hydrogenation using. for example, PdIC in a polar solvent system, such as an acidified mixture of ethanol. water and ethyl acetate.

Anilines of formula (IV) wherein W is a group of formula (i) or (ii) may also be prepared by cyclising a compound of formula ()0(Xlll) ""2 H(R4)N Hx\J\ mm") (CH2), or (X)O(lV) \ I I Ex H(n‘)N\/'\ ' s (CH2). wherein n and X. are as hereinbefore defined and R‘ is -CO,R‘ where R5 is CH . alkyl, typically by heating in the presence of a base. such as sodium methoxide.

Compounds of formula (X)0 a corresponding C14 alkyl ester using, for example. sodium bomhydride. in a polar solvent system. such as ethanollwater. at 0°C. The ester may be prepared by esterifying the conesponding carboxylic acid using. for example, the appropriate alcohol and HCl 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-nilroaminoacid, the acid by N- alkoxycarbonylation using. for example, R‘ OCOCI where R’ 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-alkoxycarbonylatlon (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.lc.HNO,, at 0°C.

Compounds of formula (XXXIV) wherein X is oxygen may be prepared by reducing the corresponding dinitm compound. typically by catalytic hydrggenation using, for example, Pd/C in a polar solvent. such as ethanol. The dinitro compound may be prepared by reacting the appropriate aldehyde with nitromethane, typically in the presence of a base, for example, sodium methoxide, in a polar solvent, such as methanol, followed by Q-nitration using. for example, c.H,SOJc.HNO,. or by Q- nitration of the appropriate aldehyde followed by reaction with nitromethane. The A aldehyde may be obtained commercially or prepared from readily available starting materials’ by methods known to those skilled in the art of obtainable from the chemical literature.

Q—Nitro compounds of formula (V) may be prepared by (a) in the case where W is a group of fonnula (i) in which Y is oxygen or sulphur, reacting a compound of formula (VI) N02 H(R)N "x\J\(cn,)., wherein n, R and X are as hereinbefore defined, with a compound of formula (Vll) (V11) wherein Y is as hereinbefore defined 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. -12.. (b) in the case where W is a group of. formula (ii) in which Y is oxygen or sulphur. reacting a compound of formula (VIII) ' ‘ _ N02 "‘ U i H X}\ ‘ f (R)N €32)" Wm) wherein n, R and X are as hereinbefore defined, with a compound of formula (Vll) wherein Y. L and L’ are as hereinbefore defined, typically using the reaction conditions described in (a); (c) in the case where W is a group of formula (iii), reacting a compound of formula (IX) HO \CH2)n ax) wherein n is as hereinbefore descnaed. with a compound of formula (X) NH (X) wherein R is as hereinbefore defined. typically in a polar aprotic solvent. such as DMF, in the presence of DEAD/Ph3P.

Compounds of formula (VI) may be prepared by ring—opening a compound of formula (V) wherein n is as hereinbefore defined and W is a group of formula (i) in which R, X and Y are as hereinbefore defined, for example, by refluxing in 2N aqu.

KOH.

Compounds of formula (VI) wherein X is oxygen 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 ethanollwater, 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 O"C.

Compounds of formula (VIII) may be prepared by ring-opening a compound of formula (V) wherein n is as hereinbefore defined and W is a group of formula (ii) in which R, X and Y are as hereinbefore defined, for example, by refluxing in 2N aqu.

KOH.

Compounds of formula (III), (Vll), (IX) and (X) 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) wherein W is a group of fonnula (i) or (ii) may also be prepared by Q-nitration of a compound of formula (XXXVI) W \ wherein n and W are as hereinbefore defined, using, for example, c.H,SO.,/c.HNO3 at 0°C.

Compounds of formula (X)0(Vl) may be prepared by reacting a compound of _ formula (>o n(R)N M X ""\J\.. or (xxxvm) "‘ D 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.

(XXXVII) Compounds of formula (XX)(V|l) and (XXXVll|) 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 (XXIV) N 2 \ V-15' wherein n is as hereinbefore defined, with paraforrnaldehyde 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, typic'ally.by treatment with thionyl chloride and an appropriate alcohol at -10°C. followed by reduction of the ester group using, for example, sodium borohydride, inra polar solvent system, such as ethanol/water at 0°C. The nitro compound corresponding to the compound of formula (XXXVIII) may be prepared by reacting the appropriate aldehyde with nitromethane. typically in the presence of a base, for example, sodium methoxide, in a polar solvent, such as methanol.

The compound of formula (XXIV) and the acid and the aldehyde 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) wherein W is a group of formula (i), (ii), or (iii) in which R is C14 alkyl may be prepared from the corresponding compound of formula (V) wherein R is hydrogen by N-alkylation using a suitable agent. such as the appropriate dialkyl sulphate, typically in the presence of a base, for example, sodium hydride, in a non-polar solvent, such as THF.

Compounds of formula (I) wherein W is a group of formula (i) or (ii) may also be prepared by reacting a compound of formula (XV) H N H(R)N ux\J\ / (cH2)n (XV) or (XXV) H N BX / H(R)N (CH2)n -16.. wherein n, R and X are as hereinbefore defined with a compound of formula (VII) wherein Y, L and L‘ are as hereinbefore defined, for example, in the case where L = L’ = ethoxy, by heating in the presence of a base, for example. potassium carbonate.

Compounds of fonnula (XV) may be prepared by ring-opening a compound of formula (I) wherein n and Z are as hereinbefore defined and W is a groupof fonnlulag (i) in which R, X and Y are as hereinbefore defined, for example, by refluxing in 2N aqu, KOH.

Compounds of formula (XV) wherein X is oxygen 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 00C. The acid may be prepared by ring-opening a compound of formula (XVI) 0 H N N R %: / (CH2), (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) wherein n¢O may be prepared by reducing a compound of formula (XVll) H N . R N CH / W $(CH2)n-I R‘ N z o (XVII) -17.. wherein n, R, R‘ and Z are as hereinbefore defined typically by. catalytic hydrogenation using, for example, PdlC in a polar solvent system‘. such as ethanollwater. Alternatively, an. enaniloselectlve reducing ‘agent, such as Rh(cod)(dipamp)’ BF. ‘(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 dioxoimidazole ring. The reduction step may be used to convert a compound of formula (XVII) wherein Z is a group of formula (v) into a compound of formula (XVI_) wherein Z is a group of fonnula (vi).

Compounds of formula (XVII) may be prepared by reacting a compound of formula (XVIII) onc\~ (Cain -1 z wherein n and Z are as hereinbefore defined. with. in the case where R" is to be hydrogen. a compound of formula‘ (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 reductionlhydrolysis of the corresponding nitrite, typically using Raney nickel and sodium hypophosphite in a mixture of water. acetic acid and pyridine. The nitrile may be prepared by reacting a compound of formula (XIX) -13..

H _ N NC \ A / .. _‘ (CH2)n-I (xnq _ wherein n is as hereinbefore defined, with, in thelcase where Z is to be a group of V formula (v) or (vi). the appropriate compound of formula (XXVIII) (XXVU1) wherein R‘ is as hereinbefore defined, typically by refluxing in a polar solvent, such as methanol. inthe presence of base, for example, potassium hydroxide. in Compounds of formula (XIX) and (XXVIII) may be obtained commercially or prepared from readily available starting materials by methods known to those skilled in the art of obtainable from the chemical literature. Compounds of fonnula (XVI) wherein n = 0 may be obtained by the same means.

Compounds of formula (XVI) wherein R‘ is benzyl and Z is as hereinbefore defined 1 5 may be prepared by reacting a compound of formula (XXXV) (C32). wherein n and R are as hereinbefore defined. with a compound of formula (lll) wherein L is as hereinbefore defined, typically using. the reaction conditions described above for the reaction of (ll) with (Ill).

Hydrazines of formula (XXXV) may be prepared from the corresponding aniline, typically using the reaction conditions described above for the conversion of (IV) to (ll). The aniline may be prepared by reducing the corresponding Q-nitro compound, typically using the reaction conditions described above for the conversion of_(V) to T (IV). The Q-nitro compound may be prepared by reacting the corresponding 2 nitroaminoacid with benzyl isocyanate 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.H2SO./c.HNO3 at 0°C.

Compounds of formula (XV) wherein R is hydrogen may be prepared by reducing a compound of formula (XX) * OZN ‘"\)\(cH,),, / (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. The same step may be used to convert a compound of formula (XX) wherein Z is a group of formula (v) into a compound of formula (XV) wherein Z is a group of formula (vi).

Compounds of formula (XX) wherein X is oxygen may be prepared by reacting a .A compound of (XXI) -20..

' H N OZN / mgg M z . 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 0°C.

Compounds of fonnula (XXI) may be prepared by reacting a compound of formula wherein n is as hereinbefore defined, with, in the case where Z is to be a group of formula (v) or (vi). the appropriate compound of formula (X)(VIlI) wherein R is as hereinbefore defined. typically by heating in glac. acetic acid.

Compounds of formula (XXII) wherein n i 0 may be prepared by reducing a compound of formula (XXIII) H I N /3 £1; \cn/ \<<=H2)...1 Wm’ ...21... wherein n is as hereinbefore defined, using. for example, sodium borohydride and 40% wlv aqu. NaOH in a polar aprotic solvent, such as acetonitrile, at 0°C.

Compounds of fonnula (XXIII) may be prepared by heating the appropriate aldehyde with nitromethane in the presence of ammonium acetate. ’The aldehyde may be prepared from a compound of fonnula (XIX) wherein n is as hereinbefore defined using the reaction conditions described above for preparing a compound of formula (XVIII) from the corresponding nitrile.

Compounds of formula (XXII) wherein n=0 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 formula (XXI) wherein n ¢ 0 may also be prepared from a compound of formula (XXXIX) wherein n and Z are as hereinbefore defined, using reaction conditions analogous to those used to convert (XXIII) to (XXII). Compounds of formula (X)(XIX) may be prepared from a compound of formula (XVIII) wherein n and Z are as hereinbefore .. .. defined using reaction conditions analogous to those used to prepare (XXIII) from the appropriate aldehyde and nitromethane.

Compounds of fonnula (XX) wherein X is other than oxygen 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 formula (XXV) may be prepared by ring-opening a compound of formula (I) wherein n and Z are as hereinbefore defined and W is a group of fonnula ‘ (ii) in which R, X and Y are as hereinbefore defined, for example, by refluxing in 2N aqu. KOH.

Compounds of formula (I) wherein W is a group of formula (i) in which Y is sulphur may be prepared by refluxing a compound of fonnula (XV) wherein n, R and X are as hereinbefore defined. with a compound of fonnula (VII) wherein Y is sulphur and L and L’ are as hereinbefore defined, for example, N,N’-thiocarbonylimidazole. typically in an aprotic solvent, such as THF.

Compounds of formula (I) wherein W is a group of formula (ii) in which Y is sulphur may be prepared by refluxing a compound of fonnula (XXV) wherein n, R and X are as hereinbefore defined, with a compound of formula (VII) wherein Y is sulphur and L and L’ are as hereinbefore defined, for example, N,N'-thiocarbonylimidazole, typically in an aprotic solvent, such as THF.

Compounds of formula (I) wherein W is a group of formula (iii) and Z is a group of formula (v) or (vi) may also be prepared by cyclising a compound of formula (XXVI) n"o2C// wherein n and R are as hereinbefore defined, is a group of formula (v) or (vi) and R’ is CH alkyl, typically by heating in aqueous acid, for example, 2N HCl.

Compounds of formula (XXVI) wherein Z is a group of formula (v) may be prepared by reacting a compound of formula (XXVII) n7o2c wherein n, R and R’ are as hereinbefore defined, with a compound of fonnula (XX\/lll) wherein R3 is as hereinbefore defined, typically by heating in a non- aqueous acid, for example, glac. acetic acid.

Compounds of formula (XXVI) wherein Z is a group of formula (vi) may be prepared by reducing a compound of fonnula (XXVI) wherein Z is a group of formula (v), typically by catalytic hydrogenation using, for example, PdlC in a polar solvent 1 5 system, such as acidified methanol/water.

Compounds of formula (XXVll) may be prepared by reacting a compound of formula (XXIX) .24. an / ~\(CH2)n wherein n is as hereinbefore defined. with a compound of fonnula (XXX) X Nco n7o2c wherein R7 is as hereinbefore defined. typically in an aprotic solvent, such as DCM.

Compounds of formula (XXIX) andé()O(X) 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 formula (I) wherein Z is a group of fonnula (iv) may also be prepared from a compound of formula (XXXl) W / (xxx!) \(cH,). 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)2. 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 CHZOIKCN to give the corresponding 3—cyanomethyl compound which -25.. 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 cycllsing a compound of formula (XXXX) C NEN=CH(CH2)2CN W (XXXX) 7 \.. i wherein n and W are as hereinbefore defined. typically 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 fonn thereof. such as the diethyl acetal. typically in an aqueous acid, for example, dil. HCI.

Compounds of formula (I) wherein Z is a group of fonnula (v) may also be prepared by reacting a compound of formula (X)O(l) wherein n and W are as hereinbefore defined, with a compound of formula (XXVIII) wherein R3 is as hereinbefore defined, typically by heating in glac. acetic acid.

Compounds of formula (XXXI) may be prepared by reducing a compound of fonnula (X)O(|l) / (mm) W\ (cH,),, SPII wherein n and W are as hereinbefore defined. typically by heating with- Rariey nickel in a polar solvent. such as IPA.

Compounds of fonnula (X)(Xll) may be prepared by reacting a hydrazine of formula (II) wherein n and Ware as hereinbefore defined with phenylthioacetaldehyde. or a carbonyl-protected form thereof. for example. the diethyl acetal. in a polar solvent. such as acidified ethanol.

Compounds of fonnula (I) wherein Z is a group of formula (vi) may also be prepared by reducing a compound of formula (I) wherein Z is a group of fonnula (V). typically by catalytic hydrogenation using, for example, Pd/C in a polar solvent system, such as acidified methanol/water.

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

SYNTHETIC EXAMPLES Synthetic Example 1 Preparation of (S)[5-(2-oxo-1 ,3-oxazoIidin—4-ylmethyl)-1H-indolvllethylamine Methanol (110ml) was treated dropvvise with tl1ionyl chloride (26.39) at -10°C and Lnitrophenylalanine (Fluka, 21.79) added to the resulting solution as a solid. The mixture was stirred overnight at room temperature and the methanol removed l_n @_<:I.1_o to give the desired product as a pale yellow solid (21.29).

Q)-2—Amino( 4-nitroraghenyllpronanol The product from step (a) (21.29) was dissolved in ethanollwater (190ml, 100/90 vlv) and the solution added dropwise_ at 0°C to a stirred solution of sodium borohydride (13.09) in ethanollwater (190ml, 100/9o vlv); The resulting mixture was refluxed for 2.5 hours, cooled and the precipitate filtered off. The ethanol was partially removed from the filtrate lg lag and the resulting precipitate filtered off and dried to give the desired product as a pale yellow solid (7.59).

(S)(4-Nitrobenzyl)-1 ,3-oxazolidin—2—one The product from step (b) (4.99) was suspended in toluene. the suspension cooled to 0°C and a solution of potassium hydroxide (7.09) in water (56m|) added dropwise. A solution of phosgene (62.5ml of a 12% wlv solution in toluene) was added dropwise to the resulting solution over 30 minutes and stirring continued for l hour. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried and evaporated in vacuo to give _a yellow oil. Crystallisation from ethyl acetate gave the desired product as pale yellow crystals (2.3g).

LS)(4-Aminobenzy|)—1,3-oxazolidinone hydrochloride 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 HCI (2.3ml) was stirred under I atmos. pressure of hydrogen until uptake ceased. The mixture was filtered through Hyflo and the filtrate evaporated ig vacuo to give the desired product as a pale yellow foam (0.799).

(S)(4-Hvdrazinobenzyll-1.3-oxazolidinone hvdrochloride The product from step (d) (0.79g) was suspended in water (4.8ml) and c.HC| (8.1ml) added dropwise. The resulting mixture was cooled to -5°C and a solution of sodium nitrite (0.24g) 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 (3.39) in c.HC| (6.9m|), followed by 31 l.o..rs+ stirring at room temperature. The solution was evaporated lg i and the residue triturated with ether to give the desired product as a pale yellow solid (0.969).

(S)—2—L5-( 2-Oxo-1 . 3-oxazolidinylmethyl)-1H-indolyllethyl-amine The product from step (e) (0.849) was dissolved in ethanollwater (125mI. :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 y_a_cy_g_ and the residue eluted through a silica column using DCMlEtOHINH.,OH (30:8:1) as eluant. The desired product was obtained as a colourless oil (0.21 g).

Salt of Synthetic Example 1 Maleate Ethanolic maleic acid (1.0 equiv.) was added dropwise to the free base (0.219) and the ethanol evaporated i_n vacuo. The resulting gurn was freeze-dried from water to give the desired product as a white lyopholate (0.229), [0,]D" -5.92° (c = 0.3, MeOH).

" ‘H NMR (DMSO-d,, 5): 2.7-3.5 (6H, m. 0H,), 3.35 (2H, s. NH2), 4.05_(2H,- m. cr_.1,), 4.25 (1H, m. Cl_-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 (1 H, s, Nl_-l_) and 10.9 (1 H, s, Nfi) Microanalysis: c 55.03 (54.96), H 5.54 (5.85), N 10.30 (1_0.6_s) Reference Example 2 Preparation of (S)-N,N-dimethyl[5-(2-oxo-1,3-oxazolidinylmethyll-1H-indol-35 yllethylamine 0,9 isogroganolate 0.5 hydrate A solution of fomtaldehyde (0.039) in methanol (1.8ml) was added to a solution of the free base from step (f) of Synthetic Example 1 (0.129) and sodium cyanoborohydride (0.04g) in a mixture of methanol (5.5ml) and glac.‘ acetic acid (0.149) and the resulting mixture stirred overnight at room temperature. The pH was adjusted to 8.0 using aqu. K200, and the mixture extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated to give a colourless oil (0.149) which crystallised from isopropanol to give the desired product as a white crystalline solid (0.109), mp 139-141 °C . ‘ ‘H NMR (DMSO-ds. 5): 2.2 (6H, s, N|\_/Igz), 2.5 (2H, m. cH,Ar), 2.7-3.0 (4H, m, c1_-11), 4.1 (2H, m, c1_-120), 4.3 (1H, m, CH). 6.9 (1H, d, Ar), 7.1 (1H, s, Ar). 7.3 (1 H, d. Ar), 7.4 (1 H, s, Ar). 7.7 (1H, s, Ni-l_C0) and 10.7 (1H, s, NH).

Microanalysis: C 64.26 (64.11). H 8.28 (8.34), N 12.02 (12.00) [a],,22 -5.79° (c = 0.5, MeOH) Salts of Reference Example 2 Maleate A solution of maleic acid (0.179) in ethanol (5ml) was added to a solution of the free base (0.5g) in ethanol (5ml). The mixture was evaporated ig vacuo and the resulting oil triturated with ether and methanol to give the maleate salt as a white solid which was recrystallised from ethanol (0.459), mp 151-152°C.

Hydrochloride Ethereal HCl (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 a_'n.oil. The mixture was evaporated lg Egg and the resulting foam crystallised from isopropanol to give the desired product as a white solid (0.369), mp 118-120°C, [(11,322 -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 .0g)' in ethanol (10ml). The mixture was evaporated in vacuo and the resulting foam triturated with isopropanol to give the succinate salt as a white solid (1 .0g). mp 122-123°C.

Benzoate A solution of benzoic acid (0.379) in ethanol (10ml) was added to a solution of the free base (1.0g) in ethanol (1 Oml). The mixture was evaporated in Lacie and the resulting foam crystallised from ethyl acetate to give the benzoate salt as a white solid (0.74g), mp 90-92°C.

Reference Example 3 Alternative preparation of (S)-N,N-dimethvl-2—[5-(2—oxo-1.3-oxazolidinylmethgd)-1 H- indolyl|ethylamlne 0.9 isopropanolate 0.5 hydrate as a white crystalline solid (3.59). mp 138-140°C. ‘H NMR, micmanalysis and MD as for product of Reference Example 2.

Synthetic Example 4 Preparation of(:)-31 1-methflpiperigyl E5-(2-oxo-1 ,3-oxazolidin-4—yl-methyl 1-1 1 1- indole (a) 3-0 —Methyl-1 .2,3.6—tetrahydro-4—pyridyl)-1 H-indolecarbo—nitrile -Cyanoindole (Aldrich, 20.09) was added to a solution of KOH (22.49) in methanol (200ml). N-Methylpiperidone (Aldrich, 40.49) was then added dropwlse 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-Methyl-1 .2,3.6-tetrahydropyridyl)-1H-indolecarbaldehyde Raney nickel (c_a 109) was added to a solution of the product from step (a) (5.0g) and sodium hypophosphite (6.09) in a mixture of water (25ml), glac.

(C) 1 o (d) 1 5 (e) 2 0 2 5 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 Hyilo and the filtrate extracted with chloroform. The combined extracts were dried and evaporated‘ in \_Ia_cgq to give the desired product as an off-white solid which was recrystallised "from ethanol (2.4g). -[3-(1-Methyl-1 2.3.6-tetrahydro-4—Dvridyl)-1H-indolvlmethvlenel-2.11; imidazolidinedione T A mixture of the product from step (b) (2.4g). 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). (:) 2 5-Dioxo—4-imidazolidin lmeth l- 1-meth l eri l-1H-indole The product from step (c) (2.4g) was suspended in a mixture of water (100ml) and ethanol (200ml) and 10% wlw PdIC (0.259) added. The mixture was stirred under 1 atrnos. pressure of hydrogen for 17 hours when uptake was complete. The mixture was filtered through Ryflo and the filtrate evaporated in ygcgg to give the desired product as a colourless solid (2.49). (1)[3-( 1 -Methylpiperigyl)-1 H—indolyl lalanine A solution of the product from step (d) (2.4g) and barium hydroxide hydrate (8.49) in water (50ml) was refluxed for 72 hours, then cooled and evaporated in vgcgg. The residue was taken up in hot methanol and filtered to remove barium salts. The filtrate was evaporated l_l'_l %, the residue dissolved in water and dry ice added to precipitate barium carbonate. The latter was filtered off and the filtrate evaporated i_n v_a_cgg_ to give the desired product as a yellow foam (1 .3g). ...33.. (1)-Methyl 3-[3-(1-methylpiperimll-1H-indolyllalanate ’ A solution of the product from step (e) (6.29) in methanol (40ml) was added dropwise 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 i_r_i 1a_c_ug and the residue eluted through a silica column using DCMIEtOHINH.OH (30:8: 1) as eluant. The eluate was evaporated i_n vag_u_g to give the desired product as a yellow foam (4.8g). (1)[3-(1-Methylpmeridyl)-1 H-indol-5—yl}2-aminoQropanol A solution of the product from step (t) (4.8g) in water (20ml) and ethanol (20m|) was added dropwise to a suspension of sodium borohydride (0.619) in a mixture of water (20m|) and ethanol (20rnl) at 0°C. The resulting mixture was refluxed for 3 hours. then evaporated 1r_I vacuo and the residue eluted through a silica column using DCMIEtOHJNH.OH (302821) as eluant. The eluate was evaporated i_n_ vacuo to give the desired product as a colourless foam (1.69). (+)-3—( 1 -Methylpiperidyl)(2-oxo-1 ,3-oxazolldinylmethyl)-1 H-indole A mixture of the product from step (g) (1.69), dlethyl carbonate (0.73ml) and potassium carbonate (0.08g) 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 ig E and the residue eluted through a silica column using DCMlEtOHJNH.OH (30:8:1) as eluant. The eluate was evaporated in yggg and the residue recrystallised from isopropanollether to give the desired product as a colourless crystalline solid (1.1g), mp 191-192" -34..

C_HJO), 4.2-4.4 (1H, m, C_l:l_N), 6.9 (1H, d, Ar). 7.1 (1H, d, Ar). 7.3 (1 H. d. Ar), 7.4 (1H, s, Ar). 7.8 (1 H, S, NH_CO) and 10.7 (1H, s, Nfl).

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 (5m|) 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 Alternative preparation of (1-)(1-methylpiperidyl)(1.3-oxazolidinylmethyI)- 1H-indole (a) lH-indolecarbaldehyde Raney nickel (6.79) was added to a solution of 5-cyanoindole (Aldrich, .09) and sodium hypophosphite (20.09) in a mixture of water (73ml). glac. acetic acid (73m|) and pyridine (145ml) at 45°C for 2 hours. then cooled and filtered through Hyflo. The filtrate was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water. 10% aqu. citric acid, IN aqu. HC1, water and brine, dried and evaporated lg fig to give the desired product as a buff solid which was recrystallised from chloroform (7.5g).

A mixture of the product from step (a) (7.59), ammonium acetate (1.59) and nitromethane (77ml) was heated at 110°C for 2 hours, then cooled and evaporated i_n ya_C:_Ll_O. The residue was triturated with water to give the desired product as a yellow solid which was filtered off and dried (9.29). -35.. -nitroeth l -1H-indole A solution of sodium borohydride (2.09) and 40% wlv aqu. NaOH was added dropwise to a solution of the product from step (b) (1.9g) in acetonitrile (55m|) at 0°C. The pH was maintained at 3-6 by periodic additions of 2N aqu. HCI. The resulting solution was stirred at 0°C for 2 hours. then diluted with water and extracted with DCM. The combined extracts were washed with brine, dried and evaporated i_n_ E. to give a yellow oil which was eluted through a silica column using chloroform as eluant to give the desired product as a pale yellow oil (0.789). -(1-Methyl-1 ,2,3,6-tetrahydro-4—pyridv|)(2-nitroehtyl)-1 H-indole N-Methyl-4—piperldone (Aldrich, 4.2g) was added to a solution of the product from step (c) 2.39) in glac. acetic acid (35m|) at 100°C. The resulting solution was heated at 100°C for 1 hour, cooled and poured into a mixture of 0.88 NH.OH (61ml) and ice (61g). The resulting solid was filtered off. dried and recrystallised from ethanol to give the desired product as a white solid (1.69).

Sodium methoxide (0.309) was added to a solution of the product from step (d) (1.59) in DMF (15m|) at 0°C. To the resulting solution was added a suspension of parafonnaldehyde (0199) in DMF (20ml). The resulting mixture was stirred at 0°C for 1.5 hours, then poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated in E to give a yellow oil which was eluted through a silica column using DCM/Et0H/NH4OH (502811) as eluant to give the desired product as an off-white solid (0.859) which was recrystallised from ethanol. -35.. (1)[3-(1-Methyl-4—niperMil)-1H-indolyllamino-1—propanoI The product from step (e) (0.08g) was dissolved in ethanol (25m|) and 10% wlw PdIC (0.239) added. The mixture was stirred under 1 atmos. pressure of hydrogen for 7 hours when uptake was complete. The mixture was filtered through celite and the filtrate evaporated in E to give the desired product as colourless oil which was eluted through a silica column using DCM/EtOHINH.0H (50:8:1) as eluant. (+)(1—Methy|piperidyl)-5—Cl -,3-oxazolidinylmethyl)—1 H-indole A mixture of the product from step (f) (1.69), diethyl carbonate (0.719) 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 in v_a_c_t_lg and theresidiue eluted through a silica column using DCMIEt0HINH.0H (302821) as eluant-to give a colourless foam which was crystallised from isopropanollether to give the desired product as a colourless crystalline solid (1.19). mp 191-192°C. ‘H NMR and microanalysis as for product of Synthetic Example 4.

Synthetic Example 6 Preparation of (R)[5-(2-oxo-1.3-oxazolidin-4»-ylmethyl)-1H-indolyljethylamine LR)(4—nitrobenzyD-1 ,3-oxazolidin—2-one A solution of Dnitrophenylalanine (Fluka, 539) in dimethoxyethane (250ml) was warmed to 67°C and BF3 .Et2 O (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 -37.. 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 chloroformate (Aldrich. 18.2ml) in DCM (23rr_1l). added at below -10°C. The pH was maintained at 9-1 1 1 by periodic additi_ons.'o’f6-N aqu.

NaOH. The resulting solution was stirred atroom fo'ri1 hour, then diluted with water and extracted with DCM. The combined extracts were washed with water and brine, dried and evaporated ya_cu_g to give the desired product as a pale bmwn solid which was recrystallised from ethyl acetate to give a pale yellow solid (359). mp 113-115°, [,~,}.,"+46.47° (c = 0.56. MeOH).

The product from step (a) (10.09) was suspended in a mixture of water (120mI). ethanol (60ml) and 2N aqu. HCI (22.5rni) and 10% wlw Pdlc (1.09) added. The mixture was stirred under 1 atrnos. pressure of hydrogen for 8 . hours when uptake was complete. The mixture was filtered through Hyflo and the filtrate evaporated i_r; vacuo to give the desired product as a colouriess gas (10.3g).

The product from step (b) (10.3g) was suspended in water (53ml) 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 to 0°C. The solution was then added at 0°C over 15 minutes to a stirred solution of tin (ll) chloride ( 51g) in c.HCl (91 ml). followed by 3 hours‘ stirring at room temperature. The solution was evaporated i3 @343 and the residue triturated with ether to give the desired product as a pale yellow solid (Hg)- (d) (R)-2—[ 5-( 2-Oxa-1 .3-oxazolidin-4—ylmethyl)-1 H-indolyl]-ethylamine The product from step (c) (8.8g) was dissolved in ethanollwater (500ml, 5:l vlv) and the solution treated with 4-chlorobutanal dimethylacetal (J.Arner.Chem.Soc. 1365 (1951), 5.5g). The mixture was refluxed for 2 5 hours, the solvent removed in vacuo and the residue eluted through a silica column using DCM/EtOHINH4OH (30:8:1 tvlvlv) 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‘(0.16g) in ethanol (2ml) at 0°C. The hydrochloride salt was precipitated as a fawn solid. mp 269-271°C, [a]D" +5.88° (c = 0.27, MeOH).

Reference Example 7 Preparation of (R)-N.N-dlmethyl(5-(2-oxo-1,3-oxazolidinyl-methyl)-1H-indol yllethylamine Salt of Reference Examge 7 drochloride c.HCl (0.1 Bml) was added dropwise to a stirred solution of the free base (0.459) in ethanol (4.5ml) at 0°C. The mixture was evaporated i_r1 vacuo and the resulting foam triturated with ethyl acetate to give the desired product as a white solid. mp 130°C,[a]D" +5.15" (c=0.77,MeOH).

Synthetic Example 8 Preparation of (S)-N,N-dimethyl-2—l5—(2-oxo-1.3-oxazolidinylmethyl)-1H-indol yflethylamine hydrochloride (S)—N,N-Dimethyll5-(2-aminopropanol)-1H-lndolyllethylamine LS)—N,N-Dimethyl[5-( 2-thia-1 .3-oxazolidinyl methyl)-1 H—indol yllethylamine hydrochloride Salt of Synthetic Example 8 Hydrochloride M Ethanolic HCI (1.0 equiv.) was added dropwise to the free base and the ethanol evaporated i_n vacuo. The resulting gum was freeze-dried from water to give the desired product as a white solid (0.179). mp 133-136°C (softens 128°C), [o,]l-,2‘-5 - 29.a° (c=0.5,water). A Synthetic Example 9 Preparation of (S)—2-[5-(3-methyloxo-1,3-oxazolidinylmethyl)-1H-indol yllethylamine hydrobromide la) 2 o (b) S -Meth l— 4-nitroben I 2-oxazolidinone A suspension of the product from step (a) (4.09) and 10% wlw Pd/C (0.209) in a mixture of ethanol (70ml) and dil. HCI (2N aqu. HCI (12m|) + water (55ml) was hydrogenated at 45 psi for 1 hour. The mixture was filtered through Hyflo and the filtrate evaporated E vacuo to give the desired product as a foam. (c) (S);3-Methyl-fi4ehydrazinoben;yl)oxazolidinone hydrochloride H hydrobromide -Chlorobutanal dimethylaoetal (J.Arner.Chem.Soc. 1365 (1951), 2.39) was added to a stirred solution of the product from step (c) (4.49) in ethanol/water (150mlI30ml) and the mixture refluxed for 2 hours. The cooled mixture was evaporated lg yacgg and the residue eluted through a silica column using DCM(MeOH/NH.0H (60:8:1) as eluant to give a brown oil (1.79). A portion of this (0.259) was taken up in ethanol and treated with an excess of HBr in acetic acid @ 45% wlv). The resulting solution was evaporated i_n Lang and the residue triturated with ether, then crystallised from ethanollhexane to give the desired product as pale yellow crystals (0.149), mp 203-205 C, [(,]D’‘ + 29.9° (c=0.5, MeOH). Elemental analysis and ‘H NMR were consistent with the proposed structure.

Synthetic Example 10 Preparation of (S)-N,N—dimethyl[5-(3-methyloxo-1;-oxazolidin—4-yl methyl)-1 H- indol—3-yllethylamine maleate 0.75 hydrate Sodium cyanoborohydride (0.149) followed by glac. acetic acid (0.54ml) were added at room temperature to a stirred solution of the free base (0.529) from step -42.. (d) of Synthetic Example 9 in methanol (9.0ml). When effervescence was complete, a solution of 37% wlv aqu. fonnaldehyde (0.169) in methanol (2.0ml) was added and the mixture stirred for 1 hour, then diluted with water, saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were evaporated in @319 and the residue eluted through a silica column ‘using DCM/MeOH/NH.OH (60:8:1) as eluant to give the free base of the desired product as a colourless oil (0.259). The latter was dissolved in ethanol (10ml), treated with a solution of maleic acid (0.099) in ethanol (1ml) and the resulting solution evaporated m @531; to give an oil which was triturated with ether, then freeze-dried from water to give the desired product as a colourless glass, [,1].," +24.5° (c=0.5,MeOH). Elemental analysis, ‘H NMR and MS were consistent with the proposed structure.

Synthetic Example 11 Preparation of (S)-N-benzvlI5-(2-oxo-1,3—oxazolidin—4-ylmethvl)-1H-indol yl|ethylamine maleate 0.75 hydrate Benzaldehyde (0.709) was added at room temperature to a stirred solution of the compound of Synthetic Example 1 (1.79) in ethanol (20ml). The solution was stirred for 36 hours, then sodium borohydride (0.259) was added in portions and stirring continued for a further 2 hours. The solution was evaporated lg ggug and the residue cooled, acidified with 2N aqu. HCl, basified with sodium bicarbonate, saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were evaporated m yflrg to give an oil which was eluted through a silica column using DCM/EtOH/NH.OH (100:8:1) as eluant to give the free base of the desired product as a yellow froth (1.69). A portion of this (0.139) was dissolved in ethanol (10ml), treated with a solution of maleic acid (43mg) in ethanol (1ml) and the resulting solution evaporated in E. The residue was freeze-dried from water to give the desired product as a pale yellow powder (0.169), [a].," +1.4" (c=0.5, MeOH). Elemental analysis, ‘H NMR and M3 were consistent with the proposed structure. _ ..

Synthetic Examge 12 Preparation of (S);N-benyl-N-methyl[5-(2-oxo-1 ,3-oxazolidinyl.-methyl)-1 H- indolyllethfiamine maleate hydrate Anhy. potassium carbonate (0.349) was added at room temperature to a solution of the free base of Synthetic Example 11 (0.459) in DMF (8.0ml). The suspension was stirred for 0.5 hour, then a solution of dimethyl sulphate (0.179) in DMF (2.0ml) was added and stirring continued for a further 3 hours. Water (40ml) was added and the mixture extracted with ethyl acetate. The combined extracts were evaporated i_rj yaggg to give a yellow oil which was eluted through a silica column using DCM(EtOHlNH..OH) (100:8:1) as eluant to give the free base of the desired product as a colourless oil (0.329). A portion of this (73mg) was dissolved in ethanol (10ml), treated with a solution of maleic acid (23mg) in ethanol (1ml) and the resulting solution evaporated i_r1 yg:_ug. The residue was freeze-dried fnorn water to give the desired product as a pale yellow powder. LIL," +3.1° (c=0.5, Me0H). Elemental analysis. ‘H NMR and M8 were consistent with the proposed structure.

Synthetic Example 13 Preparation of (S)-N-methyl[5-(2-oxo-1,3-oxazolidin—4»vlmethvl)-1H-indol yflethylamine maleate 0.5 hydrate A suspension of the free base of the product of Synthetic Example 12 (0.259) and % wlw Pd/C (0.109) in ethanol (25ml) was hydrogenated for 16 hours. The mixture was filtered through Hyflo and the filtrate evaporated ir_1 y_aggg. The residue was eluted through a silica column using DCMlEtOH/NH4OH (30:8:1) as eluant to give the free base of the desired product (0.149). The latter was dissolved in ethanol (10ml), treated with a solution of maleic acid (0.069) in ethanol (1 ml) and the resulting solution evaporated i_n_ yac_ug. The residue was freeze-dried from water to give the desired product as a hygroscopic solid. [u],,’5 -5.4° (c=0.5, MeOH).

Elemental analysis and ‘H NMR were consistent with proposed structure.

Synthetic Example 14 -ylmethyl)-1H-indol 0.33 methanolate 0.75 hydrate Phenylthioacetaldehyde diethylacetal (JCS. Chem. Comm. 924 (1978), 9.1g) was added at room temperature to a stirred solution of the product from step (e) of Synthetic Example 1 (9.89) in a mixture of ethanol (150ml) and water (100ml). c. HCI (5 drops) was added and the mixture stirred at room temperature for 2 days. then partially evaporated in yggg. The resulting aqueous suspension was extracted with ethyl acetate and the combined extracts washed with water and evaporated in yaggtg to give a brown oil.

The latter was eluted through a silica column using DCM/Et0HlNH.OH (150:8:1) as eluant to give the desired product as a pale yellow oil (5.0g).

(S);5-(2-oxo-1,3-oxazolidin-4—ylmethfl);1H-indole Raney nickel (3.0g) was added to a solution of the product from step (a) (3.1g) in IPA (150ml) and the suspension refluxed for 1 hour. More Raney nickel (2.0g) was added and refluxing continued for a further 2 hours. The suspension was filtered hot through Hyflo and the filtrate evaporated i_r_1 va_c_Lg to give an oil. The latter was eluted through a silica column using ethyl acetate as eluant to give the desired product as a froth (1.39). H NMR and MS were consistent with the proposed structure.

LS)( 1 -Methy|—1 .2,3,6-tetrahydroDvridyl)(2—oxo-1 .3~oxazolidin Llmethyl)-1H-indole 0.33 methanolate 0.75 hydrate -Methylpiperidone (0.479, Aldrich) was added to a stirred solution of the product from step (b) (0.309) in glac. acetic avid (2.0ml) and the mixture stirred at 100°C for 2 hours. The cooled mixture was poured onto -45.. ice/NH.OH (20ml) and the resulting solid filtered off. The latter was eluted through a silica column using DCMIEtOHINH.OH (60:8:1) as eluant and crystallised from ethyl acetate to give the desired product as a colourless solid (0.119), mp 255-227°C, [a],,’° -45.4° (c=0.5, IN aqu. HCI). Elemental analysis and ‘H NMR were consistent with the proposed structure.

Synthetic Example 15 Preparation of (s)(1-methyl—4-Diperidvll(2-oxo-1.3-oxazolidin-4jdmethyD—1H- indole hydrobromida A suspension of the product of Synthetic Example 14 (O.35g) and 10% w/w PdlC (0.10g) in a mixture of methanol (10ml), water (10ml) and 1N aqu. HCl was hydrogenated for 5 hours. The mixture was filtered through Hyflo and the filtrate evaporated in EE. The residue was basified with NH.0H, evaporated l_l'_I \_/egg and eluted through a silica column using DCMlEtOHlNH.OH (45:8:1) as eluant to give an oil. The latter was taken up in ethanol (5.Clml) and treated with an excess of HBr in acetic acid (ca 45% wlv) to give the desired product as a colourless crystals (0.209), mp 260-261 °C, [a],,‘" -5.2° (c=O.5, water). Elemental analysis and ‘H NMR were consistent with the proposed structure.

Synthetic Example 16 Preparation of (R)(1-methyl-1.2,3,6-tetrahydropyridyl)(2-oxo-1 ,3-oxazo|idin- 4-ylmethyl)-1H-indole hydrate (a) B)(4-Hydrozinobenzfi)-1,3-oxazolidinone hydrochloride By steps identical to steps (a) to (c) of Synthetic Example 6, D nitrophenylalanine was converted to (R)(4—hydrazinobenzyl) oxazolidinone hydrochloride. (b) R 1-Melh l-1 2 3 6-tetrah d I 2—oxo-1 3_-oxazolidin-V4: 1H-indole hydrate " « By steps analogous to steps (a) to (c) of Synthetic Example 14. the product from step (a) was converted to (R)(1-methyl-1,2,3,6-tetrahydropyridyl)- -(2-oxo-1,3-oxazolidinylmethyl)-1H-indole hydrate. mp 229-231°C, [a].,‘° +24.9° (c=O.5. lN aqu. HCI). consistent with proposed structure.

Synthetic Example 17 Preparation of (R)(1-methylpiperidyl)(2—oxo-1,3-oxazolidine4—ylmethy|)-1H-‘ lndole hydrobromide . By a method analogous to that of Synthetic Example 15, the product of Synmetic Example 16 was converted to (R)-3—(1-methylpiperidyl)(2-oxo-1.3-oxazolidin- 4-ylmethyl)-1H—indole hydrobromide. mp 260-261°C, [aL" +4}6° (c=0.5, water).

Elemental analysis and ‘H NMR were consistent with proposed structure.

Synthet ic Example ‘l 8 Preparation of (R)(1-bengyl_-_1 ,2,3,6-tetrahydropyrldynfi-_(2-oxo-1,3-oxazolidin- 4-ylmethyl)-1H-indole hydrate A Elemental analysis and’ ‘H NMR were’ -47..

Synthetic Example Synthetic Examgte 20 Erewation (i)—N, N-diIIEthY1‘2['S‘ »{1-thiothiaoxazolidin-4—vt-methvl)—1H-indol- -1!|_e_th1|amina acetate Carbon disulphide (QOPI) was added to a stirred solution of the product from step (a) buffer at pH 4.0 over 20 minutes to give the desired product (0.019) and. after structures. -48..

Synthetic Example 21 Preparation of (1)-N,N-dimethyl[5-(2-oxo-2.3-oxazolidinylmethylL1H-indol¢3- fllethylamine hydrochloride (3) 1 0 (b) 2 0 (C) 2 5 (1)Nitror;et_h1|Dhenylethanol Sodium memoxide (1.1g) was added to a stirred solution of nitromethane (Aldrich, 12.2g) in methanol (100ml) at 0°C and the mixture stirred for 10 minutes. A solution of phenylacetaldehyde (Aldrich. 24.09) in methanol (50ml) was added dropwise over 15 minutes and the mixture stirred for 45 minutes at 0°C. then brought to room temperature over 1 hour and stirred overnight. The mixture was evaporated in 1/1339 and the residue taken up in water and extracted with ether. The combined extracts were washed with water and brine and evaporated in vacuo to give the desired product as a yellow oil (29.09). (f)AminomethylQhenylethanol hydrochloride A suspension of the product from step (a) (10.09) and 10% wlw Pd/C (1.09) in ethanol (250ml) was hydrogenated until uptake ceased. The mixture was filtered through Hyflo and the filtrate evaporated ig gcfl. The residue was taken up in ethyl acetate and extracted with 2N aqu. HCl. The combined extracts were washed with ethyl acetate. then evaporated in \La_cuc_> to give the desired product as a pinkish white solid (6.89). (1)Benyl-1 ,3-oxazolidinone A solution of KOH (9.49) in water (85ml) was added to a stirred solution of the product from step (b) (5.1g) in toluene (150ml) at 0°C. A solution of phosgene (9.8g) in toluene (78.4ml = 12.5% w/v) was added dropwise over minutes and the mixture brought to room temperature, then stirred overnight. The aqueous phase was separated and extracted with ethyl -49.. acetate. The combined extracts were evaporated in vacuo to give the desired product as a white solid (21.29), mp 106-108°C. Elemental analysis was consistent with the proposed structure. c.H2SO. (1.6ml) was added to the product from step (c) at 0°C followed by c.HNO, (0.33ml. _c_a 0.05mll5 minutes) also at 0°C. The mixture was stirred for 0.5 hour at 0°C and then for 0.5 hour at room temperature. Waterfice (100ml) was added and the mixture extracted with ethyl acetate. The combined extracts were evaporated in yagg to give a yellow oil which was recrystallised from ethyl acetate to give the desired product as a white powder (0.49), mp 143-146°C. ‘ (3)(4-Aminobenm)-1 ,3—oxazolidin-2—one hydrochloride A suspension of the product from step (d) (1.49) and 10% w/w PdIC (0.149) in a mixture of water (21ml), ethanol (28ml) and 2N aqu. HCI (3.2ml) was hydrogenated for 2 hours when update ceased. The mixture was filtered through Hytlo and the filtrate evaporated in ygg to give the desired product as a pale yellow foam (1.49). (j-_);flLN-Dimethvl[5-(2-oxo-1 .3—oxazolidin-5—vlmethvl)-1H-indol yllethylamine hydrochloride structure.

Synthetic Examgle 22 white solid . (s.6g> S —N N-Dimeth I yllethylamine -axooxazolidin—4- meth I 1H-indol step (a) was converted to (S)-N,N-dimethyl[5-(2-oxo-1,3—oxa2olidin ylmethyl)-1 H-indolyl]ethylamine.

Synthetic Example 23 Preparation of (S)-N.N-dimethvl[5-(2-oxo-1.3-oxazolidin-4—ylmethvl)-1'H-indol yllethylamine EH-(4-Hvdrazinobenzyl)-1,3-oxazolidln-2—one hydrochloride By steps analogous to steps (a) to (c) of Synthetic Example 6. L-4» nitrophenylalanine was converted to (S)(4-hydrazinobenzyl)—1,3- oxazolidlnone hydrochloride. - 4- 2- 3-c ano ro lidene h drazino ben I 1.3-oxazolidinone M aqu. HCl (4.0ml) was added to a solution of the product from step (a) (2.4g) in water (35ml). 3-Cyanoproposanl diethylacetal (Aldrich. _1.7g) was added at room temperature and the mixture stirred for 2 hours. Further acetal (0.20g) 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 ya_c:u_o to give the desired product (2.59).

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 i_n ya£;u_o. The remaining aqueous phase was extracted with ethyl acetate and the combined extracts evaporated i_r1 yac_ug to give the desired product as a pale yellow oil (1.89). (d) S N-Dimethyl[5-(2-oxo-1,3-oxazolidinylmethvl)-1H-indol-3f yllethflamine A suspension of the product from step (c) (1.39) and 10% my Pd/c (1.09) in % wlw ethanolic dimethylamine (25m|) was hydrogenated ‘for 24 hours and filtered through Hyflo. Fresh Pdlc (0.79) and ethanolic dimethylamine (5ml) were added to the filtrate and hydrogenation cont_inu_ed,for of further 16 hours. The mixture was filtered through a silica . column using DCMlEtOHINH.OH (40:8:1) as eluanl to give the desired product as a colourless foam (0.3g). Elemental analysis and ‘H NMR were consistent with the proposed structure.

Synthetic Examples 24 to 31 By methods analogous to those described in Examples 1 to 23, the following compounds of fonnula (I) were prepared. The NMR and rnicroanalysis for each compound were consistent with the proposed structure. ) 2-[5-(3-Methyloxoirnidazolidinylmethyl)-1H-indol-3yl]-ethylamine maleate 0.75 hydrate, mp 94-98°C. ) 2-[5-(3-Methyloxoimidazolidin-4—ylmethyI)-1H-indolyl]N.N-dimethyl- ethylamine maleate 0.95 hydrate (white lyopholate); ) 2—{5-[2-(2,5-Dioxoirnidazolidinyl)ethy|]-1H-indolyl)ethylamine hydrochloride hydrate. mp 83-85"C. ) 2-(5-[2-(2,5-DioxolmidazolidinyI)ethyl]-1H—indolyl}-N,N-dimethylethylamine maleate hydrate (pale yellow lyopholate); ) 5-[2-(2,5-Dioxoimidazolidinyl)ethyl](1-methylpiperidinyl)-1H-indole hydrochloride, mp 320-322°C (dec); ) _ 2-[5-(5—Methyloxoimidazolidlnylethyl)-1H-indolyl} ethyianfiné maleate hydrate, mp 99°C (softens 88"C); ’ ‘ ) 5-[3-(4-Piperldyl)-1H-indolylmethyl]-2Awimidazolidinedlone acetate 1.4 hydrate. mp 92-93°C (softens 86°C); and ) 2-[5-(1-Methyl—2-oxo-4—imidazolidinylmethyl)-1H-indolyllethylamine diacetate 2.75 hydrate (pale yellow lyophylate).

PHARMACEUHCAL FORMULATION EXAMPLES _________.____.______________ ln the following Examples, the "active ingredient" may be any compound of formula (I) andlor a physiologically acceptable salt. solvate, or physiologically functional derivative thereof (1) Tablet fonnulations (ii) Sublingual Active ingredient Avicel Lactose Mannitol Sucrose Acacia Povidone Magnesium stearate Mg/t_gblet 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 Active ingredient Hydroxypropylmeth cellulose (HPMC) Polycarbophll Magnesium stearate Mg/tablet 39 The fonnulation may be prepared by direct compression of the admixed ingredients.

Formulation HA may be prepared by melting the Macrogol 4000 BP, dispersing mar active ingredient in the melt and filling two-part hard gelatin capsjules-"therewith.

Formulation I may be prepared by dispersing the active ingredient theflecithin and arachis oil and filling soft. elastic gelatin capsules with the dispersion; (iii) Controlled release Mgcapsule Active ingredient 25 Avicel 123 A Lactose 62 Triethylcitrate 3 Ethyl cellulose 12 The formulation 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 iniection formulation % by weight Active ingredient 2% Hydrochloric acid ) Citrate buffer ) q - S - t0 PH 7 Water for Injections to 100% The active ingredient is taken up in the citrate buffer and suificient 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 into sterile glass vials which are sealed and oversealed. (5) Intramuscular iniection formulation Active ingredient 0.05g 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 glyoofurol. The benzyl alcohol is added and dissolved and water added to 3 ml. The mixture is filtered through a micropore filter into sterile glass vials which are sealed and oversealed. (6) Syrug formulation Active ingredient 0.05 g Sorbitol 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) Sugmsitogg fonnulation Mglsuppository Active ingredient (63um)* 50 Hard Fat, BP (Witepsol H15 -Dynamit NoBel) 133 2000 * The active ingredient is used as a powder wherein at least 90% of the particles are of 63pm diameter or less.

One—fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C maximum.

The active ingredient is sifted through a 200p_m 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 250nm 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. -59.. (8) Pessagg fonnulation Mgpessary . Active ingredient (63"m) 50 Anhydrous dextrose 470 Potato starch 473 Magnesium stearate g_3 The above ingredients are mixed directly and pessaries prepared by compression of the resulting mixture.

BIOLOGICAL ASSAY The compounds of formula (I) prepared in Examples 1 to 17 were each 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 pentobarbitone sodium (60 mglkg). 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. NaHCO3 .00, KCl 4.75, KHZPO4 1.19, MgSO. 1.19. glucose 11.10 and CaCl, 2.50.

Cocaine (SOFM) 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% oxygenl5% 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 1.0g was applied to each preparation and re-established twice during a subsequent period of 30 minutes. During this period. tissues were exposed to pargyline (500uM) to irreversibly inhibit monoamine oxidase and to phenoxybenzamine (0.1 PM) to inactivate a,-adrenoceptors. 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 tenns of the p[A5.,] (-log,.,[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 and Synthetic Examples 415 are shown in Table 1. _61_ TOXICITY DATA The hydrochloride salt of the compound of Synthetic Examples 2/3 were Table 1' Activity E{A5_o] 7.0 administered orally by gavage to Wistar rats as a solution in distilled water at dosages of 25, 100 and 200mgIkg 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 Zmglkg on Day 1 to 100 mglkg on Day 30. The free base was also administered orally to cynomolgus monkeys at a dosage of 50 mglkg 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 (1)

1.CLAIMS 1. A compound of formula (I) (I) w\ 9:323» 2 wherein n is an integer of from 0 to 3; W is a group of fonnula (i), (ii), or (iii) Y RN N R X N.—.: X t RN _ 6, (ii) 0 (in) wherein R is hydrogen or C14 alkyl. X is , . -NH—, or —CH,-. Y is oxygen or sulphur and the chiral centre * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; and Z is a group of formula (iv), (v), or (vi) cH,cHzNR‘R2 / NR NR ' (iv) (V) (Vi) _ 63 .. A wherein R‘ and R’ are independently selected from hydrogen and C.. 4 alkyl and R’ is hydrogen or C14 alkyl; and salts, solvatesand physiologically functional derivatives thereof, provided that said compound is not N, N-dlmethyl-2—[5-(2-oxo-1,3-oxazolidin- 5 ylmethyl)~1H-lndolyl]ethylamine. ' 2. A compound of fomiula (I) according to Claim 1, wherein n is 1, or W is a group of formula (I), or Z is a group of formula (iv) or (vi), 10 and physiologically acceptable salts, solvates andphysiologically functional derivatives thereof. 3. A compound of fonnula (I) according to Claim 1, wherein n is 1, W is a group of formula (i) wherein R is hydrogen. X is and Y is 15 oxygen, and Z is a group of fonnula (iv) or (vi) wherein R’ = R’ = hydrogen or methyl. and physiologically acceptable salts. solvates and physiologically functional derivatives thereof. 20 4. A compound of formula (I) as claimed in Claim 1, which compound is 3-(1- methylpiperidyl)—5-(2-oxo—1,3-oxazolidinylmethyl)-1H-indole in either its (8) or (R) form or as a mixture thereof in any proportions, or a physiologically acceptable salt. solvate. or physiologically functional derivative thereof. ‘ A compound of formula (I) as claimed- in Claim 1, which is (S)-.N-m_ethyl[5- (2-oxo-1.3-oxazolldin-4—ylmethyl)-1H-indolyl]ethylamine. or a pi_iy'sio- logically acceptable salt or solvate thereof. V ‘ ’ ’ A A compound of formula (I) as claimed in any of Claims 1 to 5; or a physiologically acceptable salt. solvate. or physiologically functional derivative thereof for use as a therapeutic agent. A compound of formula (I) as claimed in any of Claims 1 to 5, 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 of formula (I) as claimed in any of Claims 1 to 5. or a physiologically acceptable salt. solvate. or physiologically functional derivative thereof, for use in the prophylaxis or treatment of migraine. Use of a compound of formula (I) as claimed in any of Claims 1 to 5, 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 of fonnula (l) as claimed in any of Claims 1 to 5, 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 of fonnula (I) as claimed in any Of Claims I to 5 or a physiologically acceptable salt, solvate. or physiologically functional -65.. derivative thereof, a phannaceutically acceptable carrier and, optionally, one or more other physiologically active agents. 12. A medicament as claimed in Claim 11 which is in the form of a tablet or capsule. 5 13. A process for the preparation of a compound of formula (I) E N \fl\ M12)“ _ Z 1 0 wherein n is an integerof from 0 to 3, W is a group of formula (i), (ii), or (iii) Y R ' N R X 1 5 " . “ (i) (ii) 0 (iii) wherein R is hydrogen or C14 alkyl, X is , -S-. -NH-, Or -CH2-. Y is oxygen or sulphur and the chiral centre * in formula (i) or (ii) is in its (8) or (R) fonn or is a mixture thereof in any proportions; and Z is a group of formula (iv). (v), or (vi) (V) (iv) (vi) 4 alkyl and R’ is hydrogen or CH alkyl; provided that said compound is not N,N-diniethyl[5-(2-oxo-1,3-oxazolidinyImethy|)—1H-indol- 3-yl]ethyl-amine which process comprises 10 (a) - in the case where Z is a group of formula (iv), reacting a compound of fonnula (ii) _ "RN32 w\(CH2)n i an 15 wherein n and W are as hereinbefore defined. with a compound of formula (III) wherein R‘ and R’ are independently selected from hydrogen and C1- or a carbonyl—protected fonn thereof. wherein L is a suitable leaving group or protected amino group which may be converted in fl to an amino group or is —NR'R’ wherein R‘ and R2 are as hereinbefore defined; (b) in the case where Z is a group of fomiula (v). reacting a compound of fonnula _(XXXl) ZN ‘K (XXX!) ‘°H2)n wherein n and W are as hereinbefore defined, with a compound of formula ()()(VIII) 0 NR (XXV!!!) wherein R3 is as hereinbefore defined. and (c) in the case where Z is a group of formula (vi), reducing a compound of fonnula (I) wherein n and W are as hereinbefore defined and Z is a group of formula (v) or. in the case where W is a group of fonnula (i) or (ii). reacting a compound of formula (XV) - wherein n. R and X are as hereinbefore defined and Z is a group of fonnula (vi), with a compound of formula (VII) wherein Y is as hereinbefore defined and L and L'_, which may be the same or different. ' are suitable leaving groups. and optionally converting the compound of formula (I) so formed to a corresponding salt, solvate, or physiologically functional derivative. A method of preparing a medicament which comprises (3) preparing a compound of fonnula (I) or a physiologically acceptable salt, solvate or physiologically functional derivative thereof by a process as claimed in Claim 13, and 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 14 which comprises an additional step c) wherein the admixture from step b) is formed into a tablet or capsule. A compound substantially as hereinbefore described with reference to the accompanying examples. Use of a compound substantially as hereinbefore described with reference to the accompanying examples. A medicament substantially as hereinbefore described with reference to the accompanying examples. A process substantially as hereinbefore described with reference to the accompanying examples. A method substantially as hereinbefore described with reference to the accompanying examples. CJDISKSPECS