INDOLE DERIVATIVES AS 5HT1C ANTAGONISTS

Abstract: A compound of formula (I) or a salt thereof wherein P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; R1 is hydrogen or C1-6 alkyl; R2, R3, R10 and R11 are independently hydrogen or C1-6 alkyl, or R10 and R11 together form a bond, or R2 and R10 or R3 and R11 together form a C2-6 alkylene chain; R4 is hydrogen, C1-6 alkyl, halogen, NR8R9, OR12 or COOR12, where R8, R9 and R12 are independently hydrogen or C1-6 alkyl; R5 and R6 are independently hydrogen or C1-6 alkyl; and R7 is hydrogen, C1-6 alkyl, C1-6 alkoxy or halogen; and wherein the urea moiety is attached at the 4-, 5- or 6-position of the indole or indoline ring, provided that P is not pyridyl when R10 and R11 form a bond, which has been found to have 5HT1C receptor antagonist activity.

Description: INDOLE DERIVATIVES AS 5HT1 C ANTAGONISTS This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals. P. Fludzinski et aL, J. Med. Chem. 1986 29 2415-2418 describes N-(l,2-d_ methyl-3-ethyl-lH-indol-5-yl)-N'- (3-trifluoromethylphenyl)urea which shows selectivity for the rat stomach fundus serotonin receptor. A class of compounds has now been discovered which have been found to have 5HT-J. Q receptor antagonist activity. 5HTIQ receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury, such as hydrocephalus. Accordingly, the present invention provides a compound of formula (I) or a salt thereof: (I) wherein: P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; Rl is hydrogen or Cι_6 alkyl; R2, R3, Rio and R-J ^ J are independently hydrogen or C^.g alkyl, or R-^o and 11 together form a bond, or R2 and R^Q OΓ ^3 an ^ &11 together form a C2-6 alkylene chain; R is hydrogen, Cι_g alkyl, halogen, NRgRp,, O 12 or COOR12, where Rg, Eg and R 2 are independently hydrogen or C^.g alkyl; R5 and g are independently hydrogen or Cι_g alkyl; and R7 is hydrogen, Cι_g alkyl, C _.g alkoxy or halogen; and wherein the urea moiety is attached at the 4-, 5- or 6-position of the indole or indoline ring, provided that P is not pyridyl when RJQ an ^ -^11 ^ orιn a bond. Alkyl moieties within the variables Ri to R12 are preferably C1.3 alkyl, such as methyl, ethyl, n- and iso- propyl, most preferably methyl. Suitable R4 and R7 halogens include chloro and bromo. Examples of Ri include hydrogen, methyl, ethyl and n-propyl, preferably methyl. R2 and R3 are preferably hydrogen. io and n are preferably a bond so as to form an indole structure. In an indoline structure, o and Rn are preferably hydrogen. Preferably R is hydrogen or methyl, most preferably hydrogen. Preferably R5, Rg and R7 are hydrogen. The urea moiety can be attached to a carbon or nitrogen atom of the ring P, preferably it is attached to a carbon atom. Suitable moieties when the ring P is a 5- or 6-membered aromatic heterocyclic ring include pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. When P is a quinoline or isoquinoline residue, the urea moiety can be attached at any position of the ring, preferably to the 4-position. The urea moiety is preferably attached at the 5-position of the indole or indoline ring. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable adds, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic acids. Compounds of formula (I) may also form N-oxides or solvates such as hydrates, and the invention also extends to these foπns. When referred to herein, it is understood that the term 'compound of formula (I)' also includes these forms. When Ri (in an indole) and/or R5 and/or Rg are hydrogen or when R4 is hydroxy or NRgRg and at least one of Rg and Rg are hydrogen the compounds of formula (I) may exist tautomerically in more than one form. The invention extends to these and any other tautomeric forms and mixtures thereof. Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric foπns and to mixtures thereof including racemates. The different βtereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereόspeάfic or asymmetric synthesis. The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: (a) the coupling of a compound of formula (II); -1 — τ_ -*- (H) with a compound of formula (III); (m) wherein B is attached at the 4-, 5- or 6-position of the indole or indoline ring and A and B contain the appropriate functional group(s) necessary to form the moiety -NRs'CONRg 1 - when coupled, wherein Rζ and Rg' are R5 and Rg as defined in formula (I) or groups convertible thereto, and the variables Rι\ R 2 \ R3 * , Rio', Rn', R4 and R 7 ' are R lt R 2 , R3, Rio, Rll, R4 and R7 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any Ri', R2 * , 3 * , Rio', Rll', R4'. Rβ', Re' an ^ ^7 * when other than Ri, 2, R3, Rio, Rn, R4, R5, β and R7 respectively to Ri, R2, R3, Rio, Rll, R4, R5, Rβ ^d R 7» interconverting Ri, R2, R3, io, R11, R4, R5, Rg and R7, and forming a pharmaceutically acceptable salt thereof; or (b) cyclising a compound of formula (IV): (IV) wherein R , Rζ , Rg' and R7' are as defined in formulae (II) and (HI) and C and D contain the appropriate functional group(s) necessary to form the indole or indoline ring substituted by Ri', R2 1 , R3\ Rlθ'» and Rn' as defined in formula (EH), and thereafter optionally and as necessary in any appropriate order, converting any Rι\ 2, R3', Rlθ'» Rll'» R4 * » δ'» Rβ' and R7' when other than Ri, R2, R3, Rio, Rll, R4, R5, 6 an d R7, to Ri, R2, R3, Rio, Rll, R4, R5, Rβ ^ R 7» interconverting Ri, 2, R3, RIQ, Rll, R4, R5, Rg and R7, and optionally thereafter forming a pharmaceutically acceptable salt. Suitable examples of groups A and B include: (i) A is -N=C * =0 and B is -NHRg', (ii) A is -NHR 5 ' and B is -N=C=0, (iii) A is -NR5OOL and B is -NHRg', (iv) A is -NHRδ' and B is -NRg'CO , or (v) A is halogen and B is -NRg'CONHRs * , wherein Rζ and Rg' are as defined above and L is a leaving group. Examples of suitable leaving groups L include halogen such as chloro or bromo, imidazole, or phenoxy or phenylthio optionally substituted for example with halogen. When A is -N=C=0 and B is NHRg' or when A is NHRs' and B is -N=C=0 the reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at ambient temperature. When A is -NRs'COL and B is -NHRg' or when A is -NH s' and B is -NRg'COL, the reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in dimethylformamide at ambient or elevated temperature. When A is halogen and B is -NRg'CONHRs', the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base. The cyclisation of the compound of formula (IV) to prepare indoles (RIQ and R11 are a bond) may be effected using standard methodology such as described in Comprehensive Heterocyclic Chemistry 19844, 313 et seq. or J. Het. Chem. 1988 25 p.l et seq. Examples of the more important routes include the Leimgruber synthesis, the Fischer synthesis and the Japp-KUngemann variation and the Madelung synthesis. Examples of the groups C and D in the preparation of indoles indude: (vi) C is NO2 and D is CH=CH-NZ2 where each Z is independently Cι_ alkyl or together represent C2-7 alkylene; (vϋ) C is NRι , -N-=C(R2 , )-CH2R3' and D is H; (vϋi) C is NH-N=C(C0 2 X)-CH2R3' and D is H where X is Cι_g alkyl; and (ix) C is N ι'COR2' and D is CH2R3. The preparation of indolines indudes: (x) C is NHRi and D is ( Ra'XRii CKR^XRio where Lis a . leaving group. Indolines may also be prepared by reduction, e.g. with NaCNBH3, of indoles produced by variants (vi) to (ix) above. In reaction variant (vi) (Leimgruber synthesis) the compound of formula (IV) is prepared from the 2-methylnitrophenyl urea by treatment with a dialkylacetal of the dialkylformamide OHCNZ2 with heating and the product of formula (IV) cyclised by hydrogenation over a suitable catalyst such as palladium and charcoal optionally under pressure to yield the compound of formula (I) where Rι= 2= 3=H. In reaction variant (vϋ) (Fischer synthesis) the compound of formula (IV) is prepared from the hydrazinophenyl -urea by dehydration, preferably by heating, with the appropriate ketone R2 * COCH2 3' and the product of formula (IV) cydised by heating with an add catalyst such as hydrochloric or sulphuric add. In reaction variant (viii) (Japp-Klingemann synthesis) the compound of formula (IV) is prepared from the aminophenyl urea by diazotisation followed by treatment for example with CH3COCH(CC » 2X)-CH2R3' where Xis Cχ_6 alkyl under basic conditions in aqueous alcohol as solvent. The product of formula (IV) may then be cydised as in the Fischer synthesis above. In reaction variant (ix) (Madelung synthesis) the compound of formula (IV) is cyclised with base in an inert solvent optionally with heating. In reaction variant (x), the compound of formula (IV) is cyclised by heating in an inert solvent, optionally in the presence of a base. It will be appreάated that when D is hydrogen, either or both indole isomers may be formed during the cyclisation process. Suitable examples of groups R2', R3', R4 1 , and R7 * which are convertible to R2, R3, R4, and R7 alkyl groups respectively, include acyl groups which are introduced conventionally and may be converted to the corresponding alkyl group by conventional reduction, such as using sodium borohydride in an inert solvent followed by hydrogenolysis in an inert solvent. Hydrogen substituents may be obtained from alkoxycarbonyl groups which may be converted to hydrogen by hydrolysis and decarboxylation. When R4 is hydroxy it is preferably protected in the compound of formula (II) as, for example, benzyl which is removed by hydrogenation. Suitable examples of a group R ' which is convertible to i, indude typical N-protecting groups such as alkoxycarbonyl, in particular t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and para-methoxybenzyl which are converted to i hydrogen using conventional conditions. Suitable examples of groups R5' and Rg' which are convertible to R5 and Rg respectively indude alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to R5 and/or Rg hydrogen using conventional conditions. Interconversions of Ri, R2, R3, Rio, Rll, R4» R5, Rβ an d R7 are carried out by conventional procedures. For example, in the case wherein R , R2 and R3 are Cι_ alkyl and R5 and Rg are hydrogen it is possible to introduce a Ci.g alkyl group at both the R5 and Rg positions by conventional alkylation using 2 molar equivalents of a Cι_g alkyl halide and 2 molar equivalents of a suitable base in an inert solvent. Monoalkylation can be achieved using 1 molar equivalent of a Cι_g alkyl halide and base using conventional conditions. Rl Ci-g alkyl groups may also be introduced by conventional alkylation, for example using a Cι_g alkyl halide and base such as sodium hydride, or by reduction of Cι_g acyl. R4 halo and R7 halo may be introduced by selective halogenation of the ring P or indole/indoline ring respectively using conventional conditions. It should be appreάated that it may be necessary to protect any i to R12 hydrogen variables which are not required to be interconverted. Protection, espedally of a Ri' hydrogen, may also be necessary during coupling reaction (a) and ring-forming reaction (b) above. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). It is preferable, however, to introduce and interconvert the groups i to Rl2 before coupling compounds of formulae (II) and (IE) together, or cydising the compound of formula (IV). Compounds of formula (I) which are substituted indoles, and their appropriate derivatives, can be converted to the corresponding indolines, and vice versa, by conventional methods, e.g. reduction with NaCNBH3 in acetic add and oxidation using MnC * 2 in an inert solvent. Compounds of formula (II) in which A is NHR5' are known compounds or can be prepared analogously to known compounds. For example, aminopyrazine and 4-aminoquinaldine are commerdally available from Aldrich, and 3-amino-6-chloro-pyridazine is commerdally available from Lancaster. Compounds of formula (II) in which A is -N=C=0 may be prepared by treating a compound of formula (II) in which : i) A is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent. ϋ) A is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using conventional conditions (ref L.S. Trifonov et a_L, Helv. Chim. Acta 1987 70262). iii) A is CONH2, via the nitrene intermediate using conventional conditions. Compounds of formula (II) in which A is -NRδ'COL may be prepared by reacting a compound of foπnula (II) in which A is -NHR5' with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triethylamine. Compounds of formula (II) in which A is halogen and R4' is hydrogen are commerdally available. Compounds of formula (III) in which B is NHRg' are known compounds or can be prepared analogously to known compounds, for example by reduction of the corresponding nitroindole or nitroindoline by catalytic hydrogenation over Pd/C by the method of P. Fludzinski et a_L J. Med. Chem., 1986, 29 2415. Specifically, the compound of formula (HE) in which Ri' and 2' are methyl, R3' is ethyl, Rio' and n' are a bond, Rg' and R7 1 are hydrogen and B is NH2 is prepared using a procedure similar to that described by Fludzinski. The nitroindoles and nitroindolines are commerdally available, for example 5-nitroindole and 5- nitroindoline, or may be prepared conventionally (Comprehensive Heterocyclic Chemistry Vol. 4 p. 313 et seq. (Pergamon Press 1984) and J. Het. Chem. 1988 25 p.l et seq.) An R2' alkoxycarbonyl group may be eliminated to give R2 1 hydrogen, generally under the conditions effecting formation of the nitroindole or as a subsequent step in the process. Rg' alkyl groups may be introduced conventionally, for example by reductive alkylation or acylation and reduction. R7' Cι_ alkyl groups may be introduced ortho to a nitro substituent by alkylation using a. procedure similar to that described in 6. Bartoli et aL, J. Org. Chem. 1986 51 3694 and Tetrahedron 1987 434221. Compounds of formula (IH) in which B is -N=C=O may be prepared by treating a compound of formula (III) in which : i) B is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent. ϋ) B is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using conventional conditions. iii) B is CONH2, via the nitrene intermediate using conventional conditions. Compounds of formula (IU) in which B is -NRg'COL may be prepared by reacting a compound of foπnula (HI) in which B is -NHRg' with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triethylamine. Compoimds of formula ( U) in which B is -NRg'CONHRs' can be prepared from the corresponding precursor where B is NHRg' by reaction with an R5' isocyanate under conventional conditions. Examples of phosgene equivalents indude triphosgene, carbonyldiimidazole, phenyl chloroformate and phenyl chlorothioformate. Novel intermediates of formula (III) also form part of the invention. Compounds of foπnula (IV) may be prepared from the appropriate aminophenyl derivative analogously to compounds of formula (I). Novel intermediates of formula (IV) also form part of the invention. Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate add or add derivative. N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic adds. Compounds of formula (I) and their pharmaceutically acceptable salts have 5HTιc receptor antagonist activity and are believed to be of potential use in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders aβsoriated with spinal trauma and/or head injuries, such as hydrocephalus. Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders assodated with spinal trauma and/or head injuries, such as hydrocephalus. The invention further provides a method of treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders assodated with spinal trauma and/or head injuries, in mammals induding humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders assodated with spinal trauma and/or head injuries. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional exdpients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehide before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehide and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehide. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehide instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehide. Advantageously, a surfactant or wetting agent is induded in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months. When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention. The following Examples illustrate the preparation of pharmacologically active compounds of the invention. The following Descriptions illustrate the preparation of intermediates to compounds of the present invention. Description 1 l-Methyl-5-nitro-lH-indole (Dl) To a stirred suspension of sodium hydride (5.0g; 167 mmol) in dimethylformamide (200 ml) at 0°C under nitrogen was added 5- nitroindole (2δg; 154 mmol) in dimethylformamide. After stirring for O.δh, iodomethane (lO.δ ml; 168 mmol) in dimethylformamide (δO ml) was added, and stirring was continued for 2h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (27.4g; 94%). NMR (CDC1 3 ) δ: 3.88 (3H, s), 6.68 (IH, d, J=3), 7.21 (IH, d, J=3), 7.34 (IH, d, J=8, 8.13 (IH, dd, J=8, 2), 8.59 (IH, d, J=2). Description 2 5-Amino-l-methyl-lH-indole (D2) A mixture of the nitroindole (Dl) (δg; 28.4 mmol) and 5% palladium on charcoal in ethanol (300 ml) was hydrogenated at 60 p.s.i. (4.14 x lO^Pa) at room temperature for 3h. Removal of the catalyst by filtration followed by evaporation of the solvent gave the title compound (3.39g, 95%). NMR (CDCI3) δ: 3.20 (2H, broad s), 3.70 (3H, s), 6.28 (IH, d, J=3), 6.68 (IH, dd, J=8, 2), 6.92 (IH, d, J=2), 6.96 (IH, d, J * =3), 7.12 (IH, d, J=8). Description 3 Phenyl N-(l-Methyl-lH-indol-5-yl) carba ate (D3) To a solution of phenyl chlorofoπnate (2.21 ml; 17.4 mmol) in dry -lδ- tetrahydrofuran (30 ml), cooled in a carbon tetrachloride / solid carbon dioxide bath, was added δ-amino-1-methylindole (D2) (2.3 lg; 15.8 mmol) followed by triethylamine (2.40 ml; 17.4 mmol). The mixture was stirred for 45 min at -20°C (bath temperature), then evaporated. The residue was dissolved in ethyl acetate, washed with brine, dried and evaporated to give the title compound (4.29g; 100%), m.p. 103-107°C (EtOAc/petrol). NMR (CDC1 3 ) δ: 3.80 (3H, s), 6.45 (IH, d, J=3), 6.93 (IH, broad s), 7.05 (IH, d, J=3), 7.25 (5H, m), 7.40 (2H, dd, J=8, 8), 7.74 (IH, broad s). Description 4 Pvrimidine-5-carboxylic acid (D4) n-Butyllithium (1.6M in hexane, 6.9 ml, 11 mmol) was added to dry THF (10 ml) and the solution was cooled to -100°C. A solution of 5- bromopyrimidine (l.δ9g, 10 mmol) in dry THF (δO ml) was added slowly. After 15 min at -80 to -100°C, the mixture was added dropwise onto solid carbon dioxide in dry THF. After wa ming to room temperature, the mixture was made slightly aάdic with dilute sulphuric add. The solid was filtered off and extracted with ethanol. The extract was filtered and evaporated and the residue was re-extracted with methanol. Evaporation of solvent gave the title compound (1.48g, 100%). NMR (d4 - MeOH) δ: 9.17 (IH, s), 9.20 (2H, s). m z (El): 124 (M+) Example 1 N-(l-Methyl-5-indolyl)-N -(2-pyra-rinyl) urea (El) To a suspension of sodium hydride (80% in oil, 0.66g, 22 mmol) in dry DMF (50 ml) was added 2-aminopyrazine (0.95g, 10 mmol). After hydrogen evolution had ceased (lδ min), phenyl N-(l-methyl-δ-indolyl) carbamate (D3) (2.67g, 10 mmol) was added, followed by a further portion of sodiu hydride (0.2g). The mixture was stirred overnight at room temperature and then evaporated in vacuo. The residue was dissolved in dichloromethane/methanol and washed with water and brine. The organic phase was dried and evaporated and the residue was triturated with dichloromethane/petrol. The residue was then recrystallised from DMSO/water to give the title compound (1.09g). m.p. 222-226°C. Found: C, 62.75; H, 4.83; N, 26.10 C14H13N5O requires: C, 62.91; H, 4.90; N, 26.20% NMR (Dg-DMSO) δ: 3.78 (3H, s), 6.38 (IH, d, J=3), 7.19 (IH, dd, J=8, 2), 7.30 (IH, d, J=3), 7.38 (IH, d, J=8), 7.77 (IH, d, J=2), 8.22 (IH, d, J=2), 8.30 (IH, m), 9.01- (IH, s), 9.δ2 (IH, s), 9.δ7 (IH, s). Example 2 N-(l-Methyl.5-indolyl)-N/-(3-pyridazinyl) urea (E2) The title compound (0.δ3g) was prepared by the method of Example 1, using sodium hydride (0.δ9g, 19.7 mmol), 3-aminopyridazine (0.8δg, 8.9δ mmol) and carbamate (D3) (2.39g, 8.9δ mmol) in DMF (40 ml), mp. 220-22δ°C, 96.δ% pure by HPLC. NMR (dg-DMSO) δ: 3.78 (3H, s), 6.38 (IH, d, J=3), 7.18 (IH, dd, J=8, 2), 7.30 (IH, d, J=3), 7.39 (IH, d, J=8), 7.72 (IH, dd, J=5, 9), 7.7δ (IH, d, J=2), 8.0 (IH, d, J=9), 8.8δ (IH, d, J=δ), 9.69 (IH, s), 9.73 (IH, s). m/z (El): 267 (M+), 172, 146. Example 3 N^l-Methyl-δ-indolyυ-N/^δ-pyriinidinyl) urea (E3) A mixture of add (D4, 1.22g, 9.8 mmol), 5-amino-l-methyl indole (D2, 1.43g, 9.8 mmol), triethylamine (1.4 ml) and diphenylphosphoryl azide (2.1 ml, 10 mmol) in 1,4-dioxan (100 ml) was heated under reflux overnight. The mixture was evaporated and the residue was dissolved in dichloromethane and washed with δ% dtric add, sat. sodium bicarbonate and water. The organic phase was dried and evaporated and the residue was chromatographed on silica (lOOg) eluted with 2-15% methanol/dichloromethane. Combination of appropriate fractions followed by recrystallisation from dichloromethane methanol gave pure (E3, 0.70g). mp 210-213°C. Found: C, 62.93; H, 4.84; N, 26.06. Ci4Hι 3 N 5 0 requires C, 62.91; H, 4.90; N, 26.20% NMR (dg-DMSO) δ: 3.76 (3H, s), 6.37 (IH, d, J=3), 7.17 (IH, dd, J=8, 2), 7.29 (IH, d, J=3), 7.37 (IH, d, J=8), 7.69 (IH, d, J=2), 8.78 (2H, s), 8.91 (3H, s). Example 4 N-(l-Methyl-5-indolyl)-N^-(4-pyridazinyl) urea (E4) The title compound was prepared by the method of Example 3, using pyridazine-4-carboxylic add (0.5g, 4 mmol), aminoindole (D2, 0.δ9g, 4 mmol), triethylamine (0.57 ml) and diphenylphosphoryl azide (0.86 ml, 4.1 mmol) in 1,4-dioxan (40 ml). Crude product was chromatographed on silica (7δg) eluted with δ-10% methanol/dichloromethane. The second component was extracted with hot methanol to give an insoluble residue of pure title compound (O.llg). mp 216-221°C. Found: C, 62.17; H, 4.8δ; N, 2δ.49 Ci4Hi3NδO requires: C, 62.91; H, 4.90; N, 26.20% NMR (dg-DMSO) δ: 3.78 (3H, s), 6.38 (IH, d, J-3), 7.18 (IH, dd, J=8, 2), 7.30 (IH, d, J=3), 7.38 (IH, d, J=8), 7.70 (IH, d, J=2), 7.81 (IH, dd, J=6, 3), 8.88 (IH, s), 8.91 (IH, d, J=6), 9.20 (IH, d, J=3), 9.29 (IH, s). Example δ N-(l-Methyl-5-indolyl)-N -(3-methyl-5-isothiazolyl) urea (E5) To a suspension of sodium hydride (80% in oil, 0.99mg, 3.3 mmol in dry DMF (5 ml) was added δ-amino-3-methylisothiazole hydrochloride (O.lδmg, lmmol). After hydrogen evolution had ceased (lδ min), phenyl N-(l-methyl-δ-indolyl) carbamate (D3) (0.267mg, 1 mmol) was added. The mixture was stirred overnight at room temperature and then evaporated in vacuo. The residue was dissolved in dichloromethane/methanol and the solution was washed with water and brine, dried and evaporated. The crude product was triturated with dichloromethane/petrol and the residue was chromatographed on silica (10 g) eluted with 2% methanol/dichloromethane. Recrystallisation from dichloromethane/petrol gave the title compound (0.10g). mp. 186-189°C, 99.6% pure by HPLC. NMR (CDCI3): δ: 2.32 (3H, s), 3.78 (3H, s), 6.32 (IH, s), 6.44 (IH, d, J=3), 7.08 (IH, d, J=3), 7.18 (IH, dd, J=8, 2), 7.27 (IH, d, J=8), 7.64 (IH, d, J=2). m/z (El): 286 (M+), 172, 146. Example 6 N-(l-Methyl-5-indolyl)-N / -(3-methyl-5-isoxazolyl) urea (E6) The title compound was prepared by the method of Example δ, using 5- amino-3-methylisoxazole (0.098g, 1 mmol), sodium hydride (0.066g, 2.2 mmol) and carbamate (D3, 0.267g, 1 mmol) in dry DMF (δ ml). The crude product was triturated with dichloromethane/petrol, then recrystallised from dichloromethane methanol/petrol to give the title compound (0.13δg). mp ' 186-189°C, 97.5% pure by HPLC. NMR (dg-DMSO) δ: 2.07 (3H, s), 3.67 (3H, s), δ.84 (IH, s), 6.27 (IH, d, J=3), 7.04 (IH, dd, J=8, 2), 7.18 (IH, d, J=3), 7.26 (IH, d, J=8), 7.δ8 (IH, d, J=2), 8.δ3 (IH, s). m/z (El): 270 (M+), 172 Example 7 N-(l-Methyl-5-indolyl)-N/-(2-(l,3,4-thiadiazolyl)) urea (E7) A mixture of 2-amino-l,3,4-thiadiazole (l.Olg, 10 mmol), carbamate (D3, 2.67g, 10 mmol), and N-methylmorpholine (1.2 ml) in DMF (100 ml) was heated at 100-140°C overnight, then cooled and evaporated. The residue was dissolved in dichloromethane/methanol and washed with brine and water. The organic phase was dried and evaporated, and the residue was recrystallised from dichloromethane methanol/petrol to give the title compound (1.54g). mp 217-220°C (decomp.). Found: C, 52.3δ; H, 4.07; N, 2δ.29 Ci2HnNδOS requires C, 52.73; H, 4.06; N, 2δ.62% NMR (dg-DMSO) δ: 3.78 (3H, s), 6.38 (IH, d, J=3), 7.18 (IH, d, J=8), 7.32 (IH, d, J=3), 7.39 (IH, d, J * 8), 7.73 (IH, s). Example 8 N-(l-Methyl-5-indolyl)-N/-(4.(l^,4-triazolyl)) urea (E8) To a solution of l,l/-carbonyldiimidazole (0.27g) in dichloromethane (10 ml) at 0°C was added aminomethylindole (D2, 0.22g, 1.5 mmol) in dichloromethane (10 ml). The mixture was stirred at 0°C for lδ min, then evaporated and the residue was redissolved in dry DMF (10 ml). 4-Amino- 1,2,4-triazole (0.134g, 1.6 mmol) was added in DMF (2.5 ml) and the mixture was heated at 120-140°C for lh, then poured into water. The aqueous solution was filtered and evaporated to dryness, and the residue was chromatographed on silica (25g) eluted with δ-10% methanol/dichloromethane. The second-eluted material was the title compound (0.21g). mp 202-206°C. Found: C, 56.36; H, 4.82; N, 32.6δ Cι 2 Hι 2 NgO requires: C, δ6.24; H, 4.72; N, 32.79% NMR (dg-DMSO) δ: 3.77 (3H, s), 6.3δ (IH, d, J=3), 7.18 (IH, dd, J=8, 2), 7.29 (IH, d, J=3), 7.3δ (IH, d, J=8), 7.6δ (IH, d, J=2). Example 9 N-U-Methyl-5-indolyl)-N^3-quinolyI)-urea hydrochloride (E9) A stirred suspension of carbonyl dϋmidazole (0.34g, 2.1 mmol) in dry dichloromethane (5 ml) was treated with a solution of 5-amino-l- methylindole (D2, 0.29g, 2 mmol) in dry dichloromethane (δ ml). After 0.2δh, the reaction mixture was evaporated to dryness and the residue dissolved in DMF (10 ml). 3-Aminoquinoline (0.32g 2.2 mmol) was added and the reaction mixture heated to 90°C for lh then cooled and added to water (200 ml) with vigorous stirring. The preάpitate was filtered, dried and recrystallised from ethanol affording the product as an off-white solid (0.4g, 66% yield). This was converted into the title compound using HC1 in ether, mp 230°C (from ethanol) Found: C, 64.42; H, 4.72; N, 15.71. C19H17N4OCI requires: C, 64.68; H, 4.82; N, 15.87% NMR (d6-DMSO) δ: 3.77 (3H, s), 6.38 (IH, d, J=6), 7.2-7.4 (3H, m), 7.77 (3H, m), 8.1 (2H, m), 8.80 (IH, d, J=3), 9.19 (2H, d, J=12), 9.79 (lH, s). Example 10 N-(l-Methyl-5-indolyl)-N'-(6-quinolyl)-urea hydrochloride (ElO) A stirred suspension of carbonyl diimidazole (0.34g, 2.1 mM) in dry dichloromethane (5 ml) was treated with a solution of δ-amino 1- methyl indole (D2, 0.29g, 2 mM) in dry dichloromethane (δ ml). After 0.2δh, the reaction mixture was evaporated to dryness and the residue dissolved in DMF (10 ml). 6-Aminoquinoline (0.32g, 2.2 mM) was added and the reaction mixture heated to 90°C for lh then cooled and added to water (200 ml) with vigorous stirring. The preάpitate was filtered, dried and recrystallised from ethanol, affording the product as a white solid (0.32g, 51%). This was converted into the hydrochloride salt (E2) using HC1 in ether. mp 208°C (from ethyl acetate). NMR (d6-DMSO) δ: 3.77 (3H, s), 6.38 (IH, d, J=3), 7.2-7.4 (3H, m), 7.7-8.2 (4H, m), 8.48 (IH, s), 8.8-9.1 (3H, m), 9.58 (IH, s). m/z (El): 316 (M+, Ci9HιgN 4 0) Example 11 N-(l-Methyl-5-mdolyl)-N -(-^quinolyl) urea (Ell) The title compound was prepared rom 8-aminoquinoline, 1, l^-carbonyl dϋmidazole and δ-amino- 1-methyl-indole (D2) using a procedure similar to that described for Example 10, in 31% yield, m.p. 205-209° C. NMR (Dg-DMSO)δ: 3.76 (3H, s), 6.35 (IH, d, J 3), 7.22 (IH, dd, J 6, 2), 7.27 (IH, d, J 3), 7.36 (IH, d, J 6), 7.5-7.δ4 (2H, m), 7.60-7.66 (IH, m), 7.8 (IH, s), 8.39 (IH, d, J 6), 8.δ7 (IH, m), 8.92 (IH, d, J 2), 9.62 (2H, s). Found: M+316 CιoHι N4θ requires 316 Example 12 N-(l-Methyl-5-indolyl)-N/-(5-quinolyl) urea (E12) The title compound was prepared from 5-aminoquinoline, 1, l^-carbonyl diimidazole and δ-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 10, in 20% yield r m.p 243-24δ° C. NMR (Dg-DMSO)δ: 3.76 (3H, s), 6.3δ (IH, d, J 2), 7.20 (IH, d, J 6), 7.29 (IH, d, J 2), 7.38 (IH, d, J 6), 7.60-7.6δ (IH, m), 7.72 (2H, d, J 3), 7.77 (IH, s), 8.10 (IH, t, J 2), 8.δ7 (IH, d, J 6) 8.84 (2H, d, J 3), 8.93 (IH, d, J 2) Found: M+ 316 Ci9HιgN4θ requires 316 Example 13 N-(l-Methyl-5-indolyl)-N^(2-methyl-4-quinolyl) urea hydrochloride (E13) The title compound was prepared from 4-aminoquinaldine, diimidazole and δ-amino- 1-methyl-indole (D2) using a procedure similar to that described for Example 10 and then converted to the hydrochloride salt, in 24% overall yield, m.p. 216-220° C. NMR (Dg-DMSO)δ: 2.80 (3H, s), 3.77 (3H, s), 6.39 (IH, d, J 2), 7.23-7.33 (2H, m), 7.42 (IH, d, J 6), 7.79-7.84 (2H, m), 8.0-8.11 (2H, dd J 6,6), 8.60 (IH, s), 9.08 (IH, d, J 8), 10.8 (IH, s), 10.92 (IH, s), 15.0 (IH, broad s). Found: M+ 330 C 20 H 18 N 4° requires 330 Example 14 N-U-methyl-S-mdolyD-N^β-Isoquinolyl) urea (E14) The title compound is prepared using standard methodology as described herein, such as reaction of (D2) with carbonyl diimidazole in a solvent such as dry dichloromethane, and reacting the product with 6- aminoisoquinoline in a solvent such as DMF, with heating. Example 15 N-(l-Methyl-5-indolyl)-N/-(5-isoquinolyi) urea (E15) To a solution of carbonyl diimidazole (0.31g, 2.15 mmol) in dichloromethane (20 ml) was added 5-aminoisoquinoline (0.25g, 1.7 mmol) in dichloromethane (20 ml). After stirring at room temperature for 0.5 h, the solution was evaporated to dryness. The residue was taken up in dimethylformamide (20 ml) and to this solution was added δ-amino- 1- methyl-indole (D2) (0.2δg, 1.7 mmol) in dimethylformamide (20 ml). The reaction mixture was heated to 90° C for lh, then cooled and added dropwise to water, with vigorous stirring. The resulting suspension was filtered off, washed with water and dried in vacuo to yield the title compound in δ3% yield, m.p. 2δ4-2δ9° C. NMR (Dg-DMSO)δ: 3.77 (3H, s), 6.37 (IH, d, J 3), 7.19 (IH, dd J 6,2), 7.28 (IH, d, J 3), 7.37 (IH, d, J 8), 7.6δ (IH, t, J 6), 7.75-7.8 (2H, m), 7.99 (IH, d, J 6), 8.32 (IH, d, J 6), 8.57 (IH, d, J 6), 8.84 (2H, d, J 8), 9.29 (IH, s). Found: M+ 316 Ci9HιgN4θ requires 316 Example 16 N-(l-Methyl-5-indolyl)-N/-(l-isoquinolyl) urea (E16) The title compound was prepared from 1-aminoisoquinoline, 1, l'-carbonyl diimidazole and 5-amino-l-methyl-indole (D2) using a procedure similar to that described for Example lδ, in 11% yield, m.p.230-233° C. NMR (CDCl 3 )δ: 3.81 (3H, s), 6.47 (IH, d, J 2), 7.07 (IH, d, J 3), 7.30 (2H, m), 7.46 (IH, dd J 6,2), 7.61-7.82 (3H, m), 7.97 (IH, s), 8.09-8.16 (3H, m), 12.4 (IH, broad s). Found: M+ 316 CιgHιgN4θ requires 316 Example 17 N-α-Methyl-5-indolyl)-N -(4-isoquinolyl) urea (E17) The title compound was prepared from 4-aminoisoquinoline, l.^-carbonyl diimidazole and 5-amino-l-methyl-indoIe using a procedure similar to that described for Example 1, and then converted to the hydrochloride salt using hydrogen chloride in ether/ethanol, in 26% overall yield, m.p. 195- 197° C. NMR (Dg-DMSO)δ: 3.77 (3H, s), 6.39 (IH, d, J 2), 7.22 (IH, dd J 6,2), 7.32 (IH, d, J 3), 7.4 (IH, d, J 6), 7.80 (IH, s), 7.94 (IH, t, J 6), 8.13 (IH, t, J 6), 8.39 (IH, d, J 6), 8.5δ (IH, d, J 6), 9.24 (IH, s), 9.34 (IH, s), 9.δ0 (2H, d, J 8). Found: M+ 316 CιgHιgN θ requires 316 Pharmacological data [3H]-mesulergine binding to pig choroid plexus membranes in vitro Evidence from the literature suggests that δ-HTic antagonists may have a number of therapeutic indications induding the treatment of anxiety, migraine, depression, feeding disorders and obsessive compulsion disorders. (Curzon and Kennett, 1990; Fozard and Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol.46 p.542). The affinity of test drugs for the δ-HT c binding site can be determined by assessing their ability to displace [Sffj-mesulergine from δ-HTic binding sites in pig choroid plexus membranes. The method employed was similar to that of Pazos et aL, 1984. Pooled pig choroid plexi were homogenised in 20 vols of Tris HC1 buffer (pH7.4) (containing 4mM CaCl2 nd 0.01% ascorbic add) and centrifuged at δ0,000g for lδ min at 4°C. The supernatant was removed and re-centrifuged. This was repeated a further two times with the incubation of the homogenate (37°C for lδ min) before the final centrifugation. The final pellet was resuspended in 20vols of buffer and stored at -70°C until use. The tissue suspension (δOml) was incubated with [^Hl-mesulergine (2nM) in Tris HC1 buffer (pH7.4) at 37°C (containing 0.01% ascorbic add, 4mM CaCl2) and 3 x lO'-^M spiperone for 30 minutes. Non-specific binding was measured in the presence of mianserin (10'^M). Six concentrations of test drug (10"9 to 10"^M final concentration) were added in a volume of δOml. The total assay volume was δOOml. Incubation was stopped by rapid filtration using a Skatron cell harvester and radioactivity measured by liquid scintillation spectrometry. The ICδO values were determined and the pKj (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where Kj = IC50 l±Ω Ed Kj = inhibition constant. C = concentration of [^Hl-mesulergine d = Affinity of mesulergine for 5-HTιc binding sites. Curzon, G and Kennett, G.A. (1990). TIPS, Vol. 11, 181-182. Fozard, J.R. and Gray, J . (1989). TIPS, Vol. 10, 307-309. Pazos, A. et aL (1984). Eur. J. Pharmacol., 106, 631-638. [ 3 H]-Mesulergine binding to rat 5-HTχ ; clones expressed in 293 cells in vitro The affinity of test drugs for the 5-HTιc binding site can be. determined by assessing their ability to displace [3H]-mesuleιgine from 5-HTκ ** ; dones expressed in 293 cells (Julius et al., 1988). The method employed was similar to that of Pazos et al., 1984. The cells suspension (60 μl) was incubated with [^Hl-mesulergine (0.5 nM) in Tris HC1 buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (lO'-^M). Ten concentrations of test drug (3 x 10" to 10"^M final concentration) were added in a volume of 60 μl. The total assay volume was 500 μl. Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting. The IC50 values were determined using a four parameter logistic program (DeLean 1978) and the pKj (the negative logarithm of the inhibition constant) calculated from the Cheng + Prusoff equation. Julius et al. (1988) Science 241, 558-564. DeLean A, Munson P. J., Rodbaud D. (1978) Am. J. Physiol. 235, E97- E102. The compounds of examples 3 -7, 12, 13, 15 and 17 have pKj values in the range 5.97 to 8.3. Reversal of MCPP-induced Hypolocomotion Administration of m-(chlorophenyl)piperazine (mCPP) to rats induces hypolocomotion (Kennett and Curzon 1988, Luckie et al. 1989) as seen with the related drug l-(m-trifluoromethylphenyl)piperazine (TFMPP) (Lucid and Frazer 1982, Kennett and Curzon 1988). This effect was blocked by the non specific 5-HTκ 5-HT2 receptor antagonists mianserin, cyproheptadine and metergoline and perhaps by mesulergine. It was not blocked by the 5-HT2 receptor antagonists ketanserin and ritanserin at relevant doses (Kennett and Curzon 1991) nor by antagonists of δ-HTiA, δ-HTiB, 5-HT3, 02 adrenoceptors or dompamine D2 receptors. The effect of mCPP is therefore considered to be mediated by 5-HTιc receptors (Kennett and Curzon 1988) as confirmed by subsequent studies (Lucki et al., 1989). Since mCPP causes hypolocomotion when infused into the cerebral ventrides th s effect is probably centrally mediated (Kennett and Curzon 1988). mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long x 16Vέ cm wide x 2δ cm high and made of black perspex. Two photobeams traversed the width of the cages at either end at ground level. Sequential breaking of these beams allowed the measurement of cage transits. Male Sprague Dawley rats (200-250g) (Charles River) were housed in groups of six. They were given drugs orally lh pretest and 40 mins later mCPP (7 mg kg i.p.). After a further 20 min they were placed in individual automated cages in groups of four under red light in an adjacent room. After 10 min the test was terminated. Reversal of mCPP-induced hypolocomotion was considered as evidence of in vivo central δ-HTic receptor antagonist properties. Kennett, G.A., Curzon, G., (1988). Brit. J. Pharmacol. 94, 137-147. Kennet G.A., Curzon, G., (1991). Brit.J. Pharmacol. 103, 2016-2020. Lucki, I., Frazer, A., (1982) Am. Soc. Neurosά. 8(abstr.), 101. Lucki, I., Ward, M.R., Frazer, A., (1989). J.Pharmacol. Exp. Therap. 249, 155-164. The compound of Examples 2 and 3 had ID50 values of 47.0 and 43.7 mg/kg p.o. Rat Fundus: 5-HTχc-like Receptors Introduction The 5-HT receptor in the rat fundic strip (RFS) has been characterised as 'δ-HTic-like' as its pharmacology is similar, but not identical, to that of rat δ-HT.iQ receptor dones. Hence this tissue may be used to assess the 5-HTιc-like antagonist properties of compounds. Methods Whole stomachs were obtained from male CD Rats (Charles River, 250- 350g). Strips of fundus (2cm x 0.5 cm) were cut from the greater curvature and the mucosae carefully removed. Tissues were then further dissected into smaller strips (2 rnrn 20 mm) which were mounted in organ baths containing oxygenated Tyrodes solution at 37°C containing indomethadn (3 μM). Preparations were maintained under a resting tension of O.δg and exposed to the irreversible MAO inhibitor pargyline (100 μM for 30 minutes followed by washout). Over a lh equilibration period, rat fundic strips were challenged with 1 x 10"8 M 5-HT at lδ minute intervals until constant responses were obtained. Fifteen minutes later, a complete cumulative concentration-effect curve to the standard agonist δ-HT (1 x 10"*0 upwards) was constructed to determine the individual sensitivity of each preparation. A further concentration-effect curve to either δ-HT, or other agonists was constructed no sooner than lh after completion of the previous curve. When necessary tissues were equilibrated with the antagonists over this one hour period. Antagonists affinities are expressed as pA2 estimates. Results The compound of Example 5 had a pA2 value of 7.9.

Claims: Claims: A compound of formula (I) or a salt thereof: (I) wherein: P represents a quinoline or isoquinoline residue or a δ- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; l is hydrogen or Cι_ alkyl; R2, R3, Rio and Rn are independently hydrogen or Cι_g alkyl, or IQ and 1 together form a bond, or 2 and RIQ or R3 and Rn together form a C2-g alkylene chain; R4 is hydrogen, Cι.g alkyl, halogen, N gRg, OR12 or COOR12, where Rg, R9 and R12 are independently hydrogen or Cι_g alkyl; R5 and Rg are independently hydrogen or Cι_g alkyl; and R7 is hydrogen, Cι_g alkyl, Cι. alkoxy or halogen; and wherein the urea moiety is attached at the 4-, 6- or 6-position of the indole or indoline ring, provided that P is not pyridyl when RIQ and Rn form a bond. 2. A compound according to claim 1 in which Ri is methyl. 3. A compound according to claim 2 in which R2 and R3 are hydrogen. 4. A compound according to daim 3 in which RIQ and Rn are both hydrogen or RIQ and Rn together form a bond to form an indole structure. δ. A compound according to claim 4 in which R4, R5, Rg and R7 are hydrogen. 6. A compound according to any one of daims 1 to 5 in which the urea moiety is attached at the 5-position of the indole or indoline ring. 7. A compound according to claim 1 which is selected from N-(l-methyl-δ-indolyl)-N/-(2-pyrazinyl) urea, N-(l-methyl-δ-indolyl)-N'-(3-pyridazinyl) urea, N-(l-metiιyl-δ-indolyl)-N/-(5-pyrimidinyl) urea, N-(l-methyl-δ-indolyl)-N i '-(4-pyridazinyl) urea, N-(l-methyl-δ-indolyl)-N' / -(3-methyl-5-isothiazolyl) urea, N-(l-methyl-δ-indolyl)-N/-(3-methyl-δ-isoxazolyl) urea, N-(l-methyl-δ-indolyl)-N' / -(2-(l,3,4-thiadiazolyl)) urea, N-(l-methyl-5-indolyl)-N' / -(4-(l,2,4-triazolyl)) urea, N-d-methyl-δ-indolyD-N'-O-quinolyD-urea, N-(l-methyl-δ-indolyl)-N/-(6-quinolyl)-urea, N-(l-methyl-δ-indolyl)-N/-(8-quinolyl) urea, N-(l-methyl-δ-indolyl)-N/-(5-quinolyl) urea, N-(l-methyl-δ-indolyl)-N/-(2-methyl-4-quinolyl) urea, N-(l-methyl-5-indolyl)-N/-(6-Isoquinolyl) urea, N-(l-methyl-5-indolyl)-N/-(6-isoquinolyl) urea, N-(l-methyl-5-indolyl)-N/-(l-isoquinolyl) urea, N-(l-Methyl-5-indolyl)-N/-(4-isoquinolyl) urea, or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1 to 7 for use in therapy. 9. A pharmaceutical composition which comprises a compound according to any one of daims 1-7 and a pharmaceutically acceptable carrier or exdpient. 10. A process for the preparation ofa compound offormula (I) or a pharmaceutically acceptable salt thereof, which process comprises: (a) the coupling ofa compound offormula (H); 01) with a compound offormula (HI); σπ) wherein B is attached at the 4-, 5- or 6-position of the indole or indoline ring and A and B contain the appropriate functional group(s) necessary to form the moiety -NRδ'CONRg'- when coupled, wherein Rδ' and Rg' are δ and Rg as defined in foπnula (I) or groups convertible thereto, and the variables Ri', R 2 * , R3', io', Rll', R4 ∞ ά R 7' a** Rl» R2» R3» RlO> Rll» R4 and R7 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any Ri', R2 * , R3', Rio', Rll', R4', Rδ'» Rβ' an ^ R7' when other than Ri, R2, R3, io, Rll, R4, R5, Rβ a* 10 " R7 respectively to Ri, R2, R3, io, Rll, Rδ» Rβ ^d R 7» interconverting Ri, R2, R3, Rio, Rll, R4, R5, Rg and R7, and forming a pharmaceutically acceptable salt thereof; or (b) cyclising a compound offormula (IV): ' (TV) wherein R4', R5', Rg' and R7' are as defined in formulae (II) and (III) and C and D contain the appropriate functional group(s) necessary to form the indole or indoline ring substituted by Ri', R2\ R3', Rlθ'» and Rn' as defined in formula (IH), and thereafter optionally and as necessary in any appropriate order, converting any Ri', R2', R3', Rio', Rll', R4'» Rδ > Rβ' and R7 * when other than Rj, R2, R3, io, Rll, R4, R5, Rβ and R7, to Rl» R2, R3, Rio, Rll, R4, Rδ» Rβ and R 7» interconverting Ri, R2, R3, Rio, Rll, R4, Rδ, Rβ and R7, and optionally thereafter forming a pharmaceutically acceptable salt.

Inventors: FORBES IAN THOMSON, JONES GRAHAM ELGIN, MARTIN ROGER THOMAS, FORBES, IAN, THOMSON, JONES, GRAHAM, ELGIN, MARTIN, ROGER, THOMAS
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1993
Main classification: C07D417
IPC codes: A61K31, A61P1, A61P25, C07D401, C07D403, C07D413, C07D417