WO1993018028A1 - Indole derivatives as 5ht1c antagonists - Google Patents

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 5HT 1C 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-(1,2-dimethyl-3-ethyl-1H-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_1C receptor antagonist activity. 5HT_1C 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 ***e, 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:

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 C_1-6 alkyl;

R₂, R₃, R₁₀ and R₁₁ are independently hydrogen or C_1-6 alkyl, or R₁₀ and R₁₁ together form a bond, or R₂ and R₁₀ or R₃ and R₁₁ together form a C_2-6 alkylene chain;

R₄ is hydrogen, C_1-6 alkyl, halogen, NR₈R₉, OR₁₂ or COOR₁₂, where R₈, R₉ and R₁₂ are independently hydrogen or C_1-6 alkyl;

R₅ and R₆ are independently hydrogen or C_1-6 alkyl; and

R₇ is hydrogen, C_1-6 alkyl, C_1-6 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.

Alkyl moieties within the variables R₁ to R₁₂ are preferably C_1-3 alkyl, such as methyl, ethyl, n- and iso- propyl, most preferably methyl.

Suitable R₄ and R₇ halogens include chloro and bromo.

Examples of R₁ include hydrogen, methyl, ethyl and n-propyl, preferably methyl.

R₂ and R₃ are preferably hydrogen. R₁₀ and R₁₁ are preferably a bond so as to form an indole structure. In an indoline structure, R₁₀ and R₁₁ are preferably hydrogen.

Preferably R₄ is hydrogen or methyl, most preferably hydrogen.

Preferably R₅, R₆ 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 R₁ (in an indole) and/or R₅ and/or R₆ are hydrogen or when R₄ is hydroxy or NR₈R₉ and at least one of R₈ and R₉ 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);

with a compound of formula (III);

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 -NR₅'CONR₆'- when coupled, wherein R₅' and R₆' are R₅ and R₆ as defined in formula (I) or groups convertible thereto, and the variables R₁', R₂', R₃', R₁₀', R₁₁', R₄' and R₇' are R₁, R₂, R₃, R₁₀, R₁₁, 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 R₁', R₂', R₃', R₁₀', R₁₁', R₄', R₅', R₆' and R₇' when other than Ri, R2, R3, Rio, Rn, R4, R5, Rβ and R7 respectively to R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, interconverting R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, and forming a pharmaceutically acceptable salt thereof; or

(b) cyclising a compound of formula (IV):

wherein R₄', R₅', R₆' 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 R₁', R₂', R₃', R₁₀', and R₁₁' as defined in formula (III), and thereafter optionally and as necessary in any appropriate order, converting any R₁', R₂', R₃', R₁₀', R₁₁', R₄', R₅', R₆' and R₇' when other than R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, to R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, interconverting R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, and optionally thereafter forming a

pharmaceutically acceptable salt.

Suitable examples of groups A and B include:

(i) A is -N=C=O and B is -NHR₆',

(ii) A is -NHR₅' and B is -N=C=O,

(iii) A is -NR₅'COL and B is -NHR₆',

(iv) A is -NHR₅' and B is -NR₆'COL, or

(v) A is halogen and B is -NR₆'CONHR₅',

wherein R₅' and R₆' 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=O and B is NHR₆' or when A is NHR₅' and B is -N=C=O the reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at ambient temperature. When A is -NR₅'COL and B is -NHR₆' or when A is -NHR₅' and B is

-NR₆'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 -NR₆'CONHR₅', 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 (R₁₀ 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.1 et seq. Examples of the more important routes include the Leimgruber synthesis, the Fischer synthesis and the Japp-Klingemann variation and the

Madelung synthesis. Examples of the groups C and D in the preparation of indoles include:

(vi) C is NO₂ and D is CH=CH-NZ₂ where each Z is independently

C_1-6 alkyl or together represent C_2-7 alkylene;

(vii) C is NR₁ ^,-N-=C(R₂ ^,)-CH₂R₃' and D is H;

(viii) C is NH-N=C(CO₂X)-CH₂R₃' and D is H where X is C_1-6 alkyl; and

(ix) C is NR₁'COR₂' and D is CH₂R₃.

The preparation of indolines indudes: (x) C is NHR₁' and D is C(R₃')(R₁₁')C(R₂')(R₁₀')L where L is 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 R₁=R₂=R₃=H.

In reaction variant (vii) (Fischer synthesis) the compound of formula (IV) is prepared from the hydrazinophenyl -urea by dehydration, preferably by heating, with the appropriate ketone R₂'COCH₂R₃' 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(CO₂X)-CH₂R₃' where X is C_1-6 alkyl under basic conditions in aqueous alcohol as solvent. The product of formula (IV) may then be cyclised 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 appreciated that when D is hydrogen, either or both indole isomers may be formed during the cyclisation process.

Suitable examples of groups R₂', R₃', R₄', 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 R₁' which is convertible to R₁, include typical N-protecting groups such as alkoxycarbonyl, in particular t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and

para-methoxybenzyl which are converted to R₁ hydrogen using

conventional conditions. Suitable examples of groups R₅' and R₆' which are convertible to R₅ and R₆ respectively indude alkoxycarbonyl and benzyl or

para-methoxybenzyl which are converted to R₅ and/or R₆ hydrogen using conventional conditions. Interconversions of R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R7 are carried out by conventional procedures. For example, in the case wherein R₁, R₂ and R₃ are C_1-6 alkyl and R₅ and R₆ are hydrogen it is possible to introduce a C_1-6 alkyl group at both the R5 and Rg positions by conventional alkylation using 2 molar equivalents of a C_1-6 alkyl halide and 2 molar equivalents of a suitable base in an inert solvent. Monoalkylation can be achieved using 1 molar equivalent of a C_{1- 6} alkyl halide and base using conventional conditions. R₁ C_{1- 6} alkyl groups may also be introduced by conventional alkylation, for example using a C_{1- 6} alkyl halide and base such as sodium hydride, or by reduction of C_{1- 6} 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 R₁ to R₁₂ hydrogen variables which are not required to be interconverted.

Protection, espedally of a R₁' 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 R₁ to R₁₂ before coupling compounds of formulae (II) and (III) 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 MnO₂ 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 commercially available from Aldrich, and 3-amino-6-chloro-pyridazine is commercially available from Lancaster.

Compounds of formula (II) in which A is -N=C=O 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. ii) A is acylazide (i.e. CON₃), via the nitrene, by thermal rearrangement using conventional conditions (ref L.S. Trifonov et al., Helv. Chim. Acta 1987 70262). iii) A is CONH₂, via the nitrene intermediate using conventional conditions.

Compounds of formula (II) in which A is -NR₅'COL may be prepared by reacting a compound of formula (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 commercially available.

Compounds of formula (III) in which B is NHR₆' 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 al. J. Med. Chem., 1986, 29 2415. Specifically, the compound of formula (III) in which R₁' and R₂' are methyl, R₃' is ethyl, R₁₀' and R₁₁' are a bond, R₆' and R₇' are hydrogen and B is NH₂ is prepared using a procedure similar to that described by Fludzinski. The nitroindoles and nitroindolines are commercially 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.1 et seq.)

An R₂' alkoxycarbonyl group may be eliminated to give R₂' hydrogen, generally under the conditions effecting formation of the nitroindole or as a subsequent step in the process. R₆' alkyl groups may be introduced conventionally, for example by reductive alkylation or acylation and reduction. R₇' C_{1- 6} alkyl groups may be introduced ortho to a nitro substituent by alkylation using a procedure similar to that described in G. Bartoli et al., J. Org. Chem. 1986 51 3694 and Tetrahedron 1987 434221.

Compounds of formula (III) 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. ii) 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 (III) in which B is -NR₆'COL may be prepared by reacting a compound of formula (III) in which B is -NHR₆' 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 (III) in which B is -NR₆'CONHR₅' can be prepared from the corresponding precursor where B is NHR₆' by reaction with an R₅' isocyanate under conventional conditions. Examples of phosgene equivalents include triphosgene,

carbonyldiimidazole, phenyl chloroformate and phenyl chlorothioformate.

Novel intermediates of formula (III) also form part of the invention.

Compounds of formula (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 5HT_1C 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 ***e, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders associated 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 ***e, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders associated 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 ***e, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injuries, in mammals including 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 ***e, ethanol, nicotine, and benzodiazepines, schizophrenia, and also disorders associated 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 excipients, 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 vehicle 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 vehicle 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 vehicle. 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 vehicle 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 vehicle.

Advantageously, a surfactant or wetting agent is included 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

1-Methyl-5-nitro-1H-indole (D1)

To a stirred suspension of sodium hydride (5.0g; 167 mmol) in

dimethylformamide (200 ml) at 0°C under nitrogen was added 5-nitroindole (25g; 154 mmol) in dimethylformamide. After stirring for 0.5h, iodomethane (10.5 ml; 168 mmol) in dimethylformamide (50 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 (CDCl₃) δ: 3.88 (3H, s), 6.68 (1H, d, J=3), 7.21 (1H, d, J=3), 7.34

(1H, d, J=8, 8.13 (1H, dd, J=8, 2), 8.59 (1H, d, J=2). Description 2

5-Amino-1-methyl-1H-indole (D2)

A mixture of the nitroindole (D1) (5g; 28.4 mmol) and 5% palladium on charcoal in ethanol (300 ml) was hydrogenated at 60 p.s.i. (4.14 × 10⁵Pa) 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 (CDCl₃) δ: 3.20 (2H, broad s), 3.70 (3H, s), 6.28 (1H, d, J=3), 6.68

(1H, dd, J=8, 2), 6.92 (1H, d, J=2), 6.96 (1H, d, J=3),

7.12 (1H, d, J=8).

Description 3 Phenyl N-(1-Methyl-1H-indol-5-yl) carbamate (D3)

To a solution of phenyl chloroformate (2.21 ml; 17.4 mmol) in dry tetrahydrofuran (30 ml), cooled in a carbon tetrachloride / solid carbon dioxide bath, was added 5-amino-1-methylindole (D2) (2.31g; 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 (CDCl₃) δ: 3.80 (3H, s), 6.45 (1H, d, J=3), 6.93 (1H, broad s), 7.05

(1H, d, J=3), 7.25 (5H, m), 7.40 (2H, dd, J=8, 8), 7.74 (1H, broad s).

Description 4

Pyrimidine-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 (1.59g, 10 mmol) in dry THF (50 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 warming to room temperature, the mixture was made slightly acidic 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 (1H, s), 9.20 (2H, s). m/z (EI): 124 (M⁺) Example 1

N-(1-Methyl-5-indolyl)-N/-(2-pyrazinyl) urea (E1)

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 (15 min), phenyl N-(1-methyl-5-indolyl) carbamate (D3) (2.67g, 10 mmol) was added, followed by a further portion of sodium 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 (1H, d, J=3), 7.19 (1H, dd, J=8,

2), 7.30 (1H, d, J=3), 7.38 (1H, d, J=8), 7.77 (1H, d, J=2), 8.22 (1H, d, J=2), 8.30 (1H, m), 9.01- (1H, s), 9.52 (1H, s), 9.δ7 (1H, s).

Example 2

N-(1-Methyl-5-indolyl)-N/-(3-pyridazinyl) urea (E2) The title compound (0.53g) was prepared by the method of Example 1, using sodium hydride (0.59g, 19.7 mmol), 3-aminopyridazine (0.85g, 8.95 mmol) and carbamate (D3) (2.39g, 8.95 mmol) in DMF (40 ml),

mp. 220-225°C, 96.5% pure by HPLC. NMR (d₆-DMSO) δ: 3.78 (3H, s), 6.38 (1H, d, J=3), 7.18 (1H, dd, J=8,

2), 7.30 (1H, d, J=3), 7.39 (IH, d, J=8), 7.72 (1H, dd, J=5, 9), 7.75 (1H, d, J=2), 8.0 (1H, d, J=9), 8.8δ (1H, d, J=5), 9.69 (1H, s), 9.73 (1H, s). m/z (El): 267 (M⁺), 172, 146.

Example 3

N-(1-Methyl-5-indolyl)-N/-(5-pyrimidinyl) urea (E3)

A mixture of add (D4, 1.22g, 9.8 mmol), 5-amino-1-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 5% dtric add, sat. sodium bicarbonate and water. The organic phase was dried and evaporated and the residue was chromatographed on silica (100g) 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.

C₁₄H₁₃N₅O requires C, 62.91; H, 4.90; N, 26.20%

NMR (d₆-DMSO) δ: 3.76 (3H, s), 6.37 (1H, d, J=3), 7.17 (1H, dd, J=8,

2), 7.29 (1H, d, J=3), 7.37 (1H, d, J=8), 7.69 (1H, d, J=2), 8.78 (2H, s), 8.91 (3H, s).

Example 4

N-(1-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, 0.59g, 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 (75g) eluted with 5-10% methanol/dichloromethane. The second component was extracted with hot methanol to give an insoluble residue of pure title compound (0.11g). mp 216-221°C.

Found: C, 62.17; H, 4.85; N, 25.49

C₁₄H₁₃N₅O requires: C, 62.91; H, 4.90; N, 26.20%

NMR (d₆-DMSO) δ: 3.78 (3H, s), 6.38 (1H, d, J=3), 7.18 (1H, dd, J=8,

2), 7.30 (1H, d, J=3), 7.38 (1H, d, J=8), 7.70 (1H, d, J=2), 7.81 (1H, dd, J=6, 3), 8.88 (1H, s), 8.91 (1H, d, J=6), 9.20 (1H, d, J=3), 9.29 (1H, s). Example 5

N-(1-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 5-amino-3-methylisothiazole hydrochloride

(0.15mg, 1mmol). After hydrogen evolution had ceased (15 min), phenyl N-(1-methyl-5-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 (1H, s), 6.44 (1H, d,

J=3), 7.08 (1H, d, J=3), 7.18 (1H, dd, J=8, 2), 7.27 (1H, d, J=8), 7.64 (1H, d, J=2). m/z (EI): 286 (M⁺), 172, 146. Example 6 N-(1-Methyl-5-indolyl)-N/-(3-methyl-5-isoxazolyl) urea (E6) The title compound was prepared by the method of Example 5, 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 (5 ml). The crude product was triturated with dichloromethane/petrol, then recrystallised from dichloromethane/methanol/petrol to give the title compound (0.135g). mp 186-189°C, 97.5% pure by HPLC. NMR (d₆-DMSO) δ: 2.07 (3H, s), 3.67 (3H, s), δ.84 (1H, s), 6.27 (1H, d, J=3), 7.04 (1H, dd, J=8, 2), 7.18 (1H, d, J=3), 7.26 (1H, d, J=8), 7.58 (1H, d, J=2), 8.δ3 (1H, s). m/z (El): 270 (M⁺), 172

Example 7

N-(1-Methyl-5-indolyl)-N/-(2-(1,3,4-thiadiazolyl)) urea (E7)

A mixture of 2-amino-1,3,4-thiadiazole (1.01g, 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, 52.35; H, 4.07; N, 25.29

C₁₂H₁₁N₅OS requires C, 52.73; H, 4.06; N, 25.62%

NMR (d₆-DMSO) δ: 3.78 (3H, s), 6.38 (1H, d, J=3), 7.18 (1H, d, J=8),

7.32 (1H, d, J=3), 7.39 (1H, d, J=8), 7.73 (1H, s). Example 8

N-(1-Methyl-5-indolyl)-N/-(4.(1,2,4-triazolyl)) urea (E8)

To a solution of 1,1/-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 15 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 1h, then poured into water. The aqueous solution was filtered and evaporated to dryness, and the residue was chromatographed on silica (25g) eluted with 5-10%

methanol/dichloromethane. The second-eluted material was the title compound (0.21g). mp 202-206°C.

Found: C, 56.36; H, 4.82; N, 32.65

C₁₂H₁₂N₆O requires: C, 56.24; H, 4.72; N, 32.79%

NMR (d₆-DMSO) δ: 3.77 (3H, s), 6.35 (1H, d, J=3), 7.18 (1H, dd, J=8,

2), 7.29 (1H, d, J=3), 7.35 (1H, d, J=8), 7.65 (1H, d, J=2). Example 9

N-(1-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-1-methylindole (D2, 0.29g, 2 mmol) in dry dichloromethane (5 ml).

After 0.25h, 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 1h then cooled and added to water (200 ml) with vigorous stirring. The precipitate 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 HCl in ether, mp 230°C (from ethanol)

Found: C, 64.42; H, 4.72; N, 15.71.

C₁₉H₁₇N₄OCl requires: C, 64.68; H, 4.82; N, 15.87%

NMR (d⁶-DMSO) δ: 3.77 (3H, s), 6.38 (1H, d, J=6), 7.2-7.4 (3H, m),

7.77 (3H, m), 8.1 (2H, m), 8.80 (1H, d, J=3), 9.19

(2H, d, J=12), 9.79 (1H, s).

Example 10 N-(1-Methyl-5-indolyl)-N'-(6-quinolyl)-urea hydrochloride (E10)

A stirred suspension of carbonyl diimidazole (0.34g, 2.1 mM) in dry dichloromethane (5 ml) was treated with a solution of 5-amino 1- methyl indole (D2, 0.29g, 2 mM) in dry dichloromethane (5 ml). After 0.25h, 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 1h then cooled and added to water (200 ml) with vigorous stirring. The precipitate 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 HCl in ether. mp 208°C (from ethyl acetate).

NMR (d⁶-DMSO) δ: 3.77 (3H, s), 6.38 (1H, d, J=3), 7.2-7.4 (3H, m),

7.7-8.2 (4H, m), 8.48 (1H, s), 8.8-9.1 (3H, m), 9.58 (1H, s). m/z (El): 316 (M⁺, C₁₉H₁₉N₄O)

Example 11

N-(1-Methyl-5-mdolyl)-N/-(8-quinolyl) urea (E11)

The title compound was prepared from 8-aminoquinoline, 1, 1/-carbonyl dϋmidazole and 5-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 10, in 31% yield, m.p. 205-209° C. NMR (D₆-DMSO)δ: 3.76 (3H, s), 6.35 (1H, d, J 3), 7.22 (1H, dd, J 6, 2),

7.27 (1H, d, J 3), 7.36 (1H, d, J 6), 7.5-7.54 (2H, m), 7.60-7.66 (1H, m), 7.8 (1H, s), 8.39 (1H, d, J 6), 8.57 (1H, m), 8.92 (1H, d, J 2), 9.62 (2H, s). Found: M⁺316

C₁₉H₁₆N₄O requires 316

Example 12 N-(1-Methyl-5-indolyl)-N/-(5-quinolyl) urea (E12)

The title compound was prepared from 5-aminoquinoline, 1, 1/-carbonyl diimidazole and 5-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 10, in 20% yield, m.p 243-245° C.

NMR (D₆-DMSO)δ: 3.76 (3H, s), 6.3δ (1H, d, J 2), 7.20 (1H, d, J 6), 7.29

(1H, d, J 2), 7.38 (1H, d, J 6), 7.60-7.65 (1H, m), 7.72

(2H, d, J 3), 7.77 (1H, s), 8.10 (1H, t, J 2), 8.57 (1H, d, J 6) 8.84 (2H, d, J 3), 8.93 (1H, d, J 2)

Found: M⁺ 316

C₁₉H₁₆N₄O requires 316

Example 13

N-(1-Methyl-5-indolyl)-N/-(2-methyl-4-quinolyl) urea hydrochloride (E13)

The title compound was prepared from 4-aminoquinaldine, 1,1/-carbonyl diimidazole and 5-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 (D₆-DMSO)δ: 2.80 (3H, s), 3.77 (3H, s), 6.39 (1H, d, J 2), 7.23-7.33

(2H, m), 7.42 (1H, d, J 6), 7.79-7.84 (2H, m), 8.0-8.11 (2H, dd J 6,6), 8.60 (1H, s), 9.08 (1H, d, J 8), 10.8 (1H, s), 10.92 (1H, s), 15.0 (1H, broad s).

Found: M+ 330

C₂₀H₁₈N₄O requires 330 Example 14

N-(1-methyl-S-mdolyl)-N/-(6-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-(1-Methyl-5-indolyl)-N/-(5-isoquinolyl) 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 5-amino-1- methyl-indole (D2) (0.25g, 1.7 mmol) in dimethylformamide (20 ml). The reaction mixture was heated to 90° C for 1h, 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. 254-259° C.

NMR (D₆-DMSO)δ: 3.77 (3H, s), 6.37 (1H, d, J 3), 7.19 (1H, dd J 6,2),

7.28 (1H, d, J 3), 7.37 (1H, d, J 8), 7.6δ (1H, t, J 6), 7.75-7.8 (2H, m), 7.99 (1H, d, J 6), 8.32 (1H, d, J 6), 8.57 (1H, d, J 6), 8.84 (2H, d, J 8), 9.29 (1H, s).

Found: M⁺ 316

C₁₉H₁₆N₄O requires 316 Example 16

N-(1-Methyl-5-indolyl)-N/-(1-isoquinolyl) urea (E16)

The title compound was prepared from 1-aminoisoquinoline, 1, 1'-carbonyl diimidazole and 5-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 15, in 11% yield, m.p.230-233° C.

NMR (CDCl₃)δ: 3.81 (3H, s), 6.47 (1H, d, J 2), 7.07 (1H, d, J 3), 7.30

(2H, m), 7.46 (1H, dd J 6,2), 7.61-7.82 (3H, m), 7.97 (1H, s), 8.09-8.16 (3H, m), 12.4 (1H, broad s). Found: M⁺ 316

C₁₉H₁₆N₄O requires 316

Example 17 N-(1-Methyl-5-indolyl)-N/-(4-isoquinolyl) urea (E17)

The title compound was prepared from 4-aminoisoquinoline, 1,1/-carbonyl diimidazole and 5-amino-1-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 (1H, d, J 2), 7.22 (1H, dd J

6,2), 7.32 (1H, d, J 3), 7.4 (1H, d, J 6), 7.80 (1H, s), 7.94 (1H, t, J 6), 8.13 (1H, t, J 6), 8.39 (1H, d, J 6), 8.5δ (1H, d, J 6), 9.24 (1H, s), 9.34 (1H, s), 9.50 (2H, d, J 8). Found: M⁺ 316

C₁₉H₁₆N₄O requires 316

Pharmacological data

[³H]-mesulergine binding to pig choroid plexus membranes in vitro

Evidence from the literature suggests that 5-HT_1C 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 5-HT_1C binding site can be determined by assessing their ability to displace [³H]-mesulergine from 5-HT_1C 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 HCl buffer (pH7.4) (containing 4mM CaCl₂ and 0.01% ascorbic add) and centrifuged at 50,000g for 15 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 15 min) before the final centrifugation. The final pellet was resuspended in 20vols of buffer and stored at -70°C until use.

The tissue suspension (50ml) was incubated with [³H]-mesulergine (2nM) in Tris HCl buffer (pH7.4) at 37°C (containing 0.01% ascorbic add, 4mM CaCl₂) and 3 × 10^-8M spiperone for 30 minutes. Non-specific binding was measured in the presence of mianserin (10^-6M). Six concentrations of test drug (10^-9 to 10^-4M final concentration) were added in a volume of δOml. The total assay volume was 500ml. Incubation was stopped by rapid filtration using a Skatron cell harvester and radioactivity measured by liquid scintillation spectrometry. The IC₅₀ values were determined and the pK_i (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where

K_i = inhibition constant.

C = concentration of [³H]-mesulergine

Kd = Affinity of mesulergine for 5-HT_1C binding sites. Curzon, G.A. and Kennett, G.A. (1990). TIPS, Vol. 11, 181-182.

Fozard, J.R. and Gray, J.A. (1989). TIPS, Vol. 10, 307-309.

Pazos, A. et al. (1984). Eur. J. Pharmacol., 106, 631-638.

[³H]-Mesulergine binding to rat 5-HT_1C clones expressed in 293 cells in vitro

The affinity of test drugs for the 5-HT_1C binding site can be. determined by assessing their ability to displace [³H]-mesuleιgine from 5-HT_1C 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 HCl buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (10^-6M). Ten concentrations of test drug (3 × 10^-9 to 10^-4M 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 pK_i (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 pK_i 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 1-(m-trifluoromethylphenyl)piperazine (TFMPP) (Lucid and Frazer 1982, Kennett and Curzon 1988). This effect was blocked by the non specific 5-HT_1C/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 5-HT_1A, 5-HT_1B, 5-HT₃, α₂ adrenoceptors or dompamine D2 receptors. The effect of mCPP is therefore considered to be mediated by 5-HT_1C receptors (Kennett and Curzon 1988) as confirmed by subsequent studies (Lucki et al., 1989). Since mCPP causes

hypolocomotion when infused into the cerebral ventrides this effect is probably centrally mediated (Kennett and Curzon 1988). mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long × 16½ cm wide × 25 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 5-HT_1C 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. Neurosci. 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-HT_1C-like Receptors

Introduction

The 5-HT receptor in the rat fundic strip (RFS) has been characterised as '5-HT_1C-like' as its pharmacology is similar, but not identical, to that of rat 5-HT_1C receptor dones. Hence this tissue may be used to assess the 5-HT_1C-like antagonist properties of compounds.

Methods

Whole stomachs were obtained from male CD Rats (Charles River, 250-350g). Strips of fundus (2cm × 0.5 cm) were cut from the greater curvature and the mucosae carefully removed. Tissues were then further dissected into smaller strips (2 mm × 20 mm) which were mounted in organ baths containing oxygenated Tyrodes solution at 37°C containing indomethacin (3 μM). Preparations were maintained under a resting tension of 0.5g 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 × 10^-8 M 5-HT at 15 minute intervals until constant responses were obtained. Fifteen minutes later, a complete cumulative concentration-effect curve to the standard agonist 5-HT (1 × 10^-10 upwards) was constructed to determine the individual sensitivity of each preparation. A further concentration-effect curve to either 5-HT, or other agonists was constructed no sooner than 1h 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:

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 C_1-6 alkyl;

R₂, R₃, R₁₀ and R₁₁ are independently hydrogen or C_1-6 alkyl, or R₁₀ and R₁₁ together form a bond, or R₂ and R₁₀ or R₃ and R₁₁ together form a C_2-6 alkylene chain;

R₄ is hydrogen, C_1-6 alkyl, halogen, NR₈R₉, OR12 or COOR₁₂, where R₈,

R₉ and R₁₂ are independently hydrogen or C_1-6 alkyl;

R₅ and Rg are independently hydrogen or C_1-6 alkyl; and

R₇ is hydrogen, C_1-6 alkyl, C_1-6 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 R₁₀ and R₁₁ form a bond.

2. A compound according to claim 1 in which R₁ 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 R₁₀ and R₁₁ are both hydrogen or R₁₀ and R₁₁ together form a bond to form an indole structure.

5. A compound according to claim 4 in which R₄, R₅, R₆ 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-(1-methyl-5-indolyl)-N/-(2-pyrazinyl) urea,

N-(1-methyl-5-indolyl)-N/-(3-pyridazinyl) urea,

N-(1-metiιyl-5-indolyl)-N/-(5-pyrimidinyl) urea,

N-(1-methyl-5-indolyl)-N/-(4-pyridazinyl) urea,

N-(1-methyl-5-indolyl)-N/-(3-methyl-5-isothiazolyl) urea,

N-(1-methyl-5-indolyl)-N/-(3-methyl-5-isoxazolyl) urea,

N-(1-methyl-5-indolyl)-N/-(2-(1,3,4-thiadiazolyl)) urea,

N-(1-methyl-5-indolyl)-N/-(4-(1,2,4-triazolyl)) urea,

N-(1-methyl-5-indolyD-N/-(3-quinolyl)-urea,

N-(1-methyl-5-indolyl)-N/-(6-quinolyl)-urea,

N-(1-methyl-5-indolyl)-N/-(8-quinolyl) urea,

N-(1-methyl-5-indolyl)-N/-(5-quinolyl) urea,

N-(1-methyl-5-indolyl)-N/-(2-methyl-4-quinolyl) urea,

N-(1-methyl-5-indolyl)-N/-(6-Isoquinolyl) urea,

N-(1-methyl-5-indolyl)-N/-(6-isoquinolyl) urea,

N-(1-methyl-5-indolyl)-N/-(1-isoquinolyl) urea,

N-(1-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 claims 1-7 and a pharmaceutically acceptable carrier or exdpient.

10. A process for the preparation of a compound offormula (I) or a pharmaceutically acceptable salt thereof, which process comprises: (a) the coupling ofa compound offormula (II);

with a compound offormula (III);

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 -NR₅'CONR₆'- when coupled, wherein R₅' and R₆' are R₅ and Rg as defined in formula (I) or groups convertible thereto, and the variables R₁', R₂', R₃', R₁₀', R₁₁', R₄' and R₇' are R₁, R₂, R₃, R₁₀, R₁₁, 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 R₁', R₂', R₃', R₁₀', R₁₁', R₄', R₅', R₆' and R₇' when other than R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇ respectively to R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, interconverting R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, and forming a pharmaceutically acceptable salt thereof; or

(b) cyclising a compound offormula (IV):

wherein R₄', R₅', R₆' 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 R₁', R₂', R₃', R₁₀', and R₁₁' as defined in formula (III), and thereafter optionally and as necessary in any appropriate order, converting any R₁', R₂', R₃', R₁₀', R₁₁', R₄', R₅', R₆' and R₇' when other than R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, to R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, interconverting R₁, R₂, R₃, R₁₀, R₁₁, R₄, R₅, R₆ and R₇, and optionally thereafter forming a

pharmaceutically acceptable salt.