WO1997008167A1

WO1997008167A1 - 5ht2c and 5ht2b antagonists

Info

Publication number: WO1997008167A1
Application number: PCT/EP1996/003512
Authority: WO
Inventors: Ian Thomson Forbes
Original assignee: Smithkline Beecham P.L.C.
Priority date: 1995-08-26
Filing date: 1996-08-06
Publication date: 1997-03-06
Also published as: GB9517559D0

Abstract

Compounds of formula (I) or a salt thereof, wherein R4 is a group of formula (i), a group of formula (ii) or a group of formula (iii) have been found to have 5HT¿2C? receptor antagonist activity. Some or all of the compounds of the invention also exhibit 5HT2B antagonist activity. 5HT2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders.

Description

5HT2C AND 5HT2B ANTAGONISTS

This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.

WO 94/04533 (SmithKline Beecham pic) describes indole and indoline derivatives which are described as possessing 5HT_2C receptor antagonist activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT_2C receptor antagonist activity. Some or all of the compounds of the invention also exhibit 5HT_2B antagonist activity. 5HT_2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and 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. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as micro vascular diseases such as macular oedema and retinopathy.

The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:

wherein:

A,B,C and D are all carbon, or one of A,B,C or D is nitrogen and the others are carbon;

E is oxygen, sulphur, CH₂ or NR¹ where R¹ is hydrogen or C_{1 -6} alkyl;

P is a phenyl or an optionally substituted 5-7-membered heterocyclic ring containing one to three heteroatoms selected from oxygen, nitrogen or sulphur;

R² and R³ are independently hydrogen, halogen, C_1-6 alkyl, C_1-6 alkylthio, CF₃,

NR⁹R¹⁰ or OR^{1 1} where R⁹, R¹⁰ and R^{1 1} are independently hydrogen, C_1-6 alkyl or arylC_1-6 alkyl; and R⁴ is a group of formula (i)

in which:

X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR¹⁴ group or one is a CR¹⁴ group and the other is carbon or a CR¹⁴ group;

R⁵, R⁶, R¹⁴ and R¹⁵ groups are independently hydrogen, C_1-6 alkyl optionally substituted by one or more halogen atoms, C_2-6 alkenyl, C_3-6cycloalkyl,

C_3-6cycloalkylC_1-6alkoxy, C_2-6 alkynyl, C_3-6 cycloalkyloxy, C_3-6 cycloalkyl-C_1-6 alkyl, C_{1 -6} alkylthio, C_3-6 cycloalkylthio, C_3-6 cycloalkyl-C_1-6 alkylthio,

C_1-6alkoxy, hydroxy, halogen, nitro, CF₃, C₂F₅, OCF₃, SCF₃, SO₂CF₃, SO₂F, formyl, C_2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR⁹R¹⁰or

CONR⁹R¹⁰ where R⁹ and R¹⁰ are as defined for R¹, CO₂R¹² where R¹² is hydrogen or C_1-6 alkyl;

or R⁵ and R⁶ form part of an optionally substituted 5-membered carbocyclic or heterocyclic ring;

R⁷ and R⁸ are independently hydrogen or C_1-6 alkyl; or

R⁴ is a group of formula (ii):

in which X and Y are both nitrogen, one is nitrogen and the other is a CR¹⁴ group or

X and Y are both CR¹⁴ groups and R⁵, R⁶, R¹⁴ and R¹⁵ are as defined in formula

(i); and

R¹³ is hydrogen or C_1-6 alkyl, or

R⁴ is a group of formula (iii):

in which R⁵, R⁶, X and Y are as defined for formula (i) and Z is oxygen, sulphur, CH₂ or NR¹³ where R¹³ is hydrogen or C_1-6 alkyl.

C_1-6 Alkyl groups, whether alone or as part of another group, may be straight chain or branched.

Preferably P is pyridyl, in particular a 3-pyridyl or 4-pyridyl group.

Preferably E is NR¹ where R¹ is hydrogen.

Preferably R² is hydrogen.

Preferably R⁴ is a group of formula (i). Preferably X and Y form part of a phenyl ring, that is to say one of X or Y is carbon and the other is a CH group or both of X and Y are CH groups. Most preferably R⁴ is an indoline ring, that is to say a group of formula (A):

in which R⁵ and R⁶ are as defined in formula (i).

When R⁵ and R⁶ form part of an aromatic ring suitable rings include thiophene, furan and pyrrole rings. Preferred R⁵ and R⁶ groups, which can be the same or different, include C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, halogen, CF₃, and CO₂R^{1 1} where R^{1 1} is hydrogen or C_1-6 alkyl Preferably R⁵ is trifluoromethyl or chloro and R⁶ is C_1-6alkylthio, C_1-6alkyl or C_1-6alkoxy.

Particularly preferred compounds of the invention include:

1-(5-(3-Pyridyl)-3-indolylcarbonyl-5-methoxy-6-trifluoromethylindoline,

1-(5-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,

1-(6-(3-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,

1-(6-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline, and pharmaceutically acceptable salts thereof.

The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic. Quaternary salts of intermediate compounds in which P is an aromatic group such as pyridyl can also be prepared with C_1-6alkylating agents, for example methyl iodide, and such salts also form an aspect of the invention.

Compounds of formula (I) may also form N-oxides or solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'compound of formula (I)' also includes these forms.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

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 R^{1 6} and R¹⁷ contain the appropriate functional group(s) necessary to form a bond when coupled, A, B, C, D and P are as defined in formula (I), E is as defined in formula (I) or is a group NR^{1 '} and the variables, R^{1 '}, R^2', R^3' and R^4' are R¹, R², R³ and R⁴ respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R^{1 '}, R^2', R^3' and R^4', when other than R¹, R², R³ and R⁴ respectively to R¹, R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming a pharmaceutically acceptable salt thereof, or

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

wherein P, A, B, C, D, E, R^2' and R^3' are as defined above and L is a leaving group with a compound of formula (V):

R⁴'- H (V) wherein R⁴ is as defined above and thereafter optionally and as necessary and in any appropriate order, converting any R^{1 '}, R^2', R^3' and R^4', when other than R¹ , R², R³ and R⁴ respectively to R¹, R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming a pharmaceutically acceptable salt thereof.

Preferably R¹⁷ is a leaving group such as halogen and in particular bromo. Preferably R¹⁶ is a boronic acid group. Compounds of formula (II) and (III) are reacted together using standard boronic acid coupling conditions in the presence of an organometallic catalyst. Preferred catalysts are palladium catalysts, in particular tetrakis (triphenylphosphine) palladium(O).

For process (b) L is a leaving group such as halogen, in particular chloro.

Compounds of formula (IV) and (V) can be reacted together using standard reaction conditions known in the art.

R¹ to R³ groups can be introduced at any suitable stage in the process, preferably R¹ to R³ groups are introduced at an early stage in the process. It should be appreciated that it is preferred that all groups R¹ to R³ are introduced before coupling compounds of formula (II) and (III).

Suitable examples of groups R^{1 '}, R^2' and R^3' which are convertible to R¹,

R² and R³ 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.

Interconversions of R¹, R² and R³ are carried out by conventional procedures. For example halo groups can be introduced by selective halogenation of the ring P or the benzene ring of the indoline group using conventional conditions. It should be appreciated that it may be necessary to protect any R¹ to R³ hydrogen variables which are not required to be interconverted.

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).

Compounds of formula (II), (III), (IV) and (V) may be prepared according to known methods or analogous to known methods.

Novel intermediates of formula (III) and (IV) also form part of the invention. Parmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative. N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.

Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT2B/2C receptor antagonist activity and are believed to be of potential use for the treatment or prophylasis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and 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. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.

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 the above disorders.

The invention further provides a method of treatment or prophylaxis of the above disorders, 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 the above disorders. 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 70.0 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 0.5 to 100 mg; 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 Descriptions and Examples illustrate the preparation of compounds of the invention.

Description 1

1-Methoxy-4-nitro-2-trifluoromethylbenzene (D1)

Sodium (11.78g, 0.512 mol) was dissolved in dry methanol (1 1) and to the resulting solution was added a solution of 1-chloro-4-nitro-2-trifluoromethyl-benzene (96.22g, 0.427 mol) in methanol (100 ml). The reaction mixture was refluxed for 3 h then cooled and evaporated in vacuo. The residue was partitioned between water (500 ml) and dichloromethane (3 × 400 ml). The combined organic extracts were dried

(Na₂SO₄) and evaporated to give the title compound (93.76g, 99%) as a white solid.

NMR (CDCI₃) δ: 4.05 (3H, s), 7.12 (1H, d), 8.45 (1H, dd), 8.52 (1H, d). Description 2

(5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D2)

A mixture of 1-methoxy-4-nitro 2-trifluoromethylbenzene (D1) (93g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KO^lBu (103.85g, 0.927 mol) in dry DMF (400 ml) at -10° C. After complete addition the resulting purple solution was maintained at -10° C for 1 h then poured into a mixture of ice/water (1.5 1) and 5 M aqueous HCl (1.5 1). The resulting mixture was extracted with dichloromethane (3 × 1 1). The combined extracts were washed with water (3 1), dried (Na₂SO₄) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetate/petroleum ether to afford the title compound (85.13g, 78%) as a white solid. Mp 103-104 °C. NMR (CDCI₃) δ: 4.10 (3H, s), 4.37 (2H, s), 7.34 (1H, s), 8.53 (1H, s).

Description 3

5-Methoxy-6-trifluoromethylindole (D3) (5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D2) (85g, 0.327 mol) in ethanol/water (9:1, 1.6 1) and glacial acetic acid (16 ml) was hydrogenated over 10% palladium on carbon (50 g) at 50 psi for 0.5 h at room temperature. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between aqueous K₂CO₃ (1 1) and dichloromethane (2 × 1 1) and the combined organic extract was dried (Na₂SO₄) and evaporated to afford the title indole (67.63g, 96%) as a grey solid. NMR (CDCI₃) δ: 3.94 (3H, s), 6.53 (1H, m), 7.21 (1H, s), 7.32 (1H, m), 7.64 (1H, s), 8.25 (1H, br s).

Description 4

5-Methoxy-6-trifluoromethylindoline (D4)

The indole (D3) (67.63g, 0.315 mol) was treated with sodium cyanoborohydride (40 g, 0.637 mol) in glacial acetic acid (500 ml) using standard procedures to afford the title indoline (67.73%, 99%) as an off-white solid. NMR (CDCI₃) δ: 3.07 (2H, t), 3.58 (2H, t), 3.67 (1H, br s), 3.83 (3H, s), 6.83 (1H, s), 6.88 (1H, s).

Description 5

1-(5-Bromo-3-indoIylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (D5)

A solution of 5-bromoindole-3-carboxylic acid (A.S. Katner, Org. Prep. Proced, 1970, 2, 297) (1.13g, 4.7 mmol) in dry tetrahydrofuran (50 mL) was treated with oxalyl chloride (0.43 mL, 5 mmol) and dimethylformamide (5 drops). The mixture was stirred at room temperature for 1 h, then evaporated to dryness. Tetrahydrofuran (25 mL) was added to the residue, followed by 5-methoxy-6-trifluoromethyl indoline (D4, 1.1g, 5 mmol) and triethylamine (0.7 mL, 5 mmol) in tetrahydrofuran (25 mL). The mixture was stirred overnight, then poured into water. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel eluted with 3-4% methanol/dichloromethane. Eluted product was triturated with dichloromethane/methanol to give the title compound (0.89g, 43%), Mp.

>250°C.

NMR (d₆DMSO) δ: 3.28 (2H, t, J=8), 3.88 (3H, s), 4.97 (2H, t, J=8), 7.26 (1H, s), 7.33 (1H, d, J=8), 7.47 (1H, d, J=8), 8.11 (1H, s), 8.29 (1H, s), 8.41 (1H, s)

MS (API): m/z=439 (MH+, ⁷⁹Br), 441 (MH+, ⁸¹Br)

C₁₉H₁₄N₂O₂BrF₃ requires M+1 = 439 and 441 Description 6

6-Bromo-3-(trichloroacetyl)indole (D6)

A mixture of 6-bromoindole (1.18g, 6.0 mmol), trichloroacetyl chloride (1.0 mL, 9 mmol) and pyridine (0.72 mL, 9 mmol) in dry 1,4-dioxan (12 ml) was stirred overnight at room temperature, then heated at 90°C until the reaction appeared complete by T.L.C. The mixture was poured into water and the precipitate was filtered off, washed with water and dried. The crude product was recrystallised from ethanol/water to give the title compound (1.36g, 66%), Mp. 234-40°C.

NMR (d₆DMSO) δ: 7.47 (1H, dd, J=7,1), 7.80 (1H, d, J=1), 8.23 (1H, d, J=7), 8.64 (1H,s), 12.63 (1H, s).

MS (API) m/z=338, 340, 342. 344 ([M-H]-)

Description 7

6-Bromo-3-indolecarboxylic acid (D7)

A solution of trichloroacetylindole (D6, 1.33g, 3.9 mmol) in methanol containing one drop of 60% aqueous potassium hydroxide was heated under reflux for 3h. Dilute (10%) aqueous sodium hydroxide (10 mL) was added and the mixture was heated under reflux for 2.5 h. Most of the solvent was then removed in vacuo and the residue was diluted with water and extracted with dichloromethane. The aqueous phase was then acidified with dilute hydrochloride acid and extracted with

dichloromethane/methanol. This extract was dried and evaporated to give the title-compound (0.79g, 84%).

NMR (d₆DMSO) δ: 7.32 (1H, dd, J=7,2), 7.68 (1H, s), 7.95 (1H, d, J=7), 8.04 (1H, d, J=2), 11.93 (1H, s), 12.15 (1H, s).

MS (API): m/z=238 ([M-H]-, ⁷⁹Br), 240 ([M-H]-, ⁸¹Br)

C₉H₆NO₂Br requires M-1 = 238 and 240

Description 8

1-(6-Bromo-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (D8)

The title compound was prepared by the method of Description 5, using 6-bromoindolecarboxylic acid (D7, 0.79g, 3.3 mmol). Chromatography on silica gel eluted with 3-5% methanol/dichloromethane, followed by trituration with

dichloromethane/methanol gave the title compound (0.89g, 61%), Mp. >250° C.

MHR (d₆DMSO) δ: 3.27 (2H, t, J=8), 3.88 (3H, s), 4.95 (2H, t, J=8), 7.28 (2H, m), 7.67 (1H, s), 8.05 (1H, d, J=8), 8.08 (1H, s), 8.49 (1H, s), 11.95 (1H, broad).

MS (API): m/z = 439 (MH⁺, ⁷⁸Br), 441 (MH⁺, ⁸¹Br)

C₁₉H₁₄N₂OBrF₃ requires M+1 = 439 and 441 Example 1

1-(5-(3-PyridyI)-3-indolylcarbonyl-5-methoxy-6-trifluoromethyIindoline (El)

A mixture of the 5-bromoindolecarboxamide (D5, 0.30g,0.68 mmol), 3-pyridylboronic acid (Chem Pharm Bull 1983, 31(12) 4573) (86 mg, 0.7 mmol), tetrakis (triphenylphosphine) palladium (23 mg, 0.02 mmol) and sodium carbonate (0.28g, 2.7 mmol) in 1,2-dimethoxyethane (20 ml) and water (2 ml) was heated under reflux overnight. The mixture was then cooled and poured into water. The precipitate was filtered off, washed with water and dried. The residue was chromatographed on silica gel eluted with 4-5% methanol/ dichloromethane to give the title compound (0.21g, 71%), Mp. >250°C.

NMR (d₆DMSO) δ : 3.28 (2H, t, J=8), 3.88 (3H, s), 4.48 (2H, t, J=8), 7.27 (1H, s), 7.48 (1H, dd, J=7, 5), 7.56 (1H, d, J=8), 7.62 (1H, d, J=8), 8.08 (1H, d, J=7), 8.11 (1H, d, J=2), 8.39 (1H, s), 8.42 (1H, s), 8.54 (1H, d, J=5), 8.89 (1H, s).

MS (API): Found m/z 438 (MH⁺)

C₂₄H₁₈N₃O₂F₃ requires M+1 = 438

Example 2

1-(5-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (E2)

The title compound was prepared by the method of Example 1, using

4-pyridylboronic acid (Rec Trav Chim Pay Bas 1965, 84, 439) (0.10g, 0.81 mmol). Chromatography and recrystallisation from methanol gave the title compound (0.08g, 27%), Mp. >250°C. NMR (d₆DMSO) δ: 3.28 (2H, t, J=8), 3.89 (3H, s), 4.49 (2H, t, J=8), 7.28 (1H, s), 7.62 (1H, d, J=8), 7.67 (1H, d, J=8), 7.72 (2H, d, J=7), 8.13 (1H, s), 8.42 (1H, s), 8.52 (1H, s), 8.61 (2H, d, J=7), 12.03 (1H, s). MS (API) : Found m/z 438 (MH⁺)

C₂₄H₁₈N₈O₂F₃ requires M+1 = 438

Example 3

1 -(6-(3-Pyridyl)-3-indolylcarbonyI)-5-methoxy-6-trifluoromethyl indoline (E3)

The title compound was prepared by the method of Example 1, using the

6-bromoindolecarboxamide (D8, 0.30g, 0.68 mmol) and 3-pyridylboronic acid (92 mg, 0.75 mmol). Recrystallisation from dichloromethane/methanol gave the title compound (0.15g, 50%), Mp. 242°C (decomp.)

NMR (d₆DMSO) δ: 3.28 (2H, t, J=8), 3.88 (3H, s), 4.49 (2H, t, J=8), 7.28 (1H, s), 7.50 (2H, m), 7.79 (1H, s), 8.10 and 8.13 (2H, s+d), 8.21 (1H, d, J=8), 8.42 (1H, s), 8.57 (1H, d, J=5), 8.94 (1H, s), 12.00 (1H, s). MS (API): Found m/z 438 (MH⁺)

C₂₄H₁₈N₃O₂F₃ requires M+1 = 438

Example 4

1-(6-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline (E4)

The title compound was prepared by the method of Example 1, using the

6-bromoindolecarboxamide (D8, 0.40g, 0.9 mmol) and 4-pyridylboronic acid (0.27g, 2.2 mmol). Chromatography on silica gel, eluted with 3-6%

methanol/dichloromethane gave the title compound (0.17g, 43%), Mp. >250°C.

NMR (d₆DMSO/d₆-acetone) δ: 3.29 (2H, t, J=8), 3.88 (3H, s), 4.50 (2H, t, J=8), 7.25 (1H, s), 7.61 (1H, d, J=8), 7.75 (2H, d, J=7), 7.88 (1H, s), 8.14 (1H, d, J=2), 8.25 (1H, d, J=8), 8.44 (1H, s), 8.62 (2H, d, J=7), 12.05 (1H, s). MS (API): m/z=438

C₂₄H₁₈N₃O₂F₃ requires M+1 = 438

Found: C, 65.14; H, 4.33; N, 9.49% C₂₄H₁₈N₃O₂F₃ requires C, 65.90; H, 4.15; N, 9.61% Pharmacological data [³H]-mesulergine binding to rat or human 5-HT_2C clones expressed in 293 cells in vitro

Compounds were tested following the procedure outlined in WO 94/04533. The compounds of examples 1 to 4 have pKi values of 7.5 to 8.1.

Claims

Claims: 1. A compound of formula (I) or a salt thereof:

wherein:

E is oxygen, sulphur, CH₂ or NR¹ where R¹ is hydrogen or C_1-6 alkyl;

R² and R³ are independently hydrogen, halogen, C_{1 -6} alkyl, C_1-6 alkylthio, CF₃,

NR⁹R¹⁰ or OR^{1 1} where R⁹, R¹⁰ and R^{1 1} are independently hydrogen, C_1-6 alkyl oraryl C_1-6 alkyl; and

R⁴ is a group of formula (i)

in which:

R⁵, R⁶, R¹⁴ and R^{1 5} groups are independently hydrogen, C_1-6 alkyl optionally substituted by one or more halogen atoms, C_2-6 alkenyl, C_3-6cycloalkyl,

C_3-6cycloalkylC_{1 -6}-alkoxy, C_2-6 alkynyl, C_3-6 cycloalkyloxy, C_3-6 cycloalkyl- C_1-6 alkyl, C_1-6 alkylthio, C_3-6 cycloalkylthio, C_3-6 cycloalkyl-C_1-6 alkylthio,

C_1-6alkoxy, hydroxy, halogen, nitro, CF₃, C₂F₅, OCF₃, SCF₃, SO₂CF₃, SO₂F, formyl, C_2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR⁹R ¹⁰ or CONR⁹R¹⁰ where R⁹ and R¹⁰ are as defined for R¹, CO₂R¹² where R¹² is hydrogen or C_1-6 alkyl;

R⁷ and R⁸ are independently hydrogen or C_1-6 alkyl; or

R⁴ is a group of formula (ii):

in which X and Y are both nitrogen, one is nitrogen and the other is a CR¹⁴ group or X and Y are both CR¹⁴ groups and R⁵, R⁶, R¹⁴ and R 15 are as defined in formula (i); and

R¹³ is hydrogen or C_1-6 alkyl, or

R⁴ is a group of formula (iii):

2. A compound according to claim 1 in which P is pyridyl.

3. A compound according to claim 1 or 2 in which R¹ is hydrogen.

4. A compound according to any one of claims 1 to 3 in which R² is

hydrogen.

5. A compound according to any one of claims 1 to 4 in which R⁴ is a group of formula (i).

6. A compound according to any one of claims 1 to 5 in which R⁵ and R⁶ are C_1-6alkyl and C_1-6alkylthio.

7. A compound according to claim 1 which is: 1-(5-(3-Pyridyl)-3-indolylcarbonyl-5-methoxy-6-trifluoromethylindoline,

1-(5-(4-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,

1-(6-(3-Pyridyl)-3-indolylcarbonyl)-5-methoxy-6-trifluoromethyl indoline,

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 to 7 and a pharmaceutically acceptable carrier or excipient.

10. 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 R¹⁶ and R¹⁷ contain the appropriate functional group(s) necessary to form a bond when coupled, A, B, C, D and P are as defined in formula (I), E is as defined in formula (I) or is a group NR¹ ' and the variables, R^{1 '}, R^2', R^3' and R^4' are R¹, R², R³ and R⁴ respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R^{1 '}, R^2', R³' and R^4', when other than R¹, R², R³ and R⁴ respectively to R¹, R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming a pharmaceutically acceptable salt thereof, or (b)

coupling a compound of formula (IV):

R^4'- H (V) wherein R^4' is as defined above and thereafter optionally and as necessary and in any appropriate order, converting any R^{1 '}, R^2', R^3' and R^4', when other than R¹, R², R³ and R⁴ respectively to R¹, R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming a pharmaceutically acceptable salt thereof.