EP0682656A1 - Use of phenyl heteroaryl ureas as 5ht 2c? receptor antagonists and urea compounds - Google Patents

Use of phenyl heteroaryl ureas as 5ht 2c? receptor antagonists and urea compounds

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Publication number
EP0682656A1
EP0682656A1 EP94905697A EP94905697A EP0682656A1 EP 0682656 A1 EP0682656 A1 EP 0682656A1 EP 94905697 A EP94905697 A EP 94905697A EP 94905697 A EP94905697 A EP 94905697A EP 0682656 A1 EP0682656 A1 EP 0682656A1
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EP
European Patent Office
Prior art keywords
urea
pyridyl
quinolinyl
chloro
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94905697A
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German (de)
French (fr)
Inventor
Ian Thomson Smithkline Beecham Pharma. Forbes
Peter Smithkline Beecham Pharma. Ham
Roger Thomas Smithkline Beecham Pharma. Martin
Mervyn Smithkline Beecham Pharma. Thompson
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication of EP0682656A1 publication Critical patent/EP0682656A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms

Definitions

  • This invention relates to a method of treatment of certain CNS disorders.
  • WO 92/05170 describes ce ⁇ ain area derivatives which are described as possessing 5HT ⁇ c receptor antagonist activity.
  • the 5HT ⁇ c receptor has recently been reclassified as the 5HT2C receptor [P. Hartig et al.. Trends in Pharmacological Sciences (TIPS) 1993].
  • 5HT2C 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.
  • the present invention provides the use of a compound of formula (I) or a salt thereof:
  • 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;
  • R 1 is hydrogen, Cj.g alkyl, halogen, NR 5 R 6 or OR 7 where R 5 , R 6 and R 7 are independently hydrogen or C ⁇ _ ( - alkyl;
  • R2 and R**- * are independently hydrogen or Cj.g alkyl
  • R 4 is hydrogen, C ⁇ . ( , alkyl, CF3, nitro, cyano, acyl, halogen, NR 5 R 6 , OR 7 or CO2 7 where R--, R-- and R 7 are independently hydrogen or C ⁇ g alkyl as defined for R 1 ; and n is 1, 2 or 3, in the manufacture of a medicament for the treatment or prophylaxis of CNS disorders.
  • Cj.galkyl groups whether alone or as part of another group, can be straight chain or branched.
  • R ⁇ is hydrogen or methyl.
  • R2 and R-- are hydrogen.
  • Suitable moieties when the ring P is a 5- or 6-membered aromatic heterocyclic ring include pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl.
  • P is pyridyl attached to the urea nitrogen at position 3 or 4; or P is quinoline attached to the urea nitrogen at position 3, 4 or 6, preferably at position 4.
  • n is 1 or 2.
  • the R 4 groups can be the same or different.
  • the phenyl ring is mono-substituted and R 4 is CF3 or -NMe2
  • -OMe (preferably in the meta or para position); CO2Et (preferably in the meta position) or the phenyl ring is preferably di substituted with meta chloro and para methyl.
  • Preferred compounds of formula (I) include:
  • N-(3-Chloro-4-methylphenyl)-N -(3-pyridyl) urea N-(3-Chloro-4-methylphenyl)-N -(4-pyridyl) urea
  • N-(3-Pyridyl)-N'-(3-(trifluoromethyl)phenyl)urea N-(3-Methylphenyl)-N'-(3-pyridyl)urea
  • N-(4-Chlorophenyl)-N'-(3-pyridyl)urea N-(3-Chlorophenyl)-N'-(3-pyridyl)urea
  • N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinolinyl)urea N-(3-Bromophenyl)-N'-(3-pyridyl)urea, N-(3,4-Dichlorophenyl)
  • 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.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • Compounds of formula (I) may also form N-oxides or solvates such as hydrates, and the invention also extends to these forms.
  • Certain 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 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.
  • Certain compounds of formula (I) are novel and form a further aspect of the invention. Particularly preferred novel compounds include those listed above and exemplified herein.
  • the invention further provides a method of treatment or prophylaxis of CNS disorders, in particular anxiety, depression, migraine, anorexia, obsessive compulsive disorders,
  • the invention also provides novel compounds 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, schizophrenia and/or disorders associated with spinal trauma and/or head injuries.
  • the present invention also provides a pharmaceutical composition, which comprises novel compounds 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.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • T e compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • 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.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • 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.
  • 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.
  • 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 and B contain the appropriate functional group(s) necessary to form the moiety, -NR2 CONR- ⁇ when coupled, the variables R - . R 2' , R 3' , and R 4 are R 1 , R 2 . R 3 , and R 4 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R ⁇ , R 2 , R 3 and R 4 , when other than R-, R 2 , R 3 and R 4 respectively to R-, R 2 , R 3 and R 4 , interconverting R ⁇ , R 2 . R 3 , and R 4 and forming a pharmaceutically acceptable salt thereof.
  • Suitable examples of groups A and B include:
  • A is -NR 2 COL and B is -NHR 3'
  • A is -NHR 2' and B is NR 3 COL
  • R 2 and R 3 are as defined above and L is a leaving group.
  • suitable leaving groups L include halogen such as chloro, bromo, imidazole or phenoxy or phenylthio optionally substituted for example with halogen.
  • reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at ambient temperature.
  • an inert solvent for example dichloromethane or toluene at ambient temperature.
  • 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.
  • a base such as triethylamine or in dimethylformamide at ambient or elevated temperature.
  • a is halogen and B is NR 3 CONHR 2 the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.
  • Suitable examples of groups R ⁇ and R 4 which are convertible to R* and R 4 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.
  • R-, R 2 , R 3 and R 4 Interconversions of R-, R 2 , R 3 and R 4 are carried out by conventional procedures.
  • R 2 is ⁇ . alkyl and R 3 is hydrogen it is possible to introduce a C ] _6 alkyl group at the R 3 position by conventional alkylation using 1 molar equivalent of a C j .g alkyl haiide and 1 molar equivalent of a suitable base in an inert solvent.
  • Suitable examples of a group R 2 and R 3 which is convertible to R 2 and R 3 include alkoxycarbonyl and benzyl or ⁇ r ⁇ -methoxybenzyl which are converted to R 2 and R 3 is hydrogen using conventional conditions.
  • R ! halo and R 4 halo may be introduced by selective halogenation of the ring P or the benzene ring respectively using conventional conditions.
  • Compounds of formula (II) in which A is NHR 2 are known compounds or can be prepared analogously to known compounds, see, for example, WO 92/05170 (SmithKline Beecham pic).
  • A is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent.
  • 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 7_ ⁇ 262).
  • iii) A is CONH2, via the nitrene intermediate using conventional conditions.
  • phosgene equivalents include triphosgene, carbonyldiimidazole, phenyl chloroformate and phenyl chorothioformate.
  • Compounds of formula (II) in which A is NR2'COL may be prepared by reacting a compound of formula (II) in which A is NHR2' 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 trithylamine.
  • Compounds of formula (II) in which A is halogen and R4' is hydrogen are commercially available.
  • 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.
  • the title compound (E4) was prepared in 56% yield from 6-aminoquinoline and phenylisocyanate following a procedure similar to that in Example 1. Free base precipitated from the reaction mixture and was recrystallised from ethanol.
  • 3-Methoxyphenyl isocyanate (0.83 ml, 6.3 mmol) in dry dichloromethane (30 ml) was added slowly to 4-aminoquinaldine (lg, 6.3 mmol) in dry toluene (30 ml) under a nitrogen atmosphere, and left to stir at room temperature for 19h.
  • the precipitate which formed was filtered off, washed with cold 1 : 1 toluene/dichloromethane and dried in vacuo.
  • the crude product was purified by recrvstallization from ethanol to give the title compound (0.99g, 51%) as a white solid, m.p. 191-193°C.
  • 3-Ethoxyc r onylphenyl isocyanate (lg, 5.2 mmol) in dry dichloromethane (30 ml), was added slowly to 4-aminoquinaldine (0.83g, 5.2 mmol) in dry toluene (30 ml), under a nitrogen atmosphere, and left to stir at room temperature for 19h.
  • the precipitate which formed was filtered off, washed with cold 1:1 toluene/dichloromethane and dried in vacuo.
  • the crude product was chromatographed on silica gel, using dichloromethane as the eluant to give the title compound (0.78g, 43%) as white crystals, m.p. 165-170°C.
  • Nicotinoyl azide (0.40g, 2.7 mmol) was stirred at reflux under nitrogen atmosphere in dry toluene (10 ml) for lh, with gas evolution. The solution was cooled to ambient temperature, and 3-chloro-4-methylaniline (0.30 ml, 2.4 mmol) was added. The suspension so formed was stirred for 1 h, when the solid was filtered off, washed with 1 : 1 toluene/dichloromethane, and dried in vacuo at 70°C. This gave the free base of the title compound (0.64g, 85%) as a white solid.
  • N-(3-Chloro-4-methyl)-N -(3-pyridyl) urea (0.55g, 2.1 mmol) was dissolved in hot ethanol (10 ml), and a solution of hydrogen chloride in ether (ca. 0.9M, 2.5 ml, ca. 2.3 mmol) was added. The suspension was cooled to ambient temperature, and the solid was filtered off, washed with cold ethanol, and dried in vacuo at 70°C. This gave the title compound (0.62g, 76%) as a white solid, m.p. 214.5-216°C.
  • 3-Chloro-4-methvlaniline (0.65 ml, 5.3 mmol) was stirred under nitro ⁇ en in dichloromethane ( 15 ml) at 0°C as triethylamine (0.82 ml, 5.9 mmol) was added. To this mixture was then added phosgene in toluene solution (1.93M, 4.1 ml, 7.9 mmol). After stirring at 0°C for 0.5h, triethylamine (1.6 ml, 1 1.8 mmol) was added and, after a further 0.5h, 4-aminopyridine (0.50g, 5.3 mmol) w*_s added.
  • N-(3-Chloro-4-methylphenyl)-N -(4-pyridyl) urea (1.03g, 3.9 mmol) was treated with hydrogen chloride using the method of Example 11. This gave the title compound (0.95g, 81 %) as a white solid, m.p. 235-240°C (decomp.).
  • the title compound was prepared in 91% yield from 3-pyridyl isocyanate and 3- aminobenzotrifluoride; m.p. 180-184° C.
  • the title compound was prepared in 87% yield from 3-aminopyridine and m-tolyl isocyanate, followed by salt formation with HC1; m.p. 182-183° C.
  • the title compound was prepared in 29% yield from 3-aminopyridine, 1,1'- carbonyldiimidazole and 4-chloroaniline; m.p. 207-209° C
  • the title compound was prepared in 75% yield from 3-bromopyridine and 3-pyridyl isocyanate: m.p. 190-193° C.
  • the title compound was prepared in 65% yield from 3,4-dichloroaniline and 3-pyridyl isocyanate; m.p. 206° C-210° C.
  • the title compound was prepared in 85% yield from 3-fluoro-4-methylaniline and 3- pyridyl isocyanate; m.p. 190-191 ° C.
  • the title compound was prepared in 73% yield from 3-chloro-4-tert-butylaniline & 3- pyridyl isocyanate; m.p. 190° C-193 0 C.
  • N-(3-Hydroxy-4-carboxyphenyl)-N'-(3-pyridyl)urea was prepared in 69% yield from 4- aminosalicylic acid and 3-pyridyl isocyanate in DMF/toluene. This material (0.37g, 1.4 mmol) was then stirred in methanol (20 ml) as thionyl chloride (2 ml) was cautiously added. The suspension was stirred at reflux under argon for 2 days, and evaporated to dryness. The residue was suspended in saturated sodium hydrogen carbonate solution, and the solid was filtered off, washed with water, dried, and recrystallised from ethanol/petroleum ether (b.p. 60-80° C), giving the title compound (0.16g, 41%) as a white solid, m.p. 199-200° C. NMR (DMSO d ⁇ ) ⁇ :
  • 5-HT? antagonists may have a number of therapeutic indications including the treatment f 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-HT2C binding site can be determined by assessing their ability to displace [ 3 H]-mesulergine from 5-HT2 clones expressed in 293 cells (Julius et al., 1988). The method employed was similar to that of Pazos et al, 1984.
  • the cells suspension (50ml) was incubated with [ 3 H]-mesulergine (0.5nM) in Tris HC1 buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (10""M). Ten concentrations of test drug (3 x 10"9 to 10 " M final concentration) were added in a volume of 50ml. The total assay volume was 500ml. 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 O eLean 1978) and the pKj (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:
  • Kd Affinity of mesulergine for 5-HT-J C binding sites.
  • the compound of Example 7 has a pKi of 8.28.
  • the compound of Example 11 has a pKi of 7.79.
  • mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long x 1614 cm wide x 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.
  • mice 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-HT2C receptor antagonist properties.
  • the compound of Example 11 had an ID50 of 78 mg/kg p.o.

Abstract

The use of 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, C¿1-6? alkyl, halogen, NR?5R6 or OR7¿ where R?5, R6 and R7¿ are independently hydrogen or C¿1-6? alkyl; R?2 and R3¿ are independently hydrogen or C¿1-6? alkyl; R?4¿ is hydrogen, C¿1-6? alkyl, CF3, nitro, cyano, acyl, halogen, NR?5R6, OR7¿ or CO¿2R?7 where R?5, R6 and R7¿ are independently hydrogen or C¿1-6? alkyl as defined for R?1¿; and n is 1, 2 or 3, in the manufacture of a medicament for the treatment or prophylaxis of CNS disordres.

Description

USE OF PHENYL HETEROARYL UREAS AS 5HT2C RECEPTOR ANTAGONISTS AND UREA COMPOUNDS
This invention relates to a method of treatment of certain CNS disorders.
WO 92/05170 describes ceπain area derivatives which are described as possessing 5HTιc receptor antagonist activity. The 5HTιc receptor has recently been reclassified as the 5HT2C receptor [P. Hartig et al.. Trends in Pharmacological Sciences (TIPS) 1993].
Certain phenyl heteroaryl ureas known in the art have now been found to have 5HT2Q receptor antagonist activity. 5HT2C 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 the use of 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, Cj.g alkyl, halogen, NR5R6 or OR7 where R5, R6 and R7 are independently hydrogen or C\_(- alkyl;
R2 and R**-* are independently hydrogen or Cj.g alkyl;
R4 is hydrogen, C\.(, alkyl, CF3, nitro, cyano, acyl, halogen, NR5R6, OR7 or CO2 7 where R--, R-- and R7 are independently hydrogen or Cμg alkyl as defined for R1; and n is 1, 2 or 3, in the manufacture of a medicament for the treatment or prophylaxis of CNS disorders. Cj.galkyl groups, whether alone or as part of another group, can be straight chain or branched.
Prefeidbly R ^ is hydrogen or methyl.
Preferably R2 and R-- are hydrogen.
Suitable moieties when the ring P is a 5- or 6-membered aromatic heterocyclic ring include pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. Preferably P is pyridyl attached to the urea nitrogen at position 3 or 4; or P is quinoline attached to the urea nitrogen at position 3, 4 or 6, preferably at position 4.
Preferably n is 1 or 2. When n is greater than 1, the R4 groups can be the same or different. Preferably the phenyl ring is mono-substituted and R4 is CF3 or -NMe2
(preferably in the meta position); -OMe, (preferably in the meta or para position); CO2Et (preferably in the meta position) or the phenyl ring is preferably di substituted with meta chloro and para methyl.
Preferred compounds of formula (I) include:
N-(Phenyl)-N'-(2-methyl-4-quinolinyl) urea,
N-(6-Quinolinyl)-N'-(3-trifluoromethylphenyl) urea,
N-(3-Dimethylaminophenyl)-N'-(6-quinolinyl) urea,
N-(Phenyl)-N'-(6-quinolinyl) urea, N-(4-Methoxyphenyl)-N-(2-methyl-4-quinolinyl) urea,
N-(3-Dirnethylaminophenyl)-N-(2-methyl-4-quinolinyl) urea,
N-(3-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(3-Ethoxycarbonylphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(2-Methyl-4-quinolinyl)-N -(3-trifluoromethylphenyl) urea , N-(Phenyl)-N -(3-quinolinyl) urea,
N-(3-Chloro-4-methylphenyl)-N -(3-pyridyl) urea, N-(3-Chloro-4-methylphenyl)-N -(4-pyridyl) urea, N-(3-Pyridyl)-N'-(3-(trifluoromethyl)phenyl)urea, N-(3-Methylphenyl)-N'-(3-pyridyl)urea, N-(4-Chlorophenyl)-N'-(3-pyridyl)urea, N-(3-Chlorophenyl)-N'-(3-pyridyl)urea, N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinolinyl)urea, N-(3-Bromophenyl)-N'-(3-pyridyl)urea, N-(3,4-Dichlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Fluoro-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(4-Ethoxycarbonylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pyridyl)urea, N-(3-Bromo-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-cyanophenyl)-N'-(3-pyridyl)urea,
N-(4-Nitro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(4-Chloro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-carboxyphenyl)-N'-(3-pyridyl)urea, N-(2-Methoxy-4-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-propylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-teπ-butylphenyl)-N'-(3-pyridyl)urea,
N-(3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyτidyl)urea or a pharmaceutically acceptable salt 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. Compounds of formula (I) may also form N-oxides or solvates such as hydrates, and the invention also extends to these forms.
Certain 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 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.
Certain compounds of formula (I) are novel and form a further aspect of the invention. Particularly preferred novel compounds include those listed above and exemplified herein.
The invention further provides a method of treatment or prophylaxis of CNS disorders, in particular anxiety, depression, migraine, anorexia, obsessive compulsive disorders,
Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia and/or disorders associated with spinal trauma and/or head injuries (in particular anxiety and depression) 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.
The invention also provides novel compounds 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, schizophrenia and/or disorders associated with spinal trauma and/or head injuries.
The present invention also provides a pharmaceutical composition, which comprises novel compounds 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. T e 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 present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises
the coupling of a compound of formula (II);
1 *
R T- P -i A (||)
with a compound of formula (III);
(HI)
wherein P is as defined in relation to formula (I), A and B contain the appropriate functional group(s) necessary to form the moiety, -NR2 CONR-^ when coupled, the variables R - . R2', R3', and R4 are R 1, 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^ , R2 , R3 and R4 , when other than R-, R2, R3 and R4 respectively to R-, R2, R3 and R4, interconverting R ■ , R2. R3, and R4 and forming a pharmaceutically acceptable salt thereof.
Suitable examples of groups A and B include:
(i) A is -N=C=O and B is -NHR3', (ii) A is -NR2 COL and B is -NHR3',
(iii) A is -NHR2' and B is NR3 COL,
(iv) A is NHR2' and B is -N=C=O or
(v) A is halogen and B is -NR3 CONHR2'
wherein R2 and R3 are as defined above and L is a leaving group. Examples of suitable leaving groups L include halogen such as chloro, bromo, imidazole or phenoxy or phenylthio optionally substituted for example with halogen.
When A is -N=C=O and B is NHR3' or when A is NHR2' 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 -NR2 COL and B is NHR3' or when A is -NHR2' and B is -NR3 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 NR3 CONHR2 , the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.
Suitable examples of groups R^ and R4 , which are convertible to R* and R4 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 R-, R2, R3 and R4 are carried out by conventional procedures. For example, in the case wherein R2 is \. alkyl and R3 is hydrogen it is possible to introduce a C]_6 alkyl group at the R3 position by conventional alkylation using 1 molar equivalent of a Cj.g alkyl haiide and 1 molar equivalent of a suitable base in an inert solvent. Suitable examples of a group R2 and R3 which is convertible to R2 and R3, include alkoxycarbonyl and benzyl or αrα-methoxybenzyl which are converted to R2 and R3 is hydrogen using conventional conditions.
R ! halo and R4 halo may be introduced by selective halogenation of the ring P or the benzene ring respectively using conventional conditions.
It should be appreciated that it may be necessary to protect any R^ to R7 hydrogen variables which are not required to be interconverted. Suitable protecting groups are described in 'Protective groups in organic synthesis' Greene T.W., New York, Wiley (1981). It should be appreciated that it is preferred that groups R to R7 are introduced before coupling compounds of formula (II) and (III).
Compounds of formula (II) in which A is NHR2 are known compounds or can be prepared analogously to known compounds, see, for example, WO 92/05170 (SmithKline Beecham pic). 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 7_Ω 262). iii) A is CONH2, via the nitrene intermediate using conventional conditions.
Examples of phosgene equivalents include triphosgene, carbonyldiimidazole, phenyl chloroformate and phenyl chorothioformate. Compounds of formula (II) in which A is NR2'COL may be prepared by reacting a compound of formula (II) in which A is NHR2' 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 trithylamine. Compounds of formula (II) in which A is halogen and R4' is hydrogen are commercially available.
Compounds of formula (III) are commercially available or may be prepared according to analogous methods to those outlined above for compounds of formula (II).
Pharmaceutically 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.
The following Examples illustrate the preparation of compounds of the invention. Example 1 N-(Phenyl)-N'-(2-methyl-4-quinolinyl) urea
To a solution of 2-methyl-4-amino-quinoline (1.58g; lO.OmM) in ethanol free chloroform (70 ml) ?i ioom temperature was added dropwise phenyl isocyanate (1.4 ml, 12.0 mM) in dry toluene (25 ml) over a period of 5 minutes. The whole was then stirred at room temperature for 18h followed by heating under reflux for 2h. After cooling to room temperature ethanol (20 ml) was added and after an additional lh the solvent was removed under reduced pressure to give an oil. The oil was treated with ether (50 ml) to give an off white solid which was crystallised from ethyl acetate to give the title compound (El) (1.37g, 60%) as a white solid, m.p. 201-3°C.
NMR (D6-DMSO) δ: 2.10 (3H,s), 7.05 (lH,t,J=7Hz), 7.36 (2H,t, J=7Hz), 7.47-7.64 (3H.m), 7.70 (lH,t,J=7Hz), 7.89 (lH,d.J=7Hz), 8.08-8.20 (2H,m), 9.15 (1H, broad s), 9.39 (1H, broad s).
Found: C, 73.74; H, 5.44; N, 15.29%
C17H15N O requires: C, 73.63; H, 5.45; N, 15.15%
Example 2 N-fό-QuinolinyD-N'-P-trifluoromethylphenyl) urea hydrochloride
The title compound was prepared in 87% yield from 3-trifluoromethyl phenyl isocyanate and 6-aminoquinoline following a procedure similar to that in Example 1. Free base precipitated from the reaction mixture within a total of 3h at room temperature and was converted to the hydrochloride salt using hydrogen chloride in ether/ethanol. m.p. 208-13°C
NMR (D6-DMSO) δ: 7.33-7.50 (lH,m), 7.54-7.85 (2H,m), 7.95-8.28 (3H,m), 8.49 (lH,d,J=8Hz), 8.60-8.75 (lH,m), 9.05-9.30 (2H,m), 10.19 (lH,s). 10.40 (lH,s). Found: M+ 331.0917 C^H^^O requires 331.0964
Example 3
N-(3-Dimethylaminophenyl)-N'-(6-quinolinyl) urea dihydrochloride
To a solution of carbonyl dumidazole (0.40g, 2.47 mM) in dichloromethane (5 ml) was added 3-dimethylamino aniline (0.37g, 2.26 mM) in dichloromethane (5 ml). After stirring at room temperature for 0.5h, the solution was evaporated to dryness. The residue was taken up in dimethylformamide (5ml) and to this solution was added 6-amino quinoline (0.36g, 2.50 mM) in dimethylformamide (5 ml). The reaction mixture was heated to 90°C for lh, then cooled and added dropwise to water with vigorous stirring. Later the solution was collected to give the crude product (0.65g) which was converted to the hydrochloride salt (E3) using hydrogen chloride in ether/ethanol (0 29g, 36%). m.p. 185-90°C.
NMR (D6-DMSO) δ: 3.09 (6H,s), 7.02-7.20 (lH,m), 7.21-7.49 (2H,m), 7.71 (1H, broad s), 7.90-8.15 (2H,m), 8.33 (lH,d.J=9Hz), 8.51-8.61 (lH,m), 9.02-9.18 (2H,m), 9.90 (1H, broad s), 10.39 (1H, broad s). Found: 306.1465 C18H18N4O requires: 306.1516
Example 4 N-(phenyl)-N'-(6-quinolinyl) urea
The title compound (E4) was prepared in 56% yield from 6-aminoquinoline and phenylisocyanate following a procedure similar to that in Example 1. Free base precipitated from the reaction mixture and was recrystallised from ethanol.
NMR (D6-DMSO) δ: 7.0 (lH,t,6Hz), 7.30 (2H,t,6Hz), 7.42-7.53 (3H,m), 7.71 (1H, dd, 6Hz,3Hz), 7.94 (lH,d,J=6Hz), 8.19 (lH,d,j=3Hz), 8.24-8.28 (lH,m), 8.71-8.77 (lH,m), 8.82 (lH,s), 9.08 (lH,s).
Example 5 N-(4-MethoxyphenyI)-N'-(2-methyl-4-quinolinyl) urea
4-Methoxyphenyl isocyanate (0.82 ml, 6.3 mmol), in dry dichloromethane (30 ml) was added slowly to 4-aminoquinaldine (1 g, 6.3 mmol) in dry toluene (30 ml) under a nitrogen atmosphere. This was refluxed for 2.5h, then left at room temperature for 19h. The precipitate which formed was filtered off, washed with cold 1:1 toluene/dichloromethane and dried In vacuo. The crude product was chromatographed on silica gel using dichloromethane as the eluant to give the title compound (1.31 g, 68%) as a white solid, m.p. 180-185°C.
NMR (D6-DMSO) δ: 2.59 (3H, s), 3.75 (3H, s), 6.93 (2H, m), 7.44 (2H, m), 7.6 (1H, t, J 6), 7.71 (1H, t, J 6), 7.89 (1H, d, J 8),8.13 (2H, m),
9.1 1 (1H, s), 9.17 (1H, s) Found: C, 70.32; H, 5.67; N. 13.44 % C18H17N3θ2 requires C. 70.34; H, 5.58; N. 13.67% Found: M+ 307 Cι H17N3θ2 requires 307
Example 6
N-(3-Dimethylaminophenyl)-N'.(2-methyl-4-quinolinyl) urea
l,l'-Carbonyldiimidazole (0.26g, 1.6 mmol), was added portionwise to a solution of 4- aminoquinaldine (0.23g, 1.47 mmol) in dry dichloromethane (15 ml), under a nitrogen atmosphere. After l/2h, at room temperature, the solvent was evaporated off and the residue was taken up in DMF (5 ml). After addition of 3-(dimethylamino)aniline (0.2g, 1.47 mmol) in DMF (10ml), the reaction mixture was heated at 90°C for lh. Addition of water after cooling to room temperature, gave the crude product as a precipitate, which was collected and dried in vacuo. Purification by column chromatography on silica gel, using dichloromethane as eluant gave the title compound (0.16g, 34%) as a light brown solid, m.p. 167-171 °C.
NMR (D6-DMSO) δ: 2.6 (3H, s), 2.91 (6H, s), 6.42 (1H, m), 6.77 (1H, m), 6.98
(1H, s), 7.12 (1H, t, J 6), 7.59 (1H, t, J 3), 7.72 (1H, t, J 6), 7.89 (1H, d, J 6), 8.12 (2H, m), 9.10 (1H, s), 9.19 (1H, s).
Found: M+ 320 C19H20N4O requires 320
Example 7
N-(3-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea
3-Methoxyphenyl isocyanate (0.83 ml, 6.3 mmol) in dry dichloromethane (30 ml) was added slowly to 4-aminoquinaldine (lg, 6.3 mmol) in dry toluene (30 ml) under a nitrogen atmosphere, and left to stir at room temperature for 19h. The precipitate which formed was filtered off, washed with cold 1 : 1 toluene/dichloromethane and dried in vacuo. The crude product was purified by recrvstallization from ethanol to give the title compound (0.99g, 51%) as a white solid, m.p. 191-193°C.
NMR (D6-DMSO) δ: 2.6 (3H, s), 3.77 (3H, s), 6.62 (1H, m), 6.99 (1H, d, J 6),
7.22-7.28 (2H, m), 7.61 (1H, t, J 3), 7.72 (1H, t, J 3), 7.89 (1H, d, J 6), 8.14 (2H, m), 9.18 (1H, s), 9.35 (1H, s).
Found: M+ 307 C18H17N3O2 requires 307 Example 8
N-(3-Ethoxycarbonylphenyl)-N -(2-methy|-4-quinolinvl) urea
3-Ethoxyc r onylphenyl isocyanate (lg, 5.2 mmol) in dry dichloromethane (30 ml), was added slowly to 4-aminoquinaldine (0.83g, 5.2 mmol) in dry toluene (30 ml), under a nitrogen atmosphere, and left to stir at room temperature for 19h. The precipitate which formed was filtered off, washed with cold 1:1 toluene/dichloromethane and dried in vacuo. The crude product was chromatographed on silica gel, using dichloromethane as the eluant to give the title compound (0.78g, 43%) as white crystals, m.p. 165-170°C.
NMR (Dg-DMSO) δ: 1.32 (3H, t, J 3), 2.6 (3H, s), 4.33 (2H, q, J 6), 7.48 (1H, t, J
6), 7.59-7.75 (4H, ), 7.9 (1H, d, J 6), 8.12 (2H, m), 8.22 (1H, s), 9.18 (lH, s), 9.57 (lH, s). Found: M+ 349 C2oH ] 9N3O3 requires 349
Example 9 N-(2-Methyl-4-quinolinyl)-N -(3-tifluoromethylphenyl) urea
α,α,α- Trifluoro-m-tolyl isocyanate (0.96 ml, 6.33 mmol) in dry dichloromethane (30 ml) was added slowly to 4-amino-quinaldine (lg, 6.33 mmol) in dry toluene (30 ml), under a nitrogen atmosphere. Following the procedure described in Example 4, gave the title compound (0.18g, 85%) as a white powder, m.p. 165-170°C.
NMR (D6-DMSO) δ: 2.58 (3H, s), 7.37 (1H, m), 7.55-7.61 (3H, m), 7.7 (1H, t J
6), 7.87 (1H, d, J 8), 8.10 (3H, m), 9.22 (1H, s), 9.60 (1H, s). Found: M+ 345 CjgH-^^O F3 requires 345
Example 10
N-(Phenyl)-N -(3-quinolinyI) urea
Phenyl isocyanate (0.75 ml, 7 mmol) in dry dichloromethane (30 ml) was added slowly to 3 aminoquinoline (lg, 7 mmol) in dry toluene (30 ml) under a nitrogen atmosphere. Following the procedure described in Example 7, gave the title compound (1.18g, 65%) as a white powder, m.p. 289-290°C. NMR (D6-DMSO) δ: 7.0 (1H, t, J 6), 7.30 (2H, t, J 8), 7.49-7.61 (4H, m),
7.88-7.97 (2H, m), 8.54 (1H, d, J 3), 8.82 (1H, d, J 3), 8.92 (1H, s), 9.14 (lH, s). Found: C. 72.78; H, 5.13; N, 15.98%
C16H13N3° requires C. 72.99; H, 4.98: N, 15.96%
Found: M+ 263 CjgH-^^O requires 263
Example 11 N-(3-Chloro-4-methylphenyl)-N -(3-pyridyl) urea hydrochloride
Nicotinoyl azide (0.40g, 2.7 mmol) was stirred at reflux under nitrogen atmosphere in dry toluene (10 ml) for lh, with gas evolution. The solution was cooled to ambient temperature, and 3-chloro-4-methylaniline (0.30 ml, 2.4 mmol) was added. The suspension so formed was stirred for 1 h, when the solid was filtered off, washed with 1 : 1 toluene/dichloromethane, and dried in vacuo at 70°C. This gave the free base of the title compound (0.64g, 85%) as a white solid.
NMR (D6-DMSO) δ: 2.25 (3H, s), 7.23 (2H, m), 7.31 (1H, m), 7.70 (1H, s), 7.93 (1H, m,), 8.18 (1H, d, J 4), 8.59 (1H, d, J 2), 8.90 (2H, 2xs).
N-(3-Chloro-4-methyl)-N -(3-pyridyl) urea (0.55g, 2.1 mmol) was dissolved in hot ethanol (10 ml), and a solution of hydrogen chloride in ether (ca. 0.9M, 2.5 ml, ca. 2.3 mmol) was added. The suspension was cooled to ambient temperature, and the solid was filtered off, washed with cold ethanol, and dried in vacuo at 70°C. This gave the title compound (0.62g, 76%) as a white solid, m.p. 214.5-216°C.
NMR (D6-DMSO) δ: 2.25 (3H, s), 7.25 (2H, m), 7.68 (1H, s), 7.92 (1H, dd, J 8,
5), 8.33 (1H, d, J 8), 8.49 (1H, d), 9.07 (1H, s), 9.79 (1H, s), 10.37 (1H, s).
Found: C, 51.4; H, 4.5: N, 14.5%
C13H12ClN3O. HC1. 0.25H2O requires C, 51.6; H, 4.5: N, 13.9% Found: M+ 261 , 263. C13H12ClN3θ requires 261, 263.
Example 12
N-(3-Chloro-4-methylphenyl)-N -(4-pyridyI) urea hydrochloride
3-Chloro-4-methvlaniline (0.65 ml, 5.3 mmol) was stirred under nitroεen in dichloromethane ( 15 ml) at 0°C as triethylamine (0.82 ml, 5.9 mmol) was added. To this mixture was then added phosgene in toluene solution (1.93M, 4.1 ml, 7.9 mmol). After stirring at 0°C for 0.5h, triethylamine (1.6 ml, 1 1.8 mmol) was added and, after a further 0.5h, 4-aminopyridine (0.50g, 5.3 mmol) w*_s added. The mixture was stirred at ambient temperature for 16h, and then treated with sodium hydroxide solution (5M, ca. 1 ml). After 0.5h, it was diluted with water (50 ml) and dichloromethane (50 ml), and the precipitate was filtered off, washed with water, and dried in vacuo at 70°C. This gave the free base of the title compound (1.03g, 74%) as a white solid.
NMR (D6-DMSO) δ: 2.25 (3H, s), 7.23 (2H, m), 7.41 (2H, d, J 5), 7.67 (IH, s),8.35 (2H, d, J 5) 8.99 (IH, s), 9.18 (IH, s).
N-(3-Chloro-4-methylphenyl)-N -(4-pyridyl) urea (1.03g, 3.9 mmol) was treated with hydrogen chloride using the method of Example 11. This gave the title compound (0.95g, 81 %) as a white solid, m.p. 235-240°C (decomp.).
NMR (D6-DMSO) δ: 2.27 (3H, s), 7.28 (2H, m), 7.67 (IH, s), 7.89 (2H, d, J 6),
8.60 (2H, d, J 6), 10.09 (IH, s), 11.27 (IH, s). Found: C, 50.6; H, 4.4; N, 13.7% C13H12C1N30.HC1 . 0.59 H2O requires C, 50.6; H, 4.6; N, 13.6% Found: M+ 261, 263 C13H12CIN3O requires 261, 263.
Example 13 N-(3-Pyridvl)-N'-(3-(trifluoromethyl)phenyl)urea
The title compound was prepared in 91% yield from 3-pyridyl isocyanate and 3- aminobenzotrifluoride; m.p. 180-184° C.
NMR (DMSO-d6) δ: 7.3 (2H, m), 7.55 (2H, m), 7.95 (IH, d, J 8), 8.0 (IH, s), 8.2 (IH, d, J 4), 8.6 (IH, d, J 2), 9.0 (IH, s), 9.2 (IH, s).
Example 14
N-(3-Methylphenyl)-N'-(3-pyridyl)urea hydrochloride
The title compound was prepared in 87% yield from 3-aminopyridine and m-tolyl isocyanate, followed by salt formation with HC1; m.p. 182-183° C.
NMR (DMSO-d6) δ: 2.3 (3H, s), 6.85 (IH, d, J 7), 7.2 (IH, t, J 8), 7.3 (2H, m), 7.9 (IH, dd, J 8,5), 8.3 (IH, m), 8.5 (IH, d, J 5), 9.1 (IH, d, J 2), 9.5 (IH, s), 10.35 (IH, s). Example 15 N-(4-Chlorophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 29% yield from 3-aminopyridine, 1,1'- carbonyldiimidazole and 4-chloroaniline; m.p. 207-209° C
NMR (DMSO-d6) δ: 7.3 (3H, m), 7.5 (2H, d, J 9), 7.95 (IH, m), 8.2 (IH, m), 8.6 (IH, d, J 2), 8.9 (IH, s), 9.0 (lH, s)
Example 16 N-(3-Chlorophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 86% yield from 3-aminopyridine and 3-chlorophenyl isocyanate: m.p. 185- 187° C
NMR (DMSO-d6) δ: 7.0 (IH, ), 7.3 (3H, m), 7.7 (IH, s), 7.95 (IH, m), 8.2 (IH, m), 8.6 (IH, d, J 2), 8.95 (IH, s), 9.05 (IH, s)
Example 17
N-(3-Hvdroxyphenyl)-N'-(2-methyI-4-quinolinyl)urea
The title compound was prepared in 19% yield from 4-amino-2-methylquinoline, 1,1'- carbonyldiimidazole and 3-aminophenol; m.p. 224-225° C
NMR (DMSO-d6) δ: 2.6 (3H, s), 6.45 (IH, m), 6.9 (IH, d, J 7), 7.1 (2H, m), 7.6 (IH, t, J 7), 7.7 (IH, t, J 7), 7.9 (IH, d, J 7), 8.15 (2H, m), 9.2 (IH, b), 9.3 (IH, s), 9.45 (IH, s)
Example 18 N-(3-Bromophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 75% yield from 3-bromopyridine and 3-pyridyl isocyanate: m.p. 190-193° C.
NMR (DMSO-d ) δ: 7.10-7.40 (4H, m), 7.86 (IH, s), 7.94 (IH, m), 8.22 (IH, d, J=5Hz), 8.62 (IH, d, J=2Hz), 8.93 (IH, s), 9.02 (IH, s).
Example 19 N-(3,4-Dichlorophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 65% yield from 3,4-dichloroaniline and 3-pyridyl isocyanate; m.p. 206° C-210° C.
NMR (DMSO-D6) δ: 7.25-7.42 (2H, m), 7.50 (IH, d, J=7Hz), 7.83-7.90 (2H, m), 8.23 (IH, d. J=3Hz), 8.62 (IH, d, J=lHz), 8.98 (IH, s), 9.23 (IH, s) Example 20 N-(3-Fluoro-4-methylphenyI)-N'-(3-pyridyI)urea
The title compound was prepared in 85% yield from 3-fluoro-4-methylaniline and 3- pyridyl isocyanate; m.p. 190-191 ° C.
NMR (DMSO-D6) δ: 7.02-7.48 (4H, m), 7.94 (IH, m), 8.19 (IH, m), 8.59 (IH, m), 8.87 (IH, s), 8.92 (IH, s)
Example 21 N-(4-Ethoxycarbonylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 83% yield from ethyl 4-aminobenzoate and 3-pyridyl isocyanate: m.p. 156-160° C
NMR (DMSO-D6) δ: 1.32 (3H, t, J=7.5Hz), 4.30 (2H, q, J=7.5Hz), 7.34 (IH, dd, J=7Hz & 4Hz), 7.60 (2H, m), 7.86-8.02 (3H, m), 8.21 (IH, m), 8.63 (IH, m), 8.96 (IH, s), 9.24 (lH, s)
Example 22 N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 30% yield from methyl 4-amino-2-chlorobenzoate and 3-pyridyl isocyanate m.p. 170-171° C
NMR (DMSO-D6) δ: 3.82 (3H, s), 7.30 (2H, m), 7.78-8.00 (3H, m), 8.25 (IH, m), 8.64 (IH, m), 9.08 (IH, s), 9.39 (IH, s)
Example 23
N-(3-Bromo-4-methylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 61% yield from 3-bromo-4-methylaniline and 3- pyridyl isocyanate; m.p. 168-171° C
NMR (DMSO-D6) δ: 2.28 (3H, s), 7.21-7.39 (3H, m), 7.83-8.00 (2H, m), 8.20 (IH, m), 8.61 (lH, m), 8.89 (2H, m)
Example 24 N-(3-Chloro-4-cyanophenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 22% yield from 4-amino-2-chlorobenzonitrile and 3- pyridyl isocyanate; m.p. 262-264° C NMR (DMSO-D6) δ: 7.28-7.56 (2H. m), 7.80-8.06 (3H. m), 8.26 (IH, m), 8.64 (IH, s), 9.17 (IH. s). 9.54 (IH, s)
Example 25 N-(4-Nitro-3-trifluoromethylphenvl)-N'-(3-pyridyI)urea
The title compound was prepared in 31 % yield from 4-nitro-3-trifloromethylaniline and 3- pyridyl isocyanate; m.p. 214-216° C
NMR (DMSO-D6) δ: 7.37 (IH, dd, J=7Hz & 4Hz), 7.87 (IH, m, J=7Hz), 7.97 (IH, m, J=7Hz), 8.14-8.29 (3H, m), 8.67 (IH, m), 9.22 (IH, s), 9.81 (IH, s)
Example 26 N-(4-Chloro-3-trifluoromethy|phenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 48% yield from 4-chloro-3-trifluoromethylaniline and 3-pyridyl isocyanate; m.p. 196-199° C.
NMR (DMSO-D6) δ: 7.33 (IH, dd, J=7Hz & 4Hz), 7.59-7.71 (2H, m), 7.95 (IH, m), 8.10 (IH, m), 8.22 (IH, m), 8.63 (IH, m), 9.04 (IH, s), 9.32 (IH, s)
Example 27 N-(3-Chloro-4-carboxyphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 86% yield from 4-amino-2-chlorobenzoic acid and 3- pyridyl isocyanate; m.p. 170-175° C
NMR (DMSO-D6) δ: 7.41 (2H, m), 7.76-7.88 (2H, m), 7.99 (IH, d, J=7Hz), 8.25 (IH, br s), 8.68 (IH, br s), 9.13 (IH, s), 9.37 (IH, s)
Example 28 N-(2-Methoxy-4-trifluoromethylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 91% yield from 2-methoxy-4-trifluoromethyl-aniline and 3-pyridyl isocyanate; m.p. 210° C
NMR (DMSO-D6) δ: 4.00 (3H, s), 7.16-7.45 (3H, m), 7.98 (IH, m, J=7Hz), 8.23 (IH, m), 8.48-8.74 (3H, m), 9.60 (IH, s)
Example 29
N-(2 -D«chlorophenyl)-N'-(2-methyl-4-quinolinyI)urea
The title compound was prepared in 22% yield from 2,3-dichloroaniline and 2-methyl-4- quinolinyl isocyanate; m.p. 125-127° C NMR (DMSO-D6) δ: 2.62 (3H. s), 7.34-7.46 (2H, m), 7.63 (IH, t, J=7Hz), 7.76 (IH, t, J=7Hz), 7.94 (IH, t, J=7Hz), 8.12-8.31 (3H, m), 9.27 (IH, s), 9.83 (IH, s)
Example 30 N-(3-Chloro-4-pthylphenyl)-N'-(3-pyrldyl)urea
The title compound was prepared in 85% yield from 3-chloro-4-ethylaniline & 3-pyridyl isocyanate; m.p. 193-196° C.
NMR (DMSO-d6) δ: 1.16 (3H, t, J=5Hz), 2.64 (2H, q, J=5Hz), 7.20-7.40 (3H, m), 7.67 (IH, s), 7.94 (IH, m), 8.20 (IH, d, J=2Hz), 8.60 (IH, d, J=0-lHz), 8.90 (2H, d, J=5Hz).
Example 31 N-(3-Chloro-4-propylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 78% yield from 3-Chloro-4-propylaniline & 3-pyτidyl isocyanate; m.p. 184-186° C
NMR (DMSO-D6) δ: 0.91 (3H, t, J=5Hz), 1.56 (2H, q, J=5Hz), 2.60 (2H, t, J=5Hz), 7.20-7.35 (3H, m), 7.68 (IH, s), 7.94 (IH, m), 8.19 (IH, d, J=2Hz), 8.59 (IH, d, J=0- 1Hz), 8.92 (2H, d, J=5Hz).
Example 32 N-(3-Chloro-4-tert-butylphenyl)-N'-(3-pyridyl)urea
The title compound was prepared in 73% yield from 3-chloro-4-tert-butylaniline & 3- pyridyl isocyanate; m.p. 190° C-1930 C.
NMR (DMSO-D6) δ: 1.42 (9H, s), 7.20-7.40 (3H, m), 7.66 (IH, d, J=2Hz), 7.93 (IH, ), 8.19 (IH, d, J=5Hz), 8.60 (IH, d, J=2Hz), 8.90 (2H, d, J=l 1Hz)
Example 33 N-(3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyridyl)urea
N-(3-Hydroxy-4-carboxyphenyl)-N'-(3-pyridyl)urea was prepared in 69% yield from 4- aminosalicylic acid and 3-pyridyl isocyanate in DMF/toluene. This material (0.37g, 1.4 mmol) was then stirred in methanol (20 ml) as thionyl chloride (2 ml) was cautiously added. The suspension was stirred at reflux under argon for 2 days, and evaporated to dryness. The residue was suspended in saturated sodium hydrogen carbonate solution, and the solid was filtered off, washed with water, dried, and recrystallised from ethanol/petroleum ether (b.p. 60-80° C), giving the title compound (0.16g, 41%) as a white solid, m.p. 199-200° C. NMR (DMSO dβ) δ :
3.88 (3H, s). 6.98 (IH, dd. J 8, 2), 7.27 (IH, d, J 2), 7.34 (IH, dd, J 8, 5), 7.73 (IH, d, J 9), 7.96 (I H. m), 8.24 (IH, d, J 4), 8.63 (IH, d, J 2), 9.04 (IH, s), 9.27 (IH, s), 10.69 (IH, s).
Pharmacological data
[•^HJ-mesuIergine binding to rat 5-HT2C clones expressed in 293 cells in vitro
Evidence from the literature suggests that 5-HT? antagonists may have a number of therapeutic indications including the treatment f 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-HT2C binding site can be determined by assessing their ability to displace [3H]-mesulergine from 5-HT2 clones expressed in 293 cells (Julius et al., 1988). The method employed was similar to that of Pazos et al, 1984.
The cells suspension (50ml) was incubated with [3H]-mesulergine (0.5nM) in Tris HC1 buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (10""M). Ten concentrations of test drug (3 x 10"9 to 10" M final concentration) were added in a volume of 50ml. The total assay volume was 500ml. 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 O eLean 1978) and the pKj (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:
Ki = IC50
1+ C
Kd
Kj = inhibition constant. C = concentration of [3H]-mesulergine
Kd = Affinity of mesulergine for 5-HT-J C binding sites.
Curzon. G.A. and Kennett, G.A. (1990). ΗPS, 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, 531-538. Julius et al. (1988) Science 241, 558-564 DeLean A, Munson P.J., Rodbaud D (1978) Am. J. Phvsiol 235, E97-E102. Results
The compound of Example 7 has a pKi of 8.28. The compound of Example 11 has a pKi of 7.79.
Reversal of MCPP-induced Hypolocomotion
Administration of m-(chlorophenyl)piperazine ( CPP) to rats induces hypolocomotion (Kennett and Curzon 1988, Luckie et al. 1989) as seen with the related drug l-(m- trifluoromethylphenyl)piperazine (TFMPP) (Lucki and Frazer 1982. Kennett and Curzon 1988). This effect was blocked by the non specific 5-HT2C/5-HT2A 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-HTJA- 5-HTJ B, -HT3, 0C2 adrenoceptors or dopamine D2 receptors. The effect of mCPP is therefore considered to be mediated by 5-HT2C receptors (Kennett and Curzon 1988) as confirmed by subsequent studies (Lucki er al.. 1989). Since mCPP causes hypolocomotion when infused into the cerebral ventricles this effect is probably centrally mediated (Kennett and Curzon 1988).
mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long x 1614 cm wide x 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-HT2C 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.
Result
The compound of Example 11 had an ID50 of 78 mg/kg p.o.

Claims

1. Use of 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, C\. - alkyl, halogen, NR5R6 or OR7 where R5, R6 and R7 are independently hydrogen or C . alkyl;
R2 and R3 are independently hydrogen or Cj.g alkyl; R4 is hydrogen, C\.^ alkyl, CF3, nitro, cyano, acyl, halogen, NR5R6, OR7 or CO2R7 where R--, R-- and R7 are independently hydrogen or Cj.g alkyl as defined for Rl; and n is 1, 2 or 3, in the manufacture of a medicament for the treatment or prophylaxis of CNS disorders.
2. Use according to claim 1 in which P is pyridyl or quinolyl.
3. Use according to claim 1 or 2 in which R- is hydrogen or methyl.
4. Use according to any one of claims 1 to 3 in which R2 and R3 are hydrogen.
5. Use according to any one of claims 1 to 4 in which P is pyridyl or quinolyl.
6. Use according to claim 1 in which the compound of formula (I) is selected from:
N-(Phenyl)-N'-(2-methyl-4-quinolinyl) urea, N-(6-Quinolinyl)-N'-(3-trifluoromethylphenyl) urea,
N-(3-Dimethylaminophenyl)-N'-(6-quinolinyl) urea,
N-(Phenyl)-N'-(6-quinolinyl) urea,
N- (4-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(3-Dimethylaminophenyl)-N -(2-methyl-4-quinolinyl) urea, N-(3-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea, N-(3-Ethoxycarbonylphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(2-Methyl-4-quinolinyl)-N -(3-trifluoromethylphenyl) urea ,
N-(Phenyl)-N -(3-quinolinyl) urea,
N-(3-Chloro-4-methylphenyl)-N -(3-pyridyl) urea, N-(3-Chloro-4-methylphenyl)-N -(4-pyridyl) urea,
N-(3-Pyridyl)-N'-(3-(trifluoromethyl)phenyl)urea,
N-(3-Methylphenyl)-N'-(3-pyridyl)urea,
N-(4-Chlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Chlorophenyl)-N'-(3-pyridyl)urea, N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinolinyl)urea,
N-(3-Bromophenyl)-N'-(3-pyridyl)urea,
N-(3,4-Dichlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Fluoro-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(4-Ethoxycarbonylphenyl)-N'-(3-pyτidyl)urea, N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pyridyl)urea,
N-(3-Bromo-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-cyanophenyl)-N'-(3-pyridyl)urea,
N-(4-Nitro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(4-Chloro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea, N-(3-Chloro-4-carboxyphenyl)-N'-(3-pyridyl)urea,
N-(2-Methoxy-4-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-propylphenyl)-N,-(3-pyridyl)urea,
N-(3-Chloro-4-tert-butylphenyl)-N'-(3-pyridyl)urea, N-(3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyridyl)urea or a pharmaceutically acceptable salt thereof.
7. A compound of formula (I) which is:
N-(Phenyl)-N'-(2-methyl-4-quinolinyl) urea, N-(6-Quinolinyl)-N'-(3-trifluoromethylphenyl) urea,
N-(3-Dimethylaminophenyl)-N'-(6-quinolinyl) urea,
N-(Phenyl)-N'-(6-quinolinyl) urea,
N-(4-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(3-Dimethylaminophenyl)-N -(2-methyl-4-quinolinyl) urea, N-(3-Methoxyphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(3-Ethoxycarbonylphenyl)-N -(2-methyl-4-quinolinyl) urea,
N-(2-Methyl-4-quinolinyl)-N -(3-trifluoromethylphenyl) urea ,
N-(Phenyl)-N -(3-quinolinyl) urea, N-(3-Chloro-4-methylphenyl)-N -(3-pyridyl) urea.
N-(3-Chloro-4-methylphenyl)-N -(4-pyridyl) urea.
N-(3-Pyridyl)-N'-(3-(trifluoromethyl)phenyl)urea,
N-(3-Methylphenyl)-N'-(3-pyridyl)urea, N-(4-Chlorophenyl)-N'-v3-pyridyl)urea,
N-(3-Chlorophenyl)-N'-(3-pyridyl)urea,
N-(3-Hydroxyphenyl)-N'-(2-methyl-4-quinolinyl)urea,
N-(3-Bromophenyl)-N'-(3-pyridyl)urea,
N-(3,4-Dichlorophenyl)-N'-(3-pyridyl)urea, N-(3-Fluoro-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(4-Ethoxycarbonylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-methoxycarbonylphenyl)-N'-(3-pyridyl)urea,
N-(3-Bromo-4-methylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-cyanophenyl)-N'-(3-pyridyl)urea, N-(4-Nitro-3-trifluoromethylphenyl)-N'-(3-pyτidyl)urea,
N-(4-Chloro-3-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-carboxyphenyl)-N'-(3-pyridyl)urea,
N-(2-Methoxy-4-trifluoromethylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-ethylphenyl)-N'-(3-pyridyl)urea, N-(3-Chloro-4-propylphenyl)-N'-(3-pyridyl)urea,
N-(3-Chloro-4-tert-butylphenyl)-N'-(3-pyridyl)urea,
N-(3-Hydroxy-4-(methoxycarbonyl)phenyl)-N'-(3-pyridyl)urea or a pharmaceutically acceptable salt thereof.
8. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which comprises:
the coupling of a compound of formula (II);
1 *
R A (||)
with a compound of formula (III);
(HI)
wherein P is as defined in relation to formula (I), A and B contain the appropriate functional group(s) necessary to form the moiety, -NR2 CONR3 when coupled, the variables R - R2', R3', and R4' 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- , R2 , R3 and R4 , when other than R-, R-~, R3 end R4 respectively to R - , R2, R3 and R4, interconverting R - , R2, R3, and R4 and forming a pharmaceutically acceptable salt thereof.
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