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WO1994018170A1 - Utilisation d'urees d'heteroaryle de phenyle comme antagonistes de recepteur de 5ht2c et composes d'uree - Google Patents

Utilisation d'urees d'heteroaryle de phenyle comme antagonistes de recepteur de 5ht2c et composes d'uree Download PDF

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Publication number
WO1994018170A1
WO1994018170A1 PCT/EP1994/000189 EP9400189W WO9418170A1 WO 1994018170 A1 WO1994018170 A1 WO 1994018170A1 EP 9400189 W EP9400189 W EP 9400189W WO 9418170 A1 WO9418170 A1 WO 9418170A1
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Prior art keywords
urea
pyridyl
quinolinyl
chloro
methyl
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PCT/EP1994/000189
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English (en)
Inventor
Ian Thomson Forbes
Peter Ham
Roger Thomas Martin
Mervyn Thompson
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Smithkline Beecham Plc
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Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP6517583A priority Critical patent/JPH08506114A/ja
Priority to EP94905697A priority patent/EP0682656A1/fr
Publication of WO1994018170A1 publication Critical patent/WO1994018170A1/fr

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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.

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Abstract

Utilisation d'un composé de la formule (1) ou d'un sel de ce composé, formule dans laquelle P représente un reste de quinoline ou d'isoquinoline ou un noyau hétérocyclique aromatique à 5 ou 6 éléments contenant jusqu'à trois hétéroatomes choisis entre azote, oxygène et soufre; R1 représente hydrogène, alkyle C¿1-6?, halogène, NR?5R6 ou OR7, R5, R6 et R7¿ représentant indépendamment hydrogène ou alkyle C¿1-6; R?4 représente hydrogène, alkyle C¿1-6?, CF3, nitro, cyano, acyle, halogène, NR?5R6, OR7¿ ou CO¿2?R?7, R5, R6 et R7¿ représentant indépendamment hydrogène ou alkyle C¿1-6? tels que définis pour R?1¿; et n vaut 1, 2 ou 3. Ce composé ou son sel peuvent être utilisés pour la préparation d'un médicament destiné au traitement ou à la prophylaxie de troubles du système nerveux central.
PCT/EP1994/000189 1993-02-05 1994-01-25 Utilisation d'urees d'heteroaryle de phenyle comme antagonistes de recepteur de 5ht2c et composes d'uree WO1994018170A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6517583A JPH08506114A (ja) 1993-02-05 1994-01-25 ５ＨＴ▲下２▼ｃレセプター拮抗薬としてのフェニルヘテロアリール尿素の使用および尿素化合物
EP94905697A EP0682656A1 (fr) 1993-02-05 1994-01-25 Utilisation d'urees d'heteroaryle de phenyle comme antagonistes de recepteur de 5ht 2c? et composes d'uree

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Application Number Priority Date Filing Date Title
GB939302275A GB9302275D0 (en) 1993-02-05 1993-02-05 Novel compounds
GB9302275.4 1993-02-05

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WO1994018170A1 true WO1994018170A1 (fr) 1994-08-18

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Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1028953A1 (fr) * 1997-11-03 2000-08-23 Boehringer Ingelheim Pharmaceuticals Inc. Composes heterocycliques aromatiques convenant comme anti-inflammatoires
WO2000047580A3 (fr) * 1999-02-12 2000-12-21 Smithkline Beecham Plc Derives de phenyluree et de phenylthiouree
US6242453B1 (en) 1999-02-22 2001-06-05 Boehringer Ingelheim Pharmaceuticals, Inc Polycyclo heterocyclic derivatives as antiinflammatory agents
US6297381B1 (en) 1999-03-12 2001-10-02 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
US6319921B1 (en) 1999-01-19 2001-11-20 Boerhinger Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compound as antiinflammatory agents
US6337338B1 (en) 1998-12-15 2002-01-08 Telik, Inc. Heteroaryl-aryl ureas as IGF-1 receptor antagonists
US6358945B1 (en) 1999-03-12 2002-03-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6492393B1 (en) 1999-11-16 2002-12-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
WO2002085857A3 (fr) * 2001-04-20 2003-01-16 Bayer Ag Inhibition de la kinase raf a l'aide d'urees de quinolyl, d'isoquinolyl ou de pyridyl
US6525046B1 (en) 2000-01-18 2003-02-25 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
US6608052B2 (en) 2000-02-16 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6699879B1 (en) * 1999-02-12 2004-03-02 Smithkline Beecham P.L.C. Phenyl urea and phenyl thiourea derivatives as orexin receptor antagonists
US6743788B2 (en) 2001-05-25 2004-06-01 Boehringer Ingelheim Pharmaceuticals, Inc. Carbamate and oxamide compounds
US6753426B2 (en) 1999-07-09 2004-06-22 Boehringer Ingelheim Pharmaceuticals, Inc. Polymorph and process for preparing same
EP1473292A1 (fr) * 1997-11-03 2004-11-03 Boehringer Ingelheim Pharmaceuticals, Inc. Composes heterocycliques aromatiques convenant en tant qu'agents anti-inflammatoires
US6852717B2 (en) 2001-05-16 2005-02-08 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US7041669B2 (en) 2002-02-25 2006-05-09 Boehringer Ingelheim Pharmaceuticals, Inc. 1,4-benzofused urea compounds useful in treating cytokine mediated diseases
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US7351834B1 (en) 1999-01-13 2008-04-01 Bayer Pharmaceuticals Corporation ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7371763B2 (en) 2001-04-20 2008-05-13 Bayer Pharmaceuticals Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
CZ299836B6 (cs) * 1997-12-22 2008-12-10 Bayer Corporation Aryl- a heteroaryl-substituované heterocyklické mocoviny, jejich použití a farmaceutické kompozice s jejich obsahem
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
US7528255B2 (en) 1999-01-13 2009-05-05 Bayer Pharmaceuticals Corporation Hydroxy, ω-carboxyaryl substituted diphenyl ureas and dirivatives thereof as raf kinase inhibitors
WO2009035951A3 (fr) * 2007-09-11 2009-10-29 Arete Therapeutics, Inc. Inhibiteurs d'époxyde hydrolase soluble
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8063081B2 (en) 2002-06-27 2011-11-22 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8138185B2 (en) 2007-01-09 2012-03-20 Novo Nordisk A/S Urea glucokinase activators
US8207166B2 (en) 2004-04-30 2012-06-26 Bayer Healthcare Llc Substituted pyrazolyl urea derivatives useful in the treatment of cancer
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US9181188B2 (en) 2002-02-11 2015-11-10 Bayer Healthcare Llc Aryl ureas as kinase inhibitors
CN109645019A (zh) * 2017-10-11 2019-04-19 中国疾病预防控制中心寄生虫病预防控制所 具有杀螺活性的吡啶脲类化合物的用途
CN114600893A (zh) * 2022-04-15 2022-06-10 江西省农业科学院植物保护研究所 一种吡螺脲漂浮粒剂及其制备方法和应用
US11833136B2 (en) 2018-06-12 2023-12-05 Vtv Therapeutics Llc Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs

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US6432995B2 (en) 1997-11-03 2002-08-13 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds and their use as anti-inflammatory agents
EP1028953A1 (fr) * 1997-11-03 2000-08-23 Boehringer Ingelheim Pharmaceuticals Inc. Composes heterocycliques aromatiques convenant comme anti-inflammatoires
EP1473292A1 (fr) * 1997-11-03 2004-11-03 Boehringer Ingelheim Pharmaceuticals, Inc. Composes heterocycliques aromatiques convenant en tant qu'agents anti-inflammatoires
CZ299836B6 (cs) * 1997-12-22 2008-12-10 Bayer Corporation Aryl- a heteroaryl-substituované heterocyklické mocoviny, jejich použití a farmaceutické kompozice s jejich obsahem
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
US6337338B1 (en) 1998-12-15 2002-01-08 Telik, Inc. Heteroaryl-aryl ureas as IGF-1 receptor antagonists
US7528255B2 (en) 1999-01-13 2009-05-05 Bayer Pharmaceuticals Corporation Hydroxy, ω-carboxyaryl substituted diphenyl ureas and dirivatives thereof as raf kinase inhibitors
US7351834B1 (en) 1999-01-13 2008-04-01 Bayer Pharmaceuticals Corporation ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US6319921B1 (en) 1999-01-19 2001-11-20 Boerhinger Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compound as antiinflammatory agents
US6506748B2 (en) 1999-01-19 2003-01-14 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
US6333325B1 (en) 1999-01-19 2001-12-25 Boehringer Ingelheim Pharmaceuticals, Inc. Method of treating cytokine mediated diseases or conditions
US6372773B1 (en) 1999-01-19 2002-04-16 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
US6329415B1 (en) 1999-01-19 2001-12-11 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
US6596730B1 (en) 1999-02-12 2003-07-22 Smithkline Beecham P.L.C. Phenyl urea and phenyl thiourea derivatives
WO2000047580A3 (fr) * 1999-02-12 2000-12-21 Smithkline Beecham Plc Derives de phenyluree et de phenylthiouree
US6699879B1 (en) * 1999-02-12 2004-03-02 Smithkline Beecham P.L.C. Phenyl urea and phenyl thiourea derivatives as orexin receptor antagonists
US6242453B1 (en) 1999-02-22 2001-06-05 Boehringer Ingelheim Pharmaceuticals, Inc Polycyclo heterocyclic derivatives as antiinflammatory agents
US7026476B2 (en) 1999-03-12 2006-04-11 Boehringer Ingelheim Pharmaceuticals, Inc. Intermediate arylamine compounds
US6476023B1 (en) 1999-03-12 2002-11-05 Boehringen Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
US6297381B1 (en) 1999-03-12 2001-10-02 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
US6358945B1 (en) 1999-03-12 2002-03-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US7019006B2 (en) 1999-03-12 2006-03-28 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6660732B2 (en) 1999-03-12 2003-12-09 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6656933B2 (en) 1999-03-12 2003-12-02 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6753426B2 (en) 1999-07-09 2004-06-22 Boehringer Ingelheim Pharmaceuticals, Inc. Polymorph and process for preparing same
US7241758B2 (en) 1999-11-16 2007-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6492393B1 (en) 1999-11-16 2002-12-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6525046B1 (en) 2000-01-18 2003-02-25 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
US6608052B2 (en) 2000-02-16 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7371763B2 (en) 2001-04-20 2008-05-13 Bayer Pharmaceuticals Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
WO2002085857A3 (fr) * 2001-04-20 2003-01-16 Bayer Ag Inhibition de la kinase raf a l'aide d'urees de quinolyl, d'isoquinolyl ou de pyridyl
US6852717B2 (en) 2001-05-16 2005-02-08 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6743788B2 (en) 2001-05-25 2004-06-01 Boehringer Ingelheim Pharmaceuticals, Inc. Carbamate and oxamide compounds
US9181188B2 (en) 2002-02-11 2015-11-10 Bayer Healthcare Llc Aryl ureas as kinase inhibitors
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US7041669B2 (en) 2002-02-25 2006-05-09 Boehringer Ingelheim Pharmaceuticals, Inc. 1,4-benzofused urea compounds useful in treating cytokine mediated diseases
US8063081B2 (en) 2002-06-27 2011-11-22 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8207166B2 (en) 2004-04-30 2012-06-26 Bayer Healthcare Llc Substituted pyrazolyl urea derivatives useful in the treatment of cancer
US8138185B2 (en) 2007-01-09 2012-03-20 Novo Nordisk A/S Urea glucokinase activators
WO2009035951A3 (fr) * 2007-09-11 2009-10-29 Arete Therapeutics, Inc. Inhibiteurs d'époxyde hydrolase soluble
CN109645019A (zh) * 2017-10-11 2019-04-19 中国疾病预防控制中心寄生虫病预防控制所 具有杀螺活性的吡啶脲类化合物的用途
CN109645019B (zh) * 2017-10-11 2021-12-24 中国疾病预防控制中心寄生虫病预防控制所 具有杀螺活性的吡啶脲类化合物的用途
US11833136B2 (en) 2018-06-12 2023-12-05 Vtv Therapeutics Llc Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs
US11974989B2 (en) 2018-06-12 2024-05-07 Vtv Therapeutics Llc Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs
CN114600893A (zh) * 2022-04-15 2022-06-10 江西省农业科学院植物保护研究所 一种吡螺脲漂浮粒剂及其制备方法和应用

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