WO1994014801A1 - Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b? - Google Patents

Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b? Download PDF

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WO1994014801A1
WO1994014801A1 PCT/EP1993/003666 EP9303666W WO9414801A1 WO 1994014801 A1 WO1994014801 A1 WO 1994014801A1 EP 9303666 W EP9303666 W EP 9303666W WO 9414801 A1 WO9414801 A1 WO 9414801A1
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urea
pyridyl
quinoline
methyl
alkyl
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PCT/EP1993/003666
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Ian Thomson Forbes
Roger Thomas Martin
Graham Elgin Jones
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Smithkline Beecham Plc
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Priority claimed from GB929227048A external-priority patent/GB9227048D0/en
Priority claimed from GB939304414A external-priority patent/GB9304414D0/en
Priority claimed from GB939306459A external-priority patent/GB9306459D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1994014801A1 publication Critical patent/WO1994014801A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals.
  • WO 92/05170 describes certain urea derivatives which are described as possessing 5HT ⁇ c receptor antagonist activity. Quinolyl urea derivatives are also disclosed in J. Med. Chem., 1992, 35, 252, J. Het. Chem., 1968, 5, 371 and DE 2847792.
  • the 5HT ⁇ C receptor has recently been reclassif ⁇ ed as the 5HT2C receptor [P. Hartig et al., Trends in Pharmacological Sciences (TIPS) 19931.
  • 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, ethahol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • 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, ethahol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • P is a quinoline, isoquinoline, or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur;
  • J is a ring system selected from quinoline, tetrahydroquinoline, indoline, indazole, benzothiophene, indene, indane, benzothiazole or benzofuran;
  • R 1 is hydrogen, C* _6 alkyl, halogen, NR 5 R 6 or OR 7 5 where R 5 , R 6 and R 7 are independently hydrogen or Cj.g alkyl;
  • R ⁇ and R3 are independently hydrogen or C ⁇ _(, alkyl.
  • R 4 is C j _6 alkyl, OR* or halogen, where R** is hydrogen or C ⁇ . alkyl; and n is 1 or 2; provided that
  • R 4 is not hydrogen or 6-methoxy.
  • Cj. ⁇ alkyl groups can be straight chain or branched.
  • the urea moiety can be attached to a carbon or, when present, a suitable nitrogen atom of the ring P, preferably it is attached to a carbon atom.
  • the urea moiety can be attached to any suitable carbon atom of the aromatic 6-membered ring of the ring J.
  • Suitable moieties when the ring P is a 5-membered aromatic heterocyclic ring include isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl.
  • Suitable moieties when the ring P is a 6-membered aromatic heterocyclic ring include, for example, pyridyl, pyrimidyl or pyrazinyl.
  • P is a quinoline or isoquinoline residue
  • the urea moiety can be attached at any position of the ring, preferably to the 4-position.
  • the ring J can be quinoline, tetrahydroquinoline, indoline, indazole, benzothiophene, indene, indane, benzothiazole or benzofuran.
  • J is 3- or 6-quinoline, 5-indoline, 5-benzothiophene, 5-indene, 5-indane, 5-indazole or 5-benzofuran.
  • J is 5- benzothiophene.
  • the rings P and J can be substituted at any suitable position.
  • P is 3-pyridyl.
  • R*, R ⁇ and R- ⁇ are all hydrogen.
  • R groups can be attached to any suitable carbon atom of the ring J or, when R 4 is
  • Preferred compounds of formula (I) include: N-5-(Benzofb]thienyl)-N'-(3-pyridyl)urea N-(5-Indenyl)-N'-(3-pyridyl) urea
  • 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.
  • the invention extends to these and any other tautomeric forms and mixtures thereof.
  • the present invention 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);
  • a and B contain the appropriate functional group(s) necessary to form the moiety, -Ml 2 CONR when coupled, the variables R * ', R 2 , R 3 ' and J' are R * , R 2 , R 3 , and J 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 J', when other than R , R 2 , R 3 and J respectively to R*, R 2 , R 3 and J, interconverting R*, R 2 , R 3 and J and forming a pharmaceutically acceptable salt thereof.
  • groups A and B include:
  • A is -NR 2 'COL and B is -NHR 3 ',
  • A is halogen and B is -NR 3 'CONHR 2 '
  • 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.
  • 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.
  • an inert solvent such as dichloromethane at ambient temperature
  • a base such as triethylamine or in dimethylformamide at ambient or elevated temperature.
  • 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 ⁇ ' which are convertible to R* and R ⁇ 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
  • R ⁇ is hydroxy it is preferably protected in the compound of formula (II) as, for example, benzyl which is removed by hydrogenation.
  • R 2 is ⁇ . alkyl and R 3 is hydrogen it is possible to introduce a Cj_6 * ****yl group at tne * ⁇ position by conventional alkylation using 1 molar equivalent of a Cj_6 alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
  • Suitable examples of a group R 2 and R which is convertible to R 2 and R 3 include alkoxycarbonyl and benzyl orp ⁇ r ⁇ -methoxybenzyl which are converted to R 2 and R 3 is hydrogen using conventional conditions.
  • R! halo and R ⁇ halo may be introduced by selective halogenation of the ring P or the benzene ring of J ring respectively using conventional conditions.
  • Compounds of formula (II) in which A is NR 2 COL may be prepared by reacting a compound of formula (II) in which A is NHR 2 with phosgene or a phosgene equivalent in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triethylamine.
  • Compounds of formula (III) may be prepared according to known methods or analogous to known methods. For example compounds of formula (HI) where B is NHR 3 where R is hydrogen may be prepared by conventional reduction of the corresponding 5- nitro compounds such as those outlined in description 2 to 6.
  • phosgene equivalents include triphosgene, carbonyldiimidazole, phenyl chloroformate and phenyl chorothioformate.
  • salts can be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • N-oxides and S-oxides can be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.
  • Certain intermediates of formula (III) form a further aspect of the invention.
  • Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT2C receptor antagonist activity and are believed to be of potential use in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia and/or disorders associated with spinal trauma and/or head injuries.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia and/or disorders associated with spinal trauma and/or head injuries.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides the use of a compound of formula (IA) or a salt thereof:
  • P is a quinoline, isoquinoline, or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur;
  • J is a ring system selected from quinoline, tetrahydroquinoline, indoline, indazole, benzothiophene, indene, indane, benzothiazole or benzofuran;
  • R 1 is hydrogen, C g alkyl, halogen, NR 5 R 6 or OR 7 , where R 5 , R 6 and R 7 are independently hydrogen or Cj. alkyl; and R 2 and R 3 are independently hydrogen or Cj.g alkyl.
  • R4 is C ⁇ .
  • alkyl OR* or halogen, where R° is hydrogen or Cj.g alkyl; and n is 1 or 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia and/or also disorders associated with spinal trauma and/or head injuries, in particular the treatment or prophylaxis of anxiety and depression.
  • the invention further provides a method of treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia and/or disorders associated with spinal trauma and/or head injuries, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I A) or a pharmaceutically acceptable salt thereof.
  • 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 infusible 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.
  • the 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.
  • Ethyl 5-mtrobenzo[b]thiophenecarboxylate was prepared and hydrolysed to the corresponding acid as described by S. Rossi and R. Trave (FI Farmaco - Ed. Sci., 1960, 15, 396).
  • 5-Nitrobenzo[b]thiophenecarboxylic acid (4.32 g, 19.4 mmol) was heated with copper powder (1.2 g, activated by heating for several hours at 160°C in vacu ⁇ ) in quinoline (25 ml) at 180-190°C for 2h. After cooling, the mixture was diluted with ether and washed thoroughly with 5N hydrochloric acid. The organic phase was dried and evaporated, and the crude product was recrystallised from ether to give the title compound (3.24 g, 77%), m.p. 142-145°C.
  • 5-Nitroindene was prepared by the method of P. Wan et al. (J. O ⁇ g. Chem., 1989, 54, 1354), but with chlorobenzene replacing toluene for the final dehydration step.
  • a mixture of 5-nitroindene (0.76 g, 4.7 mmol), anhydrous tin (II) chloride (5.4 g) and ethanol (100 ml) was heated under reflux for 3.5 h, then poured onto ice and extracted with dichloromethane/THF. The aqueous phase was basified with dilute ammonia and extracted again with dichlorornethane/THF. The organic extract was filtered through kieselguhr, dried and evaporated, and the residue was dissolved in dichloromethane, filtered again and evaporated to give the title compound (0.44 g, 71%) as a gummy solid.
  • l,l-Dimethyl-5-nitroindene was prepared by the method of Wan et al., as modified in Description 3, using 3,3-dimethyl-6-nitro-l-indanone (J. G. Smith and M. P. and M. P. Massicotte, Org. Prep. Proc. Int., 1978, 10, 123) as starting material.
  • a mixture of 1,1- dimethyl-5-nitroindene (0.47 g, 2.5 mmol) tin (II) chloride (2.87 g) and ethanol (50 ml) was heated under reflux overnight. The mixture was poured onto ice and extracted with dichloromethane. The aqueous phase was then basified with dilute ammonia and extracted with dichloromethane THF. The organic extract was washed with water, dried and evaporated to give the title compound (0.24 g, 61%) as an oil.
  • 5-Nitrobenzothiazole was prepared by the method of I.RN and B. Prijs (Helv. Chim. Acta., 1950, 33, 1429). To a suspension of 5-nitrobenzothiazole (0.13 g, 0.72 mmol) and Raney nickel (0.025 g) in ethanol (5 ml) was added hydrazine hydrate (0.25 ml) in small portions. The mixture was then heated under reflux for 75 mins, cooled, filtered through Kieselguhr and evaporated. The residue was chromatographed on silica gel (7 g) eluted with 2% methanol/dichloromethane, to give the title compound (27 mg, 25%).
  • 5-Nitobenzofuran was prepared from 5-nitro-2-benzofurancarboxylic acid by the method of H. Erlenmeyer et al. (Helv. Chim. Acta, 1948, 21, 75).
  • the nitrobenzofuran (0.24 g, 1.47 mmol) was reduced with Raney nickel (0.04 g) and hydrazine hydrate (85% aq. solution, 0.4 ml) in ethanol (10 ml) according to the procedure of Description 2. Further hydrazine hydrate and Raney nickel were added and reflux continued as required to obtain complete reaction.
  • the initial crude product was taken up in dichloromethane, filtered and evaporated to give the title compound (0.16 g, 82%) as a dark, rather unstable oil.
  • Nickel (I) chloride hexahydrate (3.3 g, 14 mmol) was added to a solution of 6- trifluoroacetamidoquinoline (D9) (16.5 g, 69 mmol) in methanol (250 ml) at ambient temperature with stirring.
  • Sodium borohydride (13.4 g, 350 mmol) was then added portionwise over 20 mins resulting in a large evolution of gas.
  • the mixture was stirred for a further V ⁇ hrs then concentrated in vacuo.
  • the residue was treated with 5N hydrochloric acid (500 ml) and left to stand for 20 mins.
  • the mixture was basified with 40% sodium hydroxide and extracted with dichloromethane chloride (2 x 400 ml).
  • the title compound was prepared from 2-methyl-4-aminoquinoline, 1,1 -carbonyl diimidazole and 5-aminobenzo[b]thiophene (D2) in 46% yield, m.p. 110 - 115°C.
  • the title compound was prepared in 46% yield from 4-amino-2-methylquinoline and 3- pyridyl isocyanate (D9) using a procedure similar to that described in example 8, except that chloroform was substituted for dichloromethane and the whole was heated under reflux for lh instead of being stirred at room temperature.
  • the title compound was prepared in 67% yield from 5-aminoquinoline and 3-pyridyl isocyanate (D9) using a procedure similar to that in Example 8. m.p. 251-2°.
  • the title compound was prepared in 81% yield from 8-aminoquinoline and 3-pyridyl isocyanate (D9) using a procedure similar to that in Example 8. m.p. 200-2°C.
  • the title compound was prepared in 56% yield from 5-aminoindane and nicotinoyl azide using a procedure similar to that for Example 2, m.p. 197-199° C.
  • the title compound was prepared as in the method of Example 2 from 3-nicotinoyl azide and 6-amino- 1 -methyl- 1 ,2,3,4-tetrahydroquinoline (D 13). Recrystallisation of the solid obtained from methanol/ethyl acetate gave the title compound (0.85g, 66%) as a white crystalline solid m.p. 174-6° C.
  • the title compound was prepared in 93% yield from l-methyl-5-aminoindazole and nicotinoyl azide using a procedure similar to that for Example 2, m.p. 200° C.
  • the title compound was prepared by a similar method to that described in Example 16, starting from nicotinoyl azide (0.105g, 0.68 mmol) and 5-amino-2-methyl benzo[b]thiophene (0.1 lg, 0.67mmol). The precipitate was filtered off, washed with petrol and dried in vacua to give the title compound (0.15g, 79%), mp 178-182°C.
  • This compound was prepared by the method of Example 17, starting from nicotinoyl azide (95mg, 0.65mmol) and 5-amino-4-methylbenzo[b]thiophene (0.105g, 0.64 mmol). Yield 0.15g, 83%, mp ⁇ 200°C (phase change), ⁇ 300°C (sublimation).
  • This compound was prepared by a similar method to that described in Example 19, starting from 5-amino-3-methylisothiazole hydrochloride (0.45g, 3mmol), carbonyldiimidazole (0.53g, 3.3mmol) and 5-aminobenzo[b]thiophene (0.45g, 3mmol). Triethylamine (0.42ml, 3mmol) was added to the solution of isothiazole hydrochloride before adding to the carbonyldiimidazole solution. After addition to water, the crude product was washed with water, dried, and recrystallised from dichloromethane/ethanol to give the title compound (0.64g, 83%), mp. 221-224°C.
  • 5-HT2 antagonists may have a number of therapeutic indications including the treatment of anxiety, migraine, depression, feeding disorders and obsessive compulsion disorders. (Curzon and Kennett, 1990; Fozard and Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46 p.542).
  • the affinity of test drugs for the 5-HT2C binding site can be determined by assessing their ability to displace [* *> H]-mesulergine from 5-HT2C 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 [*1H]-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"" 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 (DeLean 1978) and the pKj (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:
  • K- inhibition constant.
  • C concentration of [ J H]-mesulergine
  • Kd Affinity of mesulergine for 5-HT2C binding sites.
  • mCPP m-(chlorophenyl)piperazine
  • TFMPP l-(m-trifluoromethylphenyl)piperazine
  • mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long x W ⁇ 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.
  • Example 1 The compound of Example 1 had an ID50 of 20.3 mg/kg p.o.

Abstract

L'invention concerne un composé de formule (I) ou un de ses sels, dans laquelle P représente une quinoline, isoquilonine ou un cycle hétérocyclique aromatique à 5 ou 6 membres contenant jusqu'à trois hétéroatomes sélectionnés parmi azote, oxygène ou soufre; J représente un système cyclique sélectionné parmi quinoline, tétrahydroquinoline, indoline, indazole, benzothiophène, indène, indane, benzothiazole ou benzofuranne; R1 représente hydrogène, alkyleC¿1-6?, halogène, NR?5R6 ou OR7, où R5, R6 et R7¿ représentent indépendamment hydrogène ou alkyleC¿1-6?; et R?2 et R3¿ représentent indépendamment hydrogène ou alkyleC¿1-6; R?4 représente alkyleC¿1-6, OR?8 ou halogène, où R8 représente hydrogène ou alkyleC¿1-6?; et n vaut 1 ou 2; à condition que si P ne représente pas pyridyle, J ne représente pas indoline; que P et J ne représentent pas tous les deux 6-méthoxy quinoline, 8-hydroxy quinoline ou 2-méthyle quinoline, que si J représente quinoline ou 2 méthyle quinoline, P ne représente pas 2-thiazolyle, que si P et J représentent tous les deux quinoline et R?1, R2 et R3¿ représentent tous hydrogène, R4 ne représente pas hydrogène ou 6-méthoxy. Les composés de formule (I) et leurs sels pharmaceutiquement acceptables présentent une activité antagoniste au récepteur 5HT¿2C? et sont considérés comme potentiellement utiles dans le traitement ou la prophylaxie de l'anxiété, la dépression, la migraine, l'anorexie, les troubles obsessionnels impulsifs, la maladie d'Alzheimer, les troubles du sommeil, la boulimie, les crises de panique, le sevrage des toxicomanes, la schizoprénie et/ou les troubles liés aux traumatismes de la colonne vertébrale et/ou aux traumatismes crâniens.
PCT/EP1993/003666 1992-12-29 1993-12-21 Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b? WO1994014801A1 (fr)

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WO1995024194A1 (fr) * 1994-03-09 1995-09-14 Merrell Pharmaceuticals Inc. Traitement de psychonevroses obsessionnelles au moyen d'antagonistes de 5-ht¿2?
WO1995029177A1 (fr) * 1994-04-23 1995-11-02 Smithkline Beecham P.L.C. Derives tricycliques antagonistes de 5ht2c et de 5ht2b
WO1996002537A1 (fr) * 1994-07-13 1996-02-01 Smithkline Beecham Plc Carboxamides heterocycliques benzo-condenses a cinq elements utilises comme antagonistes de recepteur de 5ht¿2b/2c?
WO1996009287A1 (fr) * 1994-09-20 1996-03-28 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques, leur procede de production et leur utilisation medicinale
WO1996011930A1 (fr) * 1994-10-18 1996-04-25 Smithkline Beecham P.L.C. Derives de pyridinyluree actifs dans le traitement des troubles du systeme nerveux central
WO1996023769A2 (fr) * 1995-02-02 1996-08-08 Smithkline Beecham Plc Composes heterocycliques possedant une activite antagoniste vis-a-vis du recepteur de 5ht¿2c?
WO1996039382A1 (fr) * 1995-06-06 1996-12-12 Fujisawa Pharmaceutical Co., Ltd. Derives de l'uree utilises comme antagonistes de 5-ht
WO1997008167A1 (fr) * 1995-08-26 1997-03-06 Smithkline Beecham P.L.C. Antagonistes des recepteurs 5ht2c et 5ht¿2b?
WO1999014197A1 (fr) * 1997-09-12 1999-03-25 Smithkline Beecham Plc Isoquinoleines substituees en tant qu'anticonvulsifs
US5929250A (en) * 1997-01-23 1999-07-27 Smithkline Beecham Corporation IL-8 receptor antagonists
EP1047418A1 (fr) * 1997-12-22 2000-11-02 Bayer Corporation Inhibition de raf kinase au moyen d'urees heterocycliques substituees
WO2002014273A1 (fr) * 2000-08-12 2002-02-21 Smithkline Beecham P.L.C. Derives d'indoline en tant qu'antagonistes 5ht2c
US6602882B1 (en) 1998-10-14 2003-08-05 Smithkline Beecham P.L.C. Quinoline derivatives and their use as antibacterial agents
WO2003080578A1 (fr) * 2002-03-22 2003-10-02 Merck Sharp & Dohme Limited Derives heteroaromatiques d'uree en tant que modulateurs du recepteur vr-1 pour traiter la douleur
AU2006201959B2 (en) * 1997-12-22 2008-09-04 Bayer Healthcare Llc Inhibition of Raf Kinase using Substituted Heterocyclic Ureas
EP2033953A1 (fr) 2002-02-15 2009-03-11 Glaxo Group Limited Modulateurs des récepteurs vanilloides
EP2036564A1 (fr) 1999-12-06 2009-03-18 H.Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht
US7582769B2 (en) 2005-07-08 2009-09-01 Novo Nordisk A/S Dicycloalkyl urea glucokinase activators
US7598391B2 (en) 2004-01-06 2009-10-06 Novo Nordisk A/S Heteroaryl-ureas and their use as glucokinase activators
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7884210B2 (en) 2005-07-14 2011-02-08 Novo Nordisk A/S Ureido-thiazole glucokinase activators
US7897628B2 (en) 2002-06-27 2011-03-01 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US7999114B2 (en) 2005-07-08 2011-08-16 Novo Nordisk A/S Dicycloalkylcarbamoyl ureas as glucokinase activators
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
US8318778B2 (en) 2007-01-11 2012-11-27 Novo Nordisk A/S Urea glucokinase activators
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
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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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WO1995024194A1 (fr) * 1994-03-09 1995-09-14 Merrell Pharmaceuticals Inc. Traitement de psychonevroses obsessionnelles au moyen d'antagonistes de 5-ht¿2?
US5618824A (en) * 1994-03-09 1997-04-08 Merrell Pharmaceuticals Inc. Treatment of obsessive-compulsive disorders with 5-HT2 antagonists
WO1995029177A1 (fr) * 1994-04-23 1995-11-02 Smithkline Beecham P.L.C. Derives tricycliques antagonistes de 5ht2c et de 5ht2b
WO1996002537A1 (fr) * 1994-07-13 1996-02-01 Smithkline Beecham Plc Carboxamides heterocycliques benzo-condenses a cinq elements utilises comme antagonistes de recepteur de 5ht¿2b/2c?
US5922733A (en) * 1994-07-13 1999-07-13 Smithkline Beecham P.L.C. Pyridil carboxamides as 5HT2B/2C receptor antagonists
WO1996009287A1 (fr) * 1994-09-20 1996-03-28 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques, leur procede de production et leur utilisation medicinale
US6127403A (en) * 1994-09-20 2000-10-03 Sankyo Company, Ltd. Method for inhibiting acyl-CoA : cholesterol acyltransferase
US6414012B1 (en) 1994-09-20 2002-07-02 Sankyo Company, Limited Heterocyclic derivatives, method of production thereof and pharmaceutical use thereof
US5990150A (en) * 1994-09-20 1999-11-23 Sankyo Company, Ltd. Heterocyclic derivatives, method of production thereof and pharmaceutical use thereof
US6489475B2 (en) 1994-09-20 2002-12-03 Sankyo Company, Limited Method of producing heterocyclic derivatives
WO1996011930A1 (fr) * 1994-10-18 1996-04-25 Smithkline Beecham P.L.C. Derives de pyridinyluree actifs dans le traitement des troubles du systeme nerveux central
US5866586A (en) * 1994-10-18 1999-02-02 Smithkline Beecham P.L.C. CNS-active pyridinylurea derivatives
US5972937A (en) * 1995-02-02 1999-10-26 Smithkline Beecham P.L.C. Heterocyclic compounds possessing 5HT2C receptor antagonist activity
WO1996023769A3 (fr) * 1995-02-02 1996-10-24 Smithkline Beecham Plc Composes heterocycliques possedant une activite antagoniste vis-a-vis du recepteur de 5ht¿2c?
WO1996023769A2 (fr) * 1995-02-02 1996-08-08 Smithkline Beecham Plc Composes heterocycliques possedant une activite antagoniste vis-a-vis du recepteur de 5ht¿2c?
WO1996039382A1 (fr) * 1995-06-06 1996-12-12 Fujisawa Pharmaceutical Co., Ltd. Derives de l'uree utilises comme antagonistes de 5-ht
WO1997008167A1 (fr) * 1995-08-26 1997-03-06 Smithkline Beecham P.L.C. Antagonistes des recepteurs 5ht2c et 5ht¿2b?
US6015908A (en) * 1997-01-23 2000-01-18 Smithkline Beecham Corporation IL-8 receptor antagonists
US6043374A (en) * 1997-01-23 2000-03-28 Smithkline Beecham Corporation Benzisothiazolidine Compounds
US5929250A (en) * 1997-01-23 1999-07-27 Smithkline Beecham Corporation IL-8 receptor antagonists
WO1999014197A1 (fr) * 1997-09-12 1999-03-25 Smithkline Beecham Plc Isoquinoleines substituees en tant qu'anticonvulsifs
EP1047418A1 (fr) * 1997-12-22 2000-11-02 Bayer Corporation Inhibition de raf kinase au moyen d'urees heterocycliques substituees
EP1047418A4 (fr) * 1997-12-22 2001-02-07 Bayer Ag Inhibition de raf kinase au moyen d'urees heterocycliques substituees
AU2006201959B2 (en) * 1997-12-22 2008-09-04 Bayer Healthcare Llc Inhibition of Raf Kinase using Substituted Heterocyclic Ureas
US6602882B1 (en) 1998-10-14 2003-08-05 Smithkline Beecham P.L.C. Quinoline derivatives and their use as antibacterial agents
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
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US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
EP2036564A1 (fr) 1999-12-06 2009-03-18 H.Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht
WO2002014273A1 (fr) * 2000-08-12 2002-02-21 Smithkline Beecham P.L.C. Derives d'indoline en tant qu'antagonistes 5ht2c
US9181188B2 (en) 2002-02-11 2015-11-10 Bayer Healthcare Llc Aryl ureas as kinase inhibitors
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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
EP2033953A1 (fr) 2002-02-15 2009-03-11 Glaxo Group Limited Modulateurs des récepteurs vanilloides
WO2003080578A1 (fr) * 2002-03-22 2003-10-02 Merck Sharp & Dohme Limited Derives heteroaromatiques d'uree en tant que modulateurs du recepteur vr-1 pour traiter la douleur
US7285563B2 (en) 2002-03-22 2007-10-23 Rebecca Elizabeth Brown Heteroaromatic urea derivatives as VR-1 receptor modulators for treating pain
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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

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