[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO1998024785A1 - Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht - Google Patents

Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht Download PDF

Info

Publication number
WO1998024785A1
WO1998024785A1 PCT/JP1997/004390 JP9704390W WO9824785A1 WO 1998024785 A1 WO1998024785 A1 WO 1998024785A1 JP 9704390 W JP9704390 W JP 9704390W WO 9824785 A1 WO9824785 A1 WO 9824785A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salt
formula
defined above
reacting
Prior art date
Application number
PCT/JP1997/004390
Other languages
English (en)
Inventor
Kiyotaka Ito
Glen W. Spears
Toshio Yamanaka
Keiko Harada
Yuka Noda
Hiroshi Sasaki
Fumie Takahashi
Masayuki Kato
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from AUPO3954A external-priority patent/AUPO395496A0/en
Priority claimed from AUPO5930A external-priority patent/AUPO593097A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP52544498A priority Critical patent/JP2001508767A/ja
Priority to AU50682/98A priority patent/AU5068298A/en
Publication of WO1998024785A1 publication Critical patent/WO1998024785A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel urea derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to novel urea derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as 5 - hydroxytryptamine (5 - HT) antagonism and the like.
  • Said urea derivatives or a pharmaceutically acceptable salt thereof are useful as a 5 — HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimer's 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 injufy such as hydrocephalus, and the like in human being or animals.
  • CNS central nervous system
  • urea derivatives of the present invention are novel and can be represented by the following general formula (I) :
  • R 1 and R 2 are each hydrogen or linked together to form ethylene
  • R 3 is hydrogen or lower alkyl
  • R" is heterocyclic group
  • R 5 is hydrogen or nitro
  • X is CH or N.
  • the object compounds (I) can pared by the following processes :
  • R ⁇ R 2 ,R 3 ,R,R 5 and X are each as defined above.and Z is acyl.
  • object compounds (I) prepared by the above Processes 1 to 9 can be achieved conversion of their side chain within the scope of the compounds of the present invention as shown in the Examples below.
  • Suitable salt of the compounds (I) ⁇ Ia) ⁇ Ib) ⁇ Ic) ⁇ IdUIe) ⁇ If),( ⁇ ),(III), (IV) ) (V),(VI) ! (VII),(VIII),(IX),(X),(XI),(XII),(XIII),(XIV) and (XV) are conventional non — toxic pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.) , and alkaline earth metal salt (e.g.
  • an alkali metal salt e.g. sodium salt, potassium salt, cesium salt, etc.
  • alkaline earth metal salt e.g.
  • an ammonium salt a salt with an organic base, for example, an organic amine salt (e. g . triethylamine salt , pyridine salt , picoline salt , ethanolamine salt , triethanolamine salt, dicyclohexylamine salt, N,N' — dibenzylethylenediamine salt, etc.) ; inorganic acid addition salt (e . g . hydrochloride , hydrobromide , hydriodide, sulfate, phosphate, etc.) ; organic carboxylic or sulfonic acid addition salt (e.g.
  • lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • Suitable " lower alkyl” may include a straight or branched one having 1 to 6 carbon atom (s) such as methyl, ethyl, n — propyl.isopropyl, butyl, isobutyl, t — butyl, pentyl, hexyl, preferably one having 1 to 4 carbon atoms, and the like, in which the most preferred one is methyl, isopropyl or t — butyl.
  • s 1 to 6 carbon atom
  • heterocyclic group means, in detail, saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero — atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group may be heterocyclic group such as unsatureted 3 to 8 — membered (more preferably 5 or 6 — membered) heteromonocyclic group containing 1 to 4 nitrogen atom (s) , for example, pyrrolyl , pyrrolinyl , imidazolyl , pyrazolyl , pyridyl and its N — oxide , dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.4H — 1,2,4 — triazolyl, 1H - 1,2,4 - triazolyl, 1H - 1,2,3 - triazolyl, 2H - 1,2,3 - triazolyl, etc.] , tetrazolyl [ e .
  • unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom (s) for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl ( e . g . 1H - benzimidazolyl , etc .
  • quinolyl isoquinolyl , dihydroquinolyl , dihydroisoquinolyl, tetrahydroisoquinolyl (e.g.1,2, 3,4 - tetrahydroisoquinolyl, etc.) , indazolyl, benzotriazolyl, quinazolinyl, quinoxalinyl, phthalazinyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom ( s ) and 1 to 3 nitrogen atom ( s ) for example , benzothiazolyl , benzothiadiazolyl, etc.
  • unsaturated 3 to 8 — membered (more preferably 5 or 6 — membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom (s) for example, dihydrooxathiinyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom (s) for example, benzothienyl [e.g. benzo [b] thienyl, etc.] ,benzodithiinyl, etc. ; unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom (s) , for example, benzoxathiinyl, etc. and the like.
  • the heterocyclic group may have one or more suitable substituent (s) such as hydroxy, lower alkoxy, lower alkyl, mono — or di — or trihalo — (lower) alkyl (e.g. trifluoromethyl, etc.) , amino, protected amino,mono - or di — substituted lower alkyl amino, cyclic amino, nitro, halogen [e.g.fluoro, chloro, bromo, iodo, etc.] , acyl, aryl, ar (lower) alkyl, and the like.
  • suitable substituent such as hydroxy, lower alkoxy, lower alkyl, mono — or di — or trihalo — (lower) alkyl (e.g. trifluoromethyl, etc.)
  • Suitable " lower alkoxy” may include methoxy, ethoxy , propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, and the like.
  • Suitable "mono — or di — substituted lower alkylamino” may include amino group substituted by one or two lower alkyl (s) [e.g. methyl, ethyl, isopropyl, t - butyl, t - pentyl, etc.] , preferably methylamino, ethylamino, dimethylamino , diethylamino , di — n — propylamino , diisopropylamino , dibutylamino, etc.
  • s e.g. methyl, ethyl, isopropyl, t - butyl, t - pentyl, etc.
  • Amino protective group in the term “protected amino” may include acyl such as lower alkanoyl [e.g. formyl, acetyl, propionyl,pivaloyl, hexanoyl, etc.] , mono (or di or tri) halo (lower) alkanoyl [e.g. chloroacetyl, bromoacetyl, dichloroacetyl , trifluoroacetyl , etc . ] , loweralkoxycarbonyl [ e . g . methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl.
  • acyl such as lower alkanoyl [e.g. formyl, acetyl, propionyl,pivaloyl, hexanoyl, etc.] , mono (or di or tri) halo (lower) alkanoyl [e.g. chloroacetyl, bro
  • arylglyoxyloyl e.g.phenylglyoxyloyl, naphthylglyoxyloyl, etc.
  • ar (lower) alkoxycarbonyl which may have suitable substituent ( s ) [ e . g . benzyloxycarbonyl , phenethyloxycarbonyl, p — nitrobenzyloxycarbonyl, etc.]
  • ar (lower) alkyl such as ar (lower) alkylidene which may have substituent (s) [e.g.
  • benzylidene, hydroxybenzylidene, etc. mono (or di or tri) phenyl (lower) alkyl [e.g. benzyl, phenethyl,benzhydryl, trityl, etc.] ; and the like.
  • amino protective group contains the protective group which has the function to temporarily protect amino group and is often used in the field of amino acid and peptide chemistry.
  • Suitable " cyclic amino” may be an aromatic ring or an alicyclic compound which has one or more than one nitrogen atom (s) as hetero atom (s) and may be monocyclic or condensed polycyclic group which may be saturated or unsaturated. Cyclic amono group may further contain hereto atom (s) such as one more than one nitrogen atom (s), oxygen atom (s) , sulfur atom (s) , and the like.
  • cyclic amino group may be a spiro ring or a bridged cyclic compound.
  • the number of the constructive atoms of the cyclic amino group is not limited, but, for example, monocyclic group has a 3 to 8 — membered ring and bicyclic group has 7 to 11 — membered rings.
  • Example of such cyclic amino may include saturated or unsaturated monocyclic group containing one nitrogen atoms as hereto atom such as 1 - azetidinyl, pyrrolidino, 2 - pyrroline — 1 - yl, 1 — pyrrolyl, piperidino, 1,4 - dihydropyridine — 1 — yl, 1,2,5,6 — tetrahydropyridine — 1 — yl, homopiperidino ; saturated or unsaturated monocyclic group containing more than one nitrogen atoms as hetero atoms such as 1 — imidazolidinyl, 1 — imidazolyl, 1 — pyrazolyl, 1 — triazolyl, 1 — tetrazolyl, 1 — piperazinyl, 1 — homopiperazinyl, 1 , 2 — dihydropyridazin — 1 — yl , 1 , 2 — dihydro
  • Suitable "acyl” may include carbamoyl,aliphatic acyl and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or an heterocyclic ring,which is referred to as heterocyclic acyl.
  • This acyl group may be derived , for example, from an organic carboxylic acid.an organic carbonic acid, an organic sulfuric acid,an organic sulfonic acid and an organic carbamic acid.
  • Suitable example of said acyl may be illustrated as follows :
  • Aliphatic acyl such as lower or higher alkanoyl [e.g. formyl, acetyl, propanoyl, butanoyl, 2 - methylpropanoyl, pentanoyl, 2,2 - dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridacanoyl , tetradecanoyl , pentadecanoyl , hexadecanoyl , heptadecanoyl , octadecanoyl , nonadecanoyl , icosanoyl , etc .
  • alkanoyl e.g. formyl, acetyl, propanoyl, butanoyl, 2 - methylpropanoyl, pent
  • lower or higher cycloalkylcarbonyl [ e . g . cyclopropylcarbonyl , cyclobutylcarbonyl , cyclopentylcarbonyl, cyclohexylcarbonyl, etc.] ; lower or higher alkylsulfonyl [e.g. methylsulfonyl, ethylsulfonyl, etc.] ; lower or higher alkoxysulfonyl [e. g. methoxysulfonyl, ethoxysulfonyl, etc.] ; or the like ;
  • Aromatic acyl such as royl [e.g. benzoyl, toluoyl, naphthoyl.etc] ; ar ( lower ) alkanoyl [ e . g . phenyl ( lower ) alkanoyl ( e . g . phenylacetyl , phenylpropanoyl , phenylbutanoyl , phenylisobutylyl , phenylpentanoyl , phenylhexanoyl , etc . ) , naphthyl ( lower ) alkanoyl ( e . g .
  • ar (lower) alkenoyl e.g. phenyl ( lower ) alkenoyl ( e . g . phenylpropenoyl , phenylbutenoyl , phenylmethacryloyl, phenylpentenoyl,phenylhexenoyl,etc) , naphthyl ( lower) alkenoyl (e.g.
  • ar (lower) alkoxycarbonyl e.g. phenyl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl , etc . ) , etc ] ; aryloxycarbonyl [ e . g . phenoxycarbonyl , naphthyloxycarbonyl, etc.] ; aryloxy (lower) alkanoyl [e.g. phenoxyacetyl, phenoxypropionyl , etc .
  • arylcarbamoyl [ e . g . phenylcarbamoyl , etc ] ; arylthiocarbamoyl [e.g . phenylthiocarbamoyl .etc] ; arylglyoxyloyl [e.g . phenylglyoxyloyl,naphthylglyoxyloyl, etc.] ; arylsulfonyl [e.g. phenylsulfonyl, naphthylsulfonyl.etc] ; or the like ;
  • Heterocyclic acyl such as heterocycliccarbonyl ; heterocyclic (lower) alkanoyl [ e . g . thienylacetyl , thienylpropanoyl , thienylbutanoyl , thienylpentanoyl , thienylhexanoyl , thiazolylacetyl , thiadiazolylacetyl , tetrazolylacetyl,etc] ; heterocyclic (lower) alkenoyl [e.g.
  • Heterocyclic moiety in the terms “ heterocycliccarbonyl “ , heterocyclic (lower) alkanoyl”, “heterocyclic (lower) alkenoyl” and “heterocyclic glyoxyloyl” means saturated or unsaturated . monocyclic or polycyclic heterocyclic group containing at least one hetero — atom such as an oxygen, sulfur, nitrogen atom and the like.
  • Suitable "aryl” may include phenyl, naphthyl, tolyl,xylyl,mesityl, cumenyl,and the like, in which the preferable one is phenyl or naphthyl.
  • Suitable " ar ( lower ) alkyl” may include benzyl , phenethyl , phenylpropyl,benzhydryl,trityl,and the like.
  • the object compound (la) or salts thereof can be prepared by the compound (II) or a salt thereof .
  • This reaction can be carried out by reducing nitro, and reacting with carbonyldiimidazol and the compound (IV) or a salt thereof.
  • Suitable salts of the compounds (la) , (II) , (III) , and (IV) can be referred to the ones as exemplified for the compound (I) .
  • the compound (II) is subjected to reduction reaction to give the compound (III) or salts thereof.
  • the reduction reaction may include chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [ e . g . formic acid , acetic acid , propionic acid , trifluoroacetic acid , p — toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.] .
  • metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e e. g . formic acid , acetic acid , propionic acid , trifluoroacetic acid , p — toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g . platinum plate, spongy platinum , platinum black , colloidal platinum , platinum oxide, platinum wire, etc. ] .
  • palladium catalysts e.g. spongy palladium, palladium black.palladium oxide, palladium on carbon , colloidal palladium , palladium on barium sulfate , palladium on barium carbonte, etc.]
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.]
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron etc.
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper, etc.] and the like.
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N — dimethylformamide, aceton, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above — mentioned solvent, and other conventional solvent such as diethtyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling , at ambient temperature or under heating.
  • the reduction product (III) or a salt thereof is subjected to reaction with carbonyldiimidazol, and then subjected to reaction with the compound (IV) or a salt thereof.
  • the reactions are usually carried out in a conventional solvent which do not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N - dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine,triethylamine, benzene, or a mixture thereof.
  • a conventional solvent which do not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N - dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine,triethylamine, benzene, or a mixture thereof.
  • reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (I) or salts thereof can be prepared by the compound (V) or a salt thereof.
  • the compound (V) or a salt thereof is subjected to reaction with diphenylphosphorousazid, and then subjected to reaction with the compound (VI) or a salt thereof.
  • Suitable salts of the compounds (V) and (VI) can be referred to the ones as exemplified for the compound (I) .
  • the reactions are usually carried out in a conventional solvent which do not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N - dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine.triethylamine, benzene, or a mixture thereof
  • reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (Ic) or salts thereof can be prepared by subjecting the compound (lb) or a salt thereof to reduction reaction.
  • Suitable salts of the compounds (lb) and (Ic) can be referred to the ones as exemplified for the compound (I) .
  • This reaction can be carried out in a similar manner to that of the aforementioned 1st step of Process 1.
  • the object compound (Id) or salts thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (VIII) or a salt thereof.
  • Suitable salts of the compounds (Id) , (VII) , and (VIII) can be referred to the ones as exemplified for the compound (I) .
  • the reaction is preferably carried out in the presence of an acid.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trif luoroacetic acid, p — toluenesulfonic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfonic acid, hydrogen chloride, hydrogen bromide, etc.] .
  • organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trif luoroacetic acid, p — toluenesulfonic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfonic acid, hydrogen chloride, hydrogen bromide, etc.
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N - dimethylformamide, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction
  • the above - mentioned acids to be used in the reaction are liquid, they can be also be used as a solvent.
  • reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (Ie) or salts thereof can be prepared by the compound (IX) or a salt thereof.
  • the compound (IX) or a salt thereof is subjected to reaction with the compound (XVI) or a salt thereof.
  • Suitable salts of the compounds (Ie) and (IX) can be referred to the ones as exemplified for the compound (I) .
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N - dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine,triethylamine, benzene, or a mixture thereof
  • a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N - dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine,triethylamine, benzene, or a mixture thereof
  • reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (I) or salts thereof can be prepared by the compound (X) or a salt thereof.
  • the compound (X) or a salt thereof is subjected to reaction with the compound (XI) or a salt thereof.
  • Suitable salts of the compounds (X) and (XI) can be referred to the ones as exemplified for the compound (I) .
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N — dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine.triethylamine, benzene, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, diethyl ether, dioxane, tetrahydrofuran, N,N — dimethylformamide, acetone, acetonitrile, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine.triethylamine, benzene, or a mixture thereof.
  • reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (If) or salts thereof can be prepared by the compound (XII) or a salt thereof.
  • the compound (XII) or a salt thereof is subjected to reaction with carbonyldiimidazol, and then subjected to reaction with the compound (XIII) or a salt thereof.
  • Suitable salts of the compounds (If) , (XII) , and (XIII) can be referred to the ones as exemplified for the compound (I) .
  • the object compound (I) or salts thereof can be prepared by the compound (XIV) or a salt thereof.
  • the compound (XIV) or a salt thereof is subjected to reaction with the compound (XV) or a salt thereof.
  • Suitable salts of the compounds (XIV) and (XV) can be referred to the ones as exemplified for the compound (I) .
  • the object compound (I) or salts thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XVI) and then with the compound (VI) or a salt thereof.
  • Suitable salts of the compounds (VI) can be referred to the ones as exemplified for the compound (I) .
  • This reaction can be carried out in a similar manner to that of the aforementioned 2nd step of Process 1.
  • the object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional, crystallization, recrystallization, chromatography, and the like.
  • the object compound (I) thus obtained can be converted to its salt by a conventional method.
  • the object compound (I) and pharmaceutically acceptable salt thereof may include a solvate [e.g., enclosure compound (e.g., hydrate, etc.)] .
  • the object compound ( I ) of the present invention and pharmaceutically acceptable salt thereof exhibit pharmacological activities such as 5 — HT " antagonism, especially, 5HT 2C antagonism, and the like and therefore are useful as 5 - HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimer's 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, and the like.
  • CNS central nervous system
  • test drugs for the 5 - HT 2c binding site can be determined by assessing their ability to displace [ 3 H] - mesulergine in the rat prefrontal cortex. the method employed was similar to that of Pazos et al, 1984.
  • the membrane suspesion 500 ⁇ 1 was incubated with [ 3 H] - mesulergine (1 nM) in Tris HCI buffer containing CaCl 2 4mM and ascorbic acid 0.1 % (ph 7.4) at 37 °C for 30 minutes. Non - specific binding was measured in the presence of mianserin ( 1 ⁇ M) . 30 nM spiperone was used to prevent binding to 5 - HT 2A sites. Test drugs (10 ⁇ M) were added in a volume of 100 ⁇ 1. The total assay volume was 1000 ⁇ 1. Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting.
  • the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of the conventional pharmaceutical preparation which contains said compounds as an active ingredient, in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral and external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral and external administration.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like.
  • stabilizing agents such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
  • While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient , a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present Invention may be used in treating diseases.
  • N- [3- (1 - Benzyloxycarbonylpyrazol - 3 - yl)] — N' - (1 - methylindol — 5 — yl) urea (0.21g) was hydrogenated in methanol (40ml) by palladium — carbon (10%, O.lg) for 8 hours. Catalists were filtered off.
  • N - (1 - methylindol - 5 - yl) - N' - (3 - thiocarbamoylphenyl) urea (0.20g) in N,N — dimethylformamide (3ml) was added chloroacetone (0.05ml). The mixture was stirred at 100 °C for 1.5 hours. After being cooled, the solution was poured into water (30ml). The pH was adjusted to 9 with aqueous sodium bicarbonate.
  • Example 37 The following compound was obtained acoording to a similar manner to that of Example 25.
  • Example 45 To a suspension of 1 — methylindole — 5 — carboxylic acid (lOOmg) in benzene ( 5ml ) were added triethylamine ( 159 ⁇ 1 ) and diphenylphosphorous azide (121 ⁇ 1). The mixture was refluxed for 4 hours, then cooled to room temperature. 3 — (Imidazol — 1 — yl) — 6 — nitroaniline (140mg) was added to the mixture. The mixture was refluxed for 4 hours.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Addiction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un composé de la formule (I) où R1 et R2 représentent respectivement de l'hydrogène ou sont liés pour former de l'éthylène, R3 représente de l'hydrogène ou un alkyle inférieur, R4 représente un groupe hétérocyclique, R5 représente de l'hydrogène ou un nitro, et X représente CH ou N. L'invention concerne également les sels pharmaco-compatibles du composé précité, ayant une activité pharmacologique telle qu'un antagonisme envers la 5-hydroxytryptamine (5-HT).
PCT/JP1997/004390 1996-12-02 1997-12-02 Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht WO1998024785A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP52544498A JP2001508767A (ja) 1996-12-02 1997-12-02 ５―ｈｔ拮抗作用を有するインドール―ウレア誘導体
AU50682/98A AU5068298A (en) 1996-12-02 1997-12-02 Indole-urea derivatives with 5-ht antagonist properties

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AUPO3954 1996-12-02
AUPO3954A AUPO395496A0 (en) 1996-12-02 1996-12-02 Urea derivatives
AUPO5930 1997-04-01
AUPO5930A AUPO593097A0 (en) 1997-04-01 1997-04-01 Urea derivatives

Publications (1)

Publication Number Publication Date
WO1998024785A1 true WO1998024785A1 (fr) 1998-06-11

Family

ID=25645324

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/004390 WO1998024785A1 (fr) 1996-12-02 1997-12-02 Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht

Country Status (2)

Country Link
JP (1) JP2001508767A (fr)
WO (1) WO1998024785A1 (fr)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999052927A1 (fr) * 1998-04-14 1999-10-21 Arena Pharmaceuticals, Inc. Formes non endogenes a activite constitutive de recepteurs humains de la serotonine et leurs petites molecules modulatrices
EP1101759A1 (fr) * 1998-07-31 2001-05-23 Nippon Soda Co., Ltd. Composes phenylazole, procede de production desdits composes et medicaments pour le traitement de l'hyperlipidemie
WO2001044201A1 (fr) * 1999-12-16 2001-06-21 Schering Corporation Antagonistes du recepteur y5 au neuropeptide y a imidazoles substituees
EP1170288A2 (fr) * 2000-06-29 2002-01-09 Les Laboratoires Servier Dérivés de diphenylurée et leur utilisation en tant qu'antagonistes alpha2/5-HT2c
WO2002070467A1 (fr) * 2001-02-26 2002-09-12 4Sc Ag Derives de diphenyluree, de diamide d'acide diphenyloxalique et de diamide d'acide diphenylsulfurique et leur utilisation comme medicaments
WO2003062206A2 (fr) * 2002-01-23 2003-07-31 Arena Pharmaceuticals, Inc. Modulateurs a petites molecules du recepteur de serotonine 5-ht2a utiles pour la prophylaxie et le traitement de troubles associes
WO2004085433A2 (fr) * 2003-03-28 2004-10-07 Pharmacia & Upjohn Company Llc Modulateurs allosteriques positifs du recepteur nicotinique de l'acetylcholine
WO2006055734A2 (fr) * 2004-11-19 2006-05-26 Arena Pharmaceuticals, Inc. Derives de 3-phenyl-pyrazole comme modulateurs du recepteur de serotonine 5-ht2a pour traiter des troubles associes
US7618960B2 (en) 2005-11-24 2009-11-17 Eisai R&D Management Co., Ltd. Morpholine type cinnamide compound
US7667041B2 (en) 2004-05-26 2010-02-23 Eisai R&D Management Co., Ltd. Cinnamide compound
US7713993B2 (en) 2006-03-09 2010-05-11 Eisai R&D Management Co., Ltd. Multi-cycle cinnamide derivatives
US7737141B2 (en) 2006-07-28 2010-06-15 Eisai R&D Management Co., Ltd. Prodrug of cinnamide compound
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US7812176B2 (en) 2004-03-23 2010-10-12 Arena Pharmaceuticals, Inc. Processes for preparing substituted N-aryl-N′-[3-(1H-pyrazol-5-YL) phenyl] ureas and intermediates thereof
US7923563B2 (en) 2004-10-26 2011-04-12 Eisai R&D Management Co., Ltd. Amorphous object of cinnamide compound
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
US8008293B2 (en) 2007-02-28 2011-08-30 Eisai R&D Management Co., Ltd. Bicyclic oxomorpholine derivative
US8048878B2 (en) 2005-11-24 2011-11-01 Eisai R&D Management Co., Ltd. Two cyclic cinnamide compound
US8148417B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8148418B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8481535B2 (en) 2006-05-18 2013-07-09 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US8754238B2 (en) 2003-07-22 2014-06-17 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8980891B2 (en) 2009-12-18 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8987461B2 (en) 2012-12-06 2015-03-24 Quanticel Pharmaceuticals, Inc. Histone demethylase inhibitors
US9034911B2 (en) 2008-10-28 2015-05-19 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US9126946B2 (en) 2008-10-28 2015-09-08 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto
US9434692B2 (en) 2006-10-03 2016-09-06 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9453000B2 (en) 2007-08-31 2016-09-27 Eisai R&D Management Co., Ltd. Polycyclic compound
US9556149B2 (en) 2008-04-02 2017-01-31 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US9567327B2 (en) 2007-08-15 2017-02-14 Arena Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
CN111433198A (zh) * 2017-11-17 2020-07-17 合帕吉恩治疗公司 作为ask1的抑制剂的脲衍生物
WO2020172206A1 (fr) 2019-02-22 2020-08-27 Agile Sciences, Inc. Compositions fournissant une activité antibactérienne améliorée contre des bactéries à gram positif et leur utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2019093A4 (fr) * 2006-05-19 2011-02-23 Eisai R&D Man Co Ltd Dérivé de cinnamide de type urée

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005170A1 (fr) * 1990-09-13 1992-04-02 Beecham Group Plc Urees d'indole utilisees comme antagonistes de recepteur de 5-ht
WO1994004533A1 (fr) * 1992-08-20 1994-03-03 Smithkline Beecham Plc DERIVES D'INDOLE CONDENSES UTILISES COMME ANTAGONISTES DES RECEPTEURS 5HT2C et 5HT¿2B?
WO1995021844A1 (fr) * 1994-02-10 1995-08-17 Smithkline Beecham Plc Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b?
WO1995029177A1 (fr) * 1994-04-23 1995-11-02 Smithkline Beecham P.L.C. Derives tricycliques antagonistes de 5ht2c et de 5ht2b
WO1996039382A1 (fr) * 1995-06-06 1996-12-12 Fujisawa Pharmaceutical Co., Ltd. Derives de l'uree utilises comme antagonistes de 5-ht
WO1997040028A1 (fr) * 1996-04-23 1997-10-30 Vertex Pharmaceuticals Incorporated Derives d'uree agissant comme inhibiteurs de l'enzyme impdh

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005170A1 (fr) * 1990-09-13 1992-04-02 Beecham Group Plc Urees d'indole utilisees comme antagonistes de recepteur de 5-ht
WO1994004533A1 (fr) * 1992-08-20 1994-03-03 Smithkline Beecham Plc DERIVES D'INDOLE CONDENSES UTILISES COMME ANTAGONISTES DES RECEPTEURS 5HT2C et 5HT¿2B?
WO1995021844A1 (fr) * 1994-02-10 1995-08-17 Smithkline Beecham Plc Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b?
WO1995029177A1 (fr) * 1994-04-23 1995-11-02 Smithkline Beecham P.L.C. Derives tricycliques antagonistes de 5ht2c et de 5ht2b
WO1996039382A1 (fr) * 1995-06-06 1996-12-12 Fujisawa Pharmaceutical Co., Ltd. Derives de l'uree utilises comme antagonistes de 5-ht
WO1997040028A1 (fr) * 1996-04-23 1997-10-30 Vertex Pharmaceuticals Incorporated Derives d'uree agissant comme inhibiteurs de l'enzyme impdh

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FORBES ET AL: "Synthesis, Biological Activity and Molecular Modeling Studies of Selective 5-HT2c/2B Receptor Antagonists.", J.MED.CHEM., vol. 39, no. 25, 1996, pages 4966 - 4977, XP002061494 *

Cited By (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999052927A1 (fr) * 1998-04-14 1999-10-21 Arena Pharmaceuticals, Inc. Formes non endogenes a activite constitutive de recepteurs humains de la serotonine et leurs petites molecules modulatrices
EP1101759A4 (fr) * 1998-07-31 2001-12-12 Nippon Soda Co Composes phenylazole, procede de production desdits composes et medicaments pour le traitement de l'hyperlipidemie
EP1101759A1 (fr) * 1998-07-31 2001-05-23 Nippon Soda Co., Ltd. Composes phenylazole, procede de production desdits composes et medicaments pour le traitement de l'hyperlipidemie
US6444687B1 (en) 1999-12-16 2002-09-03 Schering Corporation Substituted imidazole neuropeptide Y Y5 receptor antagonists
US6632828B2 (en) 1999-12-16 2003-10-14 Schering Corporation Substituted imidazole neuropeptide Y Y5 receptor antagonists
WO2001044201A1 (fr) * 1999-12-16 2001-06-21 Schering Corporation Antagonistes du recepteur y5 au neuropeptide y a imidazoles substituees
EP1170288A2 (fr) * 2000-06-29 2002-01-09 Les Laboratoires Servier Dérivés de diphenylurée et leur utilisation en tant qu'antagonistes alpha2/5-HT2c
EP1170288A3 (fr) * 2000-06-29 2002-01-16 Les Laboratoires Servier Dérivés de diphenylurée et leur utilisation en tant qu'antagonistes alpha2/5-HT2c
KR100485018B1 (ko) * 2000-06-29 2005-04-25 르 라보레또레 쎄르비에르 디페닐우레아 화합물, 이들의 제조 방법 및 이들을 함유하는 약제 조성물
AU780022B2 (en) * 2000-06-29 2005-02-24 Les Laboratoires Servier New diphenylurea compounds, a process for their preparation and pharmaceutical compositions containing them
WO2002070467A1 (fr) * 2001-02-26 2002-09-12 4Sc Ag Derives de diphenyluree, de diamide d'acide diphenyloxalique et de diamide d'acide diphenylsulfurique et leur utilisation comme medicaments
US6949567B2 (en) 2001-02-26 2005-09-27 4Sc Ag Compounds for the treatment of protozoal diseases
WO2003062206A2 (fr) * 2002-01-23 2003-07-31 Arena Pharmaceuticals, Inc. Modulateurs a petites molecules du recepteur de serotonine 5-ht2a utiles pour la prophylaxie et le traitement de troubles associes
WO2003062206A3 (fr) * 2002-01-23 2004-01-08 Arena Pharm Inc Modulateurs a petites molecules du recepteur de serotonine 5-ht2a utiles pour la prophylaxie et le traitement de troubles associes
WO2004085433A3 (fr) * 2003-03-28 2004-12-16 Upjohn Co Modulateurs allosteriques positifs du recepteur nicotinique de l'acetylcholine
WO2004085433A2 (fr) * 2003-03-28 2004-10-07 Pharmacia & Upjohn Company Llc Modulateurs allosteriques positifs du recepteur nicotinique de l'acetylcholine
US9775829B2 (en) 2003-07-22 2017-10-03 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US9273035B2 (en) 2003-07-22 2016-03-01 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8871797B2 (en) 2003-07-22 2014-10-28 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8754238B2 (en) 2003-07-22 2014-06-17 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US7812176B2 (en) 2004-03-23 2010-10-12 Arena Pharmaceuticals, Inc. Processes for preparing substituted N-aryl-N′-[3-(1H-pyrazol-5-YL) phenyl] ureas and intermediates thereof
US7667041B2 (en) 2004-05-26 2010-02-23 Eisai R&D Management Co., Ltd. Cinnamide compound
US7687640B2 (en) 2004-05-26 2010-03-30 Eisai R&D Management Co., Ltd. Cinnamide compound
US7880009B2 (en) 2004-05-26 2011-02-01 Eisai R&D Management Co., Ltd. Cinnamide compound
US7923563B2 (en) 2004-10-26 2011-04-12 Eisai R&D Management Co., Ltd. Amorphous object of cinnamide compound
US8785441B2 (en) 2004-11-19 2014-07-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
KR101275380B1 (ko) 2004-11-19 2013-06-25 아레나 파마슈티칼스, 인크. 5―ｈｔ2ａ 세로토닌 수용체의 조절제로서 이와 관련된장애의 치료에 유용한 3―페닐―피라졸 유도체
WO2006055734A3 (fr) * 2004-11-19 2006-08-17 Arena Pharm Inc Derives de 3-phenyl-pyrazole comme modulateurs du recepteur de serotonine 5-ht2a pour traiter des troubles associes
US7884101B2 (en) 2004-11-19 2011-02-08 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
EA011935B1 (ru) * 2004-11-19 2009-06-30 Арена Фармасьютикалз, Инк. Производные 3-фенилпиразола в качестве модуляторов 5-htсеротонинового рецептора, полезные для лечения расстройств, связанных с этим рецептором
US10781180B2 (en) 2004-11-19 2020-09-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
EP1978019A1 (fr) * 2004-11-19 2008-10-08 Arena Pharmaceuticals, Inc. Dérivés de 3-phenyl-pyrazole en tant que modulateurs du récepteur de la sérotonine 5-HT2A utiles pour le traitement des troubles y étant associés
NO340656B1 (no) * 2004-11-19 2017-05-22 Arena Pharm Inc 3-fenylpyrazol derivater, farmasøytiske sammensetninger inneholdende slike, fremgangsmåte for fremstilling og anvendelse som modulatorer av 5HT2A serotoninreseptoren for behandling av forstyrrelser relatert dertil
WO2006055734A2 (fr) * 2004-11-19 2006-05-26 Arena Pharmaceuticals, Inc. Derives de 3-phenyl-pyrazole comme modulateurs du recepteur de serotonine 5-ht2a pour traiter des troubles associes
CN103012378A (zh) * 2004-11-19 2013-04-03 艾尼纳制药公司 作为5-ht2a血清素受体调节剂适用于治疗与其相关的病症的3-苯基-吡唑衍生物
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US7618960B2 (en) 2005-11-24 2009-11-17 Eisai R&D Management Co., Ltd. Morpholine type cinnamide compound
US8048878B2 (en) 2005-11-24 2011-11-01 Eisai R&D Management Co., Ltd. Two cyclic cinnamide compound
US7897632B2 (en) 2006-03-09 2011-03-01 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
US7973033B2 (en) 2006-03-09 2011-07-05 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
US7713993B2 (en) 2006-03-09 2010-05-11 Eisai R&D Management Co., Ltd. Multi-cycle cinnamide derivatives
US8664258B2 (en) 2006-05-18 2014-03-04 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8680119B2 (en) 2006-05-18 2014-03-25 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9328107B2 (en) 2006-05-18 2016-05-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8481535B2 (en) 2006-05-18 2013-07-09 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
USRE45336E1 (en) 2006-05-18 2015-01-13 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
USRE45337E1 (en) 2006-05-18 2015-01-13 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9987252B2 (en) 2006-05-18 2018-06-05 Arena Pharmaceuticals, Inc. Primary amines and derivitves thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9783502B2 (en) 2006-05-18 2017-10-10 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US8148418B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8148417B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10450276B2 (en) 2006-05-18 2019-10-22 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9199940B2 (en) 2006-05-18 2015-12-01 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US9221755B2 (en) 2006-05-18 2015-12-29 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US7737141B2 (en) 2006-07-28 2010-06-15 Eisai R&D Management Co., Ltd. Prodrug of cinnamide compound
US9434692B2 (en) 2006-10-03 2016-09-06 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9732039B2 (en) 2006-10-03 2017-08-15 Arena Pharmeceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10351531B2 (en) 2006-10-03 2019-07-16 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8008293B2 (en) 2007-02-28 2011-08-30 Eisai R&D Management Co., Ltd. Bicyclic oxomorpholine derivative
US10058549B2 (en) 2007-08-15 2018-08-28 Arena Pharmaceuticals, Inc. Imidazo[1,2-α]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9567327B2 (en) 2007-08-15 2017-02-14 Arena Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9453000B2 (en) 2007-08-31 2016-09-27 Eisai R&D Management Co., Ltd. Polycyclic compound
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
US10787437B2 (en) 2008-04-02 2020-09-29 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US9556149B2 (en) 2008-04-02 2017-01-31 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US9353064B2 (en) 2008-10-28 2016-05-31 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9745270B2 (en) 2008-10-28 2017-08-29 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9034911B2 (en) 2008-10-28 2015-05-19 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10543193B2 (en) 2008-10-28 2020-01-28 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9801856B2 (en) 2008-10-28 2017-10-31 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10071075B2 (en) 2008-10-28 2018-09-11 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US10583122B2 (en) 2008-10-28 2020-03-10 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10117851B2 (en) 2008-10-28 2018-11-06 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US9126946B2 (en) 2008-10-28 2015-09-08 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto
US8980891B2 (en) 2009-12-18 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9714230B2 (en) 2012-12-06 2017-07-25 Celgene Quantical Research, Inc. Histone demethylase inhibitors
US10173996B2 (en) 2012-12-06 2019-01-08 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US9908865B2 (en) 2012-12-06 2018-03-06 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US8987461B2 (en) 2012-12-06 2015-03-24 Quanticel Pharmaceuticals, Inc. Histone demethylase inhibitors
US9107916B2 (en) 2012-12-06 2015-08-18 Quanticel Pharmaceuticals, Inc. Histone demethylase inhibitors
US9604961B2 (en) 2012-12-06 2017-03-28 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US9458129B2 (en) 2012-12-06 2016-10-04 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
US11304932B2 (en) 2015-07-15 2022-04-19 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
CN111433198A (zh) * 2017-11-17 2020-07-17 合帕吉恩治疗公司 作为ask1的抑制剂的脲衍生物
US11427556B2 (en) * 2017-11-17 2022-08-30 Hepagene Therapeutics (HK) Limited Urea derivatives as inhibitors of ASK1
WO2020172206A1 (fr) 2019-02-22 2020-08-27 Agile Sciences, Inc. Compositions fournissant une activité antibactérienne améliorée contre des bactéries à gram positif et leur utilisation

Also Published As

Publication number Publication date
JP2001508767A (ja) 2001-07-03

Similar Documents

Publication Publication Date Title
WO1998024785A1 (fr) Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht
EP1020462B1 (fr) Composes heterocycliques et agent antitumoral contenant lesdits composes utilises comme ingredients actifs
DE60309481T2 (de) Cyclische n-aroylamine als orexinrezeptorantagonisten
EP3634958B1 (fr) Agonistes du récepteur 2 du peptide formylé et agonistes du récepteur 1 du peptide formylé à base de cyclopropyle d'urée
US6054590A (en) Imidazolone anorectic agents: II. phenyl derivatives
DE19952146A1 (de) Arylalkane, Arylalkene und Aryl-azaalkane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
KR101738866B1 (ko) 안드로겐 수용체 길항제, 항암제로서 사이클릭 n,n'-다이아릴티오우레아 및 n,n'-다이아릴우레아, 이의 제조방법 및 이의 용도
JPH10279566A (ja) Ｎ−置換複素環誘導体を含有する医薬組成物
US7442693B2 (en) Diazepine compounds as ligands of the melanocortin 1 and/or 4 receptors
NO324155B1 (no) Kinolinderivater, farmasoytisk sammensetning omfattende samme og anvendelse av samme for fremstilling av medikament
WO2003007959A1 (fr) Derives de quinoxaline ayant une action inhibitrice sur parp
KR19990008282A (ko) 아미노티아졸 유도체, 이를 함유하는 의약 및 이 화합물의 중간체
CA2471348A1 (fr) Derives de quinazolinone
IL109234A (en) History of indole, their preparation and pharmaceutical preparations containing them
GB1588166A (en) Nitrogen-containing heterocyclic compounds
JPH06145170A (ja) ヘテロ環式化合物、その製法及びこれを含有する高血圧及びうつ血性心不全治療用医薬組成物
CZ20021038A3 (cs) Piperazinové deriváty jako antagonisté 5-HT1B
DE69028934T2 (de) Tetrahydrobenzimidazol-Derivate
US3594380A (en) Isoquinolin-1(2h)-ones
DE19952147A1 (de) Neue Cyclopropane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
EP0384228A1 (fr) Médicament pour le traitement des maladies causées par une insuffisance cérébrale à base de dérivés de la 2(1-pipérazinyl)-4-phénylcycloalcanopyrimidine, et procédé de préparation
JPH11506468A (ja) ５−ｈｔ拮抗剤としての尿素誘導体
US7202249B2 (en) Antagonists of chemokine receptors
US5281613A (en) Heterocyclic compounds
DE3615180C2 (de) Disubstituierte 1,4-Piperazinylderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende pharmazeutische Mittel

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN HU IL JP KR MX US AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: JP

Ref document number: 1998 525444

Kind code of ref document: A

Format of ref document f/p: F

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1998525444

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase