WO1998024785A1 - Indole-urea derivatives with 5-ht antagonist properties - Google Patents

Indole-urea derivatives with 5-ht antagonist properties Download PDF

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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
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compound
salt
formula
defined above
reacting
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Inventor
Kiyotaka Ito
Glen W. Spears
Toshio Yamanaka
Keiko Harada
Yuka Noda
Hiroshi Sasaki
Fumie Takahashi
Masayuki Kato
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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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/en
Priority to AU50682/98A priority patent/AU5068298A/en
Publication of WO1998024785A1 publication Critical patent/WO1998024785A1/en
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    • 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.

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Abstract

A compound of formula (I) wherein R?1 and R2¿ are each hydrogen or linked together to form ethylene, R3 is hydrogen or lower alkyl, R4 is heterocyclic group, R5 is hydrogen or nitro, and X is CH or N, and pharmaceutically acceptable salts thereof, which has pharmacological activities such as 5-hydroxytryptamine (5-HT) antagonism.

Description

DESCRIPTION
INDOLE-UREA DERIVATIVES WITH 5-HT ANTAGONIST PROPERTIES
TECHNICAL FIELD
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.
BACKGROUND ART
As urea derivatives having 5 - HT C receptor antagonism activity are described in the international patent application (International Publication Number W095 / 21844 ) W095 / 29177 published based on the Patent Cooperation Treaty.
DISCLOSURE OF INVENTION
As a result of an extensive study, the inventors of the present invention could obtain the urea derivatives which have strong pharmacological activities.
The urea derivatives of the present invention are novel and can be represented by the following general formula (I) :
Figure imgf000004_0001
wherein R1 and R2 are each hydrogen or linked together to form ethylene,
R3 is hydrogen or lower alkyl, R" is heterocyclic group, R5 is hydrogen or nitro, and X is CH or N.
According to the present invention, the object compounds (I) can pared by the following processes :
Process 1
thereof
Figure imgf000005_0001
reduction reaction
thereof
Figure imgf000005_0002
thereof
Figure imgf000005_0003
Process 2
thereof
Figure imgf000006_0001
thereof
Figure imgf000006_0002
Process 3
thereof
thereof
Figure imgf000006_0003
Process 4 reof
thereof
Figure imgf000007_0001
thereof
Figure imgf000007_0002
Process 5
eof
Figure imgf000007_0003
thereof
Figure imgf000007_0004
Process 6 thereof
Figure imgf000008_0001
thereof
thereof
Figure imgf000008_0002
Process 7
thereof
Figure imgf000009_0001
thereof
Figure imgf000009_0002
Process 8
hereof
Figure imgf000009_0003
thereof
thereof
Figure imgf000009_0004
Process 9 thereof
Figure imgf000010_0001
thereof
Figure imgf000010_0002
wherein R\R2,R3,R,R5 and X are each as defined above.and Z is acyl.
Further, the 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)ΛIa)ΛIb)ΛIc)ΛIdUIe)ΛIf),(π),(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. calcium salt, magnesium salt, etc.) , 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. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p — toluenesulfonate, etc.) ; a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.) ; and the like, and the preferable example thereof is an acid addition salt.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term "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.
The "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.
And, especially preferable 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 . g . 1H — tetrazolyl , 2H — tetrazolyl , etc . ] , imidazolinyl , 2 — imidazolonyl, etc. ; saturated 3 to 8 — membered (more preferably 5 or 6 — membered) heteromonocyclic group containing 1 to 4 nitrogen atom (s) ,for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, 2 — imidazolinonyl, etc. ; 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 3 to 8 — membered (more preferably 5 or 6 — membered) heteromonocyclic group containing 1 to 2 oxygen atom (s) and 1 to 3 nitrogen atom (s) , for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4 — oxadiazolyl, 1,3,4 — oxadiazolyl, 1,2,5 - oxadiazolyl, etc.] , etc. ; saturated 3 to 8 — membered (more preferably 5 or 6 — membered) heteromonocyclic group containing 1 to 2 oxygen atom (s) and 1 to 3 nitrogen atom (s), for example, morpholinyl, sydnonyl, etc. ; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom ( s ) and 1 to 3 nitrogen atom ( s ) , for example , benzoxazolyl , benzoxadiazolyl, etc. ; unsaturated 3 to 8 — membered (more preferably 5 or 6 - membered) heteromonocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom ( s) , for example, thiazolyl, isothiazolyl , thiadiazolyl [e.g . 1 , 2, 3 — thiadiazolyl, 1,2,4 — thiadiazolyl, 1,3,4 — thiadiazolyl, 1,2,5 — thiadiazolyl, etc.] , dihydrothiazinyl, etc. ; saturated 3 to 8 - membered (more preferably 5 or 6 — membered) heteromonocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s) , for example, thiomorpholinyl, thiazolidinyl, etc. ; unsaturated 3 to 8 - membered (more preferably 5 or 6 — membered) heteromonocyclic group containing 1 to 2 sulfur atom ( s) , for example, thienyl, dihydrodithiinyl, dihydrodithionyl, 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, for example, furyl, 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 " 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.
"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. t - butoxy carbonyl, t - pentyloxycarbonyl.hexyloxycarbonyl, etc.] , carbamoyl, aroyl [e.g. benzoyl, toluoyl.naphthoyl, etc.] , ar (lower) alkanoyl [e.g. phenylacetyl, phenylpropionyl, etc.] , aryloxycarbonyl [e.g. phenoxycarbonyl,naphthyloxycarbonyl,etc] , aryloxy (lower) alkanoyl [e.g. phenoxyacetyl, phenoxypropionyl, etc.] , 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.
Above — mentioned 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.
Still further the 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 — dihydropyrimidin — 1 — yl , perhydropyrimidin — 1 - yl, 1,4 - diazacycloheptan — 1 - yl ; saturated or unsaturated monocyclic group containing 1 to 2 oxygen atom (s) and 1 to 3 nitorogen atom (s) as hereto atoms such as oxazolidin — 3 — yl, 2,3 — dihydroisoxazol — 2 — yl, morpholino ; saturated or unsaturated monocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s) as hereto atoms such as thiazolidin
— 3 — yl, isothiazolin — 2 — yl,thiomorpholino ; condensed polycyclic group such as indole — 1 — yl , 1 , 2 — dihydrobenzimidazol — 1 — yl, perhydropyrrolo [1,2 - a] pyrazin — 2 - yl ; spirocyclic group such as 2 - azaspiro [4,5] decan - 2 — yl ; bridged heterocyclic group such as 7 - azabicyclo [2,2,1] heptan — 7
- yl ; and the like.
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 :
Carbamoyl ;
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 . ] ; 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 . naphthylacetyl , naphthylpropanoyl, naphthylbutanoyl, etc.) , etc.] ; ar (lower) alkenoyl [e.g. phenyl ( lower ) alkenoyl ( e . g . phenylpropenoyl , phenylbutenoyl , phenylmethacryloyl, phenylpentenoyl,phenylhexenoyl,etc) , naphthyl ( lower) alkenoyl (e.g. naphylpropenoyl, naphthylbutenoyl, naphthylpentenoyl, etc.) , etc.] ; 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. heterocyclicpropenoyl, heterocyclicbutenoyl , heterocyclicpentenoyl , heterocyclichexenoyl , etc . ] ; heterocyclicglyoxyloyl [e.g. thiazolylglyoxyloyl, thienylglyoxyloyl, etc.] ; or the like.
" 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 processes 1 to 9 for preparing the object compounds (I ) of present invention are explained in detail in the following.
Process 1
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) .
At the 1st step, 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.] .
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. Additionally, in case that the above — mentioned acid to be used in chemical reduction are in liquid, they can also be used as a solvent, Further, 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.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling , at ambient temperature or under heating. At the 2nd step, 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.
The reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
Process 2
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
The reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
Process 3
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.
Process 4
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.] .
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.Additionally, in case that the above - mentioned acids to be used in the reaction are liquid, they can be also be used as a solvent.
The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating.
Process 5
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
The reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
Process 6
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.
The reaction temperatures of these reactions are not critical and the reactions are usually carried out under cooling, at ambient temperature or under heating.
Process 7
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) .
This reaction can be carried out in a similar manner to that of the aforementioned 2nd step of Process 1. Process 8
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) .
This reaction can be carried out in a similar manner to that of the aforementioned Process 6.
Process 9
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, 5HT2C 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.
In order to illustrate the usefulness of the object compounds (I) , pharmacological activity of the representative compounds of the present invention are shown below.
(1) Test Method
[3H] - mesulergine binding
The affinity of test drugs for the 5 - HT2c binding site can be determined by assessing their ability to displace [3H] - mesulergine in the rat prefrontal cortex. the method employed was similar to that of Pazos et al, 1984.
The membrane suspesion (500 μ 1) was incubated with [3H] - mesulergine (1 nM) in Tris HCI buffer containing CaCl2 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 μ M) . 30 nM spiperone was used to prevent binding to 5 - HT2A sites. Test drugs (10 δ M) were added in a volume of 100 μ 1. The total assay volume was 1000 μ 1. Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting.
(2) Test compounds
(a) N - (1 - Methylindol - 5 - yl) - NT - [5 - (5 - methylpyrazol - 3 _ yl) pyridin — 3 - yl] urea
(b) N - [3 - (Imidazol - 1 - yl) phenyl] - N* - (1 - methylindol - 5 - yl) urea
(c) 1 - [ [3 - (2 - Imidazolin - 2 - yl) phenyl] carbamoyl] - 5 - methyl — 2,3 — dihydropyrrolo [2,3 - f] indole hydriodide
(3) Test Results
Figure imgf000023_0001
For therapeutic or preventive administration, 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. 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.
If needed, there may be included in the above preparation auxiliary substances , stabilizing agents, wetting agents and other commonly used additives 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.
The following Examples are given for the purpose of illustrating the present invention in more detail.
Example 1
A 0.20g of 1 — methyl — 5 — nitroindole was hydrogenated in methanol (10 ml) by palladium on carbon (10%, 0.10g) for 3 hours. After catalyst was filtered off, resulting solution was evaporated and dried in vacuo. Obtained amine was dissolved in tetrahydrofuran (10ml) and carbonyldiimidazole (0.184g) was added. The mixture was stirred at ambient temperature for 1 hour. Then 3- (2 - benzylpyrazol - 3 - yl) aniline (0.31g) was added with N,N - dimethylformamide (5ml). The mixture was stirred for 66 hours at ambient temperature, and evaporated.
The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed by aqueous sodium bicarbonate, dried over sodium sulfate, and chromatographed on silica gel eluted by chloroform
- methanol (0 - 10 % v/v), to give N - [3 - (2 - benzylpyrazol - 3 - yl) phenyl] - N' — (1 - methylindol - 5 - yl) urea m.p. : 108- 112 °C
IR (Nujol, cm _ : 1640, 1605
NMR (DMSO-d6,(5) : 3.75 (3H,s), 5.41 (2H,s), 6.34 (lH,d,J = 3Hz), 6.43 (1H, d,J = 2Hz), 6.90-7.05 (2H,s), 7.10-7.50 (7H,m), 7.58 (lH,d,J = 2Hz), 7.60-7.
70 (2H,m), 8.47 (lH,s), 8.68 (lH,s)
Mass : 422 (M + 1 + )
Example 2
The following compound was obtained according to a similar manner to that of Example 1. N - [3 - (1 - Benzyloxycarbonylpyrazol - 3 - yl) phenyl] - N' - (1 - methylindol
— 5 — yl) urea
NMR (DMSO-d6,<5) : 3.76 (3H,s), 5.50 (2H,s), 6.35 (lH,d,J = 3Hz), 7.03 (1H, d,J = 3Hz), 7.10-7.60 (13H,m), 7.69 (lH.br.s), 8.05 (2H,m), 8.30-8.50 (2H,m), 8.75 (lH.br.s) -
Example 3
The following compound was obtained according to a similar manner to that of Example 1.
N - [3 - (2 - Aminothiazol - 4 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 200 - 205 °C IR (Nujol, cm" 1) : 1640, 1610
NMR (DMSO-d6,(5) : 3.76 (3H,s), 6.34 (lH,d,J = 3Hz), 6.91 (lH.s), 7.01 (2H, br.s), 7.10-7.40 (6H,m), 7.69 (lH,d,J = 2Hz), 7.96 (lH,s), 8.38 (lH,s), 8.58 (IH, s) Mass : 364 (M + 1 + )
Example 4
The following compound was obtained according to a similar manner to that of Example 1. N — [3 — (2 — Imidazol - 4 — yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea
m.p. : 200 - 203 °C
IR (Nujol, cm ~ : 1620
NMR (DMSO - d6, δ ) : 3.76 (3H,s), 6.34 (lH,d,J - 3Hz), 7.05 - 7.04 (6H,m), 7.
50 (lH,s), 7.71 (2H,d,J = lHz), 7.85 (lH,s), 8.41 (lH.br.s), 8.57 (lH.br.s), 12.21
(lH,br.s)
Mass : 332 (M + 1 + )
Example 5
The following compound was obtained according to a similar manner to that of Example 1.
N- [3- (1 - Benzylpyrazol - 3 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 165 - 170 °C
IR (Nujol, cm ~ λ) : 1620
NMR (DMSO-d6,5) : 3.75 (3H,s), 5.38 (2H,s), 6.34 (lH,d,J = 2Hz), 6.67 (IH, d,J = 2Hz), 7.00-7.40 (llH.m), 7.69 (lH,s), 7.80-7.95 (2H,m), 8.37 (lH,s), 8.
64 (lH,s)
Mass : 422 (M + 1 + )
Example 6
To a suspension of 5 — (3 — methylpyrazol — 5 — yl) pyridine — 3 — carboxylic acid ( 70mg ) were added triethylamine ( 0.048ml ) and diphenylphosphorous azide (0.073ml). The mixture was refluxed for 3 hours, then cooled. 5 — Amino — 1 — methylindole (61mg) was added to the mixture with benzene (5ml). The mixture was refluxed for 1 day. After cooled, the mixture was dissolved in chloroform, washed by agueous sodium bicarbonate, dried over sodium sulfate, and chromatographed on silica gel eluted by chloroform — methanol (9 : 1 v/v), to give N — (1 — methylindol — 5 — yl) — N' — [5— (5 — methylpyrazol — 3 — yl) pyridin - 3 - yl] urea (61mg). m.p. : 208-211 °C IR (Nujol, cm ~ : 1620
NMR (DMSO-d6,(5) : 2.29 (3H,s), 3.75 (3H,s), 6.35 (lH.d = 3Hz), 6.49 (IH, s), 7.17 QH,dd,J = 9Hz,2Hz), 7.27 (lH,d,J = 2Hz), 8.34 (lH.br.s), 8.40-8.60 (3H, m), 8.78 (lH.br.s), 12.70 (lH.br.s) Mass : 347 (M + 1 + )
Example 7
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. Filtrate was evaporated, and chromatographed on silica gel eluted by chloroform — methanol (0 - 3 % v/v), to give N - [3 - (pyrazol — 3 - yl) phenyl] — N' — (1 — methylindol - 5 - yl) urea (86mg). m.p. : 173 - 178 °C IR (Nujol, cm- 1) : 1630
NMR (DMSO-d6,<5) : 3.76 (3H,s), 6.35 (lH,d,J = 3Hz), 6.63 (lH,br.s), 7.16 (IH, dd,J-9Hz,2Hz), 7.20-7.40 (5H,m), 7.70 (lH,d,J = 2Hz), 7.77 (lH.br.s), 7.93 (IH, br.s), 8.41 (lH.br.s), 8.62 (lH.br.s), 12.86 (lH.br.s) Mass : 332 (M + 1 + )
Example 8
The following compound was obtained according to a similar manner to that of Example 1.
N- (1 -Methylindol -5 -yl) - N' - [3- (5 - methylpyrazol - 3 - yl) phenyl] urea m.p. : 185 - 188 °C IR (Nujol, cm"" 1) : 1630
NMR (DMSO-d6,5) : 2.26 (3H,s), 3.76 (3H,s), 6.30-6.40 (2H,m), 7.15 (IH, dd,J = 9Hz,2Hz), 7.20-7.40 (5H,m), 7.71 (lH,d,J = 2Hz), 7.88 (lH.br.s), 8.43 (IH, br.s), 8.61 (lH,s), 12.54 (lH.br.s) Mass : 346 (M + 1 + )
Example 9
The following compound was obtained according to a similar manner to that of Example 1.
N - [3 - (3,5 - Dimethylpyrazol - 1 - yl) phenyl] - N' - (1 - methylindol - 5 — yl) urea m.p. : 163 - 171 °C IR (Nujol, cm" 1) : 1620, 1600
NMR (DMSO-d6,<S) : 2.18 (3H,s), 2.31 (3H,s), 3.76 (3H,s), 6.06 (lH,s), 6.34 (lH,d,J = 3Hz), 7.05 (lH,d,J = 7Hz), 7.15 (lH,d,J = 9Hz), 7.20-7.40 (4H,m), 7.69 (lH,s), 7.77 (lH,s), 8.47 (lH,s), 8.78 (lH,s) Mass : 360 (M + 1 + )
Example 10
The following compound was obtained according to a similar manner to that of Example 1. N- (1 - Methylindol - 5 - yl) - N' - [3- (pyrimidin - 4 - yl) phenyl] urea
m.p. : 206 - 209 °C
IR (Nujol, cm- 1) : 1620 NMR (DMSO-d6, 5) : 3.77 (3H,s), 6.36 (lH.d.J = 3Hz), 7.17 (lH.dd.J = 9Hz, 2Hz), 7.27 (lH,d,J = 3Hz), 7.35 (lH,d,J = 8Hz), 7.43 (lH,d,J = 8Hz), 7.62 (lH.br. d,J = 9Hz), 7.70-7.80 (2H,m), 8.02 (lH.dd.J = 5Hz,lHz), 8.41 (lH,br.s), 8.48 (IH, br.s), 8.81 (lH.br.s), 8.89 (lH,d,J = 5Hz), 9.26 (lH,d,J = 1Hz) Mass : 344 (M + 1 + )
Example 11
The following compound was obtained according to a similar manner to that of Example 6.
N - (1 - Methylindol - 5 - yl) - N' - [3 - (2 - pyridyl) phenyl] urea m.p. : 199 - 200 °C IR (Nujol, cm" 1) : 3250, 1610
NMR (DMSO-d6,(5) : 3.76 (3H,s), 6.36 (lH,d,J - 2.9Hz), 7.15-7.91 ClOH.m), 8.28 (lH,s), 8.46 (lH,s), 8.67 (lH.d = 4.7Hz), 8.76 (lH.s) Mass : 343 (M + 1)
Example 12
To a solution of N - (1 - Methylindol - 5 - yl) -N' - [3- [methylthio (imino) methyl] phenyl] urea hydriodide (0.22g) in ethanol (20ml) were added ethylenediamine (0.13ml) and acetic acid (0.22ml).
The mixture was refluxed for 7hours, coold, evaporated in vacuo, and triturated with water.
Resulted precipitates were collected, washed by water and diethyl ether, and dried to give N — [3 — (2 - imidazolin - 2 - yl) phenyl] — N' - (1 — methylindol — 5 — yl) urea hydriodide. m.p. : 165 - 170 °C (dec.) IR (Nujol, cm" 1) : 1680, 1610
NMR (DMSO-d6,5) : 3.76 (3H,s), 3.89 (4H,s), 6.35 (lH,d,J = 3Hz), 7.10 - 7. 80 (7H,m), 8.11 (lH.br.s), 8.69 (lH.br.s), 8.99 (lH.br.s) Mass : 334 (M + 1 + )
Example 13
To a solution of 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. Resulted precipitates were collected, dissolved in chloroform — methanol (9 : lv/v), dried over sodium sulfate, and chromatographed on silica gel eluted with chloroform — methanol (0 - 3 % v/v) to give N - (1 - methylindol - 5 - yl) - N' - [3 - (4 — methylthiazol - 2 - yl) phenyl] urea (0.88g). m.p. : 228 - 230 °C IR (Nujol, cm" 1) : 1625
NMR (DMSO-d6,f5) : 2.44 (3H,s), 3.77 (4H,s), 6.35 (lH,d,J = 3Hz), 7.10-7. 55 (7H,m), 7.71 (lH,d,J - 2Hz), 8.23 (lH.br.s), 8.47 (lH.br.s), 8.83 (lH.br.s) Mass : 363 (M + 1 + )
Example 14
The following compound was obtained according to a similar manner to that of Example 13.
N- (1- Methylindol- 5 -yl) - NT - [3- (4 - phenylthiazol - 2 - yl) phenyl] urea m.p. : 220 - 223 °C IR (Nujol, cm" 1) : 1620
NMR (DMSO-d6,<5) : 3.77 (3H,s), 6.37 (lH,d,J = 3Hz), 7.17 (lH,dd,J = 9Hz, 2Hz), 7.25-7.65 (8H,m), 7.72 (lH,d,J = 2Hz), 8.06 (2H,d,J = 7Hz), 8.18 (lH,s), 8.29 (lH.br.s), 8.48 (lH,s), 8.89 (lH.s) Mass : 425 (M + 1 + )
Example 15
The following compound was obtained according to a similar manner to that of Example 1.
N- [3- (IH- l,2,4-Triazol-3-yl) phenyl] - NT - (1 - methylindol - 5 - yl) urea m.p. : > 220 °C IR (Nujol, cm" 1) : 1640 NMR (DMSO-d6,5) : 3.76 (3H,s), 6.35 (lH,d,J = 3Hz), 7.17 (lH,dd,J = 2,9Hz), 7.27 (lH,d,J = 3Hz), 7.33 (lH,s), 7.37 (lH,s), 7.48 (lH,m), 7.58 (lH,m), 7.70 (IH, d,J = 3Hz), 8.18 (lH.br.s), 8.44 (lH.br.s), 8.74 (lH.br.s) Mass : 333 (M + 1 + )
Example 16
The following compound was obtained according to a similar manner to that of Example 1.
N — [3 — (Thiazol — 4 — yl) phenyl] — N' — (1 — methylindol — 5 — yl) urea m.p. : 213 - 215 °C IR (Nujol, cm" 1) : 1640
NMR (DMSO - d6,(5) : 3.76 (3H,s), 6.34 (lH,d,J = 3.0Hz), 7.16 (lH,dd,J = 8.7Hz, 2.0Hz), 7.27 (lH,d,J = 3.0Hz), 7.56 (lH,d,J = 7.4Hz), 7.28-7.50 (4H,m), 7.71 (IH, d,J = 1.7Hz), 8.08 (lH,d,J = 1.9Hz), 8.15 (lH,s), 8.45 (lH,s), 8.71 (lH,s), 9.20 (IH, d,J - 1.9Hz) Mass : 349 (M + 1 + )
Example 17
The following compound was obtained acoording to a similar manner to that of Example 1.
N- [3- (2 - Methylthiazol - 4 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 198 - 199 °C IR (Nujol, cm" 1) : 1630
NMR (DMSO-d6,f5) : 2.73 (3H,s), 3.76 (3H,s), 6.35 (lH,d,J - 3.0Hz), 7.15 (IH, dd,J = 8.7Hz,1.9Hz), 7.26-7.52 (5H,m), 7.71 (lH,d,J = 1.8Hz), 7.85 (lH,s), 8.09 (IH, s), 8.41 (lH,s), 8.71 (lH.s) Mass : 363 (M + 1 + )
Example 18
The following compound was obtained acoording to a similar manner to that of Example 1. N - [3 - (5 - Methylimidazol - 4 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 229 - 231 °C
IR (Nujol, cm " !) : 1665
NMR (DMSO-d6,(5) : 2.39 (3H,br.s), 3.76 (3H,s), 6.35 (lH,d,J = 3.0Hz), 7.14
QH,dd,J = 8.8Hz,1.7Hz), 7.17-7.40 (5H,m), 7.55 (lH,s), 7.69 (lH,d,J = 1.7Hz), 7.
77 (lH.br.s), 8.41 (lH.br.s), 8.61 (lH.br.s), 11.95 (lH.br.s)
Mass : 346 (M + 1 + )
Example 19
The following compound was obtained acoording to a similar manner to that of Example 1.
N- [3- (1 - Methylimidazol -4- yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 90-110 °C IR (Nujol, cm" 1) : 1660, 1610
NMR (DMSO-d6,r5) : 3.69 (3H,s), 3.76 (3H,s), 6.34 (lH,d,J = 2Hz), 7.10-7. 40 (6H,m), 7.52 (lH,s), 7.62 (lH,s), 7.70 (lH.d.J = 2Hz), 7.87 (lH,s), 8.39 (IH, s), 8.56 (lH,s) Mass : 346 (M + 1 + )
Example 20
The following compound was obtained acoording to a similar manner to that of Example 1.
N — [3 — (Isoxazol — 5 — yl) phenyl] — N' — (1 — methylindol — 5 — yl) urea m.p. : 199 - 202 °C IR (Nujol, cm" 1) : 1630
NMR (DMSO-d6,5) : 3.77 (3H,s), 6.35 (lH,d,J = 3Hz), 6.97 (lH.d.J = 2Hz), 7.17 (lH,dd,J = 9Hz,2Hz), 7.20-7.50 (5H,m), 7.71 (lH,d,J = 2Hz), 8.09 (lH,s), 8. 54 (lH,s), 8.66 (lH,d,J = 2Hz), 8.83 (lH,s) Mass : 333 (M + 1 + )
Example 21
The following compound was obtained acoording to a similar manner to that of Example 1.
N - [3 - (Imidazol - 2 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 230 - 235 (dec.) °C
IR (Nujol, cm " l) : 1633
NMR (DMSO-dg,^) : 3.76 (3H,s), 6.35 (lH,s), 7.10-7.55 (8H,m), 7.71 (IH, s), 8.05 (lH,s), 8.47 (lH.s), 8.67 (lH,s), 12.50 (lH.br.s)
Mass : 332 (M + 1 + )
Example 22
The following compound was obtained acoording to a similar manner to that of Example 1.
N - [3 - (Imidazol - 1 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 180 - 185 °C IR (Nujol, cm" 1) : 1630
NMR (DMSO - dg, δ ) : 3.76 (3H,s), 6.35 (lH,d,J = 3Hz), 7.10 - 7.45 (7H,m), 7. 60-7.70 (2H,m), 7.78 (lH,s), 8.16 (lH,s), 8.56 (lH,s), 8.79 (lH,s) Mass : 332 (M + 1 + )
Example 23
The following compound was obtained acoording to a similar manner to that of Example 1.
N — [4 — (Imidazol — 1 — yl) phenyl] — N' - (1 — methylindol — 5 — yl) urea m.p. : 234 - 239 °C IR (Nujol, cm" 1) : 1640
NMR (DMSO-d6,5) : 3.76 (3H,s), 6.35 (lH,d,J = 3Hz), 7.08 (lH,s), 7.15 (IH, dd,J = 9Hz,2Hz), 7.27 (lH,d,J = 3Hz), 7.35 (lH,d = 9Hz), 7.50-7.65 (4H,m), 7. 66 (lH,s), 7.69 (lH,d,J = 2Hz), 8.16 (lH,s), 8.49 (lH.s), 8.76 (lH.s) Mass : 332 (M + 1 + )
Example 24
The following compound was obtained acoording to a similar manner to that of Example 1. N - [2 - (Imidazol - 1 - yl) pyridin - 5 - yl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 230 - 235 °C
IR (Nujol, cm " l) : 1630
NMR (DMSO-d6,f5) : 3.77 (3H,s), 6.36 (lH,d,J = 3Hz), 7.11 (lH,s), 7.17 (IH, dd,J = 9Hz,2Hz), 7.28 (lH,d,J = 3Hz), 7.36 (lH,d,J = 9Hz), 7.65-7.80 (2H,m), 7.
89 (lH,s), 8.15 (lH,dd,J = 9Hz,3Hz), 8.32 (lH,s), 8.54 (lH,d,J = 2Hz), 8.64 (IH, s), 8.91 (lH,s)
Mass : 333 (M + 1 + )
Example 25
To a solution of 3 - (2 - imidazolon - 1 — yl) aniline (0.17g) in N,N — dimethylformamide were added 4 — nitrophenyl N— (1 — methylindol — 5 - yl) carbamate (0.30g) and triethylamine (0.14ml). The mixture was stirred at ambient temperature for 6 hours, and partitioned between ethyl acetate and aqueous sodium hydrogencarbonate. Organic layer was dried over sodium sulfate, evaporated, and triturated with chloroform to give N - [3 — (2 - imidazolon - 1 - yl) phenyl] — N' - (1 - methylindol - 5 - yl) urea (0.21g).
m.p. : 199 - 201 °C
IR (Nujol, cm" 1) : 1680, 1640
NMR (DMSO-d6,(5) : 3.76 (3H,s), 6.35 (lH,d,J - 3Hz), 6.60 (lH,t,J = 3Hz),
6.88 (lH,t,J = 3Hz), 7.05-7.45 (6H,m), 7.70 (lH,d,J = 2Hz), 7.91 (lH,d,J = 2Hz),
8.44 (lH,s), 8.77 (lH,s), 10.32 (lH.br.s)
Mass : 348 (M + 1 + )
Example 26
The following compound was obtained acoording to a similar manner to that of Example 25.
N- [3- (2 - Imidazolinon - 1 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 198 - 200 °C
IR (Nujol, cm" 1) : 1710, 1680, 1630 NMR (DMSO-d6,5) : 3.40 (2H,t,J = 7Hz), 3.75 (3H,s), 3.83 (2H,t), 6.34 (IH, d,J = 3Hz), 6.94 (lH,s), 7.00-7.40 (6H,m), 7.65-7.80 (2H,m), 8.42 (lH,s), 8.69
(lH,s)
Mass : 350 (M + 1 + )
Example 27
The following compound was obtained acoording to a similar manner to that of Example 25.
N- [3- (Oxazol - 5 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 204 - 206 °C IR (Nujol, cm" 1) : 1630
NMR (DMSO-d6,r5) : 3.76 (3H,s), 6.35 (lH,d,J = 3.0Hz), 7.16 (lH,dd,J = 8.7Hz, 2.0Hz), 7.28 (lH,d,J = 3.0Hz), 7.30-7.36 (4H,m), 7.64 (lH,s), 7.71 (lH,d,J = 1.8Hz), 7.95 (lH,br.s), 8.45 (lH,s), 8.49 (lH.br.s), 8.76 (lH.br.s) Mass : 333 (M + 1 + )
Example 28
The following compound was obtained acoording to a similar manner to that of Example 25.
N - [3 - (Thiazol - 5 - yl) phenyl] - N' - (1 - methylindol - 5 — yl) urea m.p. : 190 - 191 °C IR (Nujol, cm" 1) : 1630
NMR (DMSO-d6,5) : 3.76 (3H,s), 6.35 (lH,d,J = 3.0Hz), 7.15 (lH,dd,J = 8.7Hz, 2.0Hz), 7.25-7.45 (5H,m), 7.70 (lH,d,J = 1.8Hz), 7.86 (lH.s), 8.26 (lH,s), 8.51 (lH,s), 8.76 (lH,s), 9.09 (lH.s) Mass : 349 (M + 1 + )
Example 29
The following compound was obtained acoording to a similar manner to that of Example 25.
N- [3- (4H - 1,2,4 - Triazol - 4 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 197 - 198 °C IR (Nujol, cm" 1) : 1690 NMR (DMSO - dg, δ ) : 3.76 (3H,s), 6.35 (lH,d,J - 2.6Hz), 7.16 (lH,dd,J = 8.7Hz, 1.9Hz), 7.20-7.48 (2H,m), 7.35 (lH,d,J = 8.7Hz), 7.44-7.48 (2H,m), 7.70 (IH, d,J = 1.9Hz), 7.80 (lH.br.s), 8.61 (lH.br.s), 8.86 (lH.br.s), 9.06 (2H,s) Mass : 333 (M + 1 + )
Example 30
The following compound was obtained acoording to a similar manner to that of Example 25.
N- [3- (IH - 1,2,4 - Triazol - 1 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 218 - 219 °C IR (Nujol, cm" 1) : 1640
NMR (DMSO-dg,f5) : 3.76 (3H,s), 6.35 (lH,d,J = 3.2Hz), 7.16 (lH,dd,J = 8.7Hz, 2.1Hz), 7.28 (lH,d,J = 3.2Hz), 7.33-7.43 (4H,m), 7.70 (lH,d,J = 1.9Hz), 8.11 (IH, br.s), 8.24 (lH,s), 8.53 (lH.br.s), 8.89 (lH.br.s), 9.25 (2H,br.s) Mass : 333 (M + 1 + )
Example 31
The following compound was obtained acoording to a similar manner to that of Example 25.
N- [3- (1 - Methylimidazol -5 -yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea
IR (Nujol, cm- 1) : 1660
NMR (DMSO-d6,r5) : 3.69 (3H,s), 3.76 (3H,s), 6.34 (lH,d,J = 2.9Hz), 7.04- 7.08 (2H,m), 7.14 (lH,dd,J = 8.7Hz,1.9Hz), 7.26-7.44 (4H,m), 7.63 (lH,s), 7.68 -7.71 (2H,m), 8.49 (lH,s), 8.69 (lH,s) Mass : 346 (M + 1 + )
Example 32
To a solution of 3 - (Imidazol - 4 - yl) aniline (0.17g) in tetrahydrofuran (15ml) was added carbonyldiimidazol (0.173g), and was stirred at ambient temperature for 5 hours. To the reaction mixture was added a solution of 5 - Methyl - 2,3 - dihydropyrrolo [2,3 - f] indole (0.18g) in tetrahydrofuran (5ml). The mixture was stirred at ambient temperature for 24 hours and evaporated. The residue was partitioned between ethyl acetate and water. Organic layer was dried over sodium sulfate and chromatographed on silica gel eluted by chloroform - methanol (0 - 10 % v
/v) to give 1— [[3— (Imidazol — 4 — yl) phenyl] carbamoyl] — 5 — methyl
- 2,3 - dihydropyrrolo [2,3 - f] indole (0.14g). m.p. : 252 - 256 °C
IR (Nujol, cm" 1) : 1635, 1610
NMR (DMSO-dg.S) : 3.26 (2H,t,J = 8Hz), 3.73 (3H,s), 4.18 (2H,t,J = 8Hz), 6.
30 (lH,d,J = 3Hz), 7.17 (lH,d,J = 3Hz), 7.20-7.50 (5H,m), 7.73 (lH.d.J = 1Hz), 7.97 (lH,s), 8.05 (lH,s), 8.43 (lH,s), 12.00-12.50 (lH.br.s)
Mass : 358 (M + 1 + )
Example 33
The following compound was obtained acoording to a similar manner to that of Example 32.
1- [[3- (IH - 1,2,4 - Triazol - 3 - yl) phenyl] carbamoyl] - 5 - methyl - 2, 3 — dihydropyrrolo [2,3 — f] indole m.p. : > 220 °C IR (Nujol, cm" 1) : 1680 NMR (DMSO-dg,f5) : 3.27 (2H,t,J = 8Hz), 3.73 (3H,s), 4.19 (2H,t,J = 8Hz), 6.
31 (lH,d,J = 3Hz), 7.18 (lH,d,J = 3Hz), 7.26 (lH,s), 7.38 (lH,m), 7.67 (2H,m), 8. 06 (lH.br.s), 8.30 (lH.br.s), 8.60 (lH.br.s), 14.10 (lH.br.s)
Mass : 359 (M + 1 + )
Example 34
The following compound was obtained acoording to a similar manner to that of Example 12.
1- [[3- (2 - Imidazolin - 2 - yl) phenyl] carbamoyl] - 5 - methyl - 2,3 - dihydropyrrolo [2,3 — f] indole hydriodide m.p. : 191 - 193 °C
IR (Nujol, cm" 1) : 1650
NMR (DMSO-dg,(5) : 3.29 (2H,t,J = 8Hz), 3.74 (3H,s), 4.02 (4H,br.s), 4.18 (2H, t,J = 8Hz), 6.31 (lH,d,J = 3Hz), 7.20 (lH,d,J = 3Hz), 7.29 (lH,s), 7.66 (3H,m), 8. 05 (lH,s), 8.31 (lH,d,J = 3Hz), 8.83 (lH.br.s), 10.45 (lH.br.s) Mass : 360 (M + 1 + )
Example 35
To a 10ml round bottom flask was added in under 4 — nitrophenyl N— [3— (thiazol — 5 — yl) phenyl] carbamate (171mg), 5 — methyl — 2,3 — dihydropyrrolo [2,3 — f] indole (86mg), dimethylformamide (1ml), and triethylamine (91 μ 1), stirred at ambient temperature for 65 hours. Diluted with water (10ml). After 30 minutes, collected by filtration, washed with water many times. Recrystallized from 95% ethanol (8ml) to give 1— [[3 — (thiazol — 5 — yl) phenyl] carbamoyl] — 5 — methyl — 2,3 — dihydropyrrolo [2, 3-f] indole (141mg). m.p. : 175- 176 °C IR (Nujol, cm" 1) : 1645
NMR (DMSO-dg.5) : 3.27 (2H,t,J = 8,2), 3.73 (3H,s), 4.18 (2H,t,J = 8,2), 6.32 (IH, d,J = 3.0), 7.19 (lH,d,J = 3.0), 7.26 (lH,s), 7.33-7.38 (2H,m), 7.58-7.70 (lH,m), 7.91 (lH.br.s), 8.05 (lH,s), 8.26 (lH,s), 8.56 (lH.br.s), 9.09 (lH,s).
Example 36
The following compound was obtained acoording to a similar manner to that of Example 25.
N - [3 - (2 - Methylimidazol - 5 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 214 - 216 (dec.) °C
FT - IR (KBr, cm"1) : 3370, 3290, 1640, 1610, 1590, 1550, 1510, 1490, 1440, 1420, 1300, 1230
NMR (DMSO-dg,5) : 2.31 (3H,s), 3.76 (3H,s), 6.35 (lH,dd,J = 3Hz), 7.1-7.4 (7H,m), 7.71 (lH,d,J = 1.7Hz), 7.83 (IH, bs), 8.40 (IH, bs), 8.56 (lH.s), 11.8 (lH.bs) APCI - Mass : 346 (M + Hτ)
Example 37 The following compound was obtained acoording to a similar manner to that of Example 25.
N - [3 — (2 — Isopropylimidazol — 5 - yl) phenyl] — N' — (1 - methylindol — 5 — yl) urea m.p. : 140 - 205 (amorphous) °C
FT - IR (KBr, cm" 1) : 3370, 3270, 2970, 1660, 1610, 1590, 1550, 1490, 1440, 1230
NMR (DMSO-dg,<5) : 1.28 (6H,d,J = 7Hz), 2.9-3.1 (lH.m), 3.76 (3H,s), 6.35 (IH, d,J = 3Hz), 7.1-7.4 (7H,m), 7.70 (lH,d,J = 1.6Hz), 7.80 (lH,s), 8.37 (lH,s), 8.60 (lH,s), 11.83 (lH,bs) APCI-Mass : 374 (M + H
Example 38
The following compound was obtained acoording to a similar manner to that of Example 25.
N - (1 - Methylindol - 5 - yl) - N' - [3 - (2 - tert - butylimidazol - 5 - yl) phenyl] urea m.p. : 129 - 150 (dec.) °C
IR (Nujol, cm" 1) : 3300 - 3100, 1650, 1580, 1530, 1450, 1320, 1280, 1220 NMR (DMSO-dg,f5) : 1.34 (9H,s), 3.76 (3H,s), 6.35 (lH,dd,J = 3Hz), 7.1-7.4 (7H,m), 7.71 (lH,d,J = 2Hz), 7.76 (lH,m), 8.36 (lH,s), 8.63 (lH,s), 11. 77 (lH,bs) APCI-Mass : 388 (M + H
Example 39
The following compound was obtained acoording to a similar manner to that of Example 25.
N - (1 - Methylindol - 5 - yl) - N' - [3 - (2 - trifluoromethylimidazol - 5 - yl) phenyl] urea m.p. : 208 - 210 °C
FT - IR (KBr, cm " : 3288, 3126, 3074, 2922, 1660, 1616, 1583, 1556, 1514, 1485, 1444, 1422, 1398, 1302, 1230 crrr1 NMR (DMSO-dg,(5) : 3.76 (3H,s), 6.35 (lH,d,J = 3Hz), 7.12-7.19 (lH.m), 7.26 -7.37 (5H,m), 7.71 (lH,d,J = 1.7Hz), 7.89 (lH.bs), 7.97 (lH.bs), 8.40 (lH.bs), 8.67 (lH,s), 13.71 (lH.bs) APCI-Mass : 400 (M + H
Example 40
The following compound was obtained acoording to a similar manner to that of Example 25.
N - [3 - (1,2 - Dimethylimidazol - 5 - yl) phenyl] - N' - (1 - methylindol - 5 — yl) urea m.p. : 209 - 210 °C
FT - IR (KBr, cm" 1) : 3325, 3099, 1703, 1583, 1543, 1493, 1429, 1296, 1250, 1211 cm '
NMR (DMSO-dg, 5) : 2.35 (3H,s), 3.53 (3H,s), 3.76 (3H,s), 6.34 (lH,d,J = 3Hz), 6.84 (lH,s), 6.9-7.0 (lH,m), 7.1-7.2 (lH.m), 7.2-7.5 (4H,m), 7.56 (lH.bs), 7.69 (lH,d,J = 2Hz), 8.47 (lH,s), 8.68 (lH.s) APCI - Mass : 360 (M + H+)
Example 41
The following compound was obtained acoording to a similar manner to that of Example 25.
N - [3 - (4 - Methylimidazol - 1 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 194 - 197 °C IR (Nujol, cm" 1) : 1640, 1605
NMR (DMSO-dg,όO : 2.17 (3H,s), 3.76 (3H,s), 6.35 (lH,d,J = 3Hz), 7.1-7.4 (7H,m), 7.70 (lH,s), 7.76 (lH,s), 8.03 (lH,s), 8.56 (lH.s), 8.78 (lH.s) APCI - Mass : 346 (M + 1 + )
Example 42
The following compound was obtained acoording to a similar manner to that of Example 25.
N- (1 -Methylindol -5 -yl) - NT - [3 - (2 - methylthiazol - 5 - yl) phenyl] urea m.p. : 209 - 212 °C
FT - IR (KBr, cm^ 1) : 3286, 1624, 1589, 1558, 1487, 1431, 1333, 1300, 1242 cπ 1
NMR (DMSO-dg,c5) : 2.68 (3H,s), 3.76 (3H,s), 6.35 (lH,d,J = 3Hz),
7.1-7.4 (6H,m), 7.70 (lH,m), 7.78 (lH,m), 7.96 (lH,s), 8.48 (lH,s),
8.72 (lH,s)
APCI-Mass : 363 (M + HO
Example 43
The following compound was obtained acoording to a similar manner to that of Example 6.
N - (1 - Methylindol - 5 - yl) - N' - [3 - (pyridin - 3 - yl) phenyl] urea m.p. : 172 - 174 °C IR (Nujol, cm- 1) : 3260, 1630
NMR (DMSO-dg,ό : 3.76 (3H,s), 6.35 (lH,d,J = 2.9Hz), 7.16 (lH,dd,J = 8.7Hz, 2.0Hz), 7.27-7.54 (lH,s), 8.59 (lH,dd,J = 4.7Hz, 1.5Hz), 8.75 (lH,s), 8.85 (lH,d, J = 1.8Hz) Mass : 343 (M + 1) +
Example 44
The following compound was obtained acoording to a similar manner to that of Example 6.
1 - [ [3 - (Pyridin — 3 — yl) phenyl] carbamoyl] — 5 - methyl — 2,3 — dihydropyrrolo [2,3 — f] indole m.p. : 181 (dec.) °C IR (Nujol, cm" 1) : 1640, 1600
NMR (DMSO-dg,όO : 3.28 (2H,t,J = 8.3Hz), 3.73 (3H,s), 4.19 (2H,t,J = 8.3Hz), 6.31 (lH,d,J = 2.8Hz), 7.18 (lH,d,J = 3.0Hz), 7.27 (lH,s), 7.33-7.54 (3H,m), 7.67 (lH,d,J = 7.8Hz), 7.95 (lH,s), 8.02-8.06 (2H,m), 8.56-8.60 (2H,m), 8.87 (lH,d, J = 1.8Hz) Mass : 369 (M + 10
Example 45 To a suspension of 1 — methylindole — 5 — carboxylic acid (lOOmg) in benzene ( 5ml ) were added triethylamine ( 159 μ 1 ) and diphenylphosphorous azide (121 μ 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. After cooled, the mixture was dissolved in ethyl acetate, washed with water and dried over sodium sulfate, and chromatographed on silica gel eluted by chloroform — methanol (10 : 1) to give N — [3 — (imidazol — 1 — yl) — 6 — nitrophenyl] — N' — (1 — methylindol - 5 - yl) urea (lOmg). m.p. : 220 °C (dec.) IR (Nujol, cm " l) : 3300, 1710, 1615
NMR (DMSO-dg.S) : 3.77 (3H,s), 6.38 (lH,d,J = 2.5Hz), 7.17-7.22 (3H,m), 7. 30 (lH,d,J = 3.0), 7.39 (lH,d,J = 8.7Hz), 7.49 (lH,dd,J = 9.2Hz, 2.3Hz), 7.77 (IH, d,J = 2.0Hz), 7.81 (lH,t,J = 1.5Hz), 8.26 (lH,s), 8.31 (lH,d,J = 3.0Hz), 8.37 (lH,s), 8.68 (lH,d,J = 2.4Hz) Mass : 377 (M + lO
Example 46
To a solution of 3 — (imidazol — 1 — yl) aniline (0.48g) in dichloromethane (50ml) was added 4 — nitrophenoxycarbonyl chloride (0.61g). The mixture was stirred at ambient temperature for 10 minutes. Then 5 — methyl — 2,3 - dihydropyrrolo [2,3 - f] indole (0.52g) and triethylamine (0. 84ml) were added. The mixture was stirred at ambient temperature for 7 hours, washed by aqueous sodium hydrogencarbonate and water successively, dried over sodium sulfate , and evaporated in vacuo . Residue was chromatographed on silica gel eluted by chloroform — methanol (0 — 3%) to give 1 — [[3- (imidazol - 1 - yl) phenyl] carbamoyl] - 5 — methyl — 2,3 - dihydropyrrolo [2,3 - f] indole (0.61g). m.p. : 211-214 °C IR (Nujol, cm" 1) : 1665, 1645
NMR (DMSO-dg,όO : 3.27 (2H,t,J = 8Hz), 3.73 (3H,s), 4.18 (2H,t,J = 8Hz), 6.31 (lH,d,J = 3Hz), 7.12 (lH.s), 7.15-7.30 (3H,m), 7.43 (lH,t,J = 8Hz), 7.50-7.70 (2H, m), 7.87 (lH,t,J = 2Hz), 8.05 (lH,s), 8.16 (lH,s), 8.64 (lH,s) APCI - Mass : 358 (M + 10
Example 47
To a solution of 3 — (1 - methylimidazol — 5 — yl) aniline (87mg), dimethylformamide (1ml), and pyridine (40 μ 1) at 5 °C was added 4 — nitrophenyl chloroformate (lOlmg). Stirred 30 minutes, then added 5 — methyl — 2,3 - dihydropyrrolo [2,3 - f] indole (86mg), then triethylamine (0.14ml).
Stirred at room tempereture overnight (lδhours.). Poured with water (30ml), after 30 minutes collected by filtration, washed with water, dissolved in silica gel column washed with brine, dried (magnesium sulfate), filtered, evaporated.
Purified by silica gel column. Stirred in isopropyl ether ( 10ml) to give 1- [[3- (1 — methylimidazol - 5 - yl) phenyl] carbamoyl] - 5 - methyl - 2, 3 — dihydropyrrolo [2,3 — f] indole. m.p. : 224 - 226 °C Mass : 372 (M + 1) IR (Nujol, cm" 1) : 1655
NMR (DMSO, δ) : 3.27 (2H,t,J = 8.2Hz), 3.71 (3H,s), 3.73 (3H,s), 4.17 (2H,t,J = 8.2Hz), 6.31 (lH,d,J = 2.5Hz), 7.03 (lH,bs), 7.11 (lH,d,J = 8.0Hz), 7.18 (lH,d,J = 3.0Hz), 7.26 (lH,s), 7.37 (lH,dd,J - 7.8Hz, 7.8Hz), 7.60 (lH,d,J = 8.1Hz), 7.70 (IH, s), 7.71 (lH,s), 8.03 (lH,s), 8.52 (lH,s).
Example 48
The following compound was obtained according to a similar manner to that of Example 47.
1— [[3- (1,2 — Dimethylimidazol — 5 - yl) phenyl] carbamoyl] - 5 - methyl - 2,3 - dihydropyrrolo [2,3 - f] indole m.p. : 224 - 227 °C
FT-IR (KBr, cm 1) : 3263, 2941, 1662, 1610, 1564, 1529, 1473, 1425, 1331, 1279, 1246cm 1
NMR (DMSO-d6)f5) : 2.36 (3H,s), 3.26 (2H,t,J = 8Hz), 3.56 (3H,s), 3.73 (3H,s), 4.17 (2H,t = 8Hz), 6.31 (lH,d,J = 3Hz), 6.85 (lH.s), 7.0-7.10 (lH.m), 7.17 (IH, d,J = 3Hz), 7.26 (lH,bs), 7.36 (lH,t,J = 8Hz), 7.5-7.6 (lH,m), 7.66 (lH,bs), 8.03 (lH,s), 8.51 (lH,bs) APCI - MS : 386" (M + HO
Example 49
The following compound was obtained according to a similar manner to that of Example 25.
N— [3— (1 — Isopropylimidazol — 5 - yl) phenyl] — N' - (1 - methylindol - 5 — yl) urea m.p. : 213- 215 °C
FT-IR (KBr, cm 1) : 3313, 3099, 2973, 1697, 1662, 1581, 1544, 1487, 1423, 1290, 1230cm 1
NMR (DMSO-d6,5) : 1.42 (6H,d,J = 7Hz), 3.76 (3H,s), 4.35-4.49 (lH,m), 6.35 (lH,d,J = 3Hz), 6.92 (lH,d,J = 0.8Hz), 6.94-6.98 (IH, m), 7.12-7.18 (IH, m), 7.26-7.47 (4H,m), 7.56 (lH,m), 7.68 (lH,d,J = 1.7Hz), 7.93 QH,m), 8.48 (lH,s), 8.71 (lH,s) APCI - MS : 374 (M + HO
Example 50
The following compound was obtained according to a similar manner to that of Example 25.
N - [3 - (2 - Imidazolon - 4 - yl) phenyl] - N' - (1 - methylindol - 5 - yl) urea m.p. : 222 - 227 °C
FT-IR (KBr, cm"1) : 3276, 3215, 3099, 1728, 1684, 1616, 1591, 1554, 1491, 1442, 1439, 1335, 1302, 1232
NMR (DMSO-d6,ό : 3.76 (3H,s), 6.34 (lH,d,J = 2.6Hz), 6.76 (lH,m) ,7.06 - 7.36 (6H,m), 7.46 (lH,m), 7.69 (lH,d,J = 1.7Hz), 8.48 (lH,s), 8.52 (lH,s), 10.0 (lH.bs), 10.5 (lH,bs) APCI - MS : 348 (M + HO
Example 51
The following compound was obtained according to a similar manner to that of Example 47. N - (1 - Methylindol - 5 - yl) - N' - [3 - (pyrimidin - 5 - yl) phenyl] urea m.p. : 228- 230 °C (dec.)
IR (KBr, cirr1) : 3300, 3140, 3101, 3041, 1649, 1608cm 1
NMR (DMSO-d6,S) : 3.76 (3H,s), 6.35 (lH,d,J = 3.0), 7.13-7.18 (lH,m), 7.27
(1H,U = 3.0), 7.33-7.49 (3H,m), 7.54-7.59 (lH,m), 7.70 (lH,s), 7.85 (lH,s),
8.55 (lH,s), 8.74 (lH.s), 9.09 (2H,s), 9.21 (lH,s)
MS : 344 (M + 10
Example 52
The following compound was obtained according to a similar manner to that of Example 46.
1- [[3- (Imidazol - 1 - yl) phenyl] carbamoyl] - 2,3 - dihydropyrrolo [2,3- f] indole m.p. : 133- 140 °C IR (Nujol, cπr1) : 1620, 1600
NMR (DMS0-d6,cO 3.24 (2H,t,J = 8Hz), 4.16 (2H,t,J = 8Hz), 6.32 (lH,s), 7.10 -7.40 (4H,m), 7.43 (lH,t,J = 8Hz), 7.50-7.70 (2H,m), 7.88 (lH,s), 8.04 (lH,s), 8.17 (lH,s), 8.63 (lH,s), 10.84 (lH,s) MS 344 (M + 10
Example 53
The following compound was obtained according to a similar manner to that of Example 46.
1 - [[3 - (1 - Methylimidazol - 5 - yl) phenyl] carbamoyl] - 2,3 - dihydropyrrolo [2,3 -f] indole. m.p. : 235 - 243 °C (dec.) IR (Nujol, cπr1) : 1665
NMR (DMSO-d6,5) : 3.24 (2H,t,J = 8Hz), 3.71 (3H,s), 4.16 (2H,t,J = 8Hz), 6.32 (lH,s), 7.04 (lH.s), 7.11 (lH,d,J = 8Hz), 7.20 (2H,s), 7.37 (lH,t,J = 8Hz), 7.60 (IH, d,J = 9Hz), 7.70-7.72 (2H,m), 8.03 (lH.s), 8.50 (lH.s), 10.83 (IH, br.s). MS : 358 (M + 10

Claims

1. A compound of the formula :
Figure imgf000045_0001
wherein R1 and R2 are each hydrogen or linked together to form ethylene,
R3 is hydrogen or lower alkyl, R4 is heterocyclic group, R5 is hydrogen or nitro, and X is CH or N, and pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein
R4 is imidazolyl , pyrazolyl , pyridyl , pyrimidinyl , triazolyl , imidazolinyl, 2 — imidazolonyl, 2 — imidazolinonyl, oxazolyl, isoxazolyl, thiazolyl, each of which may have one or more substituent (s) .
3. The compound of claim 2, wherein the substituent is phenyl , amino , lower alkyl , benzyl , benzyloxycarbonyl or trihalo (lower) alkyl.
4. A process for preparing a compound of the formula:
Figure imgf000046_0001
wherein R1 and R2 are each hydrogen or linked together to form ethylene, R3 is hydrogen or lower alkyl, R" is heterocyclic group, R5 is hydrogen or nitro, and X is CH or N, and pharmaceutically acceptable salts thereof, which comprises,
(1) subjecting a compound of the formula :
Figure imgf000046_0002
wherein R3 is as defined above, or a salt thereof, to reduction reaction, to give a compound of the formula :
Figure imgf000047_0001
wherein R3 is as defined above, or a salt thereof, and then, reacting with carbonyldiimidazole, and then, reacting with a compound of the formula
Figure imgf000047_0002
wherein R4 , R5 , and X are each as defined above, or a salt thereof, to give a compound of the formula :
Figure imgf000047_0003
wherein R3 , R4 , R5 , and X are each as defined above, or a salt thereof, or
(2)reacting a compound of the formula :
Figure imgf000048_0001
wherein R4 , R5 , and X are each as defined above, or a salt thereof, with diphenylphosphorous azide, and then, reacting with a compound of the formula :
Figure imgf000048_0002
wherein R1 , R2 , and R3 are each as defined above, or a salt thereof, to give a compound of the formula :
Figure imgf000048_0003
wherein R1 , R2 , R3 , R5 , and X are each as defined above, or a salt thereof, or
(3) subjecting a compound of the formula:
Figure imgf000049_0001
wherein R1 , R2 , R3 , R5 , and X are each as defined above, and Z is acyl, or a salt thereof, to reduction reaction, to give a compound of the formula:
Figure imgf000049_0002
wherein R1 , R2 , R3 , R4 , Rδ , and X are each as defined above, or a salt thereof, or
(4) reacting a compound of the formula :
Figure imgf000049_0003
wherein R1 , R2 , R3 , Rθ and X are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000049_0004
to give a compound of the formula
Figure imgf000050_0001
wherein R1 , R2 , R3, R5 , and X are each as defined above, or a salt thereof, or (5)reacting a compound of the formula :
Figure imgf000050_0002
wherein R1 , R2 , R3 , R5 , and X are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000050_0003
to give a compound of the formula
Figure imgf000051_0001
wherein R1 , R2 , R3, R5 , and X are each as defined above, or a salt thereof, or
(6)reacting a compound of the formula :
Figure imgf000051_0002
wherein R4 , R5 , and X are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000051_0003
wherein R1 , R2 , and R3 are each as defined above, or a salt thereof, to give a compound of the formula :
Figure imgf000052_0001
wherein R1 , R2 , R3 , R4 , R5 , and X are each as defined above, or a salt thereof, or
(7)reacting a compound of the formula :
Figure imgf000052_0002
wherein R4 , R5 , and X are each as defined above, or a salt thereof, with carbonyldiimidazole, and then, reacting with a compound of the formula :
Figure imgf000052_0003
wherein R3 is as defined above, or a salt thereof, to give a compound of the formula :
Figure imgf000053_0001
wherein R3 , R4 , R5 , and X are each as defined above, or a salt thereof, or
(8)reacting a compound of the formula
Figure imgf000053_0002
wherein R4 , Rδ , and X are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000053_0003
wherein R1 , R2 , and R3 are each as defined above, or a salt thereof, to give a compound of the formula :
Figure imgf000054_0001
wherein R1 , R2 , R3 , R4 , R5 , and X are each as defined above, or a salt thereof, or
(9)reacting a compound of the formula :
Figure imgf000054_0002
wherein R4 , R5 , and X are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000054_0003
and then, a compound of the formula
Figure imgf000054_0004
wherein R1 , R2 , and R3 are each as defined above, or a salt thereof, to give a compound of the formula :
Figure imgf000055_0001
wherein R1 , R2 , R3 , R4 , R5 , and X are each as defined above, or a salt thereof.
5. A pharmaceutical composition, which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.
6. A method 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, withdrawl 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, which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.
7. A use of a compound of claim 1 as a medicament.
8. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as a 5-hydroxytryptamine (5-HT) antagonist.
PCT/JP1997/004390 1996-12-02 1997-12-02 Indole-urea derivatives with 5-ht antagonist properties Ceased WO1998024785A1 (en)

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