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WO2003007959A1 - Quinoxaline derivatives which have parp inhibitory action - Google Patents

Quinoxaline derivatives which have parp inhibitory action Download PDF

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Publication number
WO2003007959A1
WO2003007959A1 PCT/JP2002/007078 JP0207078W WO03007959A1 WO 2003007959 A1 WO2003007959 A1 WO 2003007959A1 JP 0207078 W JP0207078 W JP 0207078W WO 03007959 A1 WO03007959 A1 WO 03007959A1
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Prior art keywords
group
optionally substituted
quinoxaline
substituent
compound
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PCT/JP2002/007078
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French (fr)
Inventor
Kouji Hattori
Hirofumi Yamamoto
Koichiro Mukoyoshi
Satoru Kuroda
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Fujisawa Pharmaceutical Co., Ltd.
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Publication date
Priority claimed from AUPR6396A external-priority patent/AUPR639601A0/en
Priority claimed from AUPS0774A external-priority patent/AUPS077402A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO2003007959A1 publication Critical patent/WO2003007959A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • C07D403/10—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 carbon chain containing aromatic 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to novel quinoxaline derivatives having poly(adenosine 5'-diphospho-ribose)polymerase inhibitory action, a process for their production and a pharmaceutical composition containing the same.
  • PARP Poly(adenosine 5'-diphospho-ribose)polymerase
  • NAD nicotinamide adenine dinucleotide
  • PARP inhibitors are expected to be useful in treatment and prevention of various diseases ascribed by NMDA- and NO-induced toxicity.
  • benzimidazole derivatives having inhibitory action of PARP have been known, for example, in WO00/29384, WO00/32579, WOOO/68206 and WOOl/21615. However, any quinoxaline derivative having inhibitory action of PARP has not been known.
  • An object of this invention is to provide novel quinoxaline derivatives and salts thereof.
  • Another object of this invention is to provide a process for the production of the quinoxaline derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition containing an effective amount of the quinoxaline derivative, its prodrug or a pharmaceutical acceptable salt thereof, which has a PARP inhibitory action, as an active ingredient in admixture of a pharmaceutically acceptable carrier.
  • Still further object of this invention is to provide a use of the quinoxaline derivative, its prodrug or a pharmaceutical acceptable salt thereof for preparing a medicament for treating or preventing diseases ascribed by excess activation of PARP.
  • Still further object of the invention is to provide a method of treating or preventing diseases ascribed by excess activation of PARP by administering the quinoxaline derivative, its prodrug or a pharmaceutical acceptable salt thereof in an effective amount to inhibit PARP activity.
  • ring A is an aryl group or a heterocyclic group
  • R 1 is hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 2 is hydrogen atom, a lower alkyl group or an aryl group optionally substituted with halogen
  • R 3 is hydrogen atom, a halogen atom, cyano group, nitro group, amino group, an ar (lower) alkylamino group optionally substituted with one or more substituent(s), a di(lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkylamino group, a N-heterocyclyl-N-ar(lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclylamino group optionally substituted with ar (lower) alkyl, a cycloalkylamino group, a (lower) alkylsulfonylamino group, an arylsul
  • R 4 is hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, or R 2 and R 3 may be combined to form a lower alkylene group, or R 3 and R 4 may be combined to form a lower alkylenedioxy group.
  • lower means a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • one or more means 1 to 6, among which the preferred one is a number of 1 to 3, and the most preferred one is 1 or 2.
  • alkyl group is straight or branched ones such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-ethylbutyl, isobutyl, tert-butyl, pentyl, n-hexyl, heptyl, octyl, nonyl, etc.
  • Suitable examples of the lower alkyl group and the lower alkyl moieties in the lower alkoxy, ar(lower)alkylamino, di(lower) alkylamino, heterocycly (lower) alkylamino , N-heterocyclyl-N-ar (lower) alkylamino, (lower) alkylsulfonylamino, halo(lower)alkyl, lower alkylthio, ar (lower) alkyl, heterocyclyl(lower) alkyl, cycloalkyl(lower)alkyl, cycloalkenyl(lower) alkyl, lower alkanoyl, heterocyclyl(lower)alkanoyl, mono- or di- (lower) alkylcarbamoyl, ar(lower)alkylcarbamoyl and diaryl(lower)alkylcarbamoyl groups are straight or branched ones having 1 to 6 carbon atoms
  • halogen atom is fluorine, chlorine, bromine or iodine.
  • halo (lower) alkyl group are C ⁇ - , preferably Ci- alkyl group containing 1 to 9, preferably 1 to 5 halogen atoms, preferably fluorine, chlorine and/ or bromine atom(s), more preferably fluorine and/ or chlorine atom(s).
  • halogen atoms preferably fluorine, chlorine and/ or bromine atom(s), more preferably fluorine and/ or chlorine atom(s).
  • Preferable examples are chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and pentafiuoroethyl.
  • Suitable examples of the aryl group and the "aryl" moieties in the ar(lower)alkylamino, N-heterocyclyl-N-ar(lower) alkylamino, arylsulfonylamino, ar (lower) alkyl, aroyl, arylcarbamoyl, ar(lower) alkylcarbamoyl, diaryl(lower)alkylcarbamoyl and arylthiocarbamoyl groups are aromatic hydrocarbon residue containing 6 to 12 carbon atoms, such as phenyl, tolyl, xylyl and naphthyl.
  • heterocyclic group and the heterocyclyl moieties in the heterocycly (lower) alkylamino, N-heterocyclyl-N-ar(lower) alkylamino, heterocyclylamino, heterocyclylsulfonylamino, heterocyclyl(lower) alkyl, heterocyclylthio, heterocyclylcarbonyl and heterocyclyl(lower)alkanoyl groups are saturated or unsaturated, monocyclic or condensed heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
  • Preferable examples of the heterocyclic group and the heterocyclyl moiety are described in the following.
  • (1) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyximidinyl, tetrahydropyrimidinyl, pyxazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
  • unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,4-oxadiazolinyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
  • unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc.;
  • (11) unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atoms e.g., benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, quinolyl, isoquinolyl, indolyl, indolinyl, 1,2,3,4-tetrahydroquinolyl, etc);
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms e.g., benzofuryl, benzodioxolyl, etc
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms e.g., benzo[b]thienyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g., benzoxazolyl, benzoxadiazolyl, phenoxazinyl, etc
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl, benzisothiazolyl, phenothiazinyl, etc.
  • more preferable heterocyclic group for R 3 is an unsaturated 5- or 6-membered heteromonocyclic group such as the one mentioned in the above (1), (7) and (9), in which the most preferable one is pyrazolyl, pyridyl, tetrahydropyridyl, tetrahydropyrimidinyl, pyxazinyl, furyl or thienyl; a saturated 5- or 6-membered heteromonocyclic group such as the one mentioned in the above (2) and (4), in which the most preferable one is pyrrolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl or morpholino; or an unsaturated condensed heterocyclic group such as the one mentioned in the above (11) and (12), in which the most preferable one is quinolyl, indolyl, indolinyl, 1,2,3,4-tetrahydroquinolyl, benzofuryl or benzodi
  • heterocyclic group for the ring A is an unsaturated 5- or 6-membered heteromonocyclic group such as the one mentioned in the above (1) and (3) in which the most preferable one is pyridyl or isoxazolyl; a saturated 5- or 6-membered heterocyclic group such as the one mentioned in the above (2) in which the most preferable one is piperidyl; or an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms or 1 to 2 sulfur atoms such as the one mentioned in the above (13) in which the most preferable one is benzo[b]thienyl.
  • Suitable examples of the lower alkylene group and the lower alkylene moiety in the lower alkylenedioxy group are straight or branched ones having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, etc.
  • Suitable examples of the cycloalkyl group and the cycloalkyl moieties in the cycloalkylamino, cycloalkyl(lower)alkyl, cycloalkylcarbonyl and cycloalkylcarbamoyl groups are the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • Suitable examples of the cycloalkenyl group and the cycloalkenyl moiety in the cycloalkenyl(lower) alkyl group are the ones having 3 to 7 carbon atoms such as cyclopentenyl, cyclohexenyl, etc.
  • Suitable examples of the ar (lower) alkyl group are benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl and naphthylmethyl.
  • Suitable examples of the di(lower) alkylamino group are dimethylamino, methyl(ethyl) amino, diethylamino, ethyl(propyl) amino and dipropylamino.
  • Suitable examples of the N-heterocyclyl-N-ar (lower) alkylamino group are N-benzyl-N-pyridylamino, N-benzyl-N-oxazolylamino, N-benzyl-N-thiazolylamino and N-phenethyl-N-furyl.
  • heterocyclyl(lower) alkyl group and the heterocyclyl(lower) alkyl moiety in the heterocyclyl(lower) alkylamino and heterocyclyl(lower)alkanoyl groups are pyrazolylmethyl, pyridylmethyl, tetrahydxopyxidylmethyl, tetrahydropyrimidinylmethyl, pyrazinylmethyl, furylethyl, furfuryl, thienylmethyl, thienylethyl, thenyl, pyrrolidinylmethyl, piperidylmethyl, piperidinomethyl, piperazinylmethyl, morpholinylmethyl, morpholinomethyl, quinolylmethyl, indolylmethyl, indolinylmethyl, 1,2,3,4-tetrahydroquinolylmethyl, benzofurylmethyl, benzodioxolylmethyl, thienylethyl and morpholin
  • Suitable examples of the cycloalkyl(lower)alkyl group are cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Suitable examples of the cycloalkenyl(lower) alkyl group are cyclopentenylethyl and cyclohexenylmethyl.
  • diaryl(lower) alkylcarbamoyl group Suitable examples of the diaryl(lower) alkylcarbamoyl group are diphenylmethylcarbamoyl, diphenylethylcarbamoyl and dinaphthylmethylcarbamoyl.
  • substituents may be hydroxy; amino; carboxy; cyano; nitro; carbamoyl; oxo; sulfamoyl; halogen (e.g., fluorine, bromine or chlorine); lower alkyl (e.g., methyl, ethyl, isopropyl or tert-butyl) optionally substituted with hydroxy; lower alkoxy (e.g., methoxy, ethoxy, butoxy or n-propoxy) optionally substituted with one or more of hydroxy and/or di(lower)alkylamino (e.g., dimethylamino); di(lower) alkylamino (e.g., dimethylamino, diethylamino); lower alkanoyl (e.g., acetyl or formyl); heterocyclylcaxbonyl (e.g., furoyl); ary
  • Suitable example of the substituent(s) of the ar(lower)alkylamino group is sulfamoyl.
  • Suitable example of the substituent(s) of the di(lower)alkylamino group is di(lower)alkyklamino.
  • Suitable example of the substituent(s) of the N-heterocyclyl-N-ar(lower) alkylamino group is lower alkoxy.
  • Suitable example of the substituent(s) of the heterocyclylsulfonylamino group is halogen.
  • Suitable examples ofthe substituent(s) ofthe ar (lower) alkyl group axe hydroxy; cyano; nitro; halogen; lower alkyl optionally substituted with hydroxy; lower alkoxy optionally substituted with one or more of hydxoxy and/ or di(lower) alkylamino ; di(lower) alkylamino ; aryl optionally substituted with hydroxy, lower alkyl ; aryloxy ; heterocyclyl optionally substituted with lower alkyl ; and (lower) alkanoylamino.
  • Suitable examples of the substituent(s) of the heterocyclyl(lower) alkyl group axe halogen, lower alkyl and aryl.
  • Suitable example of the substituent(s) of the aryl group is halogen.
  • Suitable examples of the substituent(s) of the heterocyclic group are lower alkyl optionally substituted with hydroxy; lower alkanoyl; heterocyclylcarbonyl ; aryl optionally substituted with one or more of halogen, alkoxy, lower alkyl; heterocyclyl ;and cycloalkyl.
  • Suitable example of the substituent(s) of the heterocyclylthio group is ar (lower) alkyl.
  • Suitable example of the substituent(s) of the axoyl group is di(lower) alkylamino .
  • Suitable example of the substituent(s) of the heterocyclylcarbonyl group is lower alkyl.
  • Suitable example of the substituent(s) of the arylthiocarbamoyl is halogen.
  • prodrug means a derivative of the compound of the present invention having a chemically or metabolically degradable group, which becomes pharmaceutically active substance after biotxansfoxmation.
  • Suitable salts of the compound of the present invention are pharmaceutically acceptable conventional non-toxic salts and can be an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. aspartate, glutamate, etc.), etc.
  • organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate
  • the compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomer s. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
  • the compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • the compound of the formula (I) and its salt can be in a form of a solvate, which is included within the scope of the present invention.
  • the solvate preferably include a hydrate and an ethanolate.
  • radiolabelled derivatives of compounds of formula (I) which axe suitable for biological studies.
  • Preferred embodiment of the object compounds (I) are the one wherein the acyl moiety in the acylamino group is selected from a group consisting of a lower alkanoyl, a cycloalkylcarbonyl, an axoyl optionally substituted with one or more substituent(s), a heterocyciylcarbonyl optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkanoyl, a mono- or di- (lower) alkylcarbamoyl, a cycloalkylcarbamoyl, an arylcarbamoyl, an ar (lower) alkylcarbamoyl, a diaryl(lower) alkylcarbamoyl optionally substituted with one or more substituent(s), and an arylthiocarbamoyl optionally substituted with one or more substituent(s).
  • More preferred embodiments of the object compounds (I) are the one wherein the ring A is an aryl group, a saturated or unsaturated monocyclic or an unsaturated condensed heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
  • ring A is phenyl, pyxidyl or piperidyl
  • R 1 is hydrogen ox a halogen atom
  • R 2 is hydxogen atom
  • R 3 is a halogen atom, an ax(lower) alkylamino group optionally substituted with one or more substituent(s), a di(lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkylamino group, a N-heterocyclyl-N-ar(lower)alkylamino group optionally substituted with one or more substituent(s), a heterocyclylamino group optionally substituted with ar(lower) alkyl, a cycloalkylamino group or a lower alkoxy group
  • R 4 is hydrogen atom, a halogen atom or lower alkoxy, in the case where both R 3
  • the compound (I), its prodrug or a salt thereof can be prepared by the following processes.
  • Process 1 The compound (I), its prodrug or a salt thereof can be prepared by the following processes.
  • R 1 , R 2 , R 3 , R 4 and the ring A are each as defined above, and X is a leaving group.
  • Suitable leaving group may be halogen (e.g., fluoro, chloro, bromo or iodo), arylsulfonyloxy (e.g., benzenesulfonyloxy or tosyloxy), alkylsulfonyloxy (e.g., mesyloxy or ethanesulfonyloxy), etc, among which the preferable one is halogen.
  • halogen e.g., fluoro, chloro, bromo or iodo
  • arylsulfonyloxy e.g., benzenesulfonyloxy or tosyloxy
  • alkylsulfonyloxy e.g., mesyloxy or ethanesulfonyloxy
  • the object compound (I) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt.
  • Suitable inorganic base may be an alkali metal [e.g., sodium, potassium, etc.], an alkali metal hydroxide [e.g., sodium hydroxide, potassium hydroxide, etc.], alkali metal hydrogen carbonate [e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.], alkali metal carbonate [e.g., sodium carbonate, etc.], alkaline earth metal carbonate [e.g., calcium carbonate, etc.], alkali metal hydride [e.g., sodium hydride, etc.], etc.
  • alkali metal e.g., sodium, potassium, etc.
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • alkali metal hydrogen carbonate e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • alkali metal carbonate e.g., sodium carbonate, etc.
  • alkaline earth metal carbonate e.g., calcium carbonate, etc
  • Suitable organic base may be tri(lower)alkylamine [e.g., txiethylamine, N,N-diisopropylethylamine, etc.], alkyl magnesium bromide [e.g., methyl magnesium bromide, ethyl magnesium bromide, etc.], alkyl lithium [e.g., methyl lithium, butyl lithium, etc.], lithium diisopropylamide, lithium hexamethyldisilazido, etc.
  • alkylamine e.g., txiethylamine, N,N-diisopropylethylamine, etc.
  • alkyl magnesium bromide e.g., methyl magnesium bromide, ethyl magnesium bromide, etc.
  • alkyl lithium e.g., methyl lithium, butyl lithium, etc.
  • lithium diisopropylamide lithium hexamethyldisilazido, etc.
  • the reaction is usually carried out in a conventional solvent such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], aromatic hydrocarbon [e.g., benzene, toluene, xylene, etc.], ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], aromatic hydrocarbon [e.g., benzene, toluene, xylene, etc.], ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not
  • the object compound (I) is usually prepared as a mixture of structural isomer due to the 2- and 3-substituents of the quinoxaline ring.
  • the mixture of the structural isomer can be separated by a conventional method such as recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography or the like.
  • the invention includes both of the mixture and separated individual stxuctural isomexs.
  • the compound of the present invention can be purified by a conventional purification method such as recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography or the like.
  • the object compound (I) can be identified by a conventional method such as NMR spectrography, mass spectrography, infrared spectrography, elemental analysis, or measurement of melting point.
  • R 1 , R 2 , R 3 , R 4 , the ring A and X are each as defined above, a spheric mark is an oxime resin or Rink amide resin as a solid phase material, R 5 and R 6 are each hydrogen atom or a lower alkyl group, R 7 is an alkyl, cycloalkenyl, aryl, heterocyclic or cycloalkyl group, among which the alkyl, aryl and heterocyclic groups may be optionally substituted with one or more substituent(s) and R 8 is a lower alkyl, heterocyclic, cycloalkyl, (lower) alkylsulfonyl, axylsulfonyl or heterocyclylsulfonyl group, among which the lower alkyl and heterocyclysulfonyl groups may be optionally substituted with ar (lower) alkyl and the heterocyclic group may be optionally substituted with ar (lower) alkly.
  • 3-Nitroanthranilic acid derivative (IV) or its salt is coupled to a solid support material, an oxime resin to give a substance (V) or its salt.
  • the coupling is usually carried out in the presence of a coupling reagent and a base.
  • Suitable coupling reagent may be BOP (benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), PyBOP®
  • Suitable base may be DIEA (N,N-diisopropylethylamine), txiethylamine, etc.
  • DMAP 4-dimethylaminopyridine
  • HOBt N-hydroxybenzotriazole
  • Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc, which can swell the solid support material.
  • the coupling reaction is usually carried out under cooling to heating, preferably at room temperatuxe.
  • the substance (V) or its salt is reduced to give a diamine moiety of the substance (VI) ox its salt.
  • the reduction can be carried out in the presence of a reducing agent such as Zn, Sn or Fe and acid.
  • a reducing agent such as Zn, Sn or Fe and acid.
  • Suitable solvent used in the reduction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc.
  • the xeduction is usually caxxied out under cooling to heating, preferably at room temperature.
  • the substance (VII) or its salt is prepared by coupling of the substance (VI) or its salt with a compound (III) or its salt.
  • Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc.
  • the coupling reaction is usually carried out under cooling to heating, preferably at room temperature.
  • the compound (I) or its salt can be obtained by cleavage reaction using ammonia such as ammmonic methanol.
  • Suitable solvent used in the cleavage reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc, which can swell the solid support material.
  • the cleavage reaction is usually carried out under cooling to heating, preferably at room temperature.
  • Process 3 is carried out in a way similar to the Process 2, except for using a Rink amide xesin (4-(2',
  • a quinoxaline derivative (XI) or its salt is coupled to a solid support material, a Rink amide xesin to give a substance (XII) or its salt.
  • the coupling is usually carried out under the condition as mentioned in the Process 2.
  • the substance (XII) or its salt is coupled with an amine (XIII) or its salt to give a substance (XIV) or its salt.
  • This coupling is preferably carried out in the presence of a catalyst such as copper, palladium and nickel salt, especially cuprous oxide or iodide.
  • a catalyst such as copper, palladium and nickel salt, especially cuprous oxide or iodide.
  • Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc.
  • the coupling reaction may be usually carried out under cooling to heating, preferably at room temperature.
  • a compound (1-1) or its salt can be obtained by the reaction under the acidic condition as mentioned in the Process 3.
  • a quinoxaline substance (XVIII) or its salt can be obtained by coupling of a piperidine derivative (XVII) to the substance (IX) or its salt prepared in the Process 3.
  • Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc.
  • the coupling reaction may be usually carried out under cooling to heating, preferably at room temperature.
  • a compound (1-2) or its salt can be obtained by the cleavage reaction as mentioned in the Pxocess 3.
  • a substance (VII- 1) or its salt is prepared by coupling of the moiety (VI) or its salt prepared in the Process 2 with a compound (III- 1) or its salt under the condition as mentioned in the Process 2.
  • the substance(VII-l) or its salt is reduced to give a substance (VII-2) or its salt.
  • the reduction can be carried out in the presence of a reducing agent such as Zn, Sn or Fe and acid.
  • a reducing agent such as Zn, Sn or Fe and acid.
  • Suitable solvent used in the reduction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc.
  • the reduction may be usually carried out under cooling to heating, preferably at room temperature.
  • a compound (1-3) or its salt can be obtained by a basic cleavage reaction as mentioned in the Process 2.
  • Starting compounds (IV), (XI) and (XV) can be commercially available or prepared by the well-known processes or analogous processes thereof.
  • the quinoxaline derivatives of the present invention have a potent PARP inhibitory action as shown in the above.
  • PARP inhibitors including this invention relates to novel quinoxaline derivatives were effective in preventing reduction of stxiatal DA(dopamine) and its metabolite induced by MPTP (N-methyl-l,2,3,6-tetrahydropyridine) treatment in mice. Therefore, it suggests that these compounds may have protective benefit in the treatment of neuxodegenerative disease such as Parkinson's disease.
  • Such diseases include, for example, tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Perkinson's disease; epilepsy; amyotrophic latexal scleosis (ALS); Huntington's disease; schizophxenia; chronic pain; ischemia and neuronal loss following hypoxia; hypoglycemia; ischemia; trauma; and nervous insult.
  • PARP inhibitor is useful in deducing infarct size (Thiemermann et al, Proc. Natl. Acad. Sci. USA, 94: 679-83 (1997)). Therefore, the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is useful in treatment and prevention of previously ischemic heart or skeleton muscle tissue.
  • the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is effective in treating and preventing radiosensitizing hypoxic tumox cells; tumor cells from recovering from potentially lethal damage of DNA after radiation therapy.
  • the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is useful in extending the life-span and proliferative capacity of cells and altering gene expression of senescent cells. They axe useful for treating and preventing skin aging; Alzheimer's diseases; atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy; degenerative diseases of skeletal muscle involving replicative senescence; age-related maculax degeneration; immune senescence; AIDS; and othex immune senescence diseases.
  • the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is effective in treating and preventing inflammatory bowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock; septic shock; and tumor.
  • the compounds (I) axe useful in reducing proliferation of tumox cells and making synexgistic effect when tumor cells axe co-treated with an alkylating drug.
  • the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is effective in treating and pxeventing pituitary apoplexy; conjunctivitis; retinoblastoma; retinopathy; acute retinal necrosis syndrome; Sjogren's syndrome. Accordingly, the present invention provides a method for treating or preventing diseases ascribed by NMDA- and NO-induced toxicity by administering a compound (I) in an in an effective amount to inhibit PARP activity, to a human being or an animal who needs to be treated or prevented.
  • the compound (I), its prodrug or their salt can be administered alone or in the form of a mixture, preferably, with a pharmaceutical vehicle or carrier.
  • a pharmaceutical composition comprising a compound (I), its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient in admixture of a pharmaceutically acceptable carrier such as an organic or inorganic carrier or excipient suitable for external (topical), enteral, intravenous, intramuscular, parenteral or intxamucous applications in a pharmaceutical preparation for example, in solid, semisolid or liquid form.
  • the compound (I), its prodrug or a pharmaceutical acceptable salt thereof can be formulated, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, fox example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use.
  • the carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the compound (I), its prodrug or a pharmaceutical acceptable salt thereof is included in a pharmaceutical composition in an effective amount sufficient to pxoduce the desired effect upon the process or condition of the diseases, in a combination with a pharmaceutically acceptable carrier.
  • the compound (I), its prodrug or a pharmaceutical acceptable salt thereof can be formulated into, for example, preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, preparations for application to mucous membranes.
  • the present invention provides a pharmaceutical composition containing the compound (I), its prodrug or a pharmaceutical acceptable salt thereof in admixture of a pharmaceutically acceptable salt for treating or preventing diseases ascribed by NMDA- and NO-induced toxicity, specifically for extending the lifespan or proliferative capacity of cells or altering gene expression of senescent cells, more specifically for treating or preventing tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Perkinson's disease; epilepsy; Amyotrophic Lateral Scleosis (ALS); Huntington's disease; schizopherenia; chronic pain; ischemia and nloss following hypoxia; hypoglycemia; ischemia; trauma; nervous insult; previously ischemic heart or skeleton muscle tissue; radiosensitizing hypoxic tumor cells; tumor cells from recovering from potentially lethal damage of
  • Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.
  • While the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose to a human patient of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
  • 2-Acetylamino-5-chlorobenzoic acid (10.6g, 49.6mmol) was finely pulverized and added slowly to fuming HNO 3 (30ml) under stirring at 0-5°C. After stirring for 15 minutes, the solution was poured onto ice. The resultant precipitates were collected by filtration and washed with water to give 2-acetylamino-5-chloro-3-nitxobenzoic acid (6.95g, yield 54%).
  • 3-nitroanthranilic acid was isolated by filtration, washed with DMF, MeOH, DCM and Et 2 0 successively and dried under vacuum.
  • 1,4-dioxane (5 ml) was added dropwise IN NaOH aqueous solution (5 ml), and the mixture was stirred for 30 minutes at room temperature.
  • the reaction mixture was added dropwise to IN HCI aqueous solution (5 ml) and the mixture was poured into EtOAc.
  • the separated organic layer was washed with H 2 0 three times and with brine and then dried over sodium sulfate. The dried solution was concentrated under reduced pressure to give 3-(4-bromo)phenylquinoxaline-5-carboxylic acid (0.85, yield 98.5 %).
  • the resin was split into 26 equal volume.
  • the resulting solution was desalted by using a solid-phase extraction cartridge (Waters OasisTM HLB 6cc 500 mg LP Extraction Cartridge, conditioned by using CH 3 CN (6 mL) and H 2 0 (6 mL), washed with H 2 O (6 mL) and eluted with CH3CN (6 mL)) to give a sulfonamide derivative.
  • a solid-phase extraction cartridge Waters OasisTM HLB 6cc 500 mg LP Extraction Cartridge
  • Method B Preparation of urea derivatives by using isocyanate of the foxmula R S -NCO
  • the residue was purified by HPLC (reverse phase Cis, 5 ⁇ m, 20 mm X 50 mm column, 254 nm, 0-80 % 0.1 % TFA in CH3CN / 0.1 % TFA in H 2 0, 25 mL/min.) .
  • the fractions containing an object compound were combined and evaporated.
  • the residue was dissolved in 50 % aqueous 1 ,4-dioxane and the solution was neutralized with an aqueous NaHCU3 solution.
  • the resulting solution was desalted by using a solid-phase extraction cartridge (Waters ® OasisTM HLB 6cc 500mg LP Extraction Cartridge, conditioned using CH3CN (6 mL) and H 2 0 (6 mL), washed with H 2 0 (6 mL) and eluted with CH3CN (6 mL)) to give an urea derivative. Purity of the urea derivative was determined by HPLC analysis (reverse phase Cis, 2.5 ⁇ m, 2.1 mm X 20 mm column, 254 nm, 2-100 % of 0.04 % HCO2H in CH3CN / 0.05 % HC0 2 H in H 2 0, over 4 min., 0.8 mL/min.).
  • Method C Preparation of urea derivatives by using carbonyl chloride
  • a suspension of resin-supported 3- (3 -aminophenyl) quinoxaline (70 mg) and pyridine (16 ⁇ L) in DCM (1 mL) was added carbonyl chloride (0.1 mmol) and the mixture was shaken overnight at ambient temperature.
  • the resin was isolated by filtration and washed well with DCM, DMF, MeOH and Et2 ⁇ successively and then dried under reduced pressure to give a resin-supported urea derivative.
  • the resulting resin was added to 2N NH3 in 1,4-dioxane (1 mL) and the mixture was shaken overnight at ambient temperature.
  • the resin was isolated by filtration and washed twice with DCM (0.5 mL).
  • the filtrates were combined and evaporated under reduced pressure.
  • the residue was purified by HPLC (reverse phase Cis, 5 ⁇ m, 20 mm X 50 mm column, 254 nm, 0-80 % of 0.1 % TFA in CH3CN / 0.1 % TFA in H 2 0, 25 mL/min.).
  • the fractions containing objective compound were combined and evaporated under reduced pressure.
  • the residue was dissolved in 50 % aqueous 1,4-dioxane and the solution was neutralized with an aqueous NaHC ⁇ 3 solution.
  • the resultant solution was desalted by using a solid-phase extxaction cartridge (Waters OasisTM HLB 6cc 500mg LP Extraction Cartridge, conditioned by using CH3CN (6 mL) and H 2 0 (6 mL), washed with H2O (6 mL) and eluted with CH3CN (6 mL)) to give an uxea derivative.
  • Purity of the urea derivative was determined by HPLC analysis (reverse phase Cis, 2.5 ⁇ m, 2.1 mm X 20 mm column, 254 nm, 2-100 % of 0.04 % HC0 2 H in CH3CN / 0.05 % HC0 2 H in H 2 0, over 4 min., 0.8 mL/min.).
  • the resultant solution was desalted using a solid-phase extraction cartridge (Waters OasisTM HLB 6cc 500mg LP Extraction Cartxidge, conditioned by using CH3CN (6 mL) and H 2 0 (6 mL), washed with H2O (6 mL) and eluted with CH3CN (6 mL)) to give an amide derivative. Purity of the amide derivative was determine by HPLC analysis (reverse phase Cis, 2.5 ⁇ m., 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HCO2H in CH3CN / 0.05 % HC0 2 H in H 0, over 4 min., 0.8 mL/min.).
  • the xesulting solution was desalted by using a solid-phase extraction cartxidge (Watexs OasisTM HLB 6cc 500mg LP Extraction Cartridge, conditioned by using CH3CN (6 mL) and H2O (6 mL), washed with H2O (6 mL) and eluted with CH3CN (6 mL)) to give an amide derivative. Purity of the amide derivative was determined by HPLC analysis (reverse phase Cis, 2.5 m, 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HCO2H in CH3CN / 0.05 % HCO2H in H 2 0, over 4 min., 0.8 mL/min.).

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Abstract

Quinoxaline derivatives provided by this invention are represented by the formula (I): wherein R?1, R2, R3, R4¿ and the ring A are as defined in the specification, and have poly(adenosine 5'-diphaspho-ribose)polymerase (PARP) inhibitory action.

Description

DESCRIPTION
QUINOXALINE DERIVATIVES WHICH HAVE PARP INHIBITORY ACTION
Technical Field
This invention relates to novel quinoxaline derivatives having poly(adenosine 5'-diphospho-ribose)polymerase inhibitory action, a process for their production and a pharmaceutical composition containing the same.
Background Art
Poly(adenosine 5'-diphospho-ribose)polymerase (hereinafter called as PARP) is an enzyme located in the nuclei of cells of various organs, including muscle, heart and brain cells. After recognizing strand breaks of DNA caused by NMDA(N-methyl-D-aspartate), NO, active oxygen and the like, PARP catalyzes the attachment reaction of ADP-r bose units of nicotinamide adenine dinucleotide (NAD) to a variety of nuclear proteins, including histones and PARP itself. However, excess activation of PARP leads to depletion of NAD and ATP in cells to induce cell death. Therefore, the PARP inhibitors are expected to be useful in treatment and prevention of various diseases ascribed by NMDA- and NO-induced toxicity.
Some benzimidazole derivatives having inhibitory action of PARP have been known, for example, in WO00/29384, WO00/32579, WOOO/68206 and WOOl/21615. However, any quinoxaline derivative having inhibitory action of PARP has not been known.
Disclosure of the Invention
An object of this invention is to provide novel quinoxaline derivatives and salts thereof.
Another object of this invention is to provide a process for the production of the quinoxaline derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing an effective amount of the quinoxaline derivative, its prodrug or a pharmaceutical acceptable salt thereof, which has a PARP inhibitory action, as an active ingredient in admixture of a pharmaceutically acceptable carrier.
Still further object of this invention is to provide a use of the quinoxaline derivative, its prodrug or a pharmaceutical acceptable salt thereof for preparing a medicament for treating or preventing diseases ascribed by excess activation of PARP.
Still further object of the invention is to provide a method of treating or preventing diseases ascribed by excess activation of PARP by administering the quinoxaline derivative, its prodrug or a pharmaceutical acceptable salt thereof in an effective amount to inhibit PARP activity.
The quinoxaline derivatives of this invention are represented by the following formula (I):
Figure imgf000003_0001
wherein the ring A is an aryl group or a heterocyclic group,
R1 is hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R2 is hydrogen atom, a lower alkyl group or an aryl group optionally substituted with halogen, R3 is hydrogen atom, a halogen atom, cyano group, nitro group, amino group, an ar (lower) alkylamino group optionally substituted with one or more substituent(s), a di(lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkylamino group, a N-heterocyclyl-N-ar(lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclylamino group optionally substituted with ar (lower) alkyl, a cycloalkylamino group, a (lower) alkylsulfonylamino group, an arylsulfonylamino group, a heterocyclylsulfonylamino group optionally substituted with one or more substituent(s) an acylaminio group, a lower alkoxy group, an alkyl group optionally substituted with lower alkylthio, a halo (lower) alkyl group, an ar (lower) alkyl group optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkyl group optionally substituted with one or more substituent(s), a cycloalkyl(lower) alkyl group, a cycloalkenyl(lower) alkyl group, an aryl group optionally substituted with one or more substituent(s), a heterocyclic group optionally substituted with one or more substituent(s), or a heterocyclylthio group optionally substituted with one or more substituent(s), and
R4 is hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, or R2 and R3 may be combined to form a lower alkylene group, or R3 and R4 may be combined to form a lower alkylenedioxy group.
In the above and subsequent description of the present specification, suitable examples and illustrations of the various definitions, which the present invention includes within the scope, are explained in detail as follows.
The term "lower" means a group having 1 to 6 carbon atom(s), unless otherwise provided.
The term "one or more" means 1 to 6, among which the preferred one is a number of 1 to 3, and the most preferred one is 1 or 2.
Suitable examples of alkyl group are straight or branched ones such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-ethylbutyl, isobutyl, tert-butyl, pentyl, n-hexyl, heptyl, octyl, nonyl, etc.
Suitable examples of the lower alkyl group and the lower alkyl moieties in the lower alkoxy, ar(lower)alkylamino, di(lower) alkylamino, heterocycly (lower) alkylamino , N-heterocyclyl-N-ar (lower) alkylamino, (lower) alkylsulfonylamino, halo(lower)alkyl, lower alkylthio, ar (lower) alkyl, heterocyclyl(lower) alkyl, cycloalkyl(lower)alkyl, cycloalkenyl(lower) alkyl, lower alkanoyl, heterocyclyl(lower)alkanoyl, mono- or di- (lower) alkylcarbamoyl, ar(lower)alkylcarbamoyl and diaryl(lower)alkylcarbamoyl groups are straight or branched ones having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-ethylbutyl, isobutyl, tert-butyl, pentyl, n-hexyl etc.
Suitable examples of halogen atom are fluorine, chlorine, bromine or iodine.
Suitable examples of halo (lower) alkyl group are Cι- , preferably Ci- alkyl group containing 1 to 9, preferably 1 to 5 halogen atoms, preferably fluorine, chlorine and/ or bromine atom(s), more preferably fluorine and/ or chlorine atom(s). Preferable examples are chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and pentafiuoroethyl.
Suitable examples of the aryl group and the "aryl" moieties in the ar(lower)alkylamino, N-heterocyclyl-N-ar(lower) alkylamino, arylsulfonylamino, ar (lower) alkyl, aroyl, arylcarbamoyl, ar(lower) alkylcarbamoyl, diaryl(lower)alkylcarbamoyl and arylthiocarbamoyl groups are aromatic hydrocarbon residue containing 6 to 12 carbon atoms, such as phenyl, tolyl, xylyl and naphthyl.
Suitable examples of the heterocyclic group and the heterocyclyl moieties in the heterocycly (lower) alkylamino, N-heterocyclyl-N-ar(lower) alkylamino, heterocyclylamino, heterocyclylsulfonylamino, heterocyclyl(lower) alkyl, heterocyclylthio, heterocyclylcarbonyl and heterocyclyl(lower)alkanoyl groups are saturated or unsaturated, monocyclic or condensed heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms. Preferable examples of the heterocyclic group and the heterocyclyl moiety are described in the following.
(1) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyximidinyl, tetrahydropyrimidinyl, pyxazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
(2) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, etc.);
(3) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,4-oxadiazolinyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
(4) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to' 3 nitrogen atoms (e.g., morpholinyl, morpholino, etc.);
(5) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc.;
(6) saturated 3 to 7-membered preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiomorpholinyl, thiazolidinyl, etc.);
(7) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms (e.g., furyl, pyranyl, etc);
(8) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms (e.g.,
1 ,4-dioxanyl, etc);
(9) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms (e.g., thienyl, etc);
(10) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms (e.g., tetrahydrothienyl, etc);
(11) unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atoms (e.g., benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, quinolyl, isoquinolyl, indolyl, indolinyl, 1,2,3,4-tetrahydroquinolyl, etc);
(12) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms (e.g., benzofuryl, benzodioxolyl, etc); (13) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms (e.g., benzo[b]thienyl, etc.)
(14) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl, phenoxazinyl, etc); or (15) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzisothiazolyl, phenothiazinyl, etc).
Among the above, more preferable heterocyclic group for R3 is an unsaturated 5- or 6-membered heteromonocyclic group such as the one mentioned in the above (1), (7) and (9), in which the most preferable one is pyrazolyl, pyridyl, tetrahydropyridyl, tetrahydropyrimidinyl, pyxazinyl, furyl or thienyl; a saturated 5- or 6-membered heteromonocyclic group such as the one mentioned in the above (2) and (4), in which the most preferable one is pyrrolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl or morpholino; or an unsaturated condensed heterocyclic group such as the one mentioned in the above (11) and (12), in which the most preferable one is quinolyl, indolyl, indolinyl, 1,2,3,4-tetrahydroquinolyl, benzofuryl or benzodioxolyl.
And more preferable heterocyclic group for the ring A is an unsaturated 5- or 6-membered heteromonocyclic group such as the one mentioned in the above (1) and (3) in which the most preferable one is pyridyl or isoxazolyl; a saturated 5- or 6-membered heterocyclic group such as the one mentioned in the above (2) in which the most preferable one is piperidyl; or an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms or 1 to 2 sulfur atoms such as the one mentioned in the above (13) in which the most preferable one is benzo[b]thienyl.
Suitable examples of the lower alkylene group and the lower alkylene moiety in the lower alkylenedioxy group are straight or branched ones having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, etc.
Suitable examples of the cycloalkyl group and the cycloalkyl moieties in the cycloalkylamino, cycloalkyl(lower)alkyl, cycloalkylcarbonyl and cycloalkylcarbamoyl groups are the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Suitable examples of the cycloalkenyl group and the cycloalkenyl moiety in the cycloalkenyl(lower) alkyl group are the ones having 3 to 7 carbon atoms such as cyclopentenyl, cyclohexenyl, etc.
Suitable examples of the ar (lower) alkyl group are benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl and naphthylmethyl.
Suitable examples of the di(lower) alkylamino group are dimethylamino, methyl(ethyl) amino, diethylamino, ethyl(propyl) amino and dipropylamino. Suitable examples of the N-heterocyclyl-N-ar (lower) alkylamino group are N-benzyl-N-pyridylamino, N-benzyl-N-oxazolylamino, N-benzyl-N-thiazolylamino and N-phenethyl-N-furyl.
Suitable examples of the heterocyclyl(lower) alkyl group and the heterocyclyl(lower) alkyl moiety in the heterocyclyl(lower) alkylamino and heterocyclyl(lower)alkanoyl groups are pyrazolylmethyl, pyridylmethyl, tetrahydxopyxidylmethyl, tetrahydropyrimidinylmethyl, pyrazinylmethyl, furylethyl, furfuryl, thienylmethyl, thienylethyl, thenyl, pyrrolidinylmethyl, piperidylmethyl, piperidinomethyl, piperazinylmethyl, morpholinylmethyl, morpholinomethyl, quinolylmethyl, indolylmethyl, indolinylmethyl, 1,2,3,4-tetrahydroquinolylmethyl, benzofurylmethyl, benzodioxolylmethyl, thienylethyl and morpholinylpropyl.
Suitable examples of the cycloalkyl(lower)alkyl group are cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylmethyl and cycloheptylmethyl.
Suitable examples of the cycloalkenyl(lower) alkyl group are cyclopentenylethyl and cyclohexenylmethyl.
Suitable examples of the diaryl(lower) alkylcarbamoyl group are diphenylmethylcarbamoyl, diphenylethylcarbamoyl and dinaphthylmethylcarbamoyl.
When the above groups for R3 is substituted with one or more substituent(s), said substituents may be hydroxy; amino; carboxy; cyano; nitro; carbamoyl; oxo; sulfamoyl; halogen (e.g., fluorine, bromine or chlorine); lower alkyl (e.g., methyl, ethyl, isopropyl or tert-butyl) optionally substituted with hydroxy; lower alkoxy (e.g., methoxy, ethoxy, butoxy or n-propoxy) optionally substituted with one or more of hydroxy and/or di(lower)alkylamino (e.g., dimethylamino); di(lower) alkylamino (e.g., dimethylamino, diethylamino); lower alkanoyl (e.g., acetyl or formyl); heterocyclylcaxbonyl (e.g., furoyl); aryl (e.g., phenyl or naphthyl ) optionally substituted with one or more of sulfamoyl, hydroxy, halogen (e.g., chlorine), alkoxy (e.g., methoxy), lower alkyl (e.g., methyl); aryloxy (e.g., phenoxy); aroyl (e.g., benzoyl); ax(lowex) alkyl (e.g., benzyl); heterocyclyl (e.g., pyridyl, morpholinyl, pyrroUdinyl, piperazinyl, benz[d]imidazolyl or pyrimidyl) optionally substituted with lowex alkyl (e.g., methyl), h dxoxy; cycloalkyl (e.g., cyclohexyl); lower alkoxycarbonyl (e.g., methoxycarbonyl or thoxycarbonyl); (lower) alkanoylamino (e.g., acetylamino); lower alkylenedioxy (e.g., methylenedioxy); (lower) alkylthio (e.g., methylthio); etc.
Suitable example of the substituent(s) of the ar(lower)alkylamino group is sulfamoyl.
Suitable example of the substituent(s) of the di(lower)alkylamino group is di(lower)alkyklamino.
Suitable example of the substituent(s) of the N-heterocyclyl-N-ar(lower) alkylamino group is lower alkoxy.
Suitable example of the substituent(s) of the heterocyclylsulfonylamino group is halogen. Suitable examples ofthe substituent(s) ofthe ar (lower) alkyl group axe hydroxy; cyano; nitro; halogen; lower alkyl optionally substituted with hydroxy; lower alkoxy optionally substituted with one or more of hydxoxy and/ or di(lower) alkylamino ; di(lower) alkylamino ; aryl optionally substituted with hydroxy, lower alkyl ; aryloxy ; heterocyclyl optionally substituted with lower alkyl ; and (lower) alkanoylamino. Suitable examples of the substituent(s) of the heterocyclyl(lower) alkyl group axe halogen, lower alkyl and aryl.
Suitable example of the substituent(s) of the aryl group is halogen. Suitable examples of the substituent(s) of the heterocyclic group are lower alkyl optionally substituted with hydroxy; lower alkanoyl; heterocyclylcarbonyl ; aryl optionally substituted with one or more of halogen, alkoxy, lower alkyl; heterocyclyl ;and cycloalkyl.
Suitable example of the substituent(s) of the heterocyclylthio group is ar (lower) alkyl.
Suitable example of the substituent(s) of the axoyl group is di(lower) alkylamino . Suitable example of the substituent(s) of the heterocyclylcarbonyl group is lower alkyl.
Suitable example of the substituent(s) of the arylthiocarbamoyl is halogen.
The term "prodrug" means a derivative of the compound of the present invention having a chemically or metabolically degradable group, which becomes pharmaceutically active substance after biotxansfoxmation. Suitable salts of the compound of the present invention are pharmaceutically acceptable conventional non-toxic salts and can be an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. aspartate, glutamate, etc.), etc.
The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomer s. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The compound of the formula (I) and its salt can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
Also included in the scope of invention are radiolabelled derivatives of compounds of formula (I) which axe suitable for biological studies.
Preferred embodiment of the object compounds (I) are the one wherein the acyl moiety in the acylamino group is selected from a group consisting of a lower alkanoyl, a cycloalkylcarbonyl, an axoyl optionally substituted with one or more substituent(s), a heterocyciylcarbonyl optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkanoyl, a mono- or di- (lower) alkylcarbamoyl, a cycloalkylcarbamoyl, an arylcarbamoyl, an ar (lower) alkylcarbamoyl, a diaryl(lower) alkylcarbamoyl optionally substituted with one or more substituent(s), and an arylthiocarbamoyl optionally substituted with one or more substituent(s). More preferred embodiments of the object compounds (I) are the one wherein the ring A is an aryl group, a saturated or unsaturated monocyclic or an unsaturated condensed heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
Further preferred embodiments of the object compounds (I) are the one wherein the ring A is phenyl, pyxidyl or piperidyl, R1 is hydrogen ox a halogen atom, R2 is hydxogen atom, R3 is a halogen atom, an ax(lower) alkylamino group optionally substituted with one or more substituent(s), a di(lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkylamino group, a N-heterocyclyl-N-ar(lower)alkylamino group optionally substituted with one or more substituent(s), a heterocyclylamino group optionally substituted with ar(lower) alkyl, a cycloalkylamino group or a lower alkoxy group, R4 is hydrogen atom, a halogen atom or lower alkoxy, in the case where both R3 and R4 are a lower alkoxy group they may be combined to form a lower alkylendioxy group.
The compound (I), its prodrug or a salt thereof can be prepared by the following processes. Process 1
Figure imgf000013_0001
(II) (III) (I) or its salt or its salt or its salt
wherein, R1, R2, R3, R4 and the ring A are each as defined above, and X is a leaving group.
Suitable leaving group may be halogen (e.g., fluoro, chloro, bromo or iodo), arylsulfonyloxy (e.g., benzenesulfonyloxy or tosyloxy), alkylsulfonyloxy (e.g., mesyloxy or ethanesulfonyloxy), etc, among which the preferable one is halogen.
The object compound (I) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt.
This reaction is usually carried out in the presence of an inorganic or an organic base. Suitable inorganic base may be an alkali metal [e.g., sodium, potassium, etc.], an alkali metal hydroxide [e.g., sodium hydroxide, potassium hydroxide, etc.], alkali metal hydrogen carbonate [e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.], alkali metal carbonate [e.g., sodium carbonate, etc.], alkaline earth metal carbonate [e.g., calcium carbonate, etc.], alkali metal hydride [e.g., sodium hydride, etc.], etc. Suitable organic base may be tri(lower)alkylamine [e.g., txiethylamine, N,N-diisopropylethylamine, etc.], alkyl magnesium bromide [e.g., methyl magnesium bromide, ethyl magnesium bromide, etc.], alkyl lithium [e.g., methyl lithium, butyl lithium, etc.], lithium diisopropylamide, lithium hexamethyldisilazido, etc.
The reaction is usually carried out in a conventional solvent such as an alcohol [e.g., methanol, ethanol, propanol, isopropanol, etc.], aromatic hydrocarbon [e.g., benzene, toluene, xylene, etc.], ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction. The reaction temperature is not critical , and the reaction is usually carried out under cooling to heating.
In this reaction, the object compound (I) is usually prepared as a mixture of structural isomer due to the 2- and 3-substituents of the quinoxaline ring. The mixture of the structural isomer can be separated by a conventional method such as recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography or the like. The invention includes both of the mixture and separated individual stxuctural isomexs.
The compound of the present invention can be purified by a conventional purification method such as recrystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography or the like. The object compound (I) can be identified by a conventional method such as NMR spectrography, mass spectrography, infrared spectrography, elemental analysis, or measurement of melting point.
Starting compounds (II) and (III) can be prepared by the well-known processes, for example, the processes described in the J. Med. Chem., 43, 4083-4097 (2000) or analogous processes thereof.
Process 2
Figure imgf000015_0001
(V) or its salt
Reduction
Figure imgf000015_0002
(VI) or its salt
Cleavage
Figure imgf000015_0004
Figure imgf000015_0003
(VII) (I) or its salt Process 3
Sjjg NH,
Figure imgf000016_0001
(VIII) or its salt
Reduction
Figure imgf000016_0002
(IX) or its salt
Figure imgf000016_0003
(X) (I) or its salt Process 4
Figure imgf000017_0001
(XII) or its salt
Cleavage
Figure imgf000017_0002
(XIV) or its salt
Figure imgf000017_0003
(1-1) or its salt Process 5
Figure imgf000018_0001
(K) or its salt
Figure imgf000018_0002
(XVIII) (XIX) or its salt or its salt
Figure imgf000018_0003
(XX) (1-2) or its salt or its salt Process 6
Figure imgf000019_0001
or its salt or its salt
Reduction Modification
Figure imgf000019_0002
(VII-2) or its salt
Cleavage
Figure imgf000019_0003
Figure imgf000019_0004
(VII-2) (1-3) or its salt or its salt
wherein R1, R2, R3, R4, the ring A and X are each as defined above, a spheric mark is an oxime resin or Rink amide resin as a solid phase material, R5 and R6 are each hydrogen atom or a lower alkyl group, R7 is an alkyl, cycloalkenyl, aryl, heterocyclic or cycloalkyl group, among which the alkyl, aryl and heterocyclic groups may be optionally substituted with one or more substituent(s) and R8 is a lower alkyl, heterocyclic, cycloalkyl, (lower) alkylsulfonyl, axylsulfonyl or heterocyclylsulfonyl group, among which the lower alkyl and heterocyclysulfonyl groups may be optionally substituted with ar (lower) alkyl and the heterocyclic group may be optionally substituted with ar (lower) alkly. "BOC" means tert-butoxycarbonyl group and "FMOC" means fluorenylmethoxycarbonyl group.
The amide-formation coupling reaction, protection and deprotection of the amino and carboxyl group, cleavage, etc. in the above solid-phase processes are carried out according to the solid-phase technique described by Steward, J.M. and Young, J.D. (Solid Phase Peptide Synthesis, Pierce Chemical Company (1984)), Robert C. Sheppard E. Atherton (Solid-Phase Peptide Synthesis, IRL Press, (1989)) and M.J. Gait (Oligonucleotide Synthesis, IRL Press, (1984)).
Process 2 3-Nitroanthranilic acid derivative (IV) or its salt is coupled to a solid support material, an oxime resin to give a substance (V) or its salt. The coupling is usually carried out in the presence of a coupling reagent and a base. Suitable coupling reagent may be BOP (benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), PyBOP®
(benzotriazol- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), PyBroP ® (bromo-txis-pyrrolidino-phosphonium hexafluorophosphate), HBTU (2-( lH-benzotriazol- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate), TBTU
(2- ( 1 H-benzotriazol- 1 -yl) -1,1 ,3 ,3-tetramethyluronium tetrafluoroborate) , etc or a mixture thereof. Suitable base may be DIEA (N,N-diisopropylethylamine), txiethylamine, etc. Optionally, DMAP (4-dimethylaminopyridine) or HOBt (N-hydroxybenzotriazole) may be added to enhance the coupling reaction. Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc, which can swell the solid support material. The coupling reaction is usually carried out under cooling to heating, preferably at room temperatuxe.
The substance (V) or its salt is reduced to give a diamine moiety of the substance (VI) ox its salt. The reduction can be carried out in the presence of a reducing agent such as Zn, Sn or Fe and acid. Suitable solvent used in the reduction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc. The xeduction is usually caxxied out under cooling to heating, preferably at room temperature. The substance (VII) or its salt is prepared by coupling of the substance (VI) or its salt with a compound (III) or its salt. Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc. The coupling reaction is usually carried out under cooling to heating, preferably at room temperature.
The compound (I) or its salt can be obtained by cleavage reaction using ammonia such as ammmonic methanol. Suitable solvent used in the cleavage reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc, which can swell the solid support material. The cleavage reaction is usually carried out under cooling to heating, preferably at room temperature.
Process 3 Process 3 is carried out in a way similar to the Process 2, except for using a Rink amide xesin (4-(2',
4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxy xesin)) instead of an oxime resin, and using acidic cleavage condition instead of basic condition. The acidic cleavage condition can be performed in the presence of a cocktail consisting of TFA (trifluoroacetic acid), ethanedithiol, m-cresol, thioanisole, etc, because the Rink amide resin is rather acid sensitive. Process 4
A quinoxaline derivative (XI) or its salt is coupled to a solid support material, a Rink amide xesin to give a substance (XII) or its salt. The coupling is usually carried out under the condition as mentioned in the Process 2.
The substance (XII) or its salt is coupled with an amine (XIII) or its salt to give a substance (XIV) or its salt. This coupling is preferably carried out in the presence of a catalyst such as copper, palladium and nickel salt, especially cuprous oxide or iodide. Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc. The coupling reaction may be usually carried out under cooling to heating, preferably at room temperature.
A compound (1-1) or its salt can be obtained by the reaction under the acidic condition as mentioned in the Process 3.
Process 5
A quinoxaline substance (XVIII) or its salt can be obtained by coupling of a piperidine derivative (XVII) to the substance (IX) or its salt prepared in the Process 3. Suitable solvent used in the coupling reaction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc. The coupling reaction may be usually carried out under cooling to heating, preferably at room temperature. After deprotection of Fmoc from the substance (IX) with piperidine in DMF (dimethylformamide) at room temperature, a reductive alkylation of an amino moiety of an quinoxaline derivative (XIX) or its salt with an aldehyde R7CHO and successive reduction gives an quinoxaline derivative (XX) or its salt. The reduction may be carried out by using a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, etc. Suitable solvent used in the reduction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyxxolidinone, 1,4-dioxane, etc. The reduction may be carried out under cooling to heating, preferably at room temperature.
A compound (1-2) or its salt can be obtained by the cleavage reaction as mentioned in the Pxocess 3.
Process 6
A substance (VII- 1) or its salt is prepared by coupling of the moiety (VI) or its salt prepared in the Process 2 with a compound (III- 1) or its salt under the condition as mentioned in the Process 2.
The substance(VII-l) or its salt is reduced to give a substance (VII-2) or its salt. The reduction can be carried out in the presence of a reducing agent such as Zn, Sn or Fe and acid. Suitable solvent used in the reduction may be dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, 1,4-dioxane, etc. The reduction may be usually carried out under cooling to heating, preferably at room temperature.
Modification of the amino group of the substance (VII-2) or its salt to a quinoxaline substance (VII-2) or its salt is carried out under the following method:
(A) : reaction with R8-S02C1 in the presence of a base such as pyxidine to give a quinoxaline substance having a sulfonamide moiety or its salt;
(B) : reaction with isocyanate R8-NCO in the presence of a base such as pyridine to give a quinoxaline substance having an urea moiety or its salt;
(C) : reaction with carbonyl chloride in the presence of a base such as pyridine to give a quinoxaline substance having an urea moiety or its salt;
(D) : reaction with acyl chloride R8-COCl in the presence of a base such as pyxidine to give a quinoxaline substance having an amide moiety; and
(E) : reaction with carboxylic acid R8-C02H in the presence of a coupling reagent and a base as described in the Process 2 to give a quinoxaline substance with an amide moiety.
A compound (1-3) or its salt can be obtained by a basic cleavage reaction as mentioned in the Process 2. Starting compounds (IV), (XI) and (XV) can be commercially available or prepared by the well-known processes or analogous processes thereof.
In order to illustrate the usefulness of the object compound (I), the pharmacological test of the compound (I) axe explained in the following.
A. Test Compounds
Compound A: A mixture of
2-(4-chlorophenyl)quinoxaline-5-carboxamide and 3-(4-chlorophenyl)quinoxaline-5-caxboxamide (Example 2(1)) Compound B: 3-(4-diethylaminophenyl)quinoxalin-5-carboxamide (Example 4)
B. PARP inhibitory action (In vitro assay) (1) Assay conditions:
The recombinant human PARP (5.3mg protein/ml) were incubated with a test compound in a lOOμl reaction buffer containing the indicated concentration of 1 mCi/ml 32P-NAD, 50mM Tris-HCl, 25mM MgCl2, ImM DTT (dithiothreitol), 0.05mM NAD (nicotinamido adenine dinucleotide), lmg/ml activated DNA, pH8.0. Incubation was carried out for 15 minutes at a room temperature and the reaction was stopped by the addition of 200μl of ice-cold 20% tricholoroacetic acid followed by rapid filtration through GF/B filters. The filters were treated with scintillation fluid and acid-insoluble counts were measured for quantification of unit activity. PARP inhibitory action was calculated by using the following formula: PARP inhibitory action (%) =
[l-(count obtained with test compound) /(count obtained with vehicle)] x 100 (2) Results
Table 1
PARP inhibitory action (IC50) of the test compound.
Figure imgf000025_0001
The quinoxaline derivatives of the present invention have a potent PARP inhibitory action as shown in the above. PARP inhibitors including this invention relates to novel quinoxaline derivatives were effective in preventing reduction of stxiatal DA(dopamine) and its metabolite induced by MPTP (N-methyl-l,2,3,6-tetrahydropyridine) treatment in mice. Therefore, it suggests that these compounds may have protective benefit in the treatment of neuxodegenerative disease such as Parkinson's disease.
It has been known that, during major cellular stresses, the activation of PARP can rapidly lead to cell damage or death through depletion of energy stores and PARP activation play a key role in both NMDA- and NO-induced neurotoxicity (Zhang et. al., Science, 263: 687-89 (1994)). Therefore, the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is useful in treating and preventing various diseases ascribed by NMDA- and NO-induced toxicity. Such diseases include, for example, tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Perkinson's disease; epilepsy; amyotrophic latexal scleosis (ALS); Huntington's disease; schizophxenia; chronic pain; ischemia and neuronal loss following hypoxia; hypoglycemia; ischemia; trauma; and nervous insult. It has been demonstrated that PARP inhibitor is useful in deducing infarct size (Thiemermann et al, Proc. Natl. Acad. Sci. USA, 94: 679-83 (1997)). Therefore, the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is useful in treatment and prevention of previously ischemic heart or skeleton muscle tissue.
It is also known that PARP is thought to play a role in enhancing DNA repair. So, the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is effective in treating and preventing radiosensitizing hypoxic tumox cells; tumor cells from recovering from potentially lethal damage of DNA after radiation therapy.
Further, the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is useful in extending the life-span and proliferative capacity of cells and altering gene expression of senescent cells. They axe useful for treating and preventing skin aging; Alzheimer's diseases; atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy; degenerative diseases of skeletal muscle involving replicative senescence; age-related maculax degeneration; immune senescence; AIDS; and othex immune senescence diseases.
Still further, the compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is effective in treating and preventing inflammatory bowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock; septic shock; and tumor. Also, the compounds (I) axe useful in reducing proliferation of tumox cells and making synexgistic effect when tumor cells axe co-treated with an alkylating drug.
The compound (I) of this invention or a pharmaceutically acceptable salt thereof possessing PARP inhibitory action is effective in treating and pxeventing pituitary apoplexy; conjunctivitis; retinoblastoma; retinopathy; acute retinal necrosis syndrome; Sjogren's syndrome. Accordingly, the present invention provides a method for treating or preventing diseases ascribed by NMDA- and NO-induced toxicity by administering a compound (I) in an in an effective amount to inhibit PARP activity, to a human being or an animal who needs to be treated or prevented.
The compound (I), its prodrug or their salt can be administered alone or in the form of a mixture, preferably, with a pharmaceutical vehicle or carrier. Accordingly, the present invention provides a pharmaceutical composition comprising a compound (I), its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient in admixture of a pharmaceutically acceptable carrier such as an organic or inorganic carrier or excipient suitable for external (topical), enteral, intravenous, intramuscular, parenteral or intxamucous applications in a pharmaceutical preparation for example, in solid, semisolid or liquid form.
The compound (I), its prodrug or a pharmaceutical acceptable salt thereof can be formulated, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, fox example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The compound (I), its prodrug or a pharmaceutical acceptable salt thereof is included in a pharmaceutical composition in an effective amount sufficient to pxoduce the desired effect upon the process or condition of the diseases, in a combination with a pharmaceutically acceptable carrier.
The compound (I), its prodrug or a pharmaceutical acceptable salt thereof can be formulated into, for example, preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, preparations for application to mucous membranes.
The present invention provides a pharmaceutical composition containing the compound (I), its prodrug or a pharmaceutical acceptable salt thereof in admixture of a pharmaceutically acceptable salt for treating or preventing diseases ascribed by NMDA- and NO-induced toxicity, specifically for extending the lifespan or proliferative capacity of cells or altering gene expression of senescent cells, more specifically for treating or preventing tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Perkinson's disease; epilepsy; Amyotrophic Lateral Scleosis (ALS); Huntington's disease; schizopherenia; chronic pain; ischemia and nloss following hypoxia; hypoglycemia; ischemia; trauma; nervous insult; previously ischemic heart or skeleton muscle tissue; radiosensitizing hypoxic tumor cells; tumor cells from recovering from potentially lethal damage of DNA after radiation therapy; skin aging; atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy; degenerative diseases of skeletal muscle involving replicative senescence; age-related macular degenexation; immune senescence; AIDS; and other immune senescencediseases; inflammatory bowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock; septic shock; and tumor.
Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.
While the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose to a human patient of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
Any patents, patent applications, and publications cited herein are incorporated by reference.
Best Mode for Carrying out the Invention
The following Preparation and Examples are given for the purpose of illustrating the present invention in detail, but are not to be construed to limit the scope of the present invention.
Abbreviations used in this application axe as follows :
AcOH : acetic acid
PyBOP® : benzotriazol- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
BINAP 2 , 2 ' -bis (diphenylphosphino) -1,1' -binaphythyl
DCM dichloromethane
Et O diethyl ether
DIEA diisopropylethylamine
DMF : N,N-dimethylformamide
EtOAc : ethyl acetate
Fmoc-OSt i : 9-fluoronylmethyl-N-hydroxysuccinimide iPA isopropanol
MeOH : methanol
THF : tetrahydrofuran
TFA : txifluoroacetic acid
Reference example 1
2-Amino-3-nitro-benzamide (2.07g, 11.4 mmol) was suspended in a mixture of MeOH (150 ml) and THF (150 ml), and hydrogenation was carried out by using 10 % (w/w) Pd-C catalyst (50 % wet, 780mg) and hydrogen at atmospheric pressure under stirring until hydrogen gas absorption was ceased. After filtration on celite, the filtrate was concentrated in vacuo and 4N HCI in EtOAc (6 ml) was added to the residue. After evaporation of the solvent, the residue was triturated with EtOAc and dried under reduced pressure to give 2,3-diaminobenzamide dihydxochloride (2.12g, yield 83%).
NMR (DMSO-de, δ) : 6.71 (IH, t, J=7.8 Hz), 7.31 (IH, dd, J=7.8 Hz), 7.58(1H, dd, J=7.8, 1.2 Hz). IR (KBr, v ); 1671. Mass: 174.3 (M+Na)
Reference example 2 A solution of 2-amino-5-chlorobenzoic acid (9.5g, 55.4mmmol) in acetic acid (35ml) was treated with acetic anhydride (8.4ml, 88.6mmol) at 100°C, and the mixture was kept at 100°C for 15 minutes. Water (9ml) was added to hydrolyze the excess of acetic anhydride, and after stirring for 10 minutes the solution was diluted with water to give 2-acetylamino-5-chlorobenzoic acid (10.6g, yield 90%).
NMR (DMSO-d6, δ); 2.13 (3H, s), 7.63 (IH, dd, J=9.0, 2.6 Hz), 7.89 (IH, d,
J=2.6 Hz), 8.46 (IH, d, J=9.0 Hz), 10.26 (IH, s). Mass; 212.4 (M-H)-
Reference example 3
2-Acetylamino-5-chlorobenzoic acid (10.6g, 49.6mmol) was finely pulverized and added slowly to fuming HNO3 (30ml) under stirring at 0-5°C. After stirring for 15 minutes, the solution was poured onto ice. The resultant precipitates were collected by filtration and washed with water to give 2-acetylamino-5-chloro-3-nitxobenzoic acid (6.95g, yield 54%).
NMR (DMSO-de, δ); 2.03 (3H, s), 8.10 (IH, d, J=2.5 Hz), 8.23 (IH, d, J=2.5 Hz), 10.34 (IH, br s). IR (KBr, v ); 3297, 1704, 1683, 1606. Mass; 258.1(M+H)+
Reference example 4 A suspension of 2-acetylamino-5-chloro-3-nitrobenzoic acid (5.0g,
19.6mmol) in 50% sulfuric acid (40ml) was heated at 100°C for 5 hours. After cooling, the mixture was diluted with cold water to give 2-amino-5-chloro-3-nitrobenzoic acid (4.15g, yield 99%). NMR (DMSO-de, δ); 8.13 (IH, d, J=2.7 Hz), 8.31 (IH, d, J=2.7 Hz), 8.49 (2H, bx s).
IR (KBx, v ); 1689, 1556, 1513. Mass; 215.1(M-H)-.
Reference example 5 Thionyl chloride (3.0g, 1.5eq) and catalytic amount of DMF were added to the suspension of 2-amino-5-chloro-3-nitrobenzoic acid (3.6g, 16.6mmol) in THF (35 ml) at room temperature. The mixture was stirred overnight and then added dropwise to a mixture of concentxated ammonia solution (50ml) and THF (25ml) under ice cooling. The solution was diluted with EtOAc and the resultant precipitates were collected by filtration and washed with EtOAc. The crude product was purified by column chromatography on silica-gel eluting with a mixture of n-hexane and THF to give 2-amino-5-chloxo-3-nitrobenzamide (2.7g, yield 78%). NMR (DMSO-de, δ); 7.74 (IH, br s), 8.00 (IH, d, J=2.5 Hz), 8.18 (IH, d, J=2.5 Hz), 8.25 (IH, br s), 8.47 (2H, br s). IR (KBr, v ); 3434, 3174, 1689, 1552, 1513. Mass; 214.2(M-H)-.
Reference example 6
5-Chloro-2,3-diaminobenzamide dihydrochloride (338mg, yield 50%) was obtained from 2-amino-5-chloro-3-nitxobenzamide (560mg, 2.6mmol) accoxding to a manner similar to Preparation 1. NMR (DMSO-de, δ); 7.31 (IH, d, J=2.3 Hz), 7.52 (IH, d, J=2.3 Hz). IR (KBr, v ); 3313, 2886, 1658, 1623. Mass; 208.2 (M+Na).
Example 1
To a suspension of 2,3-diaminobenzamide dihydrochloride (224mg, lmmol) in MeOH (10ml) were added txiethylamine (1.4ml, lOmmol) and 4-methoxyphenacyl bromide (343mg, 1.5mmol) at room temperature. The mixture was stirred overnight and poured into a mixture of water and chloroform. The separated organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a column chromatography on silica-gel eluting with a mixture of DCM and acetone to give a mixture (45mg, yield 16%) of 2-(4-methoxyphenyl)quinoxaline-5-carboxamide and 3-(4-methoxyphenyl)quinoxaline-5-carboxamide.
NMR (DMSO-de, δ) for the mixture : 3.87 and 3.88 (total 3H, s), 7.15-7.22 (H, m), 7.85-7.95 (IH, m), 7.98 (IH, bx s), 8.23-8.52 (4H, m), 9.44 (IH, br s), 9.63 and 9.64 (total IH, s). IR (KBr, v ) for the mixture ; 3268, 1668, 1602, 1544, 1515. Mass; 280.0 (M+H)+.
Example 2
Following compounds were prepared accoxding to a similar manner to Example 1.
(1) A mixture of 2-(4-chlorophenyl)quinoxaline-5-carboxamide and 3-(4-chlorophenyl)quinoxaline-5-carboxamide NMR (DMSO-de, δ); 7.68-7.75 (2H, m), 7.95-8.00 (2H, m), 8.25-8.50 (4H, m), 9.14 and 9.29 (total IH, br s), 9.67 and 9.69 (total IH, s).
IR (KBr, v ); 3334, 1687, 1589. Mass; 284.2(M+H)+. (2) A mixture of 2-(4-pyrrolidinophenyl)quinoxaline-5-carboxamide and 3-(4-pyrrolidinophenyl)quinoxaline-5-carboxamide NMR (DMSO-de, δ);1.9-2.1 (4H, m), 3.3-3.4 (4H, m), 6.74 (2H, d, J=8.9 Hz), 7.80 (IH, t, J=7.4 Hz), 8.01 (IH, br s), 8.14 (2H, d, J=8.9 Hz), 8.18 (IH, dd, J=7.4, 1.6 Hz), 8.50 (IH, dd, J=7.4, 1.6
Hz), 9.56 (IH, s), 9.76 (IH, br s). IR (KBr, v ); 1666, 1606, 1531. Mass; 319.2(M+H)+.
(3) A mixture of 2-(4-diethylaminophenyl)quinoxaline-5-carboxamide and 3-(4-diethylaminophenyl)quinoxaline-5-caxboxamide NMR (DMSO-de, δ); 1.15 (6H, t, J=7.0 Hz), 3.46 (4H, q, J=7.0 Hz), 6.8-6.9 (2H, m), 7.7-8.25 (5H, m), 8.51 (IH, dd, J=7.4, 1.6 Hz), 9.55 (IH, s), 9.79 (IH, br s). IR (KBr, v ); 1673, 1668, 1604, 1602, 1531.
Mass; 321.2 (M+H)+.
(4) A mixture of 2-(3,4-dichlorophenyl)quinoxaline-5-carboxamide and 3-(3,4-dichlorophenyl)quinoxaline-5-carboxamide NMR (DMSO-de, δ); 7.9-8.0 (3H, m), 8.28 (2H, d, J=8.22 Hz), 8.41
(IH, dd, J=7.2, 1.5 Hz), 8.55 (IH, s), 9.71 (IH, s). IR (KBr, v ); 3345, 1683, 1577. Mass; 318.1, 320.0(M+).
(5) A mixture of
2-(4-txifluoxomethylphenyl)quinoxaline-5-caxboxamide and 3-(4-trifluoxomethylphenyl)quinoxaline-5-caxboxamide NMR (DMSO-de, δ); 7.9-8.05 (4H, m), 8.30 (IH, dd, J=8.3, 1.5 Hz), 8.45-8.60 (3H, m), 8.59 (IH, bx s), 9.72 (IH, s). IR (KBx, v ); 3343, 1679, 1581.
Mass; 340.2 (M+Na)+.
(6) A mixture of 7-chloro-2-(4-diethylarninophenyl)quinoxaline-5-caxboxarnide and
7-chloro-3-(4-diethylaminophenyl)quinoxaline-5-carboxamide NMR (DMSO-de, δ); 1.1-1.25 (6H, m), 4.46 (4H, q, J=7.1 Hz), 6.8-6.95 (2H, m), 8.05-8.35 (5H, m), 9.26 and 9.63 (total IH, br s), 9.55 and 9.57 (total IH, each s). IR (KBr, v ); 3295, 1673, 1606, 1571, 1531. Mass; 377.2(M+Na)+.
(7) A mixture of
7-chloro-2-(4-methoxyphenyl)quinoxaline-5-carboxamide and 7-chloro-3-(4-methoxyphenyl)quinoxaline-5-carboxamide NMR (DMSO-de, δ); 3.88(3H, m), 7.15-7.25(2H, m), 8.15-8.40(5H, m), 9.20 and 9.27(total IH, br s), 9.65 and 9.67(total IH, each s). IR (KBr, v ); 3322, 1683, 1604, 1531.
Mass; 336.1 (M+Na)+.
(8) A mixture of
7-chloro-2-(4-pyrrolidinophenyl)quinoxaline-5-carboxamide and 7-chloro-3-(4-pyrrolidinophenyl)quinoxaline-5-caxboxamide
NMR (DMSO-de, δ): 1.9-2.1 (4H, m), 3.2-3.4 (4H, m), 6.73 (2H, d, J=8.8 Hz), 8.14 (2H, d, J=8.8 Hz), 8.25 (IH, d, J=2.6 Hz), 8.35 (IH, d, J=2.6 Hz), 9.56 and 9.59 (total IH, each s). IR (KBr, v ); 3349, 1604, 1531. Mass; 353.0 and 355.0 (M+).
Example 3
A mixtuxe of 2-(4-chlorophenyl)quinoxalin-5-carboxamide and 3-(4-chlorophenyl)quinoxalin-5-carboxamide (140mg) was separated by using a recycling preparative HPLC (LC908-C60). Each compound was recrystallized from chloroform to give
3-(4-chlorophenyl)quinoxalin-5-caxboxamide (60mg, yield 43%) and 2-(4-chlorophenyl)quinoxalin-5-carboxamide (33mg, yield 23%), respectively.
3-(4-chlorophenyl)quinoxalin-5-carboxarnide
NMR (DMSO-de, δ); 7.73 (2H, dd, J = 8.6, 2.2 Hz), 7.95-8.00 (2H, m), 8.25-8.45 (4H, m), 9.14(1H, br s), 9.67 (IH, s). Mass; 284.2 (M+H)+.
2-(4-chlorophenyl)quinoxalin-5-caxboxamide NMR (DMSO-de, δ ); 7.70 (2H, d, J = 8.6 Hz), 7.95-8.05 (2H, m),
8.25-8.50 (4H, m), 9.29 (IH, br s), 9.69 (IH, s). Mass; 284.2 (M+H)+.
Example 4
A mixture of 2-(4-diethylaminophenyl)quinoxaline-5-carboxamide and 3-(4-diethylaminophenyl)quinoxaline-5-caxboxamide (180mg) was separated by using a recycling preparative HPLC (LC908-C60). Each compound was recrystallized from chloroform to give
2-(4-diethylaminophenyl)quinoxaline-5-carboxamide (58mg, yield 32%) and 3-(4-diethylaminophenyl)quinoxaline-5-caxboxamide (98mg, yield 54%), xespectively. 3-(4-diethylaminophenyl)quinoxalin-5-carboxamide NMR (DMSO-de, δ); 1.15 (3H, t, J = 7.0 Hz), 3.47 (2H, q, J = 7.0 Hz),
6.86 (2H, d, J = 9.1 Hz), 8.12 (2H, d, J = 9.1 Hz), 8.13 (IH, br s), 8.25 (IH, d, J = 2.6 Hz), 8.35 (IH, d, J = 2.6 Hz), 9.58 (IH, br s), 9.61 (IH, s). Mass; 377.2 (M+Na)+. 2-(4-diethylaminophenyl)quinoxaline-5-carboxamide
NMR (DMSO-de, δ); 1.15 (3H, t, J = 7.0 Hz), 3.45 (2H, q, J = 7.0 Hz), 6.83 (2H, d, J = 9.1 Hz), 8.08 (IH, br s), 8.15-8.25 (4H, m), 9.27 (IH, br s), 9.54 (IH, s). Mass; 377.1 (M+Na)+.
Example 5
To a suspension of 2,3-diaminobenzamide dihydrochloride (224 mg, 1 mmol) in MeOH (10 ml) were added txiethylamine (1.4 ml, 10 mmol) and phenacyl bromide (343 mg, 1.5 mmol) at room temperature. The mixture was stirred overnight and poured into a mixture of water and chloroform. The separated organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a column chromatography on silica gel eluting with a mixture of DCM and acetone to give 3-phenylquinoxaline-5-caxboxamide (132mg, yield 53%). NMR (DMSO-de, δ); 7.5-8.2 (8H, m), 9.37 (IH, m), 9.68 (IH, s) Mass: 250 (M++l)
Example 6
Following compounds were prepared according to a similar manner to Example 5.
(1) 3-(4-Nitrophenyl)quinoxaline-5-carboxamide
NMR (DMSO-de, δ ): 7.8-8.5(8H, m), 8.95(1H, m), 9.75(1H, s) Mass : 295(M+H)+
(2) 3-(3-Nitrophenyl)quinoxaline-5-carboxamide NMR (DMSO-de, δ ): 7.8-8.5(8H, m), 9.20(1H, m), 9.78(1H, s) Mass : 295(M+H)+
(3) 3-(2-Naphthyl)quinoxaline-5-carboxamide
NMR (DMSO-de, δ ): 7.2-8.5(10H, m), 9.38(1H, m), 9.85(1H, s) Mass : 300(M+H)+
(4) 3-(4-Fluorophenyl)quinoxaline-5-carboxamide
NMR (DMSO-de, δ ): 7.4-8.4(7H, m), 9.25(1H, m), 9.67(1H, s) Mass : 268(M+H)+
(5) 3-(4-Bromophenyl)quinoxaline-5-carboxamide NMR (DMSO-de, δ ): 7.4-8.4(7H, m), 9.28(1H, m), 9.67(1H, s) Mass : 329(M+H)+ (6) 3-(3-Bromophenyl)quinoxaline-5-caxboxamide
NMR (DMSO-de, δ ): 7.4-8.4(7H, m), 9.04(1H, m), 9.68(1H, s) Mass : 329(M+H)+
(7) 3-(4-Cyanophenyl)quinoxaline-5-caxboxamide
NMR (DMSO-de, δ ): 7.8-8.6(7H, m), 9.04(1H, m), 9.72(1H, s) Mass : 275(M+H)+
(8) 3-(3-Methoxyphenyl)quinoxaline-5-caxboxamide
NMR (DMSO-de, δ ): 3.90(3H, s), 7.0-8.4(7H, m), 9.33(1H, m), 9.68(1H, s) Mass : 280(M+H)+
(9) 3-(3-Methoxyphenyl)quinoxaline-5-caxboxamide NMR (DMSO-de, δ ): 6.8-8.4(7H, m), 9.49(1H, s)
Mass : 265(M+H)+
(10) 3-(4-Aminophenyl)quinoxaline-5-caxboxamide
NMR (DMSO-de, δ ): 6.6-6.8(2H, m), 7.7-8.4(5H, m), 9.52(1H, s) Mass : 265(M+H)+
(11) 3-(3-Pyridyl)quinoxaline-5-carboxamide
NMR (DMSO-de, δ): 7.5-7.7 (IH, m), 7.9-8.1 (IH, m), 8.2-8.8 (4H, m), 9.48 (IH, dd, J=8.2 Hz), 9.74 (IH, d, J=3.4Hz) Mass : 273(M+Na)+
( 12) 1 lH-Indeno[ 1 ,2-b]quinoxaline-6-carboxamide
NMR (DMSO-de, δ ): 4.27(2H, s), 7.3-8.4(7H, m), 9.39(1H, m) Mass : 262(M+H)+
(13) 3-(l, l'-Biphenyl-4-yl)quinoxaline-5-caxboxamide
NMR (DMSO-de, δ ): 7.2-8.3(13H, m), 9.30(1H, m), 9.69(1H, s) Mass : 326(M+H)+ (14) 3-[3-(3,4-Dichlorophenyl)-5-isoxazolyl]quinoxaline-5-carboxamide NMR (DMSO-de, δ ): 7.8-8.3(8H, m), 9.20(1H, m), 9.61(1H, s)
Mass : 386(M+H)+
( 15) 3-(2,3-Dihydro- 1 ,4-benzodioxan-6-yl)quinoxaline-5-carboxamide NMR (DMSO-de, δ ): 4.35(4H, m), 7.0-7.2(lH, m), 7.7-8.2(6H, m), 9.33(1H, m), 9.68(1H, s)
Mass : 308(M+H)+
Example 7
(1) Preparation of resin-supported 3-nitroanthranilic acid
To a suspension of oxime xesin in DMF were added PyBOP® (3eq), DIEA (3eq) and 3-nitroanthranilic acid (3eq). The mixture was shaken for 12 hours at room temperature. The resin-supported
3-nitroanthranilic acid was isolated by filtration, washed with DMF, MeOH, DCM and Et20 successively and dried under vacuum.
(2) Preparation of resin-supported 2,3-diaminobenzoic acid Thus obtained resin-supported 3-nitroanthranilic acid suspended in a solution of SnCl2 in DMF (2M) was shaken for 3 hours at room temperature. The resin-supported 2,3-diaminobenzoic acid was isolated by filtration, washed with DMF, MeOH, DCM and Et20 successively and ' dried under vacuum. Washing with DMF, MeOH, DCM and Et20 successively and drying under vacuum were repeated twice. The resin-supported 2,3-diaminobenzoic acid was split into 11 equal volume.
(3) Preparation of quinoxaline derivatives
Various kinds of -haloketone (3eq) were added to thus obtained resin-supported 2,3-diaminobenzoic acid suspended in 1,4-dioxane, respectively. The mixture was shaken for 4 hours at room temperature. The resin-supported quinoxaline derivative was isolated by filtration, washed with DMF, MeOH, DCM and Et20 successively and dried in vacuum. Washing with DMF, MeOH, DCM and Et20 successively and drying under vacuum were repeated twice. The resin-supported quinoxaline derivative preswelled by DCM was treated with an excess amount of 2M NH3 in MeOH to cleavage the quinoxaline derivative from the resin. After stirring for 1 hour, the resin was filtered off and the filtrate was evaporated under reduced pressure. The separation of the residue was carried out using HPLC (reverse phase Cis, 2.5 t m, 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HC02H in CH3CN / 0.05 % HC02H in H20, over 4 min., 0.8 mL/min.).
Example 8
The quinoxaline derivatives shown in the following Table 2 were prepared according to a manner similar to Example 7. The Mass spectxa data of the derivatives axe shown in the same Table 2.
Table 2
Figure imgf000040_0001
Figure imgf000040_0002
Example 9
(1) Preparation of methyl 3-(4-bromo)phenylquinoxaline-5-carboxylate Methyl 3-nitroanthranilate (2.51 g, 9.03 mmol) was added to a solution of 4-bromophenacyl bromide (1.0 g, 6.02 mmol) in iPA (10 ml), and the mixture was stirred for 12 hours at room tempexature. The reaction mixture was diluted with EtOAc, washed with H2O three times and with brine and dried over sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by a column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc to give methyl 3-(4-bromo)phenylquinoxaline-5-carboxylate (0.91 g, yield 44.1 %).
(2) Preparation of 3-(4-bromo)phenylquinoxaline-5-carboxylic acid To a solution of methyl 3-(4-bromo)phenylquinoxaline-5-carboxylate (0.9 g, 2.62 mmol) in
1,4-dioxane (5 ml) was added dropwise IN NaOH aqueous solution (5 ml), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was added dropwise to IN HCI aqueous solution (5 ml) and the mixture was poured into EtOAc. The separated organic layer was washed with H20 three times and with brine and then dried over sodium sulfate. The dried solution was concentrated under reduced pressure to give 3-(4-bromo)phenylquinoxaline-5-carboxylic acid (0.85, yield 98.5 %).
(3) Preparation of resin-supported quinoxaline derivatives
To a suspension of deprotected Rink amide resin in DMF were added PyBOP® (1.5eq), DIEA (1.5eq) and
3-(4-bromo)phenylquinoxaline-5-carboxylic acid (1.5eq). The mixture was shaken for 12 hours. The resin was isolated by filtration, washed with DMF, MeOH, DCM and Et20 successively and dried under vacuum.
The resin was split into 26 equal volume.
(4) Modification of resin-supported quinoxaline derivatives
To the resin suspended in toluene were added Pd2(dba)3 (0.05eq), BINAP (0.2 eq), NaOt-Bu (20 eq) and various kinds of amines of the formula R5R6NH (3eq) under nitrogen atmosphere, respectively. The respective reaction mixtuxe was shaken for 15 hours at 100°C. The resin was isolated by filtration, washed with DMF, MeOH, DCM and Et20 respectively and dried under vacuum. The resin was treated with an excess amount of 50% TFA in DCM. After stirring for 30 minutes, the resin was filtered off and the filtrate was evaporated under reduced pressure. The separation of the residue was carried out by using HPLC (reverse phase Cis, 2.5 μ m, 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HCO2H in CH3CN / 0.05 % HCO2H in H20, over 4 min., 0.8 mL/min.).
Example 10
The compounds shown in the following Table 3 wexe pxepared according to a manner similar to Example 9. The Mass spectra data of the derivatives are shown in the same Table 3.
Table 3
Figure imgf000042_0001
Figure imgf000042_0002
able 3 (continued)
Figure imgf000043_0001
Table 3 (continued'
Example Ri R2 R3 R4 Mass
Figure imgf000044_0001
(19) H H -H 3-phenyl 428.12
Figure imgf000044_0002
(20) H H / — \ N= -H 3-phenyl 412.66
N-< ^NN //
(21) H H -H 3-phenyl 444.11
Figure imgf000044_0003
(22) H H CH30 -H 3-phenyl 440.13
(23) H H 4- -H 3-phenyl 424.69
(24) H H -H 3-phenyl 424.58
Figure imgf000044_0004
(25) H H 4- -H 3-phenyl 424.56
(26) H H -H 3-phenyl 343.37
Figure imgf000044_0005
Example 11
(1) Preparation of N-(9-fluororenylmethyloxycarbonyl)-4-acetylpiperidine
TFA (50 ml) was added dropwise to a solution of N-tert-butoxycarbonyl-4-acetylpiperidine (10 g, 44 mmol) in DCM (50 ml), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and then neutralized by adding NaHCU3 aqueous solution. The solution was poured into a mixture of THF and H20 (1 : 1)(100 ml), and Fmoc-OSu (16.3 g, 48.4 mmol) was added thereto. After stirring for 12 hours at room temperature, the reaction mixture was extracted with EtOAc. The organic layer was washed with IN HCI aqueous solution, H20 twice and with brine successively and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by a column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc to give
N-(9-fluororenylmethyloxycarbonyl)-4-acetylpiperidine (14.65 g, yield 95.3 %).
(2) Preparation of N-(9-fluororenylmethyloxycarbonyl)-piperidinyl bromomethylketone
Bromine (0.161 ml, 3.15 mmol) was added to a solution of N-(9-fluororenylmethyloxycarbonyl)-4-acetylpiperidine (1.0 g, 2.86 mmol) in MeOH (10 ml), and the mixture was stirred for 12 hours at 0 °C. The reaction mixture was diluted with EtOAc and washed with H20 three times and with brine and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by a column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (6/ 1) to give N-(9-fluororenylmethyloxycarbonyl)-piperidinyl bromomethylketone (650 mg, yield 53 %).
(3) Preparation of resin-supported quinoxaline derivatives
To a suspension of resin-supported 2,3-diaminobenzoic acid in DMF was added N-(9-fluororenylmethyloxycarbonyl)-piperidinyl bromomethylketone (1.5eq). The mixture was shaken for 12 hours at room temperature. The resin was isolated by filtration, washed with DMF, MeOH, DCM and Et20 successively and then dried under vacuum. Washing with DMF, MeOH, DCM and Et20 successively and then drying under vacuum were repeated twice.
(4) Deprotection of resin-supported quinoxaline derivatives
Thus obtained resin-supported quinoxaline derivative was treated with an excess amount of 20% piperidine in DMF for 30 minutes, and washed with DMF, MeOH, DCM and Et20 successively and then dried under vacuum. Washing with DMF, MeOH, DCM and Et20 successively and then drying under vacuum were repeated twice. The resin was split into 54 equal volume.
(5) Modification of resin-supported quinoxaline derivatives
To thus obtained resin suspended in 1% AcOH in DMF were added various kinds of aldehydes of the formula R7CHO (10 eq), respectively. After stirring for 2 hours, the resin was washed with DMF, and then NaBH(OA (lOeq) in DMF was added thereto. The mixture was shaken for 24 hours at room temperature. The resin was isolated by filtration, washed with DMF, MeOH, DCM and Et20 successively and then dried under vacuum. The resin was treated with an excess amount of 50% TFA in DCM to cleavage the quinoxaline derivative from the resin. After stirring for 30 minutes, the solvent was xemoved under reduced pressure. Purification of the object compound was carried out by using HPLC (reverse phase Cis, 2.5μ m, 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HC02H in CH3CN / 0.05 % HC02H in H20, over 4 min., 0.8 mL/min.).
Example 12
The quinoxaline derivatives shown in the following Table 4 were prepared according to a manner similar to Example 11. The Mass spectxa data of the dexivatives are shown in the same Table 4. Table 4
Figure imgf000047_0001
Figure imgf000047_0002
Table 4 (continued)
Figure imgf000048_0001
Table 4 (continued)
Figure imgf000049_0001
Table 4 (continued)
Figure imgf000050_0001
Table 4 (continued)
Figure imgf000051_0001
Table 4 (continued)
Figure imgf000052_0001
Example 13
(1) Preparation of resin-supported 3-(3-aminophenyl)quinoxaline A suspension of resin-supported 2,3-diaminobenzoic acid prepared in Example 7 (2) (2.0 g) and 3-nitxophenacyl bromide (720 mg) in 1,4-dioxane (50 mL) was shaken overnight at ambient temperature. The resin-supported 3-(3-nitrophenyl)quinoxaline was filtered, washed well with 1,4-dioxane, MeOH, DMF and Et20 successively and then dried 0 to give resin-supported 3 -(3 -nitrophenyl) quinoxaline. 2M Solution of SnQb • 2H2O in DMF (50 mL) was added to the resulting resin-supported 3-(3-nitrophenyl)quinoxaline and the resultant mixture was shaken for 3 hours at ambient temperature. To the resin isolated by filtration, 2M solution of SnCl2 • 2H20 in DMF (50 mL) was added and the resultant mixtuxe was shaken fox 3 hours at ambient temperature. The resin was filtered, washed well with DMF, MeOH, DCM and Et^O successively and then dried under reduced pressure to give resin-supported 3-(3-aminophenyl)quinoxaline.
(2) Preparation of 3-(3-substituted-phenyl)-5-quinoxaline derivatives
3-(3-substituted-phenyl)-5-quinoxaline derivatives were prepared according to any one of Methods A to E as descried below.
Method A: Preparation of sulfonamide dexivatives using sulfonyl chloxide of the formula R3-SOCl2
To a suspension of resin-supported 3- (3-aminophenyl) quinoxaline (70 mg) and pyridine (16 μ L) in DCM (1 mL) was added a compound of the formula Rs-SOCl2, wherein R8 is as defined in the above (0.1 mmol). The mixture was shaken overnight at ambient temperature. The resin was isolated by filtration and washed well with DCM, DMF, MeOH and Et20 successively and then dried under reduced pressure to give a resin-supported sulfonamide. The resulting resin was added to 2N solution of NH3 in 1,4-dioxane (1 mL) and shaken overnight at ambient temperature. The resin was isolated by filtration and washed twice with DCM (0.5 mL). The combined filtrates were evaporated and the residue was purified by HPLC (reverse phase Cis, 5 μ m, 20 mm X 50 mm column, 254 nm, 0-80 % of 0.1 % trifluoroacetic acid (TFA) in CH3CN / 0.1 % TFA in H20, 25 mL/min.). The fractions containing an objective compound were combined and evaporated, and • the residue was dissolved in 50 % aqueous 1 ,4-dioxane and neutralized with an aqueous NaHCθ3 solution. The resulting solution was desalted by using a solid-phase extraction cartridge (Waters Oasis™ HLB 6cc 500 mg LP Extraction Cartridge, conditioned by using CH3CN (6 mL) and H20 (6 mL), washed with H2O (6 mL) and eluted with CH3CN (6 mL)) to give a sulfonamide derivative. Purity of the sulfonamide derivative was determined by HPLC analysis (reverse phase Cis, 2.5 μ m, 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HC02H in CH3CN / 0.05 % HC02H in H20, over 4 min., 0.8 mL/min.).
Method B: Preparation of urea derivatives by using isocyanate of the foxmula RS-NCO
To a suspension of xesin-supported 3-(3-aminophenyl)quinoxaline (70 mg) in DCM (1 mL) was added a compound of the formula R8-NCO (0.1 mmol) and the mixture was shaken overnight at ambient temperature. The resin was isolated by filtration and washed well subsequently with DCM, DMF, MeOH and Et20 successively and then dried under reduced pressure to give a resin-supported urea derivative. The resulting resin was added to 2N NH3 in 1,4-dioxane (1 mL) and the mixture was shaken overnight at ambient temperature. The resin was isolated by filtration and washed twice with DCM (0.5 mL). The filtrates were combined and evaporated. The residue was purified by HPLC (reverse phase Cis, 5μ m, 20 mm X 50 mm column, 254 nm, 0-80 % 0.1 % TFA in CH3CN / 0.1 % TFA in H20, 25 mL/min.) . The fractions containing an object compound were combined and evaporated. The residue was dissolved in 50 % aqueous 1 ,4-dioxane and the solution was neutralized with an aqueous NaHCU3 solution. The resulting solution was desalted by using a solid-phase extraction cartridge (Waters® Oasis™ HLB 6cc 500mg LP Extraction Cartridge, conditioned using CH3CN (6 mL) and H20 (6 mL), washed with H20 (6 mL) and eluted with CH3CN (6 mL)) to give an urea derivative. Purity of the urea derivative was determined by HPLC analysis (reverse phase Cis, 2.5 μ m, 2.1 mm X 20 mm column, 254 nm, 2-100 % of 0.04 % HCO2H in CH3CN / 0.05 % HC02H in H20, over 4 min., 0.8 mL/min.).
Method C: Preparation of urea derivatives by using carbonyl chloride To a suspension of resin-supported 3- (3 -aminophenyl) quinoxaline (70 mg) and pyridine (16 μ L) in DCM (1 mL) was added carbonyl chloride (0.1 mmol) and the mixture was shaken overnight at ambient temperature. The resin was isolated by filtration and washed well with DCM, DMF, MeOH and Et2θ successively and then dried under reduced pressure to give a resin-supported urea derivative. The resulting resin was added to 2N NH3 in 1,4-dioxane (1 mL) and the mixture was shaken overnight at ambient temperature. The resin was isolated by filtration and washed twice with DCM (0.5 mL). The filtrates were combined and evaporated under reduced pressure. The residue was purified by HPLC (reverse phase Cis, 5 μ m, 20 mm X 50 mm column, 254 nm, 0-80 % of 0.1 % TFA in CH3CN / 0.1 % TFA in H20, 25 mL/min.). The fractions containing objective compound were combined and evaporated under reduced pressure. The residue was dissolved in 50 % aqueous 1,4-dioxane and the solution was neutralized with an aqueous NaHCθ3 solution. The resultant solution was desalted by using a solid-phase extxaction cartridge (Waters Oasis™ HLB 6cc 500mg LP Extraction Cartridge, conditioned by using CH3CN (6 mL) and H20 (6 mL), washed with H2O (6 mL) and eluted with CH3CN (6 mL)) to give an uxea derivative. Purity of the urea derivative was determined by HPLC analysis (reverse phase Cis, 2.5 μ m, 2.1 mm X 20 mm column, 254 nm, 2-100 % of 0.04 % HC02H in CH3CN / 0.05 % HC02H in H20, over 4 min., 0.8 mL/min.).
Method D: Preparation of amide derivatives by using acyl chloride of the formula R8-COC1
To a suspension of resin-supported 3-(3-aminophenyl)quinoxaline (70 mg) and pyridine (16 μ L) in DCM (1 mL) was added an acyl chloride of the formula R8-COCl (0.1 mmol). The mixtuxe was shaken overnight at ambient temperature. The resin was isolated by filtration and washed well with DCM, DMF, MeOH and Et^O successively and then dried under reduced pressure to give a resin-supported amide derivative. The resultant resin was added to 2N solution of NH3 in 1,4-dioxane (1 mL) the mixture was shaken overnight at ambient temperature. The resin was isolated by filtration and washed twice with DCM (0.5 mL). The combined filtrates were evaporated and the residue was purified by HPLC (reverse phase Cis, 5 μ m, 20 mm X 50 mm column, 254 nm, 0-80 % of 0.1 % TFA in CH3CN / 0.1 % TFA in H20, 25 mL/min.). The fractions containing an objective compound wexe combined and evapoxated. the residue was dissolved in 50 % aqueous 1,4-dioxane and the solution was neutralized with an aqueous NaHC03 solution. The resultant solution was desalted using a solid-phase extraction cartridge (Waters Oasis™ HLB 6cc 500mg LP Extraction Cartxidge, conditioned by using CH3CN (6 mL) and H20 (6 mL), washed with H2O (6 mL) and eluted with CH3CN (6 mL)) to give an amide derivative. Purity of the amide derivative was determine by HPLC analysis (reverse phase Cis, 2.5 μ m., 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HCO2H in CH3CN / 0.05 % HC02H in H 0, over 4 min., 0.8 mL/min.).
Method E: Preparation of amide derivatives by using carboxylic acid of the formula RS-COOH
To a suspension of resin-supported 3-(3-aminoρhenyl)quinoxaline (4, 70 mg), PyBOP ® (52 mg) and R8-COOH (0.1 mmol) in DMF (1 mL) wexe added DIEA (16 μ L) and the mixture was shaken overnight at ambient temperature. The resin was isolated by filtration, washed well with DMF, MeOH, DCM and Et2θ successively and dried under reduced pressure to give a resin-supported amide derivative. The resultant resin was added to 2N solution of NH3 in 1 ,4-dioxane ( 1 mL) and the mixture was shaken overnight at ambient temperature. The resin was isolated by filtration and washed twice with DCM (0.5 mL). The combined filtrates were evaporated and the residue was purified by HPLC (reverse phase Cis, 5μ m, 20 mm X 50 mm column, 254 nm, 0-80 % of 0.1 % TFA in CH3CN / 0.1 % TFA in H2O, 25 mL/min.). The fractions containing an objective compound were combined and evaporated. The residue was dissolved in 50 % aqueous 1,4-dioxane and the solution was neutralized with an aqueous NaHC03 solution. The xesulting solution was desalted by using a solid-phase extraction cartxidge (Watexs Oasis™ HLB 6cc 500mg LP Extraction Cartridge, conditioned by using CH3CN (6 mL) and H2O (6 mL), washed with H2O (6 mL) and eluted with CH3CN (6 mL)) to give an amide derivative. Purity of the amide derivative was determined by HPLC analysis (reverse phase Cis, 2.5 m, 2.1 mm X 20 mm column, 254 nm, 2-100 % 0.04 % HCO2H in CH3CN / 0.05 % HCO2H in H20, over 4 min., 0.8 mL/min.).
Example 14
The 3-(4-substituted-phenyl)-5-quinoxaline derivatives were prepared in a manner similar to the steps (1) and (2) of Example 13 0 except using 3- (4-nitxophenyl) quinoxaline instead of 3- (3-nitrophenyl) quinoxaline .
Example 15
The 3-(3-substituted-phenyl)-5-quinoxaline and 5 3-(4-substituted-phenyl)-5-quinoxaline derivatives shown in the Table 5 were prepared according to Examples 13 and 14, xespectively. The Mass spectra data of the derivatives are shown in the same Table 5.
Table 5 0
Figure imgf000057_0001
Figure imgf000057_0002
5
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Table 5 (continued)
Figure imgf000061_0001

Claims

C L A I M S
A compound of the formula (I):
Figure imgf000062_0001
wherein the ring A is an aryl group or a heterocyclic group,
R1 is hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R2 is hydrogen atom, a lower alkyl group or an aryl group optionally substituted with halogen, R3 is hydrogen atom, a halogen atom, cyano group, nitro group, amino gxoup, an ar (lower) alkylamino group optionally substituted with one or more substituent(s), a di (lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclyl(lower)alkylamino group, a N-heterocyclyl-N-ar (lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclylamino group optionally substituted with ar (lower) alkyl, a cycloalkylamino group, a (lower) alkylsulfonylamino group, an arylsulfonylamino group, a heterocyclylsulfonylamino group optionally substituted with one or more substituent(s) an acylaminio group, a lower alkoxy group, an alkyl group optionally substituted with lower alkylthio, a halo (lower) alkyl group, an ar (lower) alkyl group optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkyl group optionally substituted with one or more substituent(s), a cycloalkyl(lower)alkyl group, a cycloalkenyl(lower) alkyl group, an aryl group optionally substituted with one or more substituent(s), a heterocyclic group optionally substituted with one or more substituent(s), or a heterocyclylthio group optionally substituted with one or more substituent(s), and R4 is hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, or in the case where both of R2 and R3 are a lower alkyl group, they may be combined to form a lower alkylene group, or in the case where both of R3 and R4 are a lower alkoxy group, they may be combined to form a lower alkylenedioxy group or a salt thereof.
2. A compound of Claim 1, whexein the acyl moiety in the acylamino group is selected from a group consisting of a lower alkanoyl, a cycloalkylcarbonyl, an aroyl optionally substituted with one or more substituent(s), a heterocyclylcaxbonyl optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkanoyl, a mono- or di- (lower) alkylcarbamoyl, a cycloalkylcaxbamoyl, an arylcarbamoyl, an ar (lower) alkylcarbamoyl, a diaryl(lower) alkylcarbamoyl optionally substituted with one or more substituent(s), and an arylthiocarbamoyl optionally substituted with one or more substituent(s) .
3. The compound of Claim 1 or 2, wherein the ring A is an aryl group, a saturated or unsaturated monocyclic or an unsaturated condensed heterocyclic group containing 1 to 4 heteroatoms selected from nitxogen, oxygen and sulfur atoms.
4. The compound of Claim 3, wherein the ring A is phenyl, pyridyl or piperidyl, R1 is hydrogen or a halogen atom, R2 is hydrogen atom, R3 is a halogen atom, an ar (lower) alkylamino group optionally substituted with one or more substituent(s), a di(lowex) alkylamino group optionally substituted with one or more substituent(s), a heterocyclyl(lower) alkylamino group, a N-heterocyclyl-N-ar (lower) alkylamino group optionally substituted with one or more substituent(s), a heterocyclylamino group optionally substituted with ar (lower) alkyl, a cycloalkylamino group or a lower alkoxy group, R4 is hydrogen atom, a halogen atom or lower alkoxy, in the case where both R3 and R4 axe a lower alkoxy group they may be combined to form a lower alkylendioxy group.
5. The compound of Claim 4, which is selected from the group consisting of
3-(4-methoxyphenyl)quinoxaline-5-carboxamide,
3-(4-pyrrolidinophenyl)quinoxaline-5-caxboxamide,
3-(4-diethylaminophenyl)quinoxaline-5-caxboxamide,
3-(3,4-dichlorophenyl)quinoxaline-5-carboxamide, 3 - (4-trifiuoromethylphenyl) quinoxaline- 5 -carboxamide ,
3-(3-pyridyl)quinoxaline-5-carboxamide,
3-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)quinoxaline-5-carboxamide,
3-[l-(cyclopropylmethyl)-4-piperidyl]quinoxaline-5-carboxamide, 3-{l-[(4-acetanιidophenyl)methyl]-4-piperidyl}quinoxaline-5-carboxarnide
3-{ 1 - [(4-biphenyl)methyl] -4-piperidyl}quinoxaline-5-carboxamide and 3-{l-[(4-hydroxyphenyl)methyl]-4-piperidyl}quinoxaline-5-carboxamide.
6. A process for preparing a compound of the formula (I)
Figure imgf000065_0001
wherein the symbols A, R1, R2, R3 and R4 are the same meanings as defined in Claim 1, and its salt, which comprises reacting a compound of the formula (II) :
Figure imgf000065_0002
or its salt with a compound of the formula (III)
Figure imgf000065_0003
or its salt.
7. A pharmaceutically composition comprising a compound of the formula (I):
Figure imgf000066_0001
wherein the symbols A, R1, R2, R3 and R4 axe the same meanings as defined in Claim 1, its prodrug or a pharmaceutically acceptable salt thereof in admixture of a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of Claim 7 for treating or preventing diseases ascribed by excess activation of PARP.
9. The pharmaceutical composition of Claim 8 wherein diseases ascribed by excess activation of PARP are tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage xesulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Perkinson's disease; epilepsy; Amyotrophic Lateral Scleosis (ALS); Huntington's disease; schizopherenia; chronic pain; ischemia and nloss following hypoxia; hypoglycemia; ischemia; trauma; nervous insult; previously ischemic heart or skeleton muscle tissue; radio sensitizing hypoxic tumor cells; tumor cells from recovering from potentially lethal damage of DNA after radiation therapy; skin aging; atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy; degenerative diseases of skeletal muscle involving replicative senescence; age-related macular degeneration; immune senescence; AIDS; and other immune senescencediseases; inflammatory bowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock; septic shock; and/ or tumor.
10. A method of treating or preventing diseases ascribed by excess activation of PARP by administering a compound of the formula (I) :
Figure imgf000067_0001
wherein the symbols A, R1, R2, R3 and R4 are the same meanings as defined in Claim 1, its prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in an effective amount to inhibit PARP activity, to human being or an animal who needs to be txeated or prevented.
11. A use of the compound of Claim 1 as a medicament.
12. A use of the compound of Claim 1 for preparing a medicament for treating or preventing diseases ascribed by excess activation of PARP.
13. The use of Claim 12 wherein diseases ascribed by excess activation of PARP are tissue damage resulting from cell damage or death due to necrosis or apoptosis; neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; neurodegenerative diseases; head trauma; stroke; Alzheimer's disease; Perkinson's disease; epilepsy; Amyotrophic Lateral Scleosis (ALS); Huntington's disease; schizopherenia; chronic pain; ischemia and nloss following hypoxia; hypoglycemia; ischemia; trauma; nervous insult; previously ischemic heart or skeleton muscle tissue; radiosensitizing hypoxic tumor cells; tumor cells from recovering from potentially lethal damage of DNA after radiation therapy; skin aging; atheroscleosis; osteoarthritis; osteoporosis; muscular dystrophy; degenerative diseases of skeletal muscle involving replicative senescence; age-related macular degeneration; immune senescence; AIDS; and other immune senescencediseases; inflammatory bowel disorders (e.g., colitis); arthritis; diabetes; endotoxic shock; septic shock; and tumor.
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