WO2003007959A1 - Derives de quinoxaline ayant une action inhibitrice sur parp - Google Patents

Derives de quinoxaline ayant une action inhibitrice sur parp Download PDF

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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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group
optionally substituted
quinoxaline
substituent
compound
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PCT/JP2002/007078
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English (en)
Inventor
Kouji Hattori
Hirofumi Yamamoto
Koichiro Mukoyoshi
Satoru Kuroda
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Fujisawa Pharmaceutical Co., Ltd.
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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/fr

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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
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    • 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.).

Abstract

L'invention porte sur des dérivés de quinoxaline représentés par la formule (I): dans laquelle R?1, R2, R3, R4¿ et le noyau A sont tels que définis dans la demande, et ayant une action inhibitrice sur poly(adénosine 5'-diphaspho-ribose)polymérase (PARP).
PCT/JP2002/007078 2001-07-16 2002-07-11 Derives de quinoxaline ayant une action inhibitrice sur parp WO2003007959A1 (fr)

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