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WO2011093365A1 - Composé hétérocyclique azoté - Google Patents

Composé hétérocyclique azoté Download PDF

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Publication number
WO2011093365A1
WO2011093365A1 PCT/JP2011/051572 JP2011051572W WO2011093365A1 WO 2011093365 A1 WO2011093365 A1 WO 2011093365A1 JP 2011051572 W JP2011051572 W JP 2011051572W WO 2011093365 A1 WO2011093365 A1 WO 2011093365A1
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Prior art keywords
nitrogen
substituent
pharmaceutically acceptable
acceptable salt
optionally substituted
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PCT/JP2011/051572
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English (en)
Japanese (ja)
Inventor
潤一郎 山本
慶輔 金原
裕一 福田
宜資 中里
賢司 内田
知之 西川
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協和発酵キリン株式会社
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Publication of WO2011093365A1 publication Critical patent/WO2011093365A1/fr

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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
    • C07D241/52—Oxygen 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
    • C07D401/14—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
    • C07D403/06—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 only aliphatic carbon atoms
    • 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
    • C07D403/08—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 alicyclic 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
    • C07D403/14—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 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a nitrogen-containing heterocyclic compound having antitumor activity or a pharmaceutically acceptable salt thereof.
  • kinase modulators having a quinoline structure Patent Document 1
  • kinase inhibitors Patent Document 2
  • UV-decomposing compounds Patent Document 3
  • heat shock protein 90 inhibitors Patent Document 6
  • ion channel modulators Patent Document 1 Reference 7
  • Patent Document 4 a PKB inhibitor having a quinoxaline structure
  • Patent Document 5 a photostable optical filter containing a quinoxaline derivative
  • Patent Document 8 A derivative having a phenyl group at the 2-position of quinoxaline (Patent Document 8, Non-Patent Document 1) is known.
  • An object of the present invention is to provide a nitrogen-containing heterocyclic compound having antitumor activity or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the following (1) to (63).
  • Z represents a monocyclic nitrogen-containing aliphatic heterocyclic group which may have a substituent, a bridged nitrogen-containing aliphatic heterocyclic group which may have a substituent, or a substituent.
  • G 1 is nitrogen atom, N + -O - or in CR 5 ⁇ wherein, R 5 is a hydrogen atom, a halogen, cyano, carbamoyl, optionally substituted lower alkyl, which may have a substituent Good lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted lower alkanoyl, optionally substituted lower Alkylthio, optionally substituted lower alkylsulfonyl, optionally substituted aryl, —NR 6a R 6b (wherein R 6a and R 6b are the same or different and are a hydrogen atom, substituted A lower alkylsulfonyl which may have a group, a lower alkyl which may have a substituent, a lower alkoxycarbonyl which may have a substituent, or a lower alkanoyl which may have a substituent.
  • R 5 is a hydrogen atom, a halogen
  • R 6a and R 6 b forms a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom) or -OR 7 (wherein R 7 has a hydrogen atom or a substituent, Lower alkyl, which may have a substituent, cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, which may have a substituent A good aliphatic heterocyclic group, an optionally substituted aromatic heterocyclic group, or -CONR 8a R 8b (wherein R 8a and R 8b are the same or different and represent a hydrogen atom, a substituent, The lower alkylsulfonyl which may have, the lower alkyl which may have a substituent, or the lower alkanoyl which may have a substituent, or R 8a and R 8b and the adjacent nitrogen atom Together form a nitrogen-containing heterocyclic group which may have
  • G 2 is a nitrogen atom or N + -O - represents
  • Ar represents an aromatic carbocycle or an aromatic heterocycle
  • m represents an integer of 0 to 8
  • each R 1 may be the same or different
  • R 1 is cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted.
  • n represents an integer of 0 to 4, and when n is 2, 3 or 4, each R 4 may be the same or different, R 4 has halogen, cyano, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted.
  • Cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, a substituent
  • An aromatic heterocyclic group which may have, —NR 10a R 10b (wherein R 10a and R 10b are the same or different and each is a hydrogen atom, optionally substituted lower alkylsulfonyl, substituted Represents a lower alkyl which may have a group, or a lower alkanoyl which may have a substituent, or R 10a and R 10b together represent a diphenylmethylene which may have a substituent.
  • R 10a and R 10b Nitrogen atom and together form a nitrogen-containing heterocyclic group which may have a substituent) which, - OR 11 (wherein, R 11 which may have a hydrogen atom, an optionally substituted lower Alkyl, cycloalkyl which may have a substituent, lower alkanoyl which may have a substituent, lower alkylsulfonyl which may have a substituent, aryl which may have a substituent, An aliphatic heterocyclic group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, or -CONR 12a R 12b (wherein R 12a and R 12b are The same or different, a hydrogen atom, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkylsulfonyl, having a substituent Aryl which may be substituted, aromatic heterocyclic group which may have substituent or Or represents optionally substituted
  • the nitrogen-containing heterocycle according to any one of the above (1) to (4), which is an optionally substituted lower alkynyl, an optionally substituted cycloalkyl, or an optionally substituted lower alkanoyl A compound or a pharmaceutically acceptable salt thereof.
  • R 1a and R 1b are the same or different and each represents an optionally substituted lower alkoxy, and R 1c represents cyano, an optionally substituted lower alkoxy or a substituent.
  • R 17 represents a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted lower alkenyl, an optionally substituted lower alkynyl or cycloalkyl.
  • the nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (9).
  • (11) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (10), wherein p is 2.
  • (12) The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to (10) or (11), wherein R 17 is lower alkyl.
  • R 4A and Z A are respectively the same as the aforementioned R 4 and Z
  • mA represents an integer of 0 to 5
  • each R 13A may be the same or different
  • nA represents an integer of 0 to 4
  • each R 4A may be the same or different
  • R 2A and R 3A may be the same or different and each may have a hydrogen atom, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted.
  • R 13A represents cyano, carboxy, halogen, nitro, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, and optionally substituted.
  • Cycloalkyl optionally having, lower alkanoyl optionally having substituent, lower alkoxycarbonyl optionally having substituent, aryl optionally having substituent, having substituent Aroyl, which may have a substituent, arylsulfonyl which may have a substituent, lower alkylsulfonyl which may have a substituent, an aliphatic heterocyclic group which may have a substituent, and a substituent.
  • An aromatic heterocyclic group that may be substituted —NR 14a R 14b (wherein R 14a and R 14b have the same meanings as R 6a and R 6b , respectively), —OR 15a (wherein R 15a is the same as defined above) R 7 synonymous) or -CONR 16a R 16b (wherein, R 16 a and R 16b represent the same as R 8a and R 8b , respectively,] or a pharmaceutically acceptable salt thereof.
  • R 17A represents lower alkyl, and R 19A represents a hydrogen atom or hydroxy
  • (25) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (24), wherein R 17A is methyl and R 19A is a hydrogen atom.
  • (26) The nitrogen-containing heterocyclic compound or the pharmaceutically acceptable salt thereof according to (24), wherein R 17A is methyl and R 19A is hydroxy.
  • R 13A1 represents an optionally substituted lower alkoxy
  • R 13A2 represents a hydrogen atom or an optionally substituted lower alkoxy
  • R 13A3 represents a hydrogen atom, cyano, substituted
  • R 2B , R 3B , R 4B , R 13B and Z B are the same as R 2A , R 3A , R 4 , R 13A and Z, respectively, mB represents an integer of 0 to 5, and when mB is 2, 3, 4 or 5, each R 13B may be the same or different, nB represents an integer of 0 to 4, and when nB is 2, 3 or 4, each R 4B may be the same or different) or a pharmaceutically acceptable compound thereof Salt.
  • nB is 1, R 4B is halogen, cyano or —NR 10a R 10b (wherein R 10a and R 10b are as defined above), and R 4B is at the 8-position of quinoxaline
  • nB is 1, R 4B is halogen, cyano or —NR 10a R 10b (wherein R 10a and R 10b are as defined above), and R 4B is at the 6-position of quinoxaline
  • R 13B and mB are as defined above.
  • R 13B1 represents an lower alkoxy which may have a substituent
  • R 13B2 represents a hydrogen atom or a lower alkoxy which may have a substituent
  • R 13B3 is a hydrogen atom, cyano, substituted Or a nitrogen-containing heterocyclic compound according to any one of (31) to (39) above, which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent
  • Its pharmaceutically acceptable salt Its pharmaceutically acceptable salt.
  • R 2C , R 3C , R 4C , R 13C and Z C are the same as R 2A , R 3A , R 4 , R 13A and Z, respectively, mC represents an integer of 0 to 5, and when mC is 2, 3, 4 or 5, each R 13C may be the same or different, nC represents an integer of 0 to 4, and when nC is 2, 3 or 4, each R 4C may be the same or different, R 5C is a hydrogen atom, halogen, cyano, carbamoyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, substituent Cycloalkyl optionally having substituent (s), lower alkylthio optionally having substituent (s), lower alkylsulfonyl optionally having substituent (s), or -OR 18 (wherein R 18 represents R 7 and The nitrogen-containing heterocyclic compound represented by the above or a pharmaceutically acceptable salt thereof.
  • R 5C is a hydrogen atom, cyano, or —OR 18a (wherein R 18a represents a hydrogen atom, optionally substituted lower alkyl, or optionally substituted cycloalkyl.
  • R 18a represents a hydrogen atom, optionally substituted lower alkyl, or optionally substituted cycloalkyl.
  • R 5C is —OR 18a (wherein R 18a has the same meaning as described above). Salt.
  • R 17C represents lower alkyl, and R 19C represents a hydrogen atom or hydroxy
  • the nitrogen-containing heterocyclic compound according to any one of the above (44) to (50) or a pharmaceutically acceptable salt thereof Salt is a pharmaceutically acceptable salt thereof Salt.
  • R 13C and mC are as defined above.
  • R 13C1 represents an optionally substituted lower alkoxy
  • R 13C2 represents a hydrogen atom or an optionally substituted lower alkoxy
  • R 13C3 represents a hydrogen atom, cyano, substituted Or a nitrogen-containing heterocyclic compound according to any one of the above (44) to (54), which represents a lower alkoxy which may have a group or an aromatic heterocyclic group which may have a substituent
  • Its pharmaceutically acceptable salt Its pharmaceutically acceptable salt.
  • the present invention provides a nitrogen-containing heterocyclic compound having antitumor activity or a pharmaceutically acceptable salt thereof.
  • each group of formula (I), (IA), (IB) and (IC) examples include linear or branched alkyl having 1 to 10 carbon atoms.
  • Examples of lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms. Specific examples include vinyl, allyl, 1-propenyl, isopropenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, decenyl and the like.
  • lower alkynyl examples include linear or branched alkynyl having 2 to 10 carbon atoms. Specific examples include ethynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
  • cycloalkyl examples include cyclic alkyl having 3 to 10 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • aryl and the aryl moiety of arylsulfonyl and aroyl include aryl having 6 to 14 carbon atoms. Specific examples include phenyl, naphthyl, indenyl, anthryl and the like.
  • examples of the aromatic carbocycle include aromatic carbocycles corresponding to these aryls.
  • Examples of the aliphatic heterocyclic group include a 3- to 8-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 3- to 8-membered ring.
  • the monocyclic nitrogen-containing aliphatic heterocyclic group includes a 3- to 8-membered monocyclic nitrogen-containing aliphatic heterocyclic group containing at least one nitrogen atom, and the monocyclic nitrogen-containing aliphatic group
  • the group heterocyclic group may further have another hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom in the ring.
  • Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, 1,2,5,6-tetrahydropyridyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholino and the like.
  • the condensed nitrogen-containing aliphatic heterocyclic group includes a 3- to 8-membered monocyclic nitrogen-containing aliphatic heterocyclic group containing at least one nitrogen atom (the monocyclic nitrogen-containing aliphatic heterocyclic group). Group may further have another nitrogen atom, oxygen atom, sulfur atom or other hetero atom in its ring), but 1 or 2 aliphatic carbocycle, aliphatic heterocycle, aromatic carbocycle or And a group condensed with an aromatic heterocycle.
  • the bridged nitrogen-containing aliphatic heterocyclic group includes a bridged nitrogen-containing aliphatic cyclic group containing at least one nitrogen atom, specifically, diazabicyclononanyl and the like.
  • aromatic heterocyclic group for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Examples thereof include a condensed bicyclic or tricyclic ring-condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Examples of the (xi) monocyclic 5-membered aromatic heterocyclic group include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl and the like.
  • Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group).
  • the ring group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom.
  • Ring group (the condensed heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl , Imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, morpholino, thiomorpholino, Hydroindolyl, dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl,
  • the substituents in the aryl which may have a substituent shown here, the aliphatic heterocyclic group which may have a substituent and the aromatic heterocyclic group which may have a substituent (xiv- 1) is the same or different, for example, halogen having 1 to 3 substituents; lower alkyl; lower alkoxy; lower alkoxycarbonyl; N-lower alkylcarbamoyl; N, N-dilower alkylcarbamoyl; lower alkanoyl; Cyano; oxo; hydroxy; aryl and the like.
  • the substituent (xiv-2) in the lower alkyl optionally having substituent, the lower alkoxycarbonyl optionally having substituent, and the lower alkoxy optionally having substituent may be as follows: , The same or different, for example, a halogen having 1 to 3 substituents; lower alkoxy; lower alkoxycarbonyl; N-lower alkylcarbamoyl; N, N-dilower alkylcarbamoyl; lower alkanoyl; carboxy; cyano; hydroxy; Can be mentioned.
  • aryl which may have a substituent, aroyl which may have a substituent, arylsulfonyl which may have a substituent, aromatic heterocycle which may have a substituent
  • the substituents in the group, diphenylmethylene which may have a substituent, and monocyclic 5-membered aromatic heterocyclic group which may have a substituent are the same or different, for example, the number of substitutions is 1.
  • halogen hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, optionally substituted lower alkyl, cycloalkyl, optionally substituted aliphatic heterocyclic group, aryl, substituted Aromatic heterocyclic group optionally having a group, aromatic heterocyclic oxy, optionally substituted lower alkoxy, cycloalkoxy, aryloxy, lower alkanoyloxy, aroyloxy Shi, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, -NR X2 R Y2 (wherein, R X2 and R Y2 are each synonymous with the R X1 and R Y1), lower alkanoyl, aroyl, lower alkoxycarbonyl Aryloxycarbonyl, N-lower alkylcarbamoyl, N, N-dilower alkylcarbamoyl and the like.
  • the aromatic heterocyclic group which may have a substituent and the monocyclic 5-membered aromatic heterocyclic group which may have a substituent are oxadiazolyl which may have a substituent. In that case, the substituent may be oxo.
  • the substituent (xv-1) in the lower alkoxy which may have a substituent shown here is the same or different, for example, halogen, cyano, lower alkoxy, lower alkoxycarbonyl having 1 to 3 substituents, Examples thereof include aryl optionally having a substituent.
  • Examples of the substituent (xv-1-1) in the substituted aryl include halogen; lower alkyl; lower alkoxy; lower alkoxycarbonyl; N-lower alkylcarbamoyl; N, N-dilower alkylcarbamoyl; lower alkanoyl; carboxy; Oxo; hydroxy; aryl and the like.
  • the substituent (xv-2) in the lower alkyl which may have a substituent shown here is the same or different, and examples thereof include hydroxy having 1 to 3 substituents, halogen, cyano, lower alkoxy and the like.
  • the substituent (xv-3) in the aliphatic heterocyclic group which may have a substituent shown here is the same or different, and examples thereof include oxo having 1 to 3 substituents and lower alkyl.
  • the substituents (xv-4) in the aromatic heterocyclic group which may have a substituent shown here are the same or different, for example, oxo, lower alkyl, cyano lower alkyl having 1 to 3 substituents, Examples include lower alkoxy lower alkyl, cycloalkyl, carbamoyl, N-lower alkylcarbamoyl, N, N-dilower alkylcarbamoyl and the like.
  • a cycloalkyl optionally having a substituent, an aliphatic heterocyclic group optionally having a substituent, a monocyclic nitrogen-containing aliphatic heterocyclic group optionally having a substituent, Formed together with a condensed nitrogen-containing aliphatic heterocyclic group which may have a substituent, a bridged nitrogen-containing aliphatic heterocyclic group which may have a substituent, and an adjacent nitrogen atom
  • the substituents in the nitrogen-containing heterocyclic group optionally having substituents are the same or different, for example, oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl having 1 to 3 substituents, Lower alkyl optionally having a substituent [substituents in the substituted lower alkyl include the substituents mentioned in (xiv) above], lower alkenyl optionally having a substituent [the Substitution in substituted lower alkenyl As the substituent
  • the substituent (xvi-1) in the lower alkoxy which may have a substituent shown here is the same or different, for example, an aryl having a substituent having 1 to 3 substituents. Etc.
  • Examples of the substituent (xvi-1-1) in the substituted aryl include the substituents mentioned in the above (xv-1-1).
  • N-lower alkylcarbamoyl represented by the above (xiv) to (xvi)
  • Examples of the lower alkyl moiety of N, N-di-lower alkylcarbamoyl include the groups exemplified in the above-mentioned (i) lower alkyl.
  • the two lower alkyls in N, N-dilower alkylcarbamoyl may be the same or different.
  • the alkylene part in cyano lower alkyl and lower alkoxy lower alkyl has the same meaning as that obtained by removing one hydrogen atom from the group exemplified in the above-mentioned (i) lower alkyl.
  • Examples of the cycloalkyl part of cycloalkyl and cycloalkoxy include the groups exemplified in the above-mentioned (iv) cycloalkyl.
  • Examples of the aryl moiety of aryl, aryloxy, aroyl, arylsulfonyloxy, aroyloxy and aryloxycarbonyl include the groups exemplified in the above-mentioned (v) aryl.
  • Examples of the aliphatic heterocyclic group, the aromatic heterocyclic group, the aromatic heterocyclic group portion of the aromatic heterocyclic oxy, and the halogen include (vi) the aliphatic heterocyclic group and (x) the aromatic heterocyclic ring, respectively. And the groups mentioned in the examples of (xiii) halogen.
  • G 2 is preferably a nitrogen atom
  • Z is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group
  • Ar is preferably an aromatic carbocycle, more preferably a benzene ring, m is preferably 1 , 2 or 3, and R 1 is Is —OR 15a1 (wherein R 15a1 has the same meaning as described above), cyano or an optionally substituted aromatic heterocyclic group, preferably lower alkoxy, cyano or substituted
  • R 2 and R 3 are preferably the same or different lower alkyl optionally having a hydrogen atom or a substituent, and n is 0 or 1 is preferable
  • R 4 is preferably lower alkyl which may have a substituent or —NR 10a R 10b (wherein R 10a and R 10b are as defined above), and G 1 is CR 5 R 5 is a hydrogen atom, halogen, cyano, lower alkyl.
  • Lower alkylthio or carbamoyl is preferred, and a
  • Z A is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group
  • mA is preferably 1, 2 or 3
  • nA is preferably 0 or 1
  • R 2A and R 3A are the same.
  • a lower alkyl optionally having a hydrogen atom or a substituent is preferable
  • R 4A may be a lower alkyl optionally having a substituent or —NR 10a R 10b (wherein R 10a and R 10b Are preferably the same as defined above, more preferably amino
  • R 13A is —OR 15a (wherein R 15a is as defined above) or an aromatic heterocyclic ring optionally having substituent (s) Group is preferable, and lower alkoxy or a monocyclic 5-membered aromatic heterocyclic group which may have a substituent is more preferable.
  • Z B is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group
  • mB is preferably 1, nB is preferably 0 or 1, and R 2B and R 3B are the same or different and hydrogen.
  • a lower alkyl optionally having an atom or a substituent is preferred, R 4B is preferably a lower alkyl optionally having a substituent, and R 13B is —OR 15a (wherein R 15a is as defined above.
  • R 15a is as defined above.
  • an aromatic heterocyclic group which may have a substituent, and a monocyclic 5-membered aromatic heterocyclic group which may have a lower alkoxy or a substituent is more preferable.
  • Z C is preferably a monocyclic nitrogen-containing aliphatic heterocyclic group
  • mC is preferably 1, nC is preferably 0 or 1, and R 2C and R 3C are the same or different and hydrogen.
  • a lower alkyl optionally having an atom or a substituent is preferred, R 4C is preferably a lower alkyl optionally having a substituent, R 5C is preferably a hydrogen atom, and R 13C is —OR 15a (Wherein R 15a has the same meaning as described above) or an aromatic heterocyclic group which may have a substituent, preferably a lower alkoxy or a monocyclic 5-membered aromatic which may have a substituent A group heterocyclic group is more preferred.
  • Pharmaceutically acceptable salts of compounds (I), (IA), (IB) and (IC) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acids Examples include addition salts.
  • Pharmaceutically acceptable acid addition salts of compounds (I), (IA), (IB) and (IC) include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, acetate, maleic acid Organic salts such as salts, fumarate, citrate, methanesulfonate and the like
  • pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, magnesium salt, calcium Examples thereof include alkaline earth metal salts such as salts, aluminum salts, and zinc salts.
  • Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium, and pharmaceutically acceptable organic salts.
  • Examples of amine addition salts include addition salts such as morpholine and piperidine.
  • Examples of pharmaceutically acceptable amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine. Salting can be mentioned.
  • the present invention also includes prodrugs of the compounds (I), (I-A), (I-B) and (I-C).
  • Prodrugs are compounds that are converted into compounds (I), (I-A), (I-B), and (I-C) by reactions with enzymes, gastric acid, and the like in vivo.
  • Many types of prodrugs applicable to the present invention are known, and an appropriate prodrug is selected from known literature (for example, see Drug Development, Yodogawa Shoten, 1990, Vol. 7, page 163). It is possible to synthesize using this method.
  • prodrugs of compounds (I), (IA), (IB), and (IC) include compounds (I), (IA), (IB), and (IC) that have amino, , Alkylated, phosphorylated compounds; when compounds (I), (IA), (IB) and (IC) have a hydroxy, the hydroxy is acylated, alkylated, phosphorylated, borated
  • examples thereof include compounds in which the carboxy is esterified or amidated.
  • the prodrugs of the compounds (I), (IA), (IB) and (IC) may be any of hydrates, non-hydrates and solvates, and the compounds (I), (IA ), (IB) and (IC) as well as pharmaceutically acceptable salts.
  • R 4A , R 13A , mA, nA and Z A are the same as defined above, R 20 represents methyl or lower alkoxy, R 3A1 represents a hydrogen atom or methyl, and X and Y represent chlorine, respectively.
  • W is a chlorine atom, a bromine atom, an iodine atom or —OR 21 (wherein R 21 represents a lower alkylsulfonyl or an arylsulfonyl which may have a substituent; And the substituents in arylsulfonyl which may have a group are the same or different and include lower alkyl having 1 to 3 substituents, and M represents a tin atom, a boron atom, or a silicon atom.
  • R A represents halogen, hydroxy, lower alkyl, lower alkoxy, aryl or aryloxy
  • q represents an integer of 0 to 3.
  • the lower alkyl in lower alkyl and lower alkylsulfonyl and lower alkoxy are as defined above
  • the aryl moiety in aryl, arylsulfonyl and aryloxy is as defined above
  • halogen is as defined above.
  • solvent examples include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), water and the like. These may be used alone or in combination.
  • transition metal catalyst examples include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (acetonitrile) palladium, [1 , 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane complex (1: 1) and other palladium catalysts, nickel chloride, nickel acetylacetonate, bis (1,5-cyclooctadiene) nickel, Examples include nickel catalysts such as nickel bromide.
  • Examples of the additive include triphenylphosphine, tri (o-tolyl) phosphine, tricyclohexylphosphine, silver oxide, copper iodide, lithium chloride, cesium carbonate, triethylamine, diethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, Examples thereof include tripotassium phosphate, and these can be used alone or in combination.
  • Compound (II) can be obtained according to the method described in Reference Examples or a known method [for example, tetrahedron, 60, p. 2937 (2004)].
  • Compound (III) can be obtained as a commercial product or according to a known method [for example, 4th edition Experimental Chemistry Course 24, 4th edition, p.252, Maruzen (2000)].
  • Process 2 Compound (V) contains 1 to 30 equivalents of tributyl (1-ethoxyvinyl) tin in a solvent, or 1 equivalent to a large excess of alcohol in a carbon monoxide atmosphere with compound (IV).
  • the reaction can be carried out at a temperature between ⁇ 50 ° C. and 200 ° C. for 5 minutes to 100 hours.
  • 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • an acid can be added to react.
  • Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, N, N-dimethylacetamide (DMA), NMP, water, and the like. Or it can mix and use.
  • Examples of the alcohol include methanol, ethanol, n-propanol, and n-butanol.
  • transition metal catalyst examples include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium bromide, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (acetonitrile) palladium, [1 1, 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride / dichloromethane complex (1: 1) and other palladium catalysts.
  • Examples of the additive include triphenylphosphine, tri (o-tolyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) propane, 2,2′-bis ( Diphenylphosphino) -1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane, silver oxide, copper iodide, lithium chloride, cesium fluoride, cesium carbonate, triethylamine, diethylamine, N, N-diisopropyl Examples include ethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, tripotassium phosphate, and the like. These can be used alone or in combination.
  • Process 3 Compound (VI) can be produced by treating compound (V) in a solvent at a temperature between 0 ° C. and 100 ° C. with an oxidizing agent for 5 minutes to 100 hours.
  • oxidizing agent examples include aqueous hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, tert-butyl hydroperoxide, and the like, and these can be used alone or in combination.
  • solvent examples include dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMA, NMP, water and the like, and these can be used alone or in combination.
  • Process 4 Compound (VII) can be produced by treating compound (VI) in a solvent at a temperature between ⁇ 80 ° C. and 200 ° C. with 0.1 to 10 equivalents of a reducing agent for 5 minutes to 100 hours.
  • Process 5 Compound (VIII) can be produced by treating compound (VII) with a halogenating agent or sulfonylating agent in a solvent at a temperature between room temperature and 120 ° C. for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of base can be added to promote the reaction.
  • Examples of the solvent include dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMA, NMP and the like.
  • Examples of the halogenating agent include chlorine, hydrogen chloride gas, concentrated hydrochloric acid, hydrobromic acid, tetra-n-butylammonium tribromide, bromine, iodine, N-chlorosuccinimide (NCS), and N-brominated succinic acid.
  • Examples include imide (NBS), N-iodosuccinimide (NIS), iodine monochloride, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, and the sulfonylating agents include, for example, methanesulfonyl chloride, ethane Examples include sulfonyl chloride, benzenesulfonyl chloride, 4-toluenesulfonyl chloride and the like.
  • Process 6 Compound (I-Aa) can be produced by reacting compound (VIII) and compound (IX) in a solvent at a temperature between room temperature and 120 ° C. for 5 minutes to 100 hours. At this time, 0.01 to 30 equivalents of an additive can be added to promote the reaction.
  • Examples of the solvent include dichloromethane, chloroform, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, DMA, NMP, dimethyl sulfoxide (DMSO), and the like.
  • Examples of the additive include sodium iodide, Examples include potassium iodide and n-tetrabutylammonium iodide (TBAI).
  • Compound (IX) can be obtained as a commercially available product or according to a known method (for example, 5th edition Experimental Chemistry Course 14 Synthesis of Organic Compounds II Alcohol / Amine, 5th edition, p.352, Maruzen, etc.) it can. Production method 2 Among the compounds (I), the compound (I-Ba) can be produced by the following production method 2.
  • Process 1 Compound (X) can be produced according to Step 4 of Production Method 1 using Compound (VB).
  • Compound (VB) can be obtained according to Production Method 1.
  • Process 2 Compound (XI) can be produced according to Step 5 of Production Method 1 using Compound (X).
  • Process 3 Compound (I-Ba) can be produced according to production method 1, step 6 using compound (XI).
  • Production method 3 Among the compounds (I), the compound (I-Ca) can be produced by the following production method 3.
  • R 22 may have a substituent.
  • Process 1 Compound (XIV) can be produced according to Step 1 of Production Method 1 using Compound (XIII) and Compound (IIIa).
  • Compound (XIII) can be obtained according to the method described in Reference Examples or a known method [eg, Tetrahedron, Vol. 60, p. 2937 (2004), etc.].
  • Process 2 Compound (XV) can be produced according to Step 4 of Production Method 1 using Compound (XIV).
  • Process 3 Compound (XVI) can be produced according to production method 1, step 5 using compound (XV).
  • Process 4 Compound (I-Ca) can be produced according to Step 6 of Production Method 1 using Compound (XVI) and Compound (XVII).
  • Production method 4 Among the compounds (I), the compound (Ia) can also be produced by the following production method 4.
  • Process 1 Compound (XIX) can be produced by treating Compound (XVIII) at a temperature between ⁇ 80 ° C. and 25 ° C. with 0.1 to 10 equivalents of a reducing agent for 5 minutes to 10 hours.
  • Process 2 Compound (Ia) can be produced by reacting compound (XIX) and compound (XX) in the presence of a reducing agent in a solvent. At this time, 0.01 to 30 equivalents of an appropriate additive can be added to promote the reaction.
  • Examples of the solvent include methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, N, N-dimethylacetamide (DMA), NMP, water, and the like. Or it can mix and use.
  • Examples of the reducing agent include sodium borohydride, sodium cyanotrihydroborate, sodium triacetoxyborohydride, pyridine-borane complex, and the like.
  • Examples of the additive include acetic acid, molecular sieves, magnesium sulfate and the like. It is preferable to use 1 to 20 equivalents of the reducing agent and compound (XX) with respect to compound (XIX). The reaction is usually carried out at a temperature between -20 ° C and 80 ° C and is completed in 10 minutes to 100 hours.
  • G 2 is N + -O - compounds in which can be produced according to step 3 of Preparation 1 from compound G 2 is a nitrogen atom.
  • the intermediates and target compounds in each of the above production methods are isolated and purified by subjecting them to separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • stereoisomers such as geometric isomers and optical isomers, tautomers, and the like. Includes all possible isomers, including these, and mixtures thereof.
  • salts of compounds (I), (IA), (IB) and (IC) When it is desired to obtain salts of compounds (I), (IA), (IB) and (IC), and when compounds (I), (IA), (IB) and (IC) are obtained in the form of salts, they are purified as they are. In addition, when it is obtained in a free form, the compound (I), (IA), (IB) and (IC) are dissolved or suspended in an appropriate solvent, and then isolated by adding an acid or base. What is necessary is just to refine. In addition, compounds (I), (IA), (IB) and (IC) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents. Adducts are also encompassed by the present invention.
  • Test Example 1 Cell proliferation inhibition test for human fibrosarcoma cells
  • human fibrosarcoma cells HT-1080 JCRB number: 9113 were used.
  • 10% fetal calf serum SAFC Biosciences, catalog number 12203C
  • 10% / L non-Essential Amino Acids Solution 1% containing liquid (Invitrogen, catalog number 11140-050)
  • 1% containing liquid Invitrogen, catalog number 11140-050
  • Medium Earle's liquid (Invitrogen, catalog number 11095-080) was used.
  • the cells were cultured at 37 ° C. and 5% carbon dioxide.
  • HT-1080 cells 180 cells / well were seeded in each well of a 96-well plate (Nunk, catalog number 167008) and cultured overnight. Serially diluted test compounds were added and incubated for a further 72 hours (final volume 100 ⁇ L / well). 10 ⁇ L of Cell Proliferation Reagent WST-1 (Roche Diagnostics, catalog number 11644087001) was added to each well and incubated at 37 ° C. After 60 minutes, the absorbance at 450 nm (control wavelength: 655 nm) was measured with a plate reader (Molecular Device, SpectraMax 340PC 384 ). The growth rate of cells in control wells treated with a solvent (dimethyl sulfoxide (DMSO)) at 72 hours was calculated as 100%, and the growth rate of cells in wells treated with a test compound was calculated.
  • DMSO dimethyl sulfoxide
  • Compounds 3, 7, 11, 14, 53, 109, 149, 155, 158 and 161 inhibit cell proliferation by 90% or more at a concentration of 100 nmol / L against human fibrosarcoma cell line HT-1080 cells
  • Compound 55 inhibited cell proliferation by 60% or more at a concentration of 100 nmol / L against human fibrosarcoma cell line HT-1080 cells. From the above, it was found that compounds (I), (IA), (IB) and (IC) have cell growth inhibitory activity against human cancer cells. That is, the compounds (I), (IA), (IB) and (IC) are considered useful as antitumor agents.
  • compositions (I), (IA), (IB) and (IC) or pharmaceutically acceptable salts thereof can be administered alone as they are, but are usually provided as various pharmaceutical preparations. desirable. These pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention comprises compounds (I), (IA), (IB) and (IC) or pharmaceutically acceptable salts thereof as active ingredients alone or for any other treatment. It can contain as a mixture with an active ingredient.
  • these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.
  • oral or parenteral such as intravenous administration.
  • examples of the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a salt solution, a glucose solution, a mixed solution of a salt solution and a glucose solution, or the like.
  • the dosage and frequency of administration of compounds (I), (IA), (IB) and (IC) or pharmaceutically acceptable salts thereof depends on the dosage form, patient age, body weight, nature of the condition to be treated or Oral administration is usually 0.01 mg to 1 g, preferably 0.05 to 100 mg per adult once or several times daily, depending on the severity.
  • parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 10 mg per adult is administered once to several times a day.
  • the dose and the number of doses vary depending on the various conditions described above.
  • Step 2 3-acetyl-2- (2-ethoxyphenyl) quinoxaline (compound R2)
  • Compound R1 (320 mg, 1.12 mmol) was dissolved in toluene (3.00 mL), bis (triphenylphosphine) palladium dichloride (79.0 mg, 0.112 mmol), and tributyl (1-ethoxyvinyl) tin (0.456 mL, 1.35 mmol). And stirred at 120 ° C. for 1 hour under microwave irradiation. The same operation was performed twice, the crude products were combined, filtered through celite, and the filtrate was extracted with ethyl acetate.
  • Step 3 3-acetyl-2- (2-ethoxyphenyl) quinoxaline 1-oxide (compound R3)
  • Compound R2 (191 mg, 0.653 mmol) was dissolved in dichloromethane (4.0 mL), m-chloroperbenzoic acid (titer 65%, 434 mg, 1.63 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 17.5 hours.
  • the solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 4 2- (2-Ethoxyphenyl) -3- (1-hydroxyethyl) quinoxaline 1-oxide (Compound R4)
  • Compound R3 (118 mg, 0.383 mmol) is dissolved in a mixed solvent of THF (2.0 mL) and methanol (0.5 mL), sodium borohydride (15.9 mg, 0.421 mmol) is added at 0 ° C, and 10 minutes at 0 ° C. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 1 3- (2-Ethoxyphenyl) -2- (n-propoxycarbonyl) quinoxaline (Compound R6)
  • Compound R1 (1.60 g, 5.62 mmol) was dissolved in a mixed solvent of DMF (8.0 mL) and n-propanol (16 mL), and palladium acetate (252 mg, 1.12 mmol), 1,2-bis (diphenylphosphino) Propane (462 mg, 1.12 mmol) and N, N-diisopropylethylamine (2.38 mL, 26.0 mmol) were added, and the mixture was stirred at 90 ° C. for 17 hours in a carbon monoxide atmosphere.
  • Step 2 3- (2-Ethoxyphenyl) -2- (hydroxymethyl) quinoxaline (Compound R7)
  • Compound R6 (0.497 mg, 1.48 mmol) was dissolved in THF (10 mL), diisobutylaluminum hydride-hexane solution (1.00 mol / L, 4.43 mL, 4.44 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
  • Methanol 2.0 mL was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After filtration through celite, the solvent was distilled off under reduced pressure.
  • Step 2 Ethyl 3-aminoquinoline-2-carboxylate (Compound R9) Ethyl 3-bromopyruvate (1.18 g, 6.04 mmol) was dissolved in ethanol (9.76 mL), and a mixture of pyridine (0.489 mL, 6.04 mmol) and ethanol (14.6 mL) was slowly added dropwise. After dropping, the mixture was stirred at 70 ° C. for 1 hour. The mixture was allowed to cool to room temperature, a mixed solution of compound R8 (610 mg, 5.04 mmol) and pyridine (1.00 mL) was added, and the mixture was stirred at 80 ° C. for 4 and a half hours.
  • Compound R9 Ethyl 3-aminoquinoline-2-carboxylate
  • Step 3 Ethyl 3-iodoquinoline-2-carboxylate (Compound R10) Compound R9 (500 mg, 2.31 mmol) was dissolved in chloroform (10.0 mL), iodine (646 mg, 2.54 mmol) and isoamyl nitrite (0.618 mL, 4.62 mmol) were added, and the mixture was stirred at 70 ° C. for 19 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 4 Ethyl 3- (2-ethoxyphenyl) quinoline-2-carboxylate (Compound R11)
  • Compound R10 (260 mg, 0.795 mmol) was dissolved in a mixed solvent of dioxane (1.00 mL) and water (0.20 mL), and 2-ethoxyphenylboronic acid (172 mg, 1.03 mmol), tetrakis (triphenylphosphine) palladium ( 46.0 mg, 0.040 mmol) and sodium carbonate (126 mg, 1.19 mmol) were added, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation.
  • Step 5 3- (2-Ethoxyphenyl) -2- (hydroxymethyl) quinoline (Compound R12)
  • Compound R11 (183 mg, 0.569 mmol) was dissolved in THF (3.66 mL) and cooled to 0 ° C. using an ice bath.
  • Lithium aluminum hydride (23.8 mg, 0.626 mmol) was added there, and it stirred at 0 degreeC for 1 hour, lithium aluminum hydride (47.6 mg, 1.25 mmol) was added again, and it stirred at room temperature for 5 hours.
  • An excess amount of sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • Step 3 3-Ethoxycarbonyl-2- (4-tert-butoxycarbonyl-2,6-diethoxyphenyl) quinoxaline (Compound R15) 4- (tert-butoxycarbonyl)-obtained by dissolving Compound R14 (600 mg, 2.13 mmol) in a mixed solvent of DMF (15.0 mL) and water (3.00 mL) in the same manner as in Step 5 of Reference Example 7.
  • Step 5 3-Ethoxycarbonyl-2- (4-carboxy-2,6-diethoxyphenyl) quinoxaline 1-oxide (Compound R17)
  • Compound R16 (440 mg, 0.912 mmol) was dissolved in a mixed solvent of dichloromethane (6.00 mL) and trifluoroacetic acid (3.00 mL), and the mixture was stirred at room temperature for 1 hour.
  • the solvent of the reaction mixture was distilled off under reduced pressure, and toluene azeotropy was performed.
  • Step 7 3-Formyl-2- (4-carbamoyl-2,6-diethoxyphenyl) quinoxaline 1-oxide (Compound R20)
  • Compound R19 (50.0 mg, 0.118 mmol) was dissolved in THF (2.40 mL), cooled to ⁇ 78 ° C., diisobutylaluminum-toluene solution (1.00 mol / L, 0.588 mL, 0.588 mmol) was added, and then -40 Stir at 1 ° C. for 1 hour.
  • a saturated aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 Ethyl 3-bromo-7-nitroquinoxaline-2-carboxylate (Compound R24)
  • Compound R23 (1.13 g, 4.29 mmol) was dissolved in chloroform (20.0 mL), phosphorus oxybromide (2.46 g, 8.59 mmol) and DMF (1.00 mL) were added, and the mixture was stirred at 45 ° C. for 0.5 hr. The mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • Step 6 3-Ethoxy-4- [3- (hydroxymethyl) -6-nitroquinoxalin-2-yl] -5-methoxybenzonitrile (Compound R27)
  • Compound R26 (173 mg, 0.393 mmol) was dissolved in THF (7.00 mL), cooled to 0 ° C, diisobutylaluminum hydride-toluene solution (1.00 mol / L, 1.96 mL, 1.96 mmol) was added, and the mixture was brought to 0 ° C. And stirred for 0.5 hour. A saturated aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was dissolved in a mixed solvent of methanol (3.00 mL) and THF (3.00 mL), cooled to 0 ° C., sodium borohydride (22.0 mg, 0.590 mmol) was added, and the mixture was stirred at 0 ° C. for 0.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 3 4-Bromo-3-ethoxy-5-methoxybenzoic acid (Compound R31) Using compound R30 (9.50 g, 32.9 mmol) and methyl p-toluenesulfonate (5.95 mL, 39.4 mmol), quantitatively determine ethyl 4-bromo-3-ethoxy-5-methoxybenzoate in the same manner as in Step 2. I got it. This was dissolved in ethanol (80 mL), 4 mol / L aqueous sodium hydroxide solution (40 mL) was added at room temperature, and the mixture was stirred at 50 ° C. for 40 min.
  • Step 5 4-Cyano-2-ethoxy-6-methoxyphenylboronic acid (Compound R33)
  • Compound R32 (4.65 g, 18.2 mmol) was dissolved in THF (93 mL), and n-butyllithium-n-hexane solution (2.66 mol / L, 10.2 mL, 27.2 mmol) was added at -93 ° C, followed by stirring for 10 minutes. did.
  • Trimethyl borate (6.09 mL, 54.5 mmol) was added and stirred for 20 minutes. Hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • the present invention provides a nitrogen-containing heterocyclic compound having antitumor activity or a pharmaceutically acceptable salt thereof.

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Abstract

L'invention concerne un composé à noyau hétérocyclique azoté représenté par la formule (I) [dans laquelle Z représentant un groupe hétérocyclique aliphatique azoté monocyclique qui peut avoir un substituant, ou similaire ; G1 représente un atome d'azote, N+-O-, ou CR5 (R5 représentant un atome d'hydrogène ou similaire) ; G2 représente un atome d'azote, ou N+-O- ; Ar représente un noyau carbocyclique aromatique, ou similaire ; m représente un entier d'une valeur de 0 à 8, les R1 pouvant être identiques ou différents les uns des autres lorsque m représente un entier de 2 à 8 ; R1 représente -OR15a1 (R15a1 représentant un atome d'hydrogène, un groupe alkyle inférieur qui peut avoir un substituant, ou similaire) ou similaire ; R2 et R3 peuvent être identiques ou différents l'un de l'autre et représentent indépendamment un atome d'hydrogène, un groupe alkyle inférieur qui peut avoir un substituant, ou similaire ; n représente un entier d'une valeur de 0 à 4, les R4 pouvant être identiques ou différents les uns des autres lorsque n a la valeur de 2, 3 ou 4 ; et R4 représente un atome d'halogène, un groupe alkyle inférieur pouvant avoir un substituant, ou similaire] ou un sel pharmaceutiquement acceptable ou similaire de ce composé, ayant une activité anti-tumorale.
PCT/JP2011/051572 2010-01-27 2011-01-27 Composé hétérocyclique azoté WO2011093365A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159591A1 (fr) 2013-03-13 2014-10-02 Janssen Pharmaceutica Nv 7-azabicycles substitués et leur utilisation en tant que modulateurs du récepteur de l'orexine
CN107827828A (zh) * 2017-11-21 2018-03-23 南京华漫新材料科技有限公司 含苯酰肼骨架的喹喔啉衍生物及其制备方法和在制备抗肿瘤药物中的应用
CN113929634A (zh) * 2021-11-22 2022-01-14 山西永津集团有限公司 一种2,3-二溴喹喔啉的合成方法
CN117567482A (zh) * 2023-10-09 2024-02-20 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） 2-芳基-2,3,4,5-四氢-1,4-环氧苯并氮杂卓类化合物及其应用
WO2025186065A1 (fr) 2024-03-05 2025-09-12 Bayer Aktiengesellschaft Dérivés de (aza)quinoxaline substitués par hétéroaryle utilisés en tant que pesticides

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DD269620A1 (de) * 1985-01-15 1989-07-05 Inst F Pharmakologische Forsch Verfahren zur herstellung von n-substituierten 2-(aminomethyl)chinoxalinen
WO1997038665A2 (fr) * 1996-04-03 1997-10-23 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP1106612A1 (fr) * 1999-11-30 2001-06-13 Pfizer Products Inc. Derivés de Quinoline comme inhibiteurs de la proteine Farnesyle transferase
WO2005007099A2 (fr) * 2003-07-10 2005-01-27 Imclone Systems Incorporated Inhibiteurs de la pkb utilises comme agents antitumoraux
WO2007081569A2 (fr) * 2005-12-30 2007-07-19 Merck & Co., Inc. Inhibiteurs de cetp
WO2008118454A2 (fr) * 2007-03-23 2008-10-02 Amgen Inc. Composés hétérocycliques et leurs utilisations
WO2008118468A1 (fr) * 2007-03-23 2008-10-02 Amgen Inc. Composés hétérocycliques et leurs utilisations
WO2009081105A2 (fr) * 2007-12-21 2009-07-02 Ucb Pharma S.A. Dérivés de quinoxaline et de quinoléine en tant qu'inhibiteurs de kinase

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD269620A1 (de) * 1985-01-15 1989-07-05 Inst F Pharmakologische Forsch Verfahren zur herstellung von n-substituierten 2-(aminomethyl)chinoxalinen
WO1997038665A2 (fr) * 1996-04-03 1997-10-23 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP1106612A1 (fr) * 1999-11-30 2001-06-13 Pfizer Products Inc. Derivés de Quinoline comme inhibiteurs de la proteine Farnesyle transferase
WO2005007099A2 (fr) * 2003-07-10 2005-01-27 Imclone Systems Incorporated Inhibiteurs de la pkb utilises comme agents antitumoraux
WO2007081569A2 (fr) * 2005-12-30 2007-07-19 Merck & Co., Inc. Inhibiteurs de cetp
WO2008118454A2 (fr) * 2007-03-23 2008-10-02 Amgen Inc. Composés hétérocycliques et leurs utilisations
WO2008118468A1 (fr) * 2007-03-23 2008-10-02 Amgen Inc. Composés hétérocycliques et leurs utilisations
WO2009081105A2 (fr) * 2007-12-21 2009-07-02 Ucb Pharma S.A. Dérivés de quinoxaline et de quinoléine en tant qu'inhibiteurs de kinase

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159591A1 (fr) 2013-03-13 2014-10-02 Janssen Pharmaceutica Nv 7-azabicycles substitués et leur utilisation en tant que modulateurs du récepteur de l'orexine
CN107827828A (zh) * 2017-11-21 2018-03-23 南京华漫新材料科技有限公司 含苯酰肼骨架的喹喔啉衍生物及其制备方法和在制备抗肿瘤药物中的应用
CN107827828B (zh) * 2017-11-21 2021-03-30 南京华漫新材料科技有限公司 含苯酰肼骨架的喹喔啉衍生物及其制备方法和在制备抗肿瘤药物中的应用
CN113929634A (zh) * 2021-11-22 2022-01-14 山西永津集团有限公司 一种2,3-二溴喹喔啉的合成方法
CN117567482A (zh) * 2023-10-09 2024-02-20 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） 2-芳基-2,3,4,5-四氢-1,4-环氧苯并氮杂卓类化合物及其应用
WO2025186065A1 (fr) 2024-03-05 2025-09-12 Bayer Aktiengesellschaft Dérivés de (aza)quinoxaline substitués par hétéroaryle utilisés en tant que pesticides

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