WO2009119776A1 - Dérivé hétérocyclique condensé et son utilisation - Google Patents

Dérivé hétérocyclique condensé et son utilisation Download PDF

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WO2009119776A1
WO2009119776A1 PCT/JP2009/056200 JP2009056200W WO2009119776A1 WO 2009119776 A1 WO2009119776 A1 WO 2009119776A1 JP 2009056200 W JP2009056200 W JP 2009056200W WO 2009119776 A1 WO2009119776 A1 WO 2009119776A1
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alkyl
atom
optionally
compound
optionally substituted
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聡 佐々木
ひろ美 小林
俊雄 田中
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武田薬品工業株式会社
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
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    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
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    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative

Definitions

  • the present invention relates to a fused heterocyclic derivative and its use, and more particularly to a compound having strong Smo inhibitory activity and useful for the prevention and treatment of cancer and the use thereof.
  • the Hedgehog gene (hh) was found as one of the genes exhibiting morphological abnormalities in Drosophila Embryo due to its mutation.
  • the Hedgehog gene product (Hh) is a secreted protein that is produced as a precursor of approximately 45 kDa and then undergoes autolysis to form the active body, the 20 kDa N-terminal domain and the 25 kDa C-terminal domain. It is divided into.
  • the active body, the 20 kDa N-terminal domain is modified at the N-terminus with a fatty acid and at the C-terminus with cholesterol.
  • the Hedgehog signal transduction system is formed by the protein group described below.
  • the receptor for Hh is Patched (Ptch), a 12-transmembrane protein.
  • Ptch acts on Smoothened (Smo), a seven-transmembrane protein, and suppresses the function of Smo in the absence of Hh.
  • Smo Smoothened
  • a signal generated by the activation of Smo activates the transcription factor Ci, and the expression of genes involved in morphogenesis is regulated (Non-patent Document 1). Pathways corresponding to the Drosophila Hedgehog signaling system have also been identified in mammals.
  • Non-Patent Document 2 sonic hedgehog (Shh), indian hedgehog (Ihh), and desert hedgehog (Dhh), and post-translational modifications similar to those of Drosophila Hh are known.
  • Shh sonic hedgehog
  • Ihh indian hedgehog
  • Dhh desert hedgehog
  • Post-translational modifications similar to those of Drosophila Hh are known.
  • Non-Patent Document 3 In human Shh, an active body of 19 kDa is excised from a 45 kDa precursor protein by autolysis, and a fatty acid is added to the N-terminus and cholesterol is added to the C-terminus. These modifications are thought to be necessary for maintaining the activity of Shh. For example, when palmitic acid is added to E.
  • Non-patent Document 4 human Smo is known as a human gene corresponding to Drosophila Smo, and Ptch1 and Ptch2 are known as human genes corresponding to Drosophila Ptch. Furthermore, the transcription factor corresponding to Drosophila Ci is considered to be Gli in humans, and three types of Gli1, Gli2, and Gli3 are known (Non-patent Document 5).
  • Shh / Ihh / Dhh each binds to Ptch1 and activates Smo by inhibiting the binding between Ptch1 and Smo.
  • Shh / Ihh / Dhh binds Ptch2, Hip1, Gas1, Cdo / Boc in addition to Ptch1 and controls Smo activation.
  • Signal transduction from Smo causes nuclear translocation of Gli1 and Gli2, and activates transcription of Gli1 (Non-patent Document 6).
  • the Hedgehog signal is also involved in morphogenesis during development.
  • Non-patent Document 7 a mutation of Shh was found in a patient with global forebrain encephalopathy (Holoprosencephaly), a congenital developmental abnormality in humans (Non-patent Document 7).
  • the natural compound Cyclopamine derived from white hellebore (Non-patent Document 8), which is known as a compound that causes monophthalmia (Cyclopus) in sheep, is confirmed to be a compound that inhibits Smo as its mechanism of action.
  • Non-patent document 9 Shh knockout mice were prepared, and monophthalmia, limb dysplasia (Non-patent Document 10), and neural plate dysplasia (Non-patent Document 11) were observed as phenotypes.
  • the Hedgehog signal which is an originally generated signal, is increased in tumor tissue and functions as a cancer cell proliferation and survival signal.
  • Hedgehog signal is considered to function in cancer cell growth and survival in autocrine mode, and in paracrine mode between cancer cells and cancer stromal cells (non-contained) Patent Document 12).
  • Autocrine mode Gli-1 transcriptional activation increases cell cycle control due to increased Cyclin D expression, decreased p21 expression, and increased proliferation signal due to EGFR pathway activation. work.
  • Paracrine mode Shh expressed in cancer cells acts on Smo of cancer stromal cells, so that, for example, insulin-like growth factor-1, fibroblast growth factor, and platelet-derived growth factor can be obtained from cancer stromal cells.
  • Non-patent Document 13 Cancers in which the Hedgehog signal is enhanced by mutation of Ptch1 and cancers that are enhanced by overexpression of Shh, which is one of the ligands, have been reported (Non-Patent Document 14). ).
  • the basal cell carcinoma and medulloblastoma are known as cancers whose Hedgehog signal is enhanced by the mutation, and the mutation of Ptch1 observed in these cancers thereby activates the Hedgehog signal in a ligand-independent manner (non-patented) Reference 15).
  • pancreatic cancer Non-patent Document 16
  • Shh was forcibly expressed in the pancreas
  • PanIN-like lesions were observed in the pancreas, which was the early stage of cancer progression, so the Hedgehog signal was involved not only in the growth and maintenance of cancer but also in the carcinogenesis process.
  • Non-patent Document 17 Furthermore, the Hedgehog signal functions in cancer stem cell proliferation and survival, and is thought to play an important role in tumor metastasis or postoperative recurrence (Non-patent Document 18).
  • the following are known as Hedgehog signal inhibitors.
  • Cymopamine a natural product inhibitor compound of Smo, has been reported to have a tumor growth inhibitory effect against glioma (Non-patent Document 19) and the like.
  • CUR-61414 (nonpatent literature 20) and SANT-1, 2, 3, 4 are reported as a synthetic low molecular weight compound which inhibits Smo.
  • Hedgohog signal-inhibiting antibodies it has been reported that regression of cancer was observed when anti-Shh antibodies were administered to tumor-bearing nude mice transplanted with colon cancer cell line HT-29 (Patent Document 1).
  • Patent Document 2 describes the following compounds.
  • Patent Document 3 describes the following compounds.
  • Patent Document 4 describes the following compounds.
  • Patent Document 5 describes the following compounds.
  • Patent Document 6 describes the following compounds.
  • Patent Document 7 describes the following compounds.
  • Patent Document 8 describes the following compounds.
  • Patent Document 9 describes the following compounds.
  • Patent Document 10 describes the following compounds.
  • Patent Document 11 describes the following compounds.
  • Patent Document 12 describes the following compounds.
  • Non-Patent Document 22 describes the following compounds.
  • An object of the present invention is to provide a compound having excellent Smo inhibitory activity, low toxicity and sufficiently satisfactory as a pharmaceutical product.
  • the present inventors have found that a compound represented by the following formula or a salt thereof has excellent Smo inhibitory activity, and has completed the present invention. That is, the present invention is as follows.
  • R 1 is a hydrogen atom, a halogen atom, a group bonded through a carbon atom, a group bonded through an oxygen atom, a group bonded through a nitrogen atom, or a group bonded through a sulfur atom
  • R 2 represents a cyclic group which may have a substituent
  • R 3 represents a hydrogen atom, a halogen atom, a group bonded through a carbon atom, a group bonded through an oxygen atom, a group bonded through a nitrogen atom, or a group bonded through a sulfur atom
  • R 4 represents an optionally substituted cyclic group
  • R 5 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 4 and R 5 together with the adjacent nitrogen atom may form an optionally substituted ring
  • R 6 represents a hydrogen atom, a halogen atom, a group bonded through a carbon atom,
  • R 1 may have may have a substituent group C 1-6 alkyl, C 1-6 alkoxy optionally substituted, the substituent C 1-6
  • the compound according to the above (1) which is alkylthio or optionally substituted C 1-6 alkyl-carbonyl; (3) The compound according to (2) above, wherein R 1 is C 1-6 alkyl; (4) R 2 may be optionally substituted C 3-6 cycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 3 to 3
  • the compound according to the above (1), which is an optionally substituted heterocyclic group, and R 5 is a hydrogen
  • R 1 is C 1-6 alkyl
  • R 2 is optionally substituted C 3-6 cycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 3 to 6 membered A non-aromatic heterocyclic group
  • R 3 is a hydrogen atom
  • R 4 may have an optionally substituted C 6-10 aryl, an optionally substituted C 3-8 cycloalkyl group condensed with an optionally substituted benzene ring, or an optionally substituted group.
  • R 5 is a hydrogen atom or an optionally substituted C 1-6 alkyl;
  • R 6 is a hydrogen atom or a halogen atom; and
  • R 7 is a hydrogen atom;
  • 10 N- ⁇ 4-[(diethylcarbamoyl) amino] phenyl ⁇ -1- (4-fluorophenyl) -2-methyl-1H-benzimidazole-6-carboxamide or
  • the compound of the present invention or a salt thereof or a prodrug thereof has a strong Smo inhibitory action, it can provide a clinically useful preventive / therapeutic agent for cancer, a cancer growth inhibitor, and a cancer metastasis inhibitor.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • heterocyclic group includes an aromatic heterocyclic group (eg, monocyclic aromatic heterocyclic group, condensed aromatic heterocyclic group) and a non-aromatic heterocyclic group (eg, monocyclic).
  • aromatic heterocyclic group eg, monocyclic aromatic heterocyclic group, condensed aromatic heterocyclic group
  • non-aromatic heterocyclic group eg, monocyclic
  • Non-aromatic heterocyclic group, condensed non-aromatic heterocyclic group and the like.
  • examples of the “monocyclic aromatic heterocyclic group” include a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include 1 to 4 5- to 7-membered monocyclic aromatic heterocyclic groups. Specific examples of monocyclic aromatic heterocyclic groups include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-furyl).
  • the “fused aromatic heterocyclic group” includes, for example, a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • a 4- to 8-membered condensed aromatic heterocyclic group for example, a group obtained by condensing the above-mentioned 5- to 7-membered monocyclic aromatic heterocyclic group and the like with C 6-10 aryl (eg, phenyl); And a group in which the 5- to 7-membered monocyclic aromatic heterocyclic group is condensed).
  • fused aromatic heterocyclic group examples include quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl), benzofuryl (eg, 2-benzofuryl, 3-benzofuryl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (Eg, 2-benzoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (eg, benzimidazol-2-yl, benzimidazol-5-yl), indolyl (Eg, indol-3-yl, indo
  • the “monocyclic non-aromatic heterocyclic group” is, for example, a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • the “fused non-aromatic heterocyclic group” includes, for example, a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • 8 to 12-membered saturated or unsaturated condensed aromatic heterocyclic group for example, the above-mentioned 3- to 8-membered monocyclic non-aromatic heterocyclic group and the like and C 6-10 aryl (eg, Phenyl) condensed group; a group in which the above 3 to 8-membered monocyclic non-aromatic heterocyclic group is condensed; a group in which these groups are partially saturated).
  • fused non-aromatic heterocyclic group examples include dihydroindolyl (eg, 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg, 1,3-dihydro-2H-iso).
  • Indol-2-yl dihydrobenzofuryl (eg, 2,3-dihydro-1-benzofuran-5-yl), dihydroisobenzofuryl (eg, 1,3-dihydro-2-benzofuran-6-yl), Dihydrobenzodioxinyl (eg, 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (eg, 3,4-dihydro-2H-1,5-benzodioxepinyl) ), Tetrahydrobenzofuryl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), tetrahydrobenzothiazolyl (eg, 4,5,6,7-tetrahydrobenzo) Azol-2-yl), chromenyl (eg, 4H-chromen-2-yl, 2H-chromen-3-yl), dihydrochromenyl (eg,
  • heterocycle includes aromatic heterocycle (eg, monocyclic aromatic heterocycle, condensed aromatic heterocycle), non-aromatic heterocycle (eg, monocyclic non-aromatic heterocycle) , Condensed non-aromatic heterocycle) and the like.
  • the “monocyclic aromatic heterocycle” includes, for example, a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. Or a 5- to 7-membered monocyclic aromatic heterocyclic ring containing 4 or 4 units.
  • monocyclic aromatic heterocycles include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole And triazine.
  • the “fused aromatic heterocycle” includes, for example, 1 to 4 hetero atoms selected from oxygen atoms, sulfur atoms (which may be oxidized) and nitrogen atoms in addition to carbon atoms as ring-constituting atoms.
  • 8- to 12-membered condensed aromatic heterocycle for example, a ring in which the 5- to 7-membered monocyclic aromatic heterocycle and the like are condensed with a benzene ring; the 5- to 7-membered monocyclic aromatic A ring in which heterocycles are condensed with each other).
  • fused aromatic heterocycle examples include quinoline, quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, indole, indazole, pyrrolopyrazine, imidazopyridine, imidazopyrazine, benzisoxazole, benzotriazole , Pyrazolopyridine, pyrazolothiophene, and pyrazolotriazine.
  • examples of the “monocyclic non-aromatic heterocycle” include a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • examples thereof include 1 to 4 3- to 8-membered saturated or unsaturated (preferably saturated) monocyclic non-aromatic heterocyclic ring.
  • the monocyclic non-aromatic heterocycle include oxirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, thiolane, piperidine, dihydropyridine, tetrahydropyran, thiane, morpholine, thiomorpholine, piperazine, oxazolidine, thiazolidine, dihydrothio Examples include pyran, imidazolidine, oxazoline, thiazoline, imidazoline, azepan, oxepane, thiepan, oxazepan, thiazepan, azocan, oxocan, thiocan, oxazocan, thiazocan, dioxin and the like.
  • the “fused non-aromatic heterocycle” includes, for example, a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • 4 to 12-membered saturated or unsaturated condensed non-aromatic heterocyclic ring for example, a ring obtained by condensing the 3- to 8-membered monocyclic non-aromatic heterocyclic ring and a benzene ring; A ring in which member monocyclic non-aromatic heterocycles are condensed; a ring in which these rings are partially saturated).
  • fused non-aromatic heterocycle examples include dihydroindole, dihydroisoindole, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzodioxin, dihydrobenzodioxepin, tetrahydrobenzofuran, tetrahydrobenzothiazole, chromene, dihydrochromene, dihydroquinoline. , Tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine and the like.
  • examples of the “nitrogen-containing heterocycle” include a 5- to 7-membered monocyclic aromatic heterocycle having at least one nitrogen atom as a ring-constituting atom (eg, pyridine).
  • 8- to 12-membered fused aromatic heterocycles eg, quinolines
  • cyclic portion of “cyclic carbamoyl” includes a 3- to 8-membered monocyclic non-aromatic heterocycle having at least one nitrogen atom as a ring-constituting atom and optionally condensed with a benzene ring ( Examples include azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepan, oxazepan, thiazepan, azocan, oxazocan, thiazocan).
  • the ring portion of “cyclic sulfamoyl” includes a 3- to 8-membered monocyclic non-aromatic heterocycle having at least one nitrogen atom as a ring-constituting atom and optionally condensed with a benzene ring ( Examples include azetidine, pyrrolidine, piperidine, morpholine, piperazine, azepan, oxazepan, thiazepan, azocan, oxazocan, thiazocan, tetrahydroquinoline).
  • examples of the “cyclic ureido” include 3-methyl-2-oxotetrahydropyrimidin-1 (2H) -yl, 3-ethyl-2-oxotetrahydropyrimidin-1 (2H) -yl, 3- And ethyl-2-oxoimidazolidin-1-yl.
  • examples of the “cyclic phosphono” include 2-oxide-1,3,2-dioxaphosphinanyl and 2-oxide-1,3,2-dioxaphosphepanyl.
  • the “group bonded through a carbon atom” means (1) cyano, (2) optionally substituted alkyl (eg, C 1-6 alkyl), (3) an alkenyl optionally having a substituent (eg, C 2-6 alkenyl), (4) Alkynyl (eg, C 2-6 alkynyl) which may have a substituent, (5) optionally substituted cycloalkyl (eg, C 3-8 cycloalkyl), (6) optionally substituted cycloalkenyl (eg, C 3-8 cycloalkenyl), (7) aryl optionally having substituent (eg, C 6-10 aryl), (8) acyl, (9) Heterocyclic group which may have a substituent (however, having a bond at a carbon atom) Etc.
  • alkyl eg, C 1-6 alkyl
  • an alkenyl optionally having a substituent eg, C 2-6 alkenyl
  • Alkynyl eg
  • C 1-10 alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, Examples thereof include isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
  • C 1-6 alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, 1, 2-dimethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like are shown.
  • C 2-6 alkenyl for example, shown ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • C 2-6 alkynyl refers to, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • C 3-8 cycloalkyl refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C 3-8 cycloalkenyl refers to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.
  • C 6-10 aryl represents, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
  • C 1-6 alkyl-carbonyl means, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexyl. Carbonyl etc. are shown.
  • C 2-6 alkenyl-carbonyl means, for example, ethenylcarbonyl, propenylcarbonyl, butenylcarbonyl, pentenylcarbonyl, hexenylcarbonyl and the like.
  • C 2-6 alkynyl-carbonyl means, for example, ethynylcarbonyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl and the like.
  • C 3-8 cycloalkyl-carbonyl refers to, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl and the like.
  • C 3-8 cycloalkenyl-carbonyl refers to, for example, cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl, cycloheptenylcarbonyl, cyclooctenylcarbonyl and the like.
  • C 6-10 aryl-carbonyl refers to, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
  • C 1-6 alkoxy-carbonyl means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyl Oxycarbonyl, hexyloxycarbonyl, etc. are shown.
  • C 2-6 alkenyloxy-carbonyl means, for example, ethenyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl and the like.
  • C 2-6 alkynyloxy-carbonyl refers to, for example, ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl and the like.
  • C 3-8 cycloalkyloxy-carbonyl means, for example, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, cyclooctyloxycarbonyl and the like. Show.
  • C 3-8 cycloalkenyloxy-carbonyl means, for example, cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl, cycloheptenyloxycarbonyl, cyclooctyl Tenyloxycarbonyl and the like are shown.
  • C 3-8 cycloalkynyloxy-carbonyl means, for example, cyclopropynyloxycarbonyl, cyclobutynyloxycarbonyl, cyclopentynyloxycarbonyl, cyclohexynyloxycarbonyl, cycloheptynyloxycarbonyl, Cyclooctynyloxycarbonyl and the like are shown.
  • C 6-10 aryloxy-carbonyl represents, for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
  • examples of the “substituent” of “alkyl optionally having substituent (s)” include substituents selected from the following substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • Substituent group A (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); (2) Cyano; (3) Nitro; (4) hydroxy; (5) C 3-8 cycloalkyl optionally having 1 to 3 halogen atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl); (6) (a) a halogen atom, (b) cyano, (c) C 1-6 alkoxy (eg, methoxy), and (d) C 1-6 alkylsulfonyl (eg, methylsulfonyl) C 6-10 aryl optionally having 1 to 3 substituents selected from (eg, phenyl, 1-naphthyl, 2-naphthyl); (7) (a) a halogen atom, and (b
  • C 1-6 alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl
  • C 2-6 alkenylsulfonyl eg, ethenylsulfonyl, propenylsulfonyl
  • C 2-6 alkynylsulfonyl eg, ethynylsulfonyl, propynylsulfonyl, butynylsulfonyl, pentynylsulfonyl, hexynylsulfonyl
  • C 3-8 cycloalkylsulfonyl eg, cyclopropylsulfonyl, cyclobutylsulfonyl
  • C 3-8 cycloalkenylsulfonyl eg, cyclopropenylsulfonyl, cyclopropenylsulf
  • examples of the “substituent” of “alkenyl optionally having substituent (s)” include substituents selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • examples of the “substituent” of “optionally substituted alkynyl” include substituents selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • substituents of “cycloalkyl which may have a substituent” (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituents selected from Substituent group A can be mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • substituted cycloalkenyl (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituent group A (excluding oxo) The substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • substituent of “aryl optionally having substituent (s)
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • Substituent group A excluding oxo
  • the substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • acyl means (1) Formyl, (2) an optionally substituted alkyl-carbonyl (eg, C 1-6 alkyl-carbonyl), (3) alkenyl-carbonyl optionally having substituent (eg, C 2-6 alkenyl-carbonyl), (4) optionally substituted alkynyl-carbonyl (eg, C 2-6 alkynyl-carbonyl), (5) optionally substituted cycloalkyl-carbonyl (eg, C 3-8 cycloalkyl-carbonyl), (6) an optionally substituted cycloalkenyl-carbonyl (eg, C 3-8 cycloalkenyl-carbonyl), (7) aryl-carbonyl optionally having substituent (eg, C 6-10 aryl-carbonyl), (8) optionally substituted heterocycle-carbonyl, (9) Carboxyl, (10) optionally substituted alkoxy-carbonyl (eg, C 1-6 alkoxy-carbonyl), (11)
  • examples of the “substituent” of the “optionally substituted alkyl-carbonyl” include substituents selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • examples of the “substituent” of “optionally substituted alkenyl-carbonyl” include substituents selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • examples of the “substituent” of “optionally substituted alkynyl-carbonyl” include substituents selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • the “substituent” of “cycloalkyl-carbonyl optionally having substituent (s)” (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituents selected from Substituent group A can be mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • the “substituent” of “optionally substituted cycloalkenyl-carbonyl” (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituent group A (excluding oxo) The substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • substituent of “aryl-carbonyl optionally having substituent (s)”
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • Substituent group A excluding oxo
  • the substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • heterocycle of “optionally substituted heterocycle-carbonyl” means, for example, (1) 5- or 6-membered monocyclic aromatic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridine, pyrazole), (2) 8- to 12-membered condensed aromatic heterocycle (eg, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole), (3) 3- to 6-membered monocyclic non-aromatic heterocycle (eg, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, thiolane, piperidine) Etc.
  • 5- or 6-membered monocyclic aromatic heterocycle eg, furan,
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • Substituent group A excluding oxo in the case of aromatic heterocycle-carbonyl
  • the substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • the “substituent” of “alkoxy-carbonyl optionally having substituent (s)” includes a substituent selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • examples of the “substituent” of “optionally substituted alkenyloxy-carbonyl” include substituents selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • examples of the “substituent” of “optionally substituted alkynyloxy-carbonyl” include substituents selected from the substituent group A.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • the “substituent” of “cycloalkyloxy-carbonyl optionally having substituent (s)” (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituents selected from Substituent group A can be mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • substituent of “optionally substituted cycloalkenyloxy-carbonyl”
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • Substituent group A excluding oxo
  • the substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • the “substituent” of “optionally substituted cycloalkynyloxy-carbonyl” (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituent group A (excluding oxo) The substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • the “substituent” of “aryloxy-carbonyl optionally having substituent (s)” (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituent group A (excluding oxo) The substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • heterocycle of “optionally substituted heterocycle-oxy-carbonyl” means, for example, (1) 5- or 6-membered monocyclic aromatic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridine, pyrazole), (2) 8- to 12-membered condensed aromatic heterocycle (eg, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole), (3) 3- to 6-membered monocyclic non-aromatic heterocycle (eg, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, thiolane, piperidine) Etc.
  • 5- or 6-membered monocyclic aromatic heterocycle eg, fur
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • Substituent group A excluding oxo in the case of aromatic heterocycle-oxy-carbonyl
  • the substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • optionally substituted carbamoyl refers to the above-mentioned “optionally substituted alkyl (eg, C 1-6 alkyl)”, “substituent Optionally substituted alkenyl (eg, C 2-6 alkenyl) ”,“ optionally substituted alkynyl (eg, C 2-6 alkynyl) ”,“ optionally substituted cycloalkyl ” (Eg, C 3-8 cycloalkyl) ”,“ optionally substituted cycloalkenyl (eg, C 3-8 cycloalkenyl) ”and“ optionally substituted aryl (eg, C 6-10 aryl) ”represents an optionally substituted carbamoyl having 1 or 2 substituents.
  • optionally substituted alkyl eg, C 1-6 alkyl
  • substituted alkenyl eg, C 2-6 alkenyl
  • optionally substituted alkynyl eg, C 2-6 alkynyl
  • the “optionally substituted heterocyclic group (however, having a bond at a carbon atom)” is an aromatic heterocyclic group having a bond at a carbon atom (eg, Monocyclic aromatic heterocyclic group, condensed aromatic heterocyclic group), non-aromatic heterocyclic group (eg, monocyclic non-aromatic heterocyclic group, condensed non-aromatic heterocyclic group) and the like.
  • substituent of the above-mentioned “heterocyclic group optionally having substituent (however, having a bond at a carbon atom)”, (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from Substituent Group A, and (2) Substituent group A (excluding oxo in the case of an aromatic heterocyclic group) The substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • examples of the “group bonded through an oxygen atom” include hydroxy optionally having one of the above “group bonded through a carbon atom”.
  • examples of the “group bonded through a nitrogen atom” include (1) nitro and (2) one or two of the above “group bonded through a carbon atom”. Good amino is mentioned.
  • the “group bonded through a sulfur atom” includes, for example, one of the above “group bonded through a carbon atom” or “group bonded through a nitrogen atom”.
  • the mercapto may be mentioned, and the sulfur atom may be oxidized.
  • the “non-aromatic heterocyclic group bonded through a carbon atom” in the “non-aromatic heterocyclic group bonded through a carbon atom which may have a substituent” includes 3 To 8 membered (preferably 5 or 6 membered) saturated or unsaturated (preferably saturated) monocyclic non-aromatic heterocyclic group, 8 to 12 membered saturated or unsaturated condensed non-aromatic heterocyclic group, etc.
  • a group having a bond on a carbon atom can be mentioned.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituents selected from Substituent group A can be mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • the “cyclic group” of the “cyclic group optionally having substituent (s)” includes C 3-8 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl), C 3 condensed with a benzene ring.
  • cycloalkyl eg, indanyl, tetrahydrobenzocycloheptyl (eg, 6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-2-yl)
  • C 6-10 aryl eg, phenyl, Naphthyl
  • aromatic heterocyclic groups eg, monocyclic aromatic heterocyclic groups, condensed aromatic heterocyclic groups
  • non-aromatic heterocyclic groups eg, monocyclic non-aromatic heterocyclic groups, condensed non-aromatic
  • Group heterocyclic group eg, indanyl, tetrahydrobenzocycloheptyl (eg, 6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-2-yl)
  • C 6-10 aryl eg, phenyl, Naphthyl
  • aromatic heterocyclic groups eg, monocyclic aromatic heterocycl
  • substituent group A e.g, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 1-ethyl) Propyl, 2-ethylbutyl
  • substituent group A e.g, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 1-ethyl) Propyl, 2-ethylbutyl
  • Substituent group A however, in the case of an aromatic ring group, oxo is excluded
  • the substituent selected from is mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • optionally substituted hydrocarbon group means the above “optionally substituted alkyl (eg, C 1-6 alkyl)”, “substituent Optionally substituted alkenyl (eg, C 2-6 alkenyl) ”,“ optionally substituted alkynyl (eg, C 2-6 alkynyl) ”,“ optionally substituted ” Cycloalkyl (eg, C 3-8 cycloalkyl) ”,“ optionally substituted cycloalkenyl (eg, C 3-8 cycloalkenyl) ”and“ optionally substituted aryl ( Examples thereof are the same as those described above, for example, C 6-10 aryl).
  • the “ring” of the “optionally substituted ring” is a 5- or 6-membered non-aromatic (preferably saturated) nitrogen-containing heterocyclic ring (eg, pyrrolidine, piperidine, piperazine, Morpholine, thiomorpholine) and the like.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituents selected from Substituent group A can be mentioned.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 5, more preferably 1 to 3.
  • one of X and Y is a carbon atom and the other is a nitrogen atom. That is, the compound (I)
  • compound (I) examples include a compound represented by the formula (Ia) (compound (Ia)) and a compound represented by the formula (Ib) (hereinafter referred to as “compound (Ib)”). May be abbreviated).
  • R 1 is (1) hydrogen atom, (2) a halogen atom, (3) a group bonded through a carbon atom, (4) a group bonded through an oxygen atom, (5) a group bonded through a nitrogen atom, or (6) A group bonded through a sulfur atom.
  • R 1 is (1) hydrogen atom, (2) a halogen atom, (3) an optionally substituted alkyl, (4) an alkenyl optionally having a substituent, (5) an alkynyl optionally having a substituent, (6) an optionally substituted cycloalkyl, (7) aryl optionally having a substituent, (8) a non-aromatic heterocyclic group bonded via a carbon atom, which may have a substituent, (9) acyl, (10) a group bonded through an oxygen atom, (11) a group bonded through a nitrogen atom, or (12) is a group bonded through a sulfur atom; More preferably, R 1 is (1) hydrogen atom, (2) an optionally substituted C 1-6 alkyl, (3) C 1-6 alkoxy which may have a substituent, (4) an optionally substituted C 1-6 alkylthio, (5) an optionally substituted C 1-6 alkyl-carbonyl, (6) amino optionally having one
  • R 1 is (1) hydrogen atom, (2) (a) a halogen atom (eg, fluorine atom), (b) hydroxy, (c) C 1-6 alkyl-carbonyloxy (eg, acetyloxy), and (d) C 1-6 alkoxy (eg, methoxy) C 1-6 alkyl (eg, methyl, ethyl, tert-butyl, isobutyl) optionally having 1 to 3 substituents selected from (3) C 1-6 alkoxy (eg, methoxy, ethoxy), (4) C 1-6 alkylthio (eg, methylthio) optionally having one C 6-10 aryl (eg, phenyl), (5) C 1-6 alkylcarbonyl (eg, acetyl), (6) amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl), or (7) C 6-10 aryl (eg, phenyl) Is; More preferably, R 1
  • R 2 represents a cyclic group which may have a substituent.
  • R 2 is (1) an optionally substituted C 3-6 cycloalkyl, (2) C 6-10 aryl which may have a substituent, or (3) a 3- to 6-membered non-aromatic (preferably saturated) heterocyclic group which may have a substituent; More preferably, R 2 is (1) C 3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl), (2) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) C 1-6 alkoxy (eg, methoxy), (c) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), (d) C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl), (e) diC 1-6
  • C 6-10 aryl eg, phenyl, naphthyl
  • substituent selected from (3) (a) C 6-10 aryl-C 1-6 alkoxy-carbonyl (eg, benzyloxycarbonyl), (b) C 1-6 alkyl-carbonyl (eg acetyl), (c) C 1-6 alkylsulfonyl (e.g., methylsulfonyl), and (d) which may have one hydroxy C 1-6 alkyl (e.g., ethyl) A 5- or 6-membered non-aromatic heterocyclic group (eg, piperidyl) optionally having one substituent selected from: More preferably, R 2 is (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) C 1-6 alkoxy (eg, methoxy), (c) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), (d) C
  • R 3 is (1) hydrogen atom, (2) a halogen atom, (3) a group bonded through a carbon atom, (4) a group bonded through an oxygen atom, (5) a group bonded through a nitrogen atom, or (6) A group bonded through a sulfur atom.
  • R 3 is preferably a hydrogen atom.
  • R 4 represents a cyclic group which may have a substituent.
  • R 4 is preferably (1) C 6-10 aryl optionally having substituent (s), (2) C 3-8 cycloalkyl condensed with an optionally substituted benzene ring, or (3) A heterocyclic group which may have a substituent.
  • R 4 (1) (a) (i) hydroxy, (ii) C 1-6 alkoxy-carbonyl (eg ethoxycarbonyl), (iii) C 1-6 alkyl-carbamoyl (eg, ethylcarbamoyl), (iv) di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl), (v) a 5-membered cyclic carbamoyl (eg, 1-pyrrolidinylcarbonyl), (vi) 5-membered aromatic heterocyclic group (eg, pyrazolyl (eg, 1-pyrazolyl)) and (vii) C 1-6 alkyl optionally having one substituent selected from carboxy (eg, Methyl, isopropyl, 1-ethylpropyl, 2-ethylbutyl), (b) C 1-6 alkoxy (
  • R 4 (1) (a) (i) hydroxy, (ii) C 1-6 alkoxy-carbonyl (eg ethoxycarbonyl), (iii) 1) Halogen atom (eg, fluorine atom) 2) hydroxy, 3) C 1-6 alkoxy (eg, methoxy), 4) 1) Halogen atom (eg, chlorine atom), and 2) C 1-6 alkoxy (eg, methoxy) C 6-10 aryl (eg, phenyl) optionally having one substituent selected from: 5) Carbamoyl, 6) DiC 1-6 alkylamino (eg, dimethylamino), and 7) C 3-8 cycloalkyl (eg, cyclohexyl) C 1-10 alkyl-carbamoyl optionally having 1 to 3 substituents selected from (for example, methylcarbamoyl, ethylcarbamoyl, isopropylcarbam
  • Ethoxycarbonyl) Cyclic sulfamoyl optionally having one substituent selected from (for example, piperidinosulfonyl, 1-piperazinylsulfonyl, tetrahydroquinolinylsulfonyl), (r) (i) C 1-6 alkoxy (eg, methoxy), and (ii) hydroxy, Mono (C 1-6 alkyl-carbonyl) amino (eg, ethylcarbonylamino, isopropylcarbonylamino, isobutylcarbonylamino, (1-ethylpropyl) carbonylamino) optionally having one substituent selected from (s) amino, (t) C 6-10 aryl-carbonylamino (eg, benzoylamino) optionally having one halogen atom (eg, fluorine atom), (u) N—C 1-6 alkyl-N— (C 1-6 alkyl-carbonyl) amino (e
  • R 5 represents a hydrogen atom or a hydrocarbon group which may have a substituent.
  • R 5 (1) hydrogen atom, or (2) C 1-6 alkyl which may have a substituent is preferable, (1) hydrogen atom, or (2) C 1-6 alkyl (eg, methyl) is preferred.
  • R 4 and R 5 may form a ring optionally having a substituent together with the adjacent nitrogen atom.
  • R 4 and R 5 may have a substituent which may be formed together with the adjacent nitrogen atom, and the optionally substituted 5- or 6-membered non-aromatic ring (preferably saturated) nitrogen-containing heterocyclic (e.g., pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine) are preferred,, C 1-6 alkoxy - carbonyl (e.g., which may have one ethoxycarbonyl) C 6 1-piperazine which may have one -10 aryl (eg, phenyl) is preferred.
  • R 6 is (1) hydrogen atom, (2) a halogen atom, (3) a group bonded through a carbon atom, (4) a group bonded through an oxygen atom, (5) a group bonded through a nitrogen atom, or (6) A group bonded through a sulfur atom.
  • R 6 (1) hydrogen atom, or (2) Halogen atoms (eg, fluorine atoms) Of these, a hydrogen atom is preferable.
  • R 7 is (1) hydrogen atom, (2) a group bonded through a carbon atom, (3) a group bonded through an oxygen atom, (4) a group bonded through a nitrogen atom, or (5) A group bonded through a sulfur atom.
  • R 7 is preferably a hydrogen atom.
  • Preferred embodiments of compound (I) include the following: formula
  • R 1 is (1) hydrogen atom, (2) a halogen atom, (3) an optionally substituted alkyl, (4) an alkenyl optionally having a substituent, (5) an alkynyl optionally having a substituent, (6) an optionally substituted cycloalkyl, (7) a non-aromatic heterocyclic group bonded via a carbon atom, which may have a substituent, (8) a group bonded through an oxygen atom, (9) a group bonded through a nitrogen atom, or (10) a group bonded via a sulfur atom (preferably a C 1-6 alkyl which may have a substituent, a C 1-6 alkoxy which may have a substituent, a substituent An optionally substituted C 1-6 alkylthio, or an optionally substituted C 1-6 alkyl-carbonyl, More preferably C 1-6 alkyl); R 2 may be a
  • R 5 is a hydrogen atom or an optionally substituted hydrocarbon group (preferably a hydrogen atom or an optionally substituted C 1-6 alkyl); Alternatively, R 4 and R 5 may form an optionally substituted ring with an adjacent nitrogen atom;
  • R 6 is (1) hydrogen atom, (2) a halogen atom, (3) a group bonded through a carbon atom, (4) a group bonded through an oxygen atom, (5) a group bonded through a nitrogen atom, or (6) a group bonded through a sulfur atom (preferably a hydrogen atom or a halogen atom);
  • R 7 is (1) hydrogen atom, (2) a group bonded through a carbon atom, (3) a group bonded through an oxygen atom, (4) a group bonded through a nitrogen atom, or (5) a group bonded through a sulfur atom (preferably a hydrogen atom); and
  • Compound (I) includes a benzimidazole derivative represented by compound (Ia) and an imidazopyridine derivative represented by compound (Ib).
  • compound (Ia) an imidazopyridine derivative represented by compound (Ib).
  • R 1 is (1) hydrogen atom, (2) an optionally substituted C 1-6 alkyl, (3) C 1-6 alkoxy which may have a substituent, (4) an optionally substituted C 1-6 alkylthio, (5) an optionally substituted C 1-6 alkyl-carbonyl, (6) C 6-10 aryl optionally having a substituent, or (7) is amino optionally having one or two groups bonded via a carbon atom;
  • R 2 is (1) an optionally substituted C 3-6 cycloalkyl, (2) C 6-10 aryl which may have a substituent, or (3) a 3- to 6-membered non-aromatic (preferably saturated) heterocyclic group which may have a substituent;
  • R 3 is a hydrogen atom;
  • R 4 is (1) C 6-10 aryl optionally having substituent (s), (2) C 3-8 cycloalkyl condensed with an optionally substituted benzene ring, or (3) a heterocyclic group which
  • R 1 is C 1-6 alkyl
  • R 2 is optionally substituted C 3-6 cycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 3 to 6 membered
  • R 3 is a hydrogen atom
  • R 4 may have an optionally substituted C 6-10 aryl, an optionally substituted C 3-8 cycloalkyl group condensed with an optionally substituted benzene ring, or an optionally substituted group.
  • R 5 is a hydrogen atom or an optionally substituted C 1-6 alkyl
  • R 6 is a hydrogen atom or a halogen atom
  • Compound (Ia) wherein R 7 is a hydrogen atom.
  • R 1 is (1) hydrogen atom, (2) (a) a halogen atom (eg, fluorine atom), (b) hydroxy, and (c) C 1-6 alkyl-carbonyloxy (eg, acetyloxy) C 1-6 alkyl (eg, methyl, ethyl, tert-butyl, isobutyl) optionally having 1 to 3 substituents selected from (3) C 1-6 alkoxy (eg, methoxy, ethoxy) or (4) C 1-6 alkylthio (eg, methylthio) optionally having one C 6-10 aryl (eg, phenyl);
  • R 2 is (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) C 1-6 alkoxy (eg, methoxy), (c) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), (d) C 1-6 alkyl-carb
  • Phenyl (2) (a) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), and (b) diC 1-6 alkyl-carbamoyl (eg, diethylcarbamoyl) A 5- or 6-membered aromatic heterocyclic group (eg, thiazolyl (eg, 2-thiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl)), which may have one substituent selected from Or (3) (a) C 1-6 alkoxy (e.g., methoxy) and one or two have good C 6-10 aryl (e.g., phenyl) which may be optionally having C 1-6 alkyl ( E.g.
  • R 5 is (1) hydrogen atom, or (2) C 1-6 alkyl (eg, methyl); Alternatively, R 4 and R 5 together with the adjacent nitrogen atom form 1-piperazine which may have 1 C 1-6 alkoxy-carbonyl which may have 1 C 6-10 aryl.
  • R 6 is a hydrogen atom; Compound (Ia), wherein R 7 is a hydrogen atom.
  • R 1 is (1) hydrogen atom, (2) (a) a halogen atom (eg, fluorine atom), (b) hydroxy, (c) C 1-6 alkyl-carbonyloxy (eg, acetyloxy), and (d) C 1-6 alkoxy (eg, methoxy) C 1-6 alkyl (eg, methyl, ethyl, tert-butyl, isobutyl) optionally having 1 to 3 substituents selected from (3) C 1-6 alkoxy (eg, methoxy, ethoxy), (4) C 1-6 alkylthio (eg, methylthio) optionally having one C 6-10 aryl (eg, phenyl), (5) C 1-6 alkylcarbonyl (eg, acetyl), (6) amino optionally having 1 or 2 C 1-6 alkyl (eg, methyl), or (7) C 6-10 aryl (eg, phenyl) Is; R
  • C 6-10 aryl eg, phenyl, naphthyl
  • C 6-10 aryl optionally having one substituent selected from (3) (a) C 6-10 aryl-C 1-6 alkoxy-carbonyl (eg, benzyloxycarbonyl), (b) C 1-6 alkyl-carbonyl (eg acetyl), (c) C 1-6 alkylsulfonyl (e.g., methylsulfonyl), and (d) which may have one hydroxy C 1-6 alkyl (e.g., ethyl) Piperidyl optionally having one substituent selected from: R 3 is a hydrogen atom; R 4 is (1) (a) (i) hydroxy, (ii) C 1-6 alkoxy-carbonyl (eg ethoxycarbonyl), (iii) 1) Halogen atom (eg, fluorine atom) 2) hydroxy, 3) C 1-6 alkoxy (eg, methoxy), 4) 1) Hal
  • Ethoxycarbonyl) Cyclic sulfamoyl optionally having one substituent selected from (for example, piperidinosulfonyl, 1-piperazinylsulfonyl, tetrahydroquinolinylsulfonyl), (r) (i) C 1-6 alkoxy (eg, methoxy), and (ii) hydroxy, Mono (C 1-6 alkyl-carbonyl) amino (eg, ethylcarbonylamino, isopropylcarbonylamino, isobutylcarbonylamino, (1-ethylpropyl) carbonylamino) optionally having one substituent selected from (s) amino, (t) C 6-10 aryl-carbonylamino (eg, benzoylamino) optionally having one halogen atom (eg, fluorine atom), (u) N—C 1-6 alkyl-N— (C 1-6 alkyl-carbonyl) amino (e
  • R 1 is (1) (a) a halogen atom (eg, fluorine atom), (b) hydroxy, and (c) C 1-6 alkyl-carbonyloxy (eg, acetyloxy) C 1-6 alkyl (eg, methyl, ethyl, tert-butyl, isobutyl) optionally having 1 to 3 substituents selected from (2) C 1-6 alkoxy (eg, methoxy, ethoxy), or (3) C 1-6 alkylthio (eg, methylthio) Is;
  • R 2 is (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) C 1-6 alkoxy (eg, methoxy), (c) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), (d) C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethyl
  • Ethoxycarbonyl) Cyclic sulfamoyl optionally having one substituent selected from (for example, piperidinosulfonyl, 1-piperazinylsulfonyl, tetrahydroquinolinylsulfonyl), (r) (i) C 1-6 alkoxy (eg, methoxy), and (ii) hydroxy, Mono (C 1-6 alkyl-carbonyl) amino (eg, ethylcarbonylamino, isopropylcarbonylamino, isobutylcarbonylamino, (1-ethylpropyl) carbonylamino) optionally having one substituent selected from (s) amino, (t) C 6-10 aryl-carbonylamino (eg, benzoylamino) optionally having one halogen atom (eg, fluorine atom), (u) N—C 1-6 alkyl-N— (C 1-6 alkyl-carbonyl) amino (e
  • R 1 is C 1-6 alkyl (especially methyl);
  • R 2 is phenyl having one fluorine atom;
  • R 3 is a hydrogen atom;
  • R 4 is (1) (a) (i) hydroxy, (ii) C 1-6 alkoxy-carbonyl (eg ethoxycarbonyl), (iii) 1) Halogen atom (eg, fluorine atom) 2) hydroxy, 3) C 1-6 alkoxy (eg, methoxy), 4) 1) Halogen atom (eg, chlorine atom), and 2) C 1-6 alkoxy (eg, methoxy) C 6-10 aryl (eg, phenyl) optionally having one substituent selected from: 5) Carbamoyl, 6) DiC 1-6 alkylamino (eg, dimethylamino), and 7) C 3-8 cycloalkyl (eg, cyclohexyl) C 1-10 alkyl-carbamoyl optionally having 1 to 3 substituent selected from
  • Ethoxycarbonyl) Cyclic sulfamoyl optionally having one substituent selected from (for example, piperidinosulfonyl, 1-piperazinylsulfonyl, tetrahydroquinolinylsulfonyl), (r) (i) C 1-6 alkoxy (eg, methoxy), and (ii) hydroxy, Mono (C 1-6 alkyl-carbonyl) amino (eg, ethylcarbonylamino, isopropylcarbonylamino, isobutylcarbonylamino, (1-ethylpropyl) carbonylamino) optionally having one substituent selected from (s) amino, (t) C 6-10 aryl-carbonylamino (eg, benzoylamino) optionally having one halogen atom (eg, fluorine atom), (u) N—C 1-6 alkyl-N— (C 1-6 alkyl-carbonyl) amino (e
  • R 1 is (1) hydrogen atom, (2) an optionally substituted C 1-6 alkyl, (3) C 1-6 alkoxy which may have a substituent, or (4) is an optionally substituted C 1-6 alkylthio
  • R 2 is (1) an optionally substituted C 3-6 cycloalkyl, (2) C 6-10 aryl which may have a substituent, or (3) a 3- to 6-membered non-aromatic (preferably saturated) heterocyclic group which may have a substituent
  • R 3 is a hydrogen atom
  • R 4 is (1) C 6-10 aryl optionally having substituent (s), (2) a monocyclic aromatic heterocyclic group which may have a substituent, or (3) a monocyclic non-aromatic heterocyclic group which may have a substituent
  • R 5 is (1) hydrogen atom, or (2) C 1-6 alkyl which may have a substituent;
  • R 4 and R 5 form a 5- or 6-membered non-aromatic (preferably
  • R 1 is (1) hydrogen atom, (2) (a) a halogen atom (eg, fluorine atom), (b) hydroxy, and (c) C 1-6 alkyl-carbonyloxy (eg, acetyloxy) C 1-6 alkyl (eg, methyl, ethyl, tert-butyl, isobutyl) optionally having 1 to 3 substituents selected from (3) C 1-6 alkoxy (eg, methoxy, ethoxy) or (4) C 1-6 alkylthio (eg, methylthio) optionally having one C 6-10 aryl (eg, phenyl);
  • R 2 is (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) C 1-6 alkoxy (eg, methoxy), (c) C 1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), (d) C 1-6 alkyl-carbamo
  • R 5 is a hydrogen atom or C 1-6 alkyl (eg, methyl); Alternatively, R 4 and R 5 together with the adjacent nitrogen atom form 1-piperazinyl which may have one C 1-6 alkoxy-carbonyl which may have one C 6-10 aryl. ; R 6 is a hydrogen atom; A compound in which R 7 is a hydrogen atom is more preferable.
  • the compound described in Example 84 described later is preferable.
  • Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the production method of the compound of the present invention is described below.
  • alkylation reaction amidation reaction (condensation reaction), esterification reaction, reduction reaction, reductive amination reaction, amination reaction, halogenation reaction, oxidation reaction, etc.
  • these reactions are performed according to a known method. Examples of such methods include the methods described in Organic Functional Group Preparations 2nd edition, Academic Press, Inc. 1989, Comprehensive Organic Transformations, VCH Publishers Inc., 1989, and the like.
  • the protection reaction and the deprotection reaction are performed by a known method, for example, a method described in Protective Groups in Organic Synthesis 3rd edition, John Wiley and Sons, Inc. 1999, or a method analogous thereto.
  • alcohols include methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, and the like.
  • ethers include diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like.
  • esters include ethyl acetate, methyl acetate, tert-butyl acetate and the like.
  • hydrocarbons examples include benzene, toluene, xylene, cyclohexane, hexane, pentane, and the like.
  • amides for example, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide and the like are used.
  • halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene, chlorobenzene and the like.
  • nitriles for example, acetonitrile, propionitrile and the like are used.
  • ketones for example, acetone, 2-butanone and the like are used.
  • organic acids include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and the like.
  • aromatic amines include pyridine, 2,6-lutidine, quinoline and the like.
  • sulfoxides include dimethyl sulfoxide.
  • Compound (I) can be produced, for example, by the production method shown below or a method analogous thereto.
  • the raw material compound or production intermediate may be used as a salt, and examples of such a salt include the same salts as the salt of compound (I).
  • the raw material compound or production intermediate when the raw material compound or production intermediate has an amino group, carboxy group or hydroxy group as a substituent, these groups are protected with a protecting group generally used in peptide chemistry and the like. May be.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • examples of the protecting group for the amino group include a formyl group, a C 1-6 alkyl-carbonyl group, a C 1-6 alkoxy-carbonyl group, a benzoyl group, a C 7-10 aralkyl-carbonyl group (eg, Benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, Trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • a formyl group eg, a C 1-6 alkyl-carbonyl
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • the protecting group for the carboxy group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like.
  • a C 1-6 alkyl group eg, phenyl group, a trityl group, a C 7-10
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group and a nitro group.
  • substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group and a nitro group.
  • Examples of the method for removing the protecting group include methods known per se, such as the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980).
  • R 8 represents C 1-6 alkyl or benzyl, and other symbols are as defined above.
  • Examples of the C 1-6 alkyl represented by R 8 include methyl, ethyl, tert-butyl, and the like, preferably methyl and ethyl.
  • the conversion from compound (III) to compound (II) can be performed by a hydrolysis reaction in a solvent that does not adversely influence the reaction under acidic or basic conditions.
  • R 8 is benzyl
  • a catalytic hydrogenation reaction can be used in a solvent that does not adversely influence the reaction.
  • Examples of the acid used for the hydrolysis reaction include hydrochloric acid and sulfuric acid, and examples of the base include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • the amount to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (III).
  • As the catalyst for the catalytic hydrogenation reaction for example, Raney nickel, platinum oxide, or palladium, ruthenium, rhodium, iridium supported on activated carbon, barium sulfate, calcium carbonate, or the like is used.
  • the amount thereof to be used is generally 0.01-1 molar equivalent, preferably 0.05-0.5 molar equivalent, relative to compound (III).
  • the hydrogen source for the catalytic hydrogenation reaction hydrogen, cyclohexene, hydrazine, ammonium formate, or the like is used.
  • the solvent that does not adversely influence the reaction include ethers, alcohols, hydrocarbons, ketones, nitriles, amides, esters, water, etc., preferably alcohols, ethers, and water. . Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.
  • the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
  • the condensation reaction of compound (II) and amine (1) can be performed in a solvent that does not adversely influence the reaction, for example, using a condensing agent.
  • the condensing agent include carbodiimide (eg, dicyclohexylcarbodiimide (DCCD), water-soluble carbodiimide (WSCD), etc.), phosphate ester (eg, diethyl cyanophosphonate, diethyl chlorophosphonate, diphenylphosphoroazide, etc.), BOP reagent (1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), carbonyl
  • Amine (1) is commercially available, or can be produced from the corresponding raw material by applying a known method.
  • the amount of amine (1) and condensing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (II).
  • the solvent that does not adversely influence the reaction include ethers, hydrocarbons, ketones, nitriles, amides, esters, and the like, preferably ethers and amides. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.
  • the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
  • compound (I) in which X is a carbon atom and Y is a nitrogen atom can be produced, for example, by the following [Method B] or a method analogous thereto.
  • [Method B] The compound (4) is obtained by hydrolysis or catalytic hydrogenation of the compound (2), followed by reaction with the compound (1), and the compound (Ia) can be produced from the obtained compound (4).
  • Q is a leaving group, and other symbols are as defined above.
  • Examples of the leaving group represented by Q include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methyl atom) optionally having a halogen atom.
  • Hydrolysis or catalytic hydrogenation of compound (2) can be carried out according to the hydrolysis or catalytic hydrogenation method of compound (III) to compound (II) in [Method A], followed by amine (1) Can be carried out according to the conversion method of compound (II) to compound (I) in [Method A].
  • the reaction from the compound (3) to the compound (4) can also be carried out by reacting the compound (3) with an amine (1) after making the compound (3) an acid halide.
  • the reaction using the compound (3) as an acid halide can be carried out using thionyl chloride, phosphorus oxychloride, oxalyl chloride or the like in a solvent that does not affect the reaction or without solvent.
  • the amount of thionyl chloride, phosphorus oxychloride, oxalyl chloride and the like to be used is generally 1 to 10 molar equivalents, preferably 1 to 4 molar equivalents, relative to compound (3).
  • Examples of the solvent that does not adversely influence the reaction include ethers, hydrocarbons, ketones, nitriles, amides, esters and the like, preferably ethers and amides. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 60 ° C.
  • the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
  • the reaction between the acid halide and amine (1) can be carried out in a solvent that does not affect the reaction, if necessary, in the presence of a base.
  • the amount of amine (1) to be used is generally 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to the acid halide.
  • Examples of the base used if necessary include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the amount used is usually 1 to 3 mole equivalents, preferably 1 to 2 moles, based on the acid halide. Is equivalent.
  • Examples of the solvent that does not adversely influence the reaction include ethers, hydrocarbons, ketones, nitriles, amides, esters, and the like, preferably ethers and amides. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 60 ° C.
  • the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
  • reaction from compound (4) to compound (Ia) can be carried out using a method according to the method described in International Publication WO2006 / 038738.
  • Compound (2) may be commercially available, or can be produced from the corresponding raw material by applying a known method.
  • compound (III) in which X is a carbon atom and Y is a nitrogen atom is produced from compound (2) according to the method described in International Publication WO2006 / 038738, for example. be able to.
  • Compound (IIIb) in which X is a nitrogen atom and Y is a carbon atom in compound (III) can be produced, for example, by [Method C] or a method analogous thereto.
  • [Method C] Compound (IIIb-2) is obtained by the reaction of Compound (5) and Compound (6), and then Compound (IIIb-1) into which leaving group Q ′′ has been introduced is further produced as Compound (IIIb)) Can do.
  • the leaving group Q ′ or Q ′′ is the same as the above Q, and is preferably a halogen atom (eg, chlorine atom, bromine atom, iodine atom).
  • the conversion from compound (5) to compound (IIIb-2) can be carried out in a solvent that does not adversely influence the reaction, if necessary, in the presence of a base.
  • the amount of compound (6) to be used is generally 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (5).
  • Examples of the base used if necessary include sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like.
  • the amount to be used is generally 2 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (5).
  • the solvent that does not adversely influence the reaction include ethers, alcohols, hydrocarbons, ketones, nitriles, amides, esters, water, and the like, preferably alcohols, ethers, and water. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually 0 to 150 ° C., preferably 20 to 120 ° C.
  • the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
  • Compound (5) may be commercially available, or can be produced from the corresponding starting material by applying a known method.
  • Conversion of compound (IIIb-2) to compound (IIIb-1) can be carried out using a halogenating reagent or the like in a solvent that does not adversely influence the reaction.
  • a halogenating reagent N-chlorosuccinimide, N-bromosuccinimide, bromine and the like are used, and the amount used is usually 1 to 2 molar equivalents, preferably 1 to 2 moles relative to compound (IIIb-2). 1.5 molar equivalents.
  • the solvent that does not adversely influence the reaction include ethers, hydrocarbons, carbon halides, nitriles, amides, esters, etc., preferably ethers, hydrocarbons, halogenated carbons. is there. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 10 to 50 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • Conversion of compound (IIIb-1) to compound (IIIb) can be carried out in a solvent that does not adversely influence the reaction using a coupling reaction with a boric acid derivative or the like in the presence of a base.
  • a boric acid derivative a commercially available one can be used, or it can be produced from the corresponding raw material by applying a known method, and the amount used is usually 1 to 2 molar equivalents relative to compound (IIIb-1), preferably Is 1 to 1.5 molar equivalents.
  • the catalyst used in the coupling reaction for example, tetrakis (triphenylphosphine) palladium, palladium acetate and the like are used, and the amount used is usually 0.01 to 1 molar equivalent, preferably about compound (IIIb-1). 0.05 to 0.5 molar equivalent.
  • the base for example, sodium carbonate, potassium carbonate, sodium phosphate, triethylamine and the like are used.
  • the amount thereof to be used is generally 2 to 10 molar equivalents, preferably 2 to 3 molar equivalents, relative to compound (IIIb-1).
  • the solvent that does not adversely influence the reaction include water, alcohols, ethers, hydrocarbons, amides and the like.
  • the reaction temperature is usually 20 to 150 ° C., preferably 40 to 120 ° C.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • a compound within the scope of the present invention can also be produced by applying means known per se to compound (I) to further introduce substituents or convert functional groups.
  • substituent conversion known general methods are used. For example, conversion to carboxy by hydrolysis of ester, conversion to carbamoyl by amidation of carboxy, conversion to hydroxymethyl by reduction of carboxy, reduction of carbonyl or alkyl To alcohol by rehydration, reductive amination of carbonyl, oximation of carbonyl, acylation / urealation / sulfonylation / alkylation of amino, substitution / amination of active halogen with amine, amination by reduction of nitro , Hydroxy alkylation, hydroxy substitution / amination.
  • a protective group is introduced into the reactive substituent in advance by a publicly known means as necessary.
  • the protecting group can be removed by means known per se to produce compounds within the scope of the present invention.
  • Compound (I) can be isolated and purified by known means such as phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
  • Compound (I) may be used as a prodrug.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated for example, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • compounds ( I) hydroxy-acylated, alkylated, phosphorylated, borated compounds for example, compound (I) hydroxy-acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, Dimethylaminomethylcarbonylated compounds, etc.); carboxy of compound (I) is an este
  • prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
  • any one of the isomers and a mixture are included in the compound (I).
  • the optical isomer resolved from the racemate is also encompassed in compound (I).
  • Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a co-crystal.
  • Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
  • Compounds labeled with isotopes eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.
  • the compound (I) may be a deuterium converter obtained by converting 1 H into 2 H (D).
  • the compound (I) of the present invention, a salt thereof, and a prodrug thereof (hereinafter sometimes abbreviated as a compound of the present invention) interact with, for example, a human Smo protein and change its three-dimensional structure, thereby changing its cytoplasm. Inhibits Hedgehog signal transduction system by inhibiting complex formation with proteins involved in signal transduction. Alternatively, the compound of the present invention interacts with the human Smo protein and inhibits the Hedgehog signaling system by directly inhibiting the complex formation of the human Smo protein and the protein involved in the Hedgehog signaling system in the cytoplasm.
  • the compound of the present invention inhibits modifications such as phosphorylation of Smo by interacting with a modification site received from a protein involved in the Hedgehog signaling system of the Smo protein, such as a phosphorylation site, thereby inhibiting the Hedgehog signaling system.
  • Inhibit Inhibition of the Hedgehog signal transduction system can be measured, for example, by quantifying the decrease in the expression level of a reporter gene linked downstream of the Gli binding site according to the test example described below, using fluorescence intensity. Alternatively, it can be measured by quantifying the expression of Gli-1 mRNA in the cell extract by quantitative PCR or the like.
  • a compound that inhibits the Hedgehog signal targets Smo.
  • the amount of fluorescence of the cell is measured, and the value is determined based on the test compound. This can be confirmed by a decrease compared to the case of no addition.
  • the compound of the present invention is useful as a Smo inhibitor for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.).
  • the compounds of the present invention can be affected by diseases that may be affected by Smo, such as cancer (eg, colon cancer (eg, familial colon cancer, hereditary nonpolyposis colon cancer, gastrointestinal stromal tumor, etc.), lung cancer ( For example, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, pancreatic endocrine tumor, etc.), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous epithelium) Cancer), breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer, etc.), ovarian
  • the compound of the present invention is effective for glioma, medulloblastoma, basal cell cancer, small cell lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, stomach cancer, colon cancer and breast cancer.
  • the compound of the present invention can be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier.
  • dosage forms for oral administration of the compound of the present invention include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), and syrups.
  • dosage forms for parenteral administration include injections, infusions, drops, suppositories, and the like.
  • an appropriate base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid ester, etc. It is also effective to make a combined sustained release preparation.
  • the compound of the present invention when the compound of the present invention is produced into tablets, it can be produced by containing excipients, binders, disintegrants, lubricants, etc., and when produced into pills and granules, It can be produced by containing an excipient, a binder, a disintegrant and the like.
  • excipients when producing powders and capsules, excipients, etc., when producing syrups, sweeteners, etc., when producing emulsions or suspensions, suspending agents, surfactants It can be produced by containing an emulsifier and the like.
  • excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
  • binder examples include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
  • disintegrant include starch and calcium carbonate.
  • lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
  • sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
  • surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
  • suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
  • emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
  • intravenous injections In addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous infusions and the like are included as injections, and iontophoretic transdermal agents and the like are included as sustained-release preparations.
  • Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid.
  • Aqueous solutions for injection include isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) containing physiological saline, glucose and other adjuvants, and suitable solubilizing agents such as You may use together with alcohol (for example, ethanol), polyalcohol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50), etc.
  • the oily liquid include sesame oil and soybean oil.
  • benzyl benzoate As a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.) may be blended.
  • the prepared injection solution is usually filled in an ampoule.
  • the content of the compound of the present invention in the preparation of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 2 to 85% by weight, more preferably based on the whole preparation. Is about 5 to 70% by weight.
  • the content of the additive in the preparation of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.9% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
  • the compound of the present invention can be used safely with stable, low toxicity.
  • the daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc.
  • the daily dose for an adult (body weight of about 60 kg) Is about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg as the active ingredient (the compound of the present invention), and these can be administered once or divided into 2 to 3 times.
  • the compound of the present invention When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, an injection).
  • a liquid for example, an injection.
  • the single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but is usually about 0.01 to about 100 mg per kg body weight, preferably about 0.01 in the form of injection. It is convenient to administer from about 50 mg, more preferably from about 0.01 to about 20 mg by intravenous injection.
  • the compound of the present invention can be used in combination with other drugs.
  • the compound of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and drugs that inhibit the action of the receptors.
  • drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and drugs that inhibit the action of the receptors.
  • a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.
  • ⁇ hormone therapeutic agent '' examples include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, Raloxifene, olmeroxifene, levormeroxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, Buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozo
  • chemotherapeutic agent for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like are used.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide Zinostatin Lamar, ado
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emiteful, capecitabine, etc.), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine pendant, hydroxycarbamide pendant , Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and those DDS formulation or the like is used.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT,
  • anticancer antibiotic examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations.
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and their DDS preparations are used.
  • Examples of the “immunotherapy agent (BRM)” include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacteria Umparbum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody and the like are used.
  • the “cell growth factor” in the “drug that inhibits the action of the cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less.
  • Examples of peptides include factors that exert an action at a low concentration by binding to a receptor.
  • EGF epidermal growth factor
  • IGF insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.
  • FGF fibroblast growth factor
  • Other cell growth factors eg, CSF (erythropoietin), EPO (erythropoietin), IL-2 (interleukin-2) , NGF (near growth factor), PDGF (platelet-derived growth factor), TGF ⁇ (transforming growth factor ⁇ ), HGF (hepatocyte growth factor, thor factor).
  • the “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor. Specifically, EGF receptor, heregulin receptor (HER3, etc.) Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (Tie2, etc.), PDGF receptor and the like are used.
  • “Agents that inhibit the action of cell growth factors and their receptors” include EGF inhibitors, TGF ⁇ inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGF ⁇ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor Agent, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, S rc inhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERK In
  • anti-VEGF antibodies Bevacizumab, etc.
  • anti-HER2 antibodies Trastuzumab, Pertuzumab, etc.
  • anti-EGFR antibodies Cetuximab, Panitumumab, Matsuzumab, Matsuzu) Matuzumab), Nimotuzumab etc.
  • anti-VEGFR antibody anti-HGF antibody, imatinib mesylate, erlotinib, gefitinib, sorafenib, sinib, unitiib , Lapatinib, Vatalanib, 4- (4-Fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (1-pyrrolidinyl) propoxy] quinazoline (AZD) -2171), Restaurtinib (Lestaurtinib), Pazopanib, Canertinib Tandutinib, 3- (4-bromo-2
  • topoisomerase I inhibitor eg, iri
  • the compound of the present invention By combining the compound of the present invention and a concomitant drug, (1) The dose can be reduced compared to the case where the compound of the present invention or the concomitant drug is administered alone. (2) The drug used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.) (3) The treatment period can be set longer. (4) The therapeutic effect can be sustained. (5) By using the compound of the present invention and a concomitant drug in combination, excellent effects such as a synergistic effect can be obtained.
  • the combination agent of the present invention the case where the compound of the present invention is used in combination with the concomitant drug is referred to as “the combination agent of the present invention”.
  • the timing of administration of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject, with a time difference. It may be administered.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • Examples of administration forms when the compound of the present invention is used in combination with the concomitant drug include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) concomitant use with the compound of the present invention.
  • Simultaneous administration of two preparations obtained by separately formulating a drug by the same administration route (3) By the same administration route of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug (4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (5) Combining the compound of the present invention and the concomitant drug Administration of two types of preparations obtained by separate formulation at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention ⁇ concomitant drug, or administration in the reverse order), etc. .
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the administration subject is a human
  • 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, and a pharmaceutical composition such as a tablet ( (Including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, topical , Rectal, intravenous administration, etc.).
  • the injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.
  • the pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention
  • the pharmacologically acceptable carrier that may be used when the aforementioned compound of the present invention is produced into a dosage form.
  • carrier is mentioned.
  • additives such as colorants, preservatives, fragrances, flavoring agents, stabilizers, thickeners and the like that may be used in the production of the above-described compound of the present invention into a dosage form. An appropriate amount can be used as appropriate.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 90% by weight, preferably about 0.1 to 50% by weight, more preferably based on the whole preparation. About 0.5 to 20% by weight.
  • the content of the additive in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • the compound of the present invention or the concomitant drug includes a dispersing agent (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, Dextrin, etc.), stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.), buffers (eg, phosphorus) Acids and alkali metal salts thereof, citric acid and alkali metal salts thereof), isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydrochloric acid, sodium hydrochloric acid, sodium hydrochloric acid, sodium hydroch
  • the compound of the present invention or the concomitant drug is mixed with, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate etc.), a binder (eg, starch) , Gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) etc., and compression molded, and if necessary, taste masking,
  • an oral preparation can be obtained by coating by a method known per se.
  • Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, Germany, methacrylic acid / acrylic acid copolymer), pigments (eg, Bengala, titanium dioxide, etc.) are used.
  • the preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
  • the compound of the present invention or the concomitant drug is mixed with an oily base, an aqueous base or an aqueous gel base to thereby form an oily or aqueous solid, semi-solid or liquid suppository.
  • oily base include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), glycerides of medium chain fatty acids [eg, miglyols (manufactured by Dynamite Nobel, Germany)] Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.).
  • the aqueous base include polyethylene glycols and propylene glycol.
  • the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.
  • sustained-release preparation examples include sustained-release microcapsules.
  • the sustained-release microcapsule is produced according to a method known per se, for example, the method shown in the following [2].
  • the compound of the present invention is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.
  • a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository.
  • preparations for oral administration are particularly preferred.
  • the concomitant drug can be in the above-mentioned dosage form depending on the type of drug.
  • injection of compound of the present invention or concomitant drug and preparation thereof As an injection of the compound of the present invention or concomitant drug, an injection obtained by dissolving the compound of the present invention or concomitant drug in water is preferable.
  • the injection may contain benzoate and / or salicylate.
  • the injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, if desired, benzoate and / or salicylate in water.
  • benzoic acid and salicylic acid salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and salts with other organic bases such as trometamol. It is done.
  • the concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the concentration of benzoate or / and salicylate is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the present injection includes additives generally used in injections, such as stabilizers (eg, ascorbic acid, sodium pyrosulfite), surfactants (eg, polysorbate 80, macrogol, etc.), acceptable Solvent (eg, glycerin, ethanol, etc.), buffer (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, sodium chloride, potassium chloride, etc.), dispersing agents (Eg, hydroxypropylmethylcellulose, dextrin), pH adjuster (eg, hydrochloric acid, sodium hydroxide, etc.), preservative (eg, ethyl paraoxybenzoate, benzoic acid, etc.), solubilizer (eg, concentrated glycerin, meglumine, etc.) , Solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.),
  • the injection may be adjusted to pH 2 to 12, preferably pH 2.5 to 8.0 by adding a pH adjusting agent.
  • An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, optionally, benzoate and / or salicylate, and if necessary, the above-mentioned additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
  • the aqueous solution for injection is preferably heated, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, or the like, as in a normal injection.
  • the aqueous solution for injection is preferably sterilized by high-pressure heat at a temperature of 100 to 121 ° C. for 5 to 30 minutes. Furthermore, it is good also as a formulation which provided the antibacterial property of the solution so that it could be used as a multi-dose preparation.
  • Sustained-release preparation or immediate-release preparation of the compound of the present invention or a concomitant drug and preparation thereof As a sustained-release preparation of the compound of the present invention or a concomitant drug, a nucleus comprising the compound of the present invention or the concomitant drug is optionally provided. Sustained-release preparations coated with a coating agent such as a water-insoluble substance or a swellable polymer are preferred. For example, a once-daily administration type sustained-release preparation for oral administration is preferred.
  • water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, and acrylic acid.
  • cellulose ethers such as ethyl cellulose and butyl cellulose
  • cellulose esters such as cellulose acetate and cellulose propionate
  • polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate
  • acrylic acid acrylic acid
  • swellable polymer a polymer having an acidic dissociation group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as the small intestine and large intestine.
  • a polymer having an acidic dissociation group is preferred.
  • the polymer having an acidic dissociable group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, 1342, polycarbophil, calcium polycarbophil, and the like. (Calcium polycarbophil) (all of which are manufactured by BF Goodrich), Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.), etc.
  • the film agent used in the sustained release preparation may further contain a hydrophilic substance.
  • the hydrophilic substance include polysaccharides that may have a sulfate group such as pullulan, dextrin, and alkali metal alginate, hydroxyalkyl or carboxyalkyl such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose sodium.
  • examples thereof include polysaccharides, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol.
  • the content of the water-insoluble substance in the coating agent of the sustained release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to 75%.
  • the swellable polymer content is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w).
  • the coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w). More preferably, it is about 5 to about 35% (w / w).
  • the above% (w / w) represents the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent solution.
  • the sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then the obtained core is a film agent solution in which a water-insoluble substance, a swellable polymer or the like is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
  • nucleus containing a drug coated with a coating agent is not particularly limited, but is preferably formed into a granular shape such as a granule or a fine granule.
  • the average particle size is preferably about 150 to about 2,000 ⁇ m, more preferably about 500 to about 1,400 ⁇ m.
  • the preparation of the nucleus can be carried out by a usual production method. For example, suitable excipients, binders, disintegrants, lubricants, anti-aggregation agents, lubricants, stabilizers, etc.
  • the drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.
  • excipients contained in the core include saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Of these, crystalline cellulose and corn starch are preferable.
  • binder for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used.
  • disintegrant for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low substituted hydroxypropylcellulose (L-HPC) and the like are used. . Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable.
  • talc magnesium stearate and inorganic salts thereof, and as the lubricant, polyethylene glycol or the like is used.
  • the stabilizer acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
  • the core is a drug while spraying a binder dissolved in an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) on an inert carrier particle that becomes the center of the core.
  • an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.)
  • it can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little.
  • the inert carrier particles for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size of about 100 ⁇ m to about 1,500 ⁇ m are preferable.
  • the surface of the nucleus may be coated with a protective agent.
  • a protective agent for example, the hydrophilic substance, the water-insoluble substance and the like are used.
  • a polysaccharide having polyethylene glycol, hydroxyalkyl or carboxyalkyl, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose is used.
  • the protective agent may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid or a lubricant such as talc as a stabilizer.
  • the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% of the core ( w / w).
  • the protective agent can be coated by a normal coating method, and specifically, the protective agent can be coated by spraying the nucleus by, for example, a fluidized bed coating method or a pan coating method.
  • the core obtained in I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent.
  • a sustained-release preparation is produced.
  • the coating method using the core coating solution include a spray coating method.
  • the composition ratio of the water-insoluble substance, the swellable polymer, or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the film is the above content.
  • the coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w) with respect to the core (excluding the coating amount of the protective agent), more preferably About 5 to about 35% (w / w).
  • water or an organic solvent can be used alone or a mixture of the two can be used.
  • the mixing ratio of water and organic solvent (water / organic solvent: weight ratio) in the case of using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%.
  • the organic solvent is not particularly limited as long as it dissolves water-insoluble substances.
  • lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform , Methylene chloride and the like are used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred.
  • Water and a mixed solution of water and an organic solvent are preferably used as a solvent for the film agent.
  • an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, etc. may be added to the coating agent solution to stabilize the coating agent solution.
  • the operation in the case of coating by spray coating can be carried out by a normal coating method, specifically, for example, by coating the core with a coating solution by a fluidized bed coating method, pan coating method or the like can do. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as a lubricant. You may add as an agent.
  • an antistatic agent such as talc may be mixed.
  • the immediate-release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particles, pills, tablets, etc.).
  • a parenterally administered agent such as an orally administered agent and an injectable agent is used, and an orally administered agent is preferable.
  • the immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient.
  • the excipient used is not particularly limited as long as it is an excipient commonly used as a pharmaceutical excipient.
  • excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, carbonate Calcium, L-cysteine and the like can be mentioned, preferably corn starch and mannitol.
  • excipients can be used alone or in combination of two or more.
  • the content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30, relative to the total amount of the immediate-release preparation. Or about 97 w / w%.
  • the content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95 w / w%, preferably about 1 to about 60 w / w%, based on the total amount of the immediate release preparation.
  • the immediate-release preparation When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components.
  • disintegrants include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (for example, Asahi Kasei Co., Ltd., Akizol), crospovidone (for example, BASF Corp., Kollidon CL ), Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (manufactured by Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Protab), partially pregelatinized starch (Asahi Kasei ( Co., Ltd., PCS), etc.
  • disintegrants are used, for example, those that disintegrate granules by contacting with water, absorbing water, swelling, or creating channels between the active ingredient constituting the core and excipients. Can be used. These disintegrants can be used alone or in combination of two or more. The amount of the disintegrant is appropriately selected depending on the type and amount of the drug to be used, the design of the releasable preparation, and the like. For example, about 0.05 to about 30 w / w%, Preferably, it is about 0.5 to about 15 w / w%.
  • an additive commonly used in the solid preparation may be further included as desired.
  • additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, pullulan, dextrin, etc.)
  • Reagents for example, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (for example, Aerosil (manufactured by Nippon Aerosil)
  • surfactants for example, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid) Esters, polyoxyethylene sorbitan fatty acid esters, nonionic surfactants such as polyoxyethylene castor oil derivatives, etc.
  • colorants eg tar dyes, caramels, bengaras, oxides
  • binder hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.
  • the immediate-release preparation can be prepared by mixing the above-mentioned components, further kneading and molding if necessary, based on a normal preparation manufacturing technique.
  • the above mixing is performed by a generally used method, for example, mixing, kneading and the like.
  • a vertical granulator when the immediate-release preparation is formed into particles, a vertical granulator, a universal kneader (manufactured by Hata Iron Works), by a method similar to the preparation method of the core of the sustained-release preparation, It can be prepared by mixing using a fluidized bed granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.
  • FD-5S manufactured by POWREC
  • the immediate-release preparation and the sustained-release preparation thus obtained are administered as they are or as appropriate, together with preparation excipients, etc., separately according to a conventional method, and then simultaneously or in combination with an arbitrary administration interval.
  • both of them may be formulated into a single oral preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate together with formulation excipients.
  • Both preparations may be produced into granules or fine granules and filled in the same capsule or the like to prepare a preparation for oral administration.
  • Sublingual tablet, buccal or buccal fast disintegrating agent of the compound of the present invention or concomitant drug and preparation thereof may be a solid preparation such as a tablet, Oral mucosa patch (film) may be used.
  • a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer.
  • ⁇ -cyclodextrin or ⁇ -cyclodextrin derivatives may be contained in order to facilitate absorption and increase bioavailability.
  • Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable.
  • Examples of the isotonic agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, and mannitol is particularly preferable.
  • hydrophilic carrier examples include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose, etc. ) Is preferred.
  • swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose, etc. ) Is preferred.
  • water-dispersible polymers examples include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), Gelatin, water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, polycarbophil, ascorbic acid, palmitate, etc., hydroxypropyl methylcellulose, polyacrylic acid, Alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable.
  • gums eg, tragacanth gum, acacia gum, guar gum
  • alginates eg, sodium alginate
  • cellulose derivatives eg, methylcellulose, carboxymethylcellulose, hydroxy
  • Hydroxypropyl methylcellulose is particularly preferable.
  • the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, and citric acid and ascorbic acid are particularly preferable.
  • a sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se.
  • auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed as desired.
  • a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting.
  • it may be produced by humidifying and wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.
  • the compound of the present invention or the concomitant drug and the above-mentioned water-dispersible polymer preferably hydroxypropylcellulose, hydroxypropylmethylcellulose
  • excipients etc.
  • a solvent such as water
  • the resulting solution is cast into a film.
  • additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a colorant, a buffering agent, and a sweetener may be added.
  • Bioadhesive polymers eg, polycarbophil, carbopol, etc. to contain glycols such as polyethylene glycol and propylene glycol in order to give the film moderate elasticity and to enhance the adhesion of the film to the mucosal lining of the oral cavity ) May be included.
  • Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved.
  • the film thus formed may be dried at room temperature or under heating and cut to a desired surface area.
  • a solid rapid diffusion agent comprising a network of a compound of the present invention or a concomitant drug and a water-soluble or water-diffusible carrier that is inactive with the compound of the present invention or the concomitant drug.
  • the network is obtained by sublimating a solvent from the solid composition composed of the compound of the present invention or a concomitant drug dissolved in an appropriate solvent.
  • composition of the intraoral quick disintegrating agent preferably contains a matrix-forming agent and a secondary component in addition to the compound of the present invention or the concomitant drug.
  • Examples of the matrix forming agent include gelatins, dextrins, soy, wheat, psyllium seed protein and other animal proteins or vegetable proteins; gum arabic, guar gum, agar, xanthan and other rubbery substances; Examples include sugars, alginic acids, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such as polyvinylpyrrolidone, gelatin-gum arabic complex, and the like.
  • saccharides such as mannitol, dextrose, lactose, galactose, trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride, aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, and L-phenylalanine.
  • One or more of the matrix forming agents can be introduced into a solution or suspension before solidification.
  • a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded.
  • the matrix-forming agent can help maintain the diffusion state of the compound of the present invention or the concomitant drug in the solution or suspension.
  • Secondary components include preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavoring agents, sweeteners, taste masking agents, and the like.
  • Suitable colorants include red, black or yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis & Everard.
  • Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavor, and combinations thereof.
  • Suitable pH adjusters include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K, thaumatin and the like.
  • Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials and microencapsulated apomorphine.
  • the preparation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of the compound of the present invention or a concomitant drug, and is about 1 to about 60 minutes, preferably about 1 minute.
  • the content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight.
  • the content of ⁇ -cyclodextrin or ⁇ -cyclodextrin derivative in the whole preparation is 0 to about 30% by weight.
  • the content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight.
  • the content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight.
  • the content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight.
  • the content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent, and a preservative as necessary.
  • the dose of the concomitant drug of the present invention varies depending on the kind of the compound of the present invention, the age, weight, symptom, dosage form, administration method, administration period, etc. of the subject of administration, but for example, cancer patient (adult, body weight about 60 kg) per person
  • the compound of the present invention and the concomitant drug are each about 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg per day, In particular, about 0.1 to about 50 mg / kg, particularly about 1.5 to about 30 mg / kg is intravenously administered once to several times a day.
  • the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of a mammal, for example, by oral administration. Is usually administered in 1 to 4 divided doses per day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, but after administering the concomitant drug first, the compound of the present invention may be administered.
  • the inventive compound may be administered first, followed by the concomitant drug.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method.
  • administering the concomitant drug first within 1 minute to 3 days after administering the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • a method of administering the concomitant drug within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention Is mentioned.
  • a concomitant drug molded into an orally administered preparation is orally administered, and about 0.005 to 100 mg of the compound of the present invention formed into an orally administered preparation after about 15 minutes. / Kg is orally administered as a daily dose.
  • the compound of the present invention or the concomitant drug of the present invention can be used in combination with non-drug therapy.
  • the compound of the present invention or the concomitant agent of the present invention includes, for example, (1) surgery, (2) pressor chemotherapy using angiotensin II, (3) gene therapy, (4) hyperthermia, (5) It can also be combined with non-drug therapies such as cryotherapy, (6) laser ablation, and (7) radiation therapy.
  • the use of the compound of the present invention or the concomitant agent of the present invention before or after surgery, etc., or before or after treatment combining these two or three kinds prevents the development of resistance, disease-free (Disease-Free Survival) Effects such as prolongation of cancer, suppression of cancer metastasis or recurrence, and life extension.
  • treatment with the compound of the present invention or the concomitant drug of the present invention and supportive therapy [(i) antibiotics for concurrent occurrence of various infectious diseases (for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin, etc.) (Ii) administration of high calorie infusions for improving nutritional disorders, amino acid preparations, administration of multivitamins, (iii) administration of morphine for pain relief, (iv) nausea, vomiting, loss of appetite, diarrhea, leukopenia , Thrombocytopenia, decreased hemoglobin concentration, hair loss, liver damage, kidney damage, DIC, administration of drugs to improve side effects such as fever, (v) administration of drugs to suppress multidrug resistance of cancer, etc.] It can also be combined.
  • antibiotics for concurrent occurrence of various infectious diseases for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin, etc.
  • the compound of the present invention or the concomitant drug of the present invention is orally administered (including sustained release), intravenously administered (including bolus, infusion, clathrate), subcutaneously administered and muscle It is preferable to administer by injection (including bolus, infusion, sustained release), transdermal administration, intratumoral administration, proximal administration and the like.
  • the time when the compound of the present invention or the concomitant drug of the present invention is administered before surgery or the like can be administered once, for example, about 30 minutes to 24 hours before surgery or the like.
  • the administration can be divided into 1 to 3 cycles 3 to 6 months before.
  • the compound of the present invention or the concomitant drug of the present invention when administered after surgery or the like, it can be repeatedly administered, for example, in units of several weeks to 3 months, about 30 minutes to 24 hours after surgery.
  • the effect of surgery or the like can be enhanced by administering the compound of the present invention or the combination agent of the present invention after surgery or the like.
  • Measuring equipment Micromass Platform II or Waters ZMD Ionization method: Atmospheric Pressure Chemical Ionization (APCI) or Electron Spray Ionization (ESI)
  • APCI Atmospheric Pressure Chemical Ionization
  • ESI Electron Spray Ionization
  • HPLC-mass spectrum LC-MS was measured under the following conditions.
  • Measuring instruments Micromass ZMD, Agilent Technologies HP1100 and 1200 LC / MSD Column: CAPCELL PAK C18UG120, S-3 ⁇ m, 1.5 X 35 mm
  • Injection volume 2 ⁇ l, flow rate: 0.5 ml / min
  • detection method UV 220 nm
  • Ionization method Electron Spray Ionization (ESI) 1 H-NMR spectra were measured with Bruker AVANCE DPX-300 (300 MHz) and VARIAN Mercury-
  • Emrys Optimizer manufactured by Biotage was used as the microwave reaction apparatus.
  • the numerical value shown in the mixed solvent is a volume mixing ratio of each solvent unless otherwise specified.
  • % Means weight percent unless otherwise specified.
  • the room temperature (normal temperature) in this specification represents a temperature of about 10 ° C. to about 35 ° C., but is not particularly limited. Other abbreviations used in the text have the following meanings.
  • Diisopropylethylamine (0.310 mL, 3.4 mmol) and 4-aminopiperidine-1-carboxylic acid benzyl hydrochloride (690 mg, 2.6 mmol) were added to a solution of the compound of Reference Example 6 (600 mg, 1.7 mmol) in DMSO (5.0 mL). In addition, the mixture was stirred at 60 ° C. for 18 hours. Diisopropylethylamine (0.310 mL, 3.4 mmol) and benzyl 4-aminopiperidine-1-carboxylate hydrochloride (230 mg, 0.85 mmol) were further added, and the mixture was stirred at 70 ° C. for 3 hours.
  • O-Chloroaniline (2.0 mL, 19 mmol) was added to the compound of Reference Example 6 (500 mg, 1.4 mmol), and the mixture was stirred at 150 ° C. for 2 days.
  • the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (7.5 mL) -water (7.5 mL), iron powder (369 mg, 6.6 mmol) and ammonium chloride (382 mg, 7.2 mmol) were added, and the mixture was heated to reflux for 21 hours.
  • the reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure.
  • the reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure.
  • 1,1′-thiocarbonyldiimidazole 250 mg, 1.4 mmol was added to a solution of the compound of Reference Example 47 (600 mg, 1.4 mmol) in THF (10 mL) and heated at 70 ° C. for 16 hours in a nitrogen atmosphere. .
  • the reaction mixture was diluted with water and extracted twice with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • N-bromosuccinimide (793 mg, 4.45 mmol) was added to a chloroform (15 mL) solution of the compound of Reference Example 49 (770 mg, 4.05 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours.
  • the reaction mixture was diluted with ethyl acetate and washed 3 times with saturated aqueous sodium hydrogen carbonate.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.04 g, 95%) as a beige solid.
  • 1,1-carbonyldiimidazole (482 mg, 2.98 mmol) was added to a THF (30 mL) solution of the compound of Reference Example 47 (500 mg, 1.19 mmol), and the mixture was stirred at 50 ° C. for 16 hours.
  • the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (490 mg, 92%) as colorless crystals.
  • a mixture of the obtained solid, 10% palladium / carbon (0.86 g), ethanol (100 mL), THF (100 mL) and acetic acid (50 mL) was stirred at room temperature for 18 hours under a hydrogen atmosphere (0.4 MPa). .
  • the filtrate was concentrated under reduced pressure, and the residue was diluted with water and extracted twice with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Acetic anhydride (0.20 mL) was added to a solution of the compound of Reference Example 36 (120 mg, 0.28 mmol) in acetic acid (1.0 mL), and the mixture was stirred at 120 ° C. for 1.5 hours.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Example 2 In the same manner as in Example 1, the title compound (125 mg, 38%) was obtained from the compound of Reference Example 29 (200 mg, 0.740 mmol) and 4- (1H-pyrazol-1-yl) aniline (153 mg, 0.962 mmol). ) was obtained as a white powder.
  • Example 86 A solution of Example 86 described later (250 mg, 0.589 mmol) and an 8N aqueous sodium hydroxide solution (1 mL) in ethanol (7 mL) were stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with water, and extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2-( ⁇ [1- (4-fluorophenyl) -2-methyl-1H-benzimidazol-6-yl. ] Carbonyl ⁇ amino) -1,3-thiazole-4-carboxylic acid was obtained.
  • Example 2 In the same manner as in Example 1, the title compound (445 mg, 89%) was obtained from the compound of Reference Example 29 (300 mg, 1.11 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (289 mg, 1.44 mmol). ) was obtained as a white powder.
  • Example 2 In the same manner as in Example 1, the title compound (172 mg, 80%) was obtained from the compound of Example 24 (202 mg, 0.5 mmol), diethylamine hydrochloride (82 mg, 1.0 mmol) and triethylamine (0.277 mL, 2.0 mmol). ) was obtained as colorless crystals.
  • Example 2 In the same manner as in Example 1, the title compound (159 mg, 70 mmol) was obtained from the compound of Reference Example 29 (135 mg, 0.5 mmol), the compound of Reference Example 21 (177 mg, 0.75 mmol) and triethylamine (0.416 mL, 3.0 mmol). %) As colorless crystals.
  • Propionyl chloride (68 ⁇ L, 0.78 mmol) and triethylamine (198 ⁇ L, 1.42 mmol) were added to a mixed solution of the compound of Reference Example 47 (300 mg, 0.71 mmol) in acetonitrile (20 mL) -THF (5 mL) at room temperature. Stir for 2 days. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Concentrated hydrochloric acid (2 mL) was added to a solution of the residue in ethanol (20 mL), and the mixture was stirred at 90 ° C. for 3 hours.
  • Acetoxyacetyl chloride 100 ⁇ L, 0.85 mmol
  • triethylamine 198 ⁇ L, 1.42 mmol
  • acetonitrile 20 mL
  • room temperature room temperature was added.
  • the reaction mixture was diluted with water and extracted twice with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Example 42 By a method similar to that in Example 42, the title compound was obtained from the compound of Reference Example 29 (110 mg, 0.406 mmol) and 1- (4-aminophenyl) tetrahydropyrimidin-2 (1H) -one (74 mg, 0.387 mmol). (77 mg, 45%) was obtained as light brown crystals.
  • Tetramethoxymethane (3 mL) and acetic acid (47 ⁇ L, 0.82 mmol) were added to the compound of Reference Example 47 (300 mg, 0.71 mmol), and the mixture was stirred at 90 ° C. for 4 hours.
  • the reaction mixture was diluted with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol-hexane to give the title compound (290 mg, 80%) as pale brown crystals.
  • Iron powder 49 mg, 0.87 mmol was added to a solution of the compound of Reference Example 34 (100 mg, 0.17 mmol) in acetic acid (1.5 mL), and the mixture was heated to reflux for 3 hours. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid (1.5 mL), acetic anhydride (0.20 mL) was added, and the mixture was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Example 88 to Example 177 In the same manner as in Example 87, the compounds shown in Tables 1-1 to 1-25 were obtained from the compound of Example 24 and the corresponding amine.

Abstract

Cette invention concerne un dérivé hétérocyclique condensé ayant une forte activité d'inhibition de kinase, et l'utilisation dudit dérivé hétérocyclique condensé. Un composé représenté par la formule (I) (dont les symboles sont tels que définis dans la description) ou un de ses sels est spécifiquement décrit. Un produit pharmaceutique contenant le composé ou un promédicament de celui-ci, qui est un inhibiteur de kinase ou un agent destiné à prévenir/traiter les cancers, est également décrit.
PCT/JP2009/056200 2008-03-27 2009-03-26 Dérivé hétérocyclique condensé et son utilisation WO2009119776A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013538209A (ja) * 2010-08-25 2013-10-10 ネオファーム カンパニー， リミテッド 新規の複素環化合物及びこれを用いた炎症性疾患治療用組成物
WO2018057805A1 (fr) * 2016-09-23 2018-03-29 Gilead Sciences, Inc. Dérivés de benzimidazole et leur utilisation en tant qu'inhibiteurs de phosphatidylinositol 3-kinase
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
CN116041366A (zh) * 2022-03-16 2023-05-02 成都大学 手性3-螺环氧化吲哚并苯并噻吩砜类衍生物、其制备方法及用途
CN116041366B (zh) * 2022-03-16 2023-12-22 成都大学 手性3-螺环氧化吲哚并苯并噻吩砜类衍生物、其制备方法及用途
WO2023236820A1 (fr) * 2022-06-06 2023-12-14 沈阳药科大学 Dérivé d'imidazole à cycle condensé aromatique à six chaînons, son procédé de préparation et son utilisation

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