WO2010021381A1 - Dérivé hétérocyclique fusionné et son utilisation - Google Patents

Dérivé hétérocyclique fusionné et son utilisation Download PDF

Info

Publication number
WO2010021381A1
WO2010021381A1 PCT/JP2009/064659 JP2009064659W WO2010021381A1 WO 2010021381 A1 WO2010021381 A1 WO 2010021381A1 JP 2009064659 W JP2009064659 W JP 2009064659W WO 2010021381 A1 WO2010021381 A1 WO 2010021381A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
imidazo
tetrahydro
compound
alkyl
Prior art date
Application number
PCT/JP2009/064659
Other languages
English (en)
Japanese (ja)
Inventor
英人 福士
聡 佐々木
ひろ美 小林
滋 近藤
Original Assignee
武田薬品工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武田薬品工業株式会社 filed Critical 武田薬品工業株式会社
Publication of WO2010021381A1 publication Critical patent/WO2010021381A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 produce an 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 deseart hedgehog (Dhh) are known as gene products corresponding to Drosophila Hh.
  • Shh a 19 kDa active body 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.
  • 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 to Ptch1, Ptch2, Hip1, Gas1, and 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).
  • Cyclopamine non-patent document 8
  • white hellebore 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 produced, and monocular disease, limb dysplasia (Non-patent Document 10), and neural plate dysplasia (Non-patent Document 11) were recognized as the expression system.
  • 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. Reference 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 are 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). ).
  • Non-patent Document 15 The basal cell carcinoma and medulloblastoma are known as cancers in which the Hedgehog signal is enhanced by the mutation, and the mutation of Ptch1 observed in these cancers activates the Hedgehog signal in a ligand-independent manner.
  • pancreatic cancer (Non-patent Document 16) has been reported as a cancer whose Hedgehog signal is enhanced by overexpression of Shh.
  • transgenic mice in which Shh was forcibly expressed in the pancreas PanIN-like lesions were observed in the pancreas, which is the early stage of cancer progression. (Non-patent Document 17).
  • Hedgehog signal functions in the growth and survival of cancer stem cells and plays an important role in tumor metastasis or recurrence after surgery (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 on glioma (Non-patent Document 19) and the like.
  • CUR-61414 nonpatent literature 20
  • SANT-1, 2, 3, 4 nonpatent literature 21
  • Hedgohog signal-inhibiting antibodies it has been reported that cancer regression 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 Documents 2 to 8 and Non-Patent Documents 22 and 23 describe fused heterocyclic 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.
  • R 1 is (1) C 6-10 aryl optionally having a substituent, or (2) a monocyclic aromatic heterocyclic group which may have a substituent
  • R 2 is (1) a hydrogen atom, or (2) an aliphatic hydrocarbon group which may have a substituent
  • R 3 is (1) hydrogen atom, (2) a group via a carbon atom, (3) a group via a nitrogen atom, (4) a group through an oxygen atom, or (5) a group via a sulfur atom
  • R 4 is (1) hydrogen atom, (2) a group via a carbon atom, (3) a group via a nitrogen atom, (4) a group through an oxygen atom, or (5) a group via a sulfur atom
  • R 3 and R 4 may form a carbonyl with adjacent carbon atoms
  • R 5 is (1) (a) C 6-10 aryl-carbonyl, and (b) C 1-2 alkyl having one or two substituents selected from C 6-10 aryl-C 1-6 alkoxy, (2) C 1-2 al
  • R 2 is an aliphatic hydrocarbon group which may have a substituent
  • R 1 is (1) C 6-10 aryl optionally having a substituent, or (2) an optionally substituted monocyclic aromatic heterocyclic group
  • R 2 is a hydrogen atom, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom
  • R 3 and R 4 may form a carbonyl with adjacent carbon atoms
  • R 5 is (1) (a) C 6-10 aryl-carbonyl, and (b) C 1-2 alkyl having one or two substituents selected from C 6-10 aryl-C 1-6 alkoxy, (2) C 1-2 alkyl having two C 6-10 aryls, (3) C 3-6 alkyl optionally having one C 1-6 alkylthio, (4) an optionally substituted C 2-10 al
  • 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.
  • the “group via a carbon atom” represented by R 3 , R 4 , R 6 , R 7 , R 8 or R 9 is (1) cyano, (2) an optionally substituted C 1-6 alkyl, (3) an optionally substituted C 2-10 alkenyl, (4) an optionally substituted C 3-10 alkadienyl, (5) an optionally substituted C 2-6 alkynyl, (6) C 3-6 cycloalkyl which may have a substituent, (7) an optionally substituted C 3-6 cycloalkenyl, (8) C 6-10 aryl optionally having a substituent, (9) acyl, (10) Heterocyclic group which may have a substituent (however, having a bond at a carbon atom) Etc.
  • C 1-6 alkyl in the above “optionally substituted C 1-6 alkyl” is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Examples include pentyl and hexyl.
  • substituents selected from the following substituent group A, and the number of substituents can be any number that can be substituted. Although not particularly limited, it is preferably 1 to 5, more preferably 1 to 3.
  • Substituent group A (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); (2) Cyano; (3) Nitro; (4) hydroxy; (5) C 3-6 cycloalkyl optionally having 1 to 3 halogen atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); (6) C 6-10 aryl (eg, phenyl, 1-naphthyl, 2-amino) optionally having 1 to 3 substituents selected from a halogen atom, cyano and C 1-6 alkoxy (eg, methoxy) Naphthyl); (7) 1 to 4 substituents selected from a halogen atom, C 1-6 alkoxy (eg, methoxy), C 6-10 aryl (eg, phenyl) and a 5-membered aromatic heterocyclic group (eg, thiazolyl)
  • 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 3-6 cycloalkylsulfonyl eg, cyclopropylsulfonyl, cyclobutylsulfonyl
  • C 48) C 3-6 cycloalkenylsulfonyl eg, cyclopropenylsulfonyl, cyclo
  • (75) (a) hydroxy, (b) C 1-6 alkyl (eg, methyl, propyl, isopropyl, tert-butyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom, bromine atom) ), (C) C 3-6 cycloalkyl (eg, cyclopentyl), (d) cyano, (e) carbamoyl, (f) C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl) and (g) C 1- 5- or 6-membered monocyclic aromatic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl) which may have one substituent selected from 6 alkoxy-carbonyl (eg, ethoxycarbonyl), Thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl, triazo
  • C 2-10 alkenyl in the above “optionally substituted C 2-10 alkenyl” includes, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 2- Methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 2,2-dimethyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 3,7-dimethyl-6-octenyl, 1- Nonenyl, 1-decenyl and the like are shown.
  • substituted C 2-10 alkenyl includes a substituent selected from the group of substituent A, and the number of substituents is not particularly limited as long as it is a substitutable number. However, it is preferably 1 to 5, more preferably 1 to 3.
  • C 3-10 alkadienyl in the above “optionally substituted C 3-10 alkadienyl” includes, for example, allenyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl, 1, 3-pentadienyl, 1,3-hexadienyl, 2,4-nonadienyl and the like are shown.
  • Examples of the “substituent” in the above “optionally substituted C 3-10 alkadienyl” include substituents selected from the substituent group A, and the number of substituents is not particularly limited as long as it is a substitutable number. However, it is preferably 1 to 5, more preferably 1 to 3.
  • C 2-6 alkynyl in the above “optionally substituted C 2-6 alkynyl” includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- Butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like are shown.
  • substituents selected from the substituent group A include substituents selected from the substituent group A, and the number of substituents is not particularly limited as long as the number can be substituted. However, it is preferably 1 to 5, more preferably 1 to 3.
  • C 3-6 cycloalkyl in the above “optionally substituted C 3-6 cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • substituent of the above-mentioned “optionally substituted C 3-6 cycloalkyl”, (1) an optionally substituted C 1 to 3 substituent selected from a halogen atom and cyano 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl), and (2) substituents selected from substituent group A.
  • the number of substituents is the number that can be substituted. The number is not particularly limited, but is preferably 1 to 5, more preferably 1 to 3.
  • C 3-6 cycloalkenyl in the above “optionally substituted C 3-6 cycloalkenyl” is, for example, 2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2 -Cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like are shown.
  • the “substituent” in the above “optionally substituted C 3-6 cycloalkenyl” is (1) C 1 -C 3 optionally having a substituent selected from a halogen atom and cyano.
  • substituent group A 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl), and (2) substituents selected from substituent group A.
  • the number of substituents is the number that can be substituted. The number is not particularly limited, but is preferably 1 to 5, more preferably 1 to 3.
  • the “C 6-10 aryl” of the “ optionally substituted C 6-10 aryl” includes, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
  • the C 6-10 aryl may be condensed with a C 3-6 cycloalkane (eg, cyclopentane) condensed with a benzene ring.
  • acyl (1) Formyl, (2) an optionally substituted C 1-6 alkyl-carbonyl, (3) an optionally substituted C 2-6 alkenyl-carbonyl, (4) an optionally substituted C 2-6 alkynyl-carbonyl, (5) an optionally substituted C 3-6 cycloalkyl-carbonyl, (6) an optionally substituted C 3-6 cycloalkenyl-carbonyl, (7) an optionally substituted C 6-10 aryl-carbonyl, (8) an optionally substituted heterocyclic carbonyl, (9) Carboxy, (10) an optionally substituted C 1-6 alkoxy-carbonyl, (11) an optionally substituted C 2-6 alkenyloxy-carbonyl, (12) an optionally substituted C 2-6 alkynyloxy-carbonyl, (13) an optionally substituted C 3-6 cycloalkyloxy-carbonyl, (14) an optionally substituted C 3-6 cycloalkenyloxy-carbonyl, (15) an optionally substitute
  • C 1-6 alkyl-carbonyl in the above “optionally substituted C 1-6 alkyl-carbonyl” means, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3- Examples thereof include methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl and the like.
  • substituents in the above-mentioned “C 1-6 alkyl-carbonyl optionally having substituent (s)” include substituents selected from Substituent group A, and the number of substituents is any number that can be substituted. Although not particularly limited, it is preferably 1 to 5, more preferably 1 to 3.
  • C 2-6 alkenyl-carbonyl in the above “optionally substituted C 2-6 alkenyl-carbonyl” means, for example, ethenylcarbonyl, 1-propenylcarbonyl, 2-propenylcarbonyl, 2- Methyl-1-propenylcarbonyl, 1-butenylcarbonyl, 2-butenylcarbonyl, 3-butenylcarbonyl, 3-methyl-2-butenylcarbonyl, 1-pentenylcarbonyl, 2-pentenylcarbonyl, 3-pentenylcarbonyl, 4-pentenylcarbonyl, 4-methyl-3-pentenylcarbonyl, 1-hexenylcarbonyl, 2-hexenylcarbonyl, 3-hexenylcarbonyl, 4-hexenylcarbonyl, 5-hexenylcarbonyl and the like are shown.
  • substituents selected from the substituent group A include substituents selected from the substituent group A, and the number of substituents is any number that can be substituted. Although not particularly limited, the number is preferably 1 to 5, more preferably 1 to 3.
  • C 2-6 alkynyl-carbonyl in the above “optionally substituted C 2-6 alkynyl-carbonyl” means, for example, ethynylcarbonyl, 1-propynylcarbonyl, 2-propynylcarbonyl, 1-butynyl.
  • substituents selected from the substituent group A include substituents selected from the substituent group A, and the number of substituents is any number that can be substituted. Although not particularly limited, it is preferably 1 to 5, more preferably 1 to 3.
  • C 3-6 cycloalkyl-carbonyl examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like. Indicates.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituents selected from Substituent Group A can be mentioned, and 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.
  • C 3-6 cycloalkenyl-carbonyl in the above “optionally substituted C 3-6 cycloalkenyl-carbonyl” means, for example, 2-cyclopropen-1-ylcarbonyl, 2-cyclobutene- 1-ylcarbonyl, 2-cyclopenten-1-ylcarbonyl, 3-cyclopenten-1-ylcarbonyl, 2-cyclohexen-1-ylcarbonyl, 3-cyclohexen-1-ylcarbonyl and the like are shown.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituents selected from Substituent Group A can be mentioned, and 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.
  • C 6-10 aryl-carbonyl in the above “optionally substituted C 6-10 aryl-carbonyl” refers to, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituent group A excluding oxo
  • the number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3.
  • heterocycle of the above-mentioned “optionally substituted heterocyclic carbonyl” is, 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) 3-6 membered non-aromatic heterocycle (eg, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, thiolane, piperidine) Etc.
  • 5- or 6-membered monocyclic aromatic heterocycle eg,
  • substituents of the “optionally substituted heterocyclic carbonyl” (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from a halogen atom and cyano, and (2) Substituent group A (excluding oxo when "heterocycle” of "optionally substituted heterocyclic carbonyl” is an aromatic heterocyclic ring)
  • the number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3.
  • C 1-6 alkoxy-carbonyl in the above “optionally substituted C 1-6 alkoxy-carbonyl” is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, And isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • substituents in the above-mentioned “C 1-6 alkoxy-carbonyl optionally having substituent (s)” include substituents selected from Substituent group A, and the number of substituents is any number that can be substituted. Although not particularly limited, it is preferably 1 to 5, more preferably 1 to 3.
  • C 2-6 alkenyloxy-carbonyl in the above “optionally substituted C 2-6 alkenyloxy-carbonyl” means, for example, ethenyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyl Oxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, 3-methyl-2-butenyloxycarbonyl, 1-pentenyloxycarbonyl, 2-pentenyloxycarbonyl, 3-pentenyl Examples thereof include oxycarbonyl, 4-pentenyloxycarbonyl, 1-hexenyloxycarbonyl, 2-hexenyloxycarbonyl, 3-hexenyloxycarbonyl, 4-hexenyloxycarbonyl, 5-hexenyloxycarbonyl and the like.
  • substituents selected from the substituent group A include substituents selected from the substituent group A, and the number of substituents may be any number that can be substituted. Although not particularly limited, it is preferably 1 to 5, more preferably 1 to 3.
  • C 2-6 alkynyloxy-carbonyl in the above “optionally substituted C 2-6 alkynyloxy-carbonyl” means, for example, ethynyloxycarbonyl, 1-propynyloxycarbonyl, 2-propynyloxy Carbonyl, 1-butynyloxycarbonyl, 2-butynyloxycarbonyl, 3-butynyloxycarbonyl, 1-pentynyloxycarbonyl, 2-pentynyloxycarbonyl, 3-pentynyloxycarbonyl, 4-pentynyloxycarbonyl 1-hexynyloxycarbonyl, 2-hexynyloxycarbonyl, 3-hexynyloxycarbonyl, 4-hexynyloxycarbonyl, 5-hexynyloxycarbonyl and the like.
  • substituted C 2-6 alkynyloxy-carbonyl examples include substituents selected from the group of substituent A, and the number of substituents may be any number that can be substituted. Although not particularly limited, it is preferably 1 to 5, more preferably 1 to 3.
  • C 3-6 cycloalkyloxy-carbonyl in the above “optionally substituted C 3-6 cycloalkyloxy-carbonyl” means, for example, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxy Carbonyl, cyclohexyloxycarbonyl and the like are shown.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituents selected from Substituent Group A can be mentioned, and 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.
  • C 3-6 cycloalkenyloxy-carbonyl in the above “optionally substituted C 3-6 cycloalkenyloxy-carbonyl” means, for example, 2-cyclopropen-1-yloxycarbonyl, 2 -Cyclobuten-1-yloxycarbonyl, 2-cyclopenten-1-yloxycarbonyl, 3-cyclopenten-1-yloxycarbonyl, 2-cyclohexen-1-yloxycarbonyl, 3-cyclohexen-1-yloxycarbonyl, etc. Show.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituents selected from Substituent Group A can be mentioned, and 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.
  • C 6-10 aryloxy-carbonyl in the above “optionally substituted C 6-10 aryloxy-carbonyl” means, for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl. Etc.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • substituent group A excluding oxo
  • the number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3.
  • heterocycle of the “optionally substituted heterocyclic oxycarbonyl” is, 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) 3-6 membered non-aromatic heterocycle (eg, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, thiolane, piperidine) Etc.
  • 5- or 6-membered monocyclic aromatic heterocycle eg, furan,
  • substituents of the above-mentioned “heterocyclic oxycarbonyl 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 a halogen atom and cyano, and (2) Substituent group A (excluding oxo when “heterocycle” of “optionally substituted heterocyclic oxycarbonyl” is an aromatic heterocyclic ring)
  • the number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3.
  • optionally substituted carbamoyl refers to “optionally substituted C 1-6 alkyl” and “substituent” exemplified in the above “group via carbon atom”. “ Optionally substituted C 2-10 alkenyl”, “ optionally substituted C 2-6 alkynyl”, “optionally substituted C 3-6 cycloalkyl”, “substituted” 1 or 2 optionally substituted carbamoyl selected from “optionally substituted C 3-6 cycloalkenyl” and “optionally substituted C 6-10 aryl” Indicates.
  • heterocyclic group which may have a substituent is an aromatic heterocyclic group (eg, monocyclic aromatic heterocyclic group, condensed aromatic heterocyclic group). Ring group), non-aromatic heterocyclic group and the like.
  • Examples of the monocyclic aromatic heterocyclic group include 5- to 7-membered monocyclic aromatics containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring-constituting atoms.
  • Group heterocyclic group and the like are examples of the monocyclic aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl ( Examples, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), thiazolyl (eg, 2 -Thiazolyl, 4-
  • condensed aromatic heterocyclic group examples include 5- to 7-membered monocyclic aromatic heterocycles containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
  • a group derived from a condensed ring of a ring or the like and 1 to 2 C 6-10 arenes; a group derived from a condensed ring of the above 5 to 7-membered monocyclic aromatic heterocycle .
  • condensed aromatic heterocyclic group examples include quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl), 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, indole-4-) Yl, indol-5-yl, indol, in
  • non-aromatic heterocyclic group examples include a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group.
  • specific examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, oxepanyl, thiepanyl, oxazepanyl , Thiazepanyl, azocanyl, oxocanyl, thiocanyl, oxazocanyl, thiazocanyl, dioxynyl and the like.
  • heterocyclic group which may have a 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 a halogen atom and cyano, and (2) Substituent group A (provided that the “heterocycle” of “optionally substituted heterocyclic group (provided having a bond to a carbon atom)” is an aromatic heterocyclic ring, except)
  • the number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3.
  • examples of the “group through nitrogen atom” represented by R 3 , R 4 , R 6 , R 7 , R 8 or R 9 include (1) nitro, (2) the above “ Examples include amino optionally having one or two “groups via a carbon atom”.
  • examples of the “group via a sulfur atom” represented by R 3 , R 4 , R 6 , R 7 , R 8 or R 9 include the above-mentioned “group via a carbon atom” or “ Examples include mercapto which may have one “group through a nitrogen atom”, and the sulfur atom of the group may be oxidized.
  • the “optionally substituted C 6-10 aryl” represented by R 1 is the above R 3 , R 4 , R 6 , R 7 , R 8 or R 9. And the same as “C 6-10 aryl optionally having substituent (s)” exemplified by “Group via carbon atom”.
  • the “monocyclic aromatic heterocyclic group” in the “optionally substituted monocyclic aromatic heterocyclic group” represented by R 1 is a 5- or 6-membered member.
  • An aromatic heterocyclic group specifically, furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl) 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 2 -Pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 2-imidazolyl, 4-imidazolyl, 5-imid
  • substituents in the “monocyclic aromatic heterocyclic group optionally having substituent (s)” represented by R 1 (1) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally having 1 to 3 substituents selected from a halogen atom and cyano, and (2) Substituent group A (excluding oxo)
  • the number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3.
  • the “optionally substituted aliphatic hydrocarbon group” represented by R 2 includes “optionally substituted C 1-6 alkyl”, “substituted “ Optionally substituted C 2-10 alkenyl”, “optionally substituted C 3-10 alkadienyl”, “optionally substituted C 2-6 alkynyl”, “ C 3-6 cycloalkyl optionally having substituent (s) ”and“ C 3-6 cycloalkenyl optionally having substituent (s) ”, and these include R 3 , R 4 , R “Optionally substituted C 1-6 alkyl” and “having a substituent” exemplified by “group via carbon atom” represented by 6 , R 7 , R 8 or R 9 which may C 2-10 alkenyl ",” optionally C 3-10 alkadienyl optionally having a substituent "," Which may have a substituent C 2-6 alkynyl ",” optionally substituted C 3-6 cycloalkyl "and” optionally substitute
  • the compound (I) it has 1 or 2 substituents selected from “(a) C 6-10 aryl-carbonyl and (b) C 6-10 aryl-C 1-6 alkoxy” represented by R 5 “C 6-10 aryl-C 1-6 alkoxy” in “C 1-2 alkyl” includes benzyloxy, phenethyloxy, naphthylmethyloxy, naphthylethyloxy and the like.
  • it has 1 or 2 substituents selected from “(a) C 6-10 aryl-carbonyl and (b) C 6-10 aryl-C 1-6 alkoxy” represented by R 5 “C 1-2 alkyl” in “C 1-2 alkyl” includes methyl or ethyl.
  • compound (I), represented by R 5 as “C 6-10 aryl” of the "a C 6-10 aryl C 1-2 alkyl which two presence” are phenyl, naphthyl and the like.
  • “C 1-2 alkyl” in “C 1-2 alkyl having two C 6-10 aryls” represented by R 5 includes methyl and ethyl.
  • the "C 1-6 alkylthio" of the "C 1-6 alkylthio one has to have a good C 3-6 alkyl optionally” represented by R 5 are methylthio, ethylthio, propylthio, Butylthio etc. are mentioned.
  • “C 3-6 alkyl” in “C 3-6 alkyl optionally having one C 1-6 alkylthio” represented by R 5 includes propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • Alkenyl “ optionally substituted C 3-10 alkadienyl ”,“ optionally substituted C 3-6 cycloalkyl ”,“ optionally substituted C 3 -6 cycloalkenyl ", and” optionally substituted C 6-10 aryl " The like, and the like.
  • -6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.
  • the “optionally substituted carbamoyl” represented by R 5 is represented by the above R 3 , R 4 , R 6 , R 7 , R 8 or R 9. Examples thereof include those similar to “optionally substituted carbamoyl” exemplified by “acyl” exemplified by “group via carbon atom”.
  • R 1 is (1) C 6-10 aryl optionally having a substituent, or (2) A monocyclic aromatic heterocyclic group which may have a substituent.
  • R 1 (1) (a) Halogen atom (eg, fluorine atom, chlorine atom), (b) cyano, (c) Nitro, (d) C 1-6 alkyl (eg, methyl, isopropyl, tert-butyl) optionally having 1 to 3 substituents selected from a halogen atom (eg, fluorine atom) and hydroxy, (e) C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 halogen atoms (eg, fluorine atoms), (f) carboxy, (g) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl), (h) carbamoyl, (i) C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl,
  • R 1 (1) (a) a fluorine atom, (b) a chlorine atom, (c) cyano, (d) Nitro, (e) methyl, (f) trifluoromethyl, (g) 1-hydroxy-1-methylethyl, (h) tert-butyl, (i) trifluoromethoxy, (j) carboxy, (k) methoxycarbonyl, (l) Carbamoyl, (m) methylcarbamoyl, (n) ethylcarbamoyl, (o) 2- (pyrrolidinyl-1-yl) ethylcarbamoyl, (p) methoxycarbamoyl, (q) piperidinocarbonyl, (r) amino, (s) Acetylamino, (t) propanoylamino, (u) 2-methylpropanoylamino, (v) methylsulfonylamino, (w) 2-methyl-6-
  • R 2 is (1) a hydrogen atom, or (2) An aliphatic hydrocarbon group which may have a substituent.
  • R 2 is preferably a hydrogen atom, C 1-6 alkyl (eg, methyl, ethyl, propyl) or C 3-6 cycloalkyl (eg, cyclopropyl).
  • R 2 is preferably a hydrogen atom, methyl, ethyl, propyl or cyclopropyl.
  • R 2 is an aliphatic hydrocarbon group that may have a substituent.
  • R 2 is preferably C 1-6 alkyl (eg methyl, ethyl, propyl) or C 3-6 cycloalkyl (eg cyclopropyl), especially methyl, ethyl, propyl or cyclopropyl Is preferred.
  • R 3 and R 4 are the same or different, (1) hydrogen atom, (2) a group via a carbon atom, (3) a group via a nitrogen atom, (4) a group through an oxygen atom, or (5) A group through a sulfur atom.
  • R 3 and R 4 together with adjacent carbon atoms form a carbonyl.
  • R 5 is (1) (a) C 6-10 aryl-carbonyl, and (b) C 1-2 alkyl having one or two substituents selected from C 6-10 aryl-C 1-6 alkoxy, (2) C 1-2 alkyl having two C 6-10 aryls, (3) C 3-6 alkyl optionally having one C 1-6 alkylthio, (4) an optionally substituted C 2-10 alkenyl, (5) an optionally substituted C 3-10 alkadienyl, (6) C 3-6 cycloalkyl which may have a substituent, (7) an optionally substituted C 3-6 cycloalkenyl, (8) an optionally substituted C 6-10 aryl, (9) (C 3-6 cycloalkyl optionally having substituent) -C 1-6 alkyl, (10) (C 3-6 cycloalkenyl optionally having substituent) -C 1-6 alkyl, (11) (C 6-10 aryl optionally having substituent) -C 1-6 alkyl,
  • R 5 is, (1) (a) C 6-10 aryl-carbonyl, and (b) C 1-2 alkyl having one or two substituents selected from C 6-10 aryl-C 1-6 alkoxy, (2) C 1-2 alkyl having two C 6-10 aryls, (3) C 3-6 alkyl optionally having one C 1-6 alkylthio, (4) an optionally substituted C 2-10 alkenyl, (5) an optionally substituted C 3-10 alkadienyl, (6) C 6-10 aryl optionally having substituent (s), (7) (C 3-6 cycloalkyl optionally having substituent) -C 1-6 alkyl, (8) (C 3-6 cycloalkenyl optionally having substituent) -C 1-6 alkyl, (9) (C 6-10 aryl optionally having substituent) -C 1-6 alkyl, (10) (heterocycle optionally having substituent) -C 1-6 alkyl, or (11) Carbamoyl which may have
  • R 5 is, (1) (a) C 6-10 aryl-carbonyl (eg, benzoyl), and (b) C 6-10 aryl-C 1-6 alkoxy (eg, benzyloxy) C 1-2 alkyl (eg, methyl, ethyl) having one substituent selected from (2) C 1-2 alkyl (eg ethyl) having two C 6-10 aryl (eg phenyl), (3) C 3-6 alkyl (eg, propyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl) optionally having one C 1-6 alkylthio (eg, methylthio), (4) (a) (i) nitro, and (ii) C 1-6 alkoxy (eg, methoxy) C 6-10 aryl optionally having one substituent selected from (eg, phenyl), and (b) a 5-membered aromatic heterocyclic group (eg, furyl
  • C 2-10 alkenyl optionally having 1 or 2 substituents selected from (for example, 2-propenyl, 2-methyl-2-propenyl, 2,2-dimethyl-4-pentenyl, 3,7 -Dimethyl-6-octenyl), (5) C 3-10 alkadienyl (eg, nonane-2,4-dienyl), (6) (a) a halogen atom (eg, fluorine atom), and (b) C 1-6 alkoxy (eg, methoxy) C 6-10 aryl (eg, phenyl) optionally having one substituent selected from: (7) (C 3-6 cycloalkyl (eg, cyclohexyl))-C 1-6 alkyl (eg, methyl), (8) (C 3-6 cycloalkenyl (eg, cyclohexenyl) optionally having one C 1-4 alkylene (eg, methylene))-C 1-6 alkyl (eg, methyl), (
  • R 6 and R 7 are the same or different and are respectively (1) a hydrogen atom, (2) a group via a carbon atom, (3) a group via a nitrogen atom, and (4) an oxygen atom. A group or (5) a group via a sulfur atom. Among these, as R 6 and R 7 , both are preferably hydrogen atoms.
  • R 8 and R 9 are the same or different and are respectively (1) a hydrogen atom, (2) a group via a carbon atom, (3) a group via a nitrogen atom, and (4) an oxygen atom. A group or (5) a group via a sulfur atom. Among these, as R 8 and R 9 , both are preferably hydrogen atoms.
  • R 1 is (1) C 6-10 aryl optionally having a substituent, or (2) a monocyclic aromatic heterocyclic group which may have a substituent
  • R 2 is a hydrogen atom, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom
  • R 3 and R 4 may form a carbonyl with adjacent carbon atoms
  • R 5 is (1) (a) C 6-10 aryl-carbonyl, and (b) C 1-2 alkyl having one or two substituents selected from C 6-10 aryl-C 1-6 alkoxy, (2) C 1-2 alkyl having two C 6-10 aryls, (3) C 3-6 alkyl optionally having one C 1-6 alkylthio, (4) an optionally substituted C 2-10 alkenyl, (5) an optionally substituted C 3-10 alkadienyl, (6) C 3-6 cycloalkyl
  • R 1 is (1) (a) Halogen atom (eg, fluorine atom, chlorine atom), (b) cyano, (c) Nitro, (d) C 1-6 alkyl (eg, methyl, isopropyl, tert-butyl) optionally having 1 to 3 substituents selected from a halogen atom (eg, fluorine atom) and hydroxy, (e) C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 halogen atoms (eg, fluorine atoms), (f) carboxy, (g) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl), (h) carbamoyl, (i) C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl) optionally having one cyclic amino (eg, 1-pyrrolidinyl), (j) C 1-6 alkoxy
  • R 1 is (1) (a) a fluorine atom, (b) a chlorine atom, (c) cyano, (d) Nitro, (e) methyl, (f) trifluoromethyl, (g) 1-hydroxy-1-methylethyl, (h) tert-butyl, (i) trifluoromethoxy, (j) carboxy, (k) methoxycarbonyl, (l) Carbamoyl, (m) methylcarbamoyl, (n) ethylcarbamoyl, (o) 2- (pyrrolidinyl-1-yl) ethylcarbamoyl, (p) methoxycarbamoyl, (q) piperidinocarbonyl, (r) amino, (s) Acetylamino, (t) propanoylamino, (u) 2-methylpropanoylamino, (v) methylsulfonylamino, (w) 2-
  • 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 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), alkaline earth metal salts (eg, calcium salts, magnesium salts), ammonium salts, etc.
  • 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, oxalic acid
  • organic acids such as tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • the raw material compound and the production intermediate may be a salt.
  • salts include the same salts as those in the aforementioned compound (I).
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but from the reaction mixture according to a conventional method (for example, separation means such as recrystallization, distillation, chromatography, etc.). It may be isolated.
  • the raw material compound when the raw material compound has amino, carboxyl, or hydroxyl as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry or the like.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • the protection reaction and the deprotection reaction are carried out by a known method, for example, the method described in Protective Groups in Organic Synthesis 3rd edition, John Wiley and Sons, Inc. 1999, or a method analogous thereto.
  • amino protecting groups include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7 -14 Aralkyloxy-carbonyl groups (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl groups, phthaloyl groups, N, N-dimethylaminomethylene groups, substituted silyl groups (eg, trimethylsilyl, triethylsilyl, dimethyl) Phenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • amino protecting groups include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoy
  • 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 carboxyl protecting 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 group (eg, 1-allyl) and the like.
  • hydroxyl protecting group examples 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 groups (eg, 1-allyl) and the like. 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 alk
  • 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 following [Method A] or a method analogous thereto. [Method A] Compound (I) can be produced by alkylating compound (II).
  • alkylation reaction reductive alkylation using a carbonyl compound or an alkylation method using an alkyl halide can be used.
  • the corresponding carbonyl compound can be used.
  • R 5 is C 1-2 alkyl having 1 or 2 substituents selected from (a) C 6-10 aryl-carbonyl and (b) C 6-10 aryl-C 1-6 alkoxy
  • substituents selected from (a) C 6-10 aryl-carbonyl and (b) C 6-10 aryl-C 1-6 alkoxy Is a 2-substituted acetaldehyde or substituted formaldehyde having 1 or 2 substituents selected from (a) C 6-10 aryl-carbonyl and (b) C 6-10 aryl-C 1-6 alkoxy as a carbonyl compound Etc.
  • a reduction method a method using a metal hydride or a catalytic hydrogenation reaction can be used in a solvent that does not adversely influence the reaction under acidic conditions if necessary.
  • the metal hydride sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like are used, and the amount used is usually 1 to 20 mol, preferably 1 mol, relative to 1 mol of compound (II). 1 to 2 moles.
  • 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 mol, preferably 0.05-0.5 mol, relative to 1 mol of compound (II).
  • the hydrogen source hydrogen, cyclohexene, hydrazine, ammonium formate, or the like is used.
  • acids used for acid conditions include hydrochloric acid, methanesulfonic acid, acetic acid, and the like.
  • the solvent that does not adversely influence the reaction include ethers, alcohols, hydrocarbons, ketones, nitriles, amides, esters, water and the like, preferably alcohols and ethers. 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 (Ia) in which R 4 , R 7 and R 9 are hydrogen atoms in compound (I) can be produced, for example, by [Method B] or a method analogous thereto.
  • [Method B] Compound (Ia) can be produced by reacting compound (1) with an alkyl halide (R 5 -X) to obtain compound (2), followed by reduction.
  • X represents a halogen atom, and other symbols are as defined above.
  • halogen atom represented by X for example, a chlorine atom, a bromine atom, an iodine atom and the like can be used.
  • the conversion from compound (1) to compound (2) can be carried out in a solvent that does not adversely influence the reaction or in the absence of a solvent.
  • the amount of the alkyl halide (R 5 —X) to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound (1).
  • Examples of the solvent that does not adversely influence the reaction include ethers, hydrocarbons, ketones, nitriles, amides, esters, and the like, preferably ethers, hydrocarbons, 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 160 ° C., preferably 20 to 140 ° C.
  • the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
  • the conversion from compound (2) to compound (Ia) can be carried out using a reduction with a metal hydride or a catalytic hydrogenation reaction in a solvent that does not adversely influence the reaction.
  • the metal hydride sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, or the like is used.
  • the amount thereof to be used is generally 1 to 20 mol, preferably 1 to 2 mol, per 1 mol of compound (2).
  • 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 mol, preferably 0.05-0.5 mol, per 1 mol of compound (2).
  • the hydrogen source 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 and the like, preferably alcohols and ethers. 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 (1) can be produced by applying the method described in Journal of Heterocyclic Chemistry, 1990, page 563.
  • the alkyl halide (R 5 -X) a commercially available product can be used, or it can be produced from the corresponding raw material by applying a known method.
  • Compound (II) can be produced, for example, by the following [Method C] or a method analogous thereto.
  • [Method C] Compound (II) can be produced by converting compound (3) to compound (4) and deprotecting the resulting compound (4).
  • P represents an amino-protecting group, and other symbols are as defined above.
  • the protecting group represented by P for example, a benzyloxycarbonyl group or the like can be used.
  • Compound (4) can be synthesized, for example, by reacting compound (3) with compound (5) according to the method described in Journal of Organic Chemistry, 1993, page 7093.
  • Compound (5) may be commercially available, or can be produced from the corresponding raw material by applying a known method.
  • the deprotection reaction of the compound (4) can be carried out in a solvent that does not adversely influence the compound (4) by, for example, a usual operation such as a catalytic hydrogenation reaction.
  • Examples of the solvent that does not adversely influence the reaction include ethers, hydrocarbons, ketones, nitriles, amides, esters, etc., 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.
  • Compound (3) may be a commercially available product, or can be produced from the corresponding raw material by applying a known method.
  • Compound (IIa) in which R 4 , R 7 and R 9 are hydrogen atoms in compound (II) can be produced, for example, by the following [Method D] or a method analogous thereto.
  • [Method D] Compound (IIa) can be produced by reducing compound (1).
  • a catalytic hydrogenation reaction or the like can be used in a solvent that does not adversely influence the reaction.
  • 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 mol, preferably 0.05-0.5 mol, per 1 mol of compound (1).
  • hydrogen source hydrogen, cyclohexene, hydrazine, ammonium formate, or the like is used.
  • the hydrogen pressure is 1 to 100 atm, preferably 1 to 60 atm.
  • the solvent that does not adversely influence the reaction include ethers, alcohols, hydrocarbons, ketones, nitriles, amides, esters, water and the like, preferably alcohols and ethers. 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 (4) can be produced, for example, according to [Method E] or a method analogous thereto.
  • [E method] Compound (7) is obtained by halogenating compound (6), and compound (4) can be produced by a coupling reaction of this compound (7).
  • X ′ represents a halogen atom, and other symbols are as defined above.
  • halogen atom represented by X ′ for example, a chlorine atom, a bromine atom, an iodine atom and the like can be used.
  • Compound (6) can be produced by applying the method described in the above-mentioned Journal of Heterocyclic Chemistry, 1990, page 563. The conversion from compound (6) to compound (7) can be carried out using a halogenating reagent or the like in a solvent that does not adversely influence the reaction.
  • halogenating reagent for example, N-chlorosuccinimide, N-bromosuccinimide, chlorine, bromine, iodine and the like can be used, and the amount used is usually 1 with respect to 1 mol of compound (6). -4 mol, preferably 1-1.5 mol.
  • Solvents that do not adversely affect the reaction include ethers, hydrocarbons, halogenated hydrocarbons, ketones, nitriles, amides, esters, etc., preferably halogenated hydrocarbons, ethers, amideskind. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • 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.
  • Conversion from compound (7) to compound (4) can be carried out in a solvent that does not adversely influence the reaction, if necessary, in the presence of a base, using a coupling reaction with a corresponding boric acid derivative or the like.
  • a commercially available boric acid derivative or the like can be used, or can be produced from a corresponding raw material by applying a known method.
  • the amount thereof to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (7).
  • 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 mol, preferably 0. 05-0.5 mol.
  • 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 mol, preferably 2 to 3 mol, per 1 mol of compound (7).
  • the solvent that does not adversely influence the reaction include water, alcohols, ethers, hydrocarbons, amides and the like. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • 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 a known general method is 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, Conversion to alcohol form by alkylation, reductive amination of carbonyl, oximation of carbonyl, acylation / urealation / sulfonylation / alkylation of amino, substitution of active halogen with amine / amination, amino by reduction of nitro , Hydroxy alkylation, hydroxy substitution / amination.
  • a protective group may be added to the reactive substituent beforehand by means known per se, if necessary. After the introduction and the intended reaction, 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 eg, hydroxy of compound (I) acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, Dimethylaminomethylcarbonylated compounds, etc.
  • carboxy of compound (I) is an amino of the compound (I) is acy
  • 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 mixture of crystal forms. Crystals 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, non-hydrate, solvate or non-solvate. Compounds labeled with isotopes (eg, 2 H, 3 H, 14 C, 35 S, 125 I) and the like are also encompassed in compound (I). Further, compound (I) may be a deuterium converter.
  • the compound (I) of the present invention or a prodrug thereof interacts with, for example, a human Smo protein and changes its three-dimensional structure to thereby change its cytoplasm. Inhibits the Hedgehog signal transduction system by inhibiting complex formation with proteins involved in signal transduction.
  • the compound of the present invention interacts with the human Smo protein and directly inhibits the complex formation of the human Smo protein and the protein involved in the Hedgehog signal transduction system in the cytoplasm, thereby inhibiting the Hedgehog signal transduction system.
  • the compound of the present invention interacts with a modified site received from a protein involved in the Hedgehog signal transduction system of the Smo protein, for example, phosphorylation site, etc., thereby inhibiting modification such as phosphorylation of Smo, and the Hedgehog signal transduction system Inhibits.
  • Inhibition of the Hedgehog signal transduction system can be measured, for example, by quantifying the decrease in the expression level of the reporter gene linked downstream of the Gli binding site according to the test example 1 described below. 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 fluorescence of the cell is measured, and the value is the test compound. This can be confirmed by the decrease compared to the case where no is added.
  • 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).
  • the compounds of the present invention may be used to treat diseases that may be affected by Smo, such as cancer (eg, colon cancer (eg, colon cancer, rectal cancer, anal cancer, familial colon cancer, hereditary nonpolyposis colon cancer, digestion).
  • cancer eg, colon cancer (eg, colon cancer, rectal cancer, anal cancer, familial colon cancer, hereditary nonpolyposis colon cancer, digestion).
  • lung cancer eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, Gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (eg , Epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-grade tumor), testicular tumor, prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate cancer), liver cancer ( Eg, hepatocellular carcinoma, primary liver cancer, bil
  • the compound of the present invention is effective for brain tumor, skin cancer, lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, stomach cancer, colon cancer, sarcoma and breast cancer.
  • the compound of the present invention is effective for glioma, medulloblastoma, basal cell tumor, small cell lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, gastric cancer, colon cancer, rhabdomyosarcoma and breast cancer.
  • the compound of the present invention can be administered orally or parenterally as it is or 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.
  • examples of the dosage form for parenteral administration include injections, infusions, drops, suppositories, and the like.
  • a sustained-release preparation is also effective.
  • an appropriate base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, butyric acid polymer and glycolic acid polymer mixture, polyglycerol fatty acid ester
  • 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 adding 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.
  • disintegrants include starch and calcium carbonate.
  • the lubricant 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 physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride) and the like.
  • Suitable solubilizers such as alcohol (Eg, ethanol), polyalcohol (eg, propylene glycol, polyethylene glycol), nonionic surfactant (eg, polysorbate 80, HCO-50), etc. may be used in combination.
  • 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), stabilizers (eg, human serum albumin, polyethylene glycol), preservatives (eg, , Benzyl alcohol, phenol) and the like.
  • Buffers eg, phosphate buffer, sodium acetate buffer
  • soothing agents eg, benzalkonium chloride, procaine hydrochloride
  • stabilizers eg, human serum albumin, polyethylene glycol
  • preservatives eg, , Benzyl alcohol, phenol
  • 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 (eg, injection).
  • a liquid eg, 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), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, buserelin acetate) , Leuprorelin), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole
  • 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), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbpyramide, pendant Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and their DDS A preparation or the like is used.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT, doxy
  • anticancer antibiotics 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.
  • immunotherapeutic agent examples 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 receptor ase IGF
  • IGF insulin receptor ase IGF
  • FGF fibroblast growth factor
  • Substances having substantially the same activity [eg, acidic FG , Basic FGF, KGF (keratinocyte growth factor), FGF-10], (4) other cell growth factors (eg, CSF (erythropoietin), EPO (erythropoietin), IL-2 (interleukin-2), NGF) (Never grow growth factor), PDGF (platelet-derived growth factor), TGF ⁇ (transforming growth factor ⁇ ), HGF (hepatocyte growth factor), VEGFv
  • 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 inhibitor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (Tie2, etc.), PDGF receptor, etc. .
  • 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 Body, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor Harmful agent, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERK inhibitor An agent
  • anti-VEGF antibody Bevacizumab etc.
  • anti-HER2 antibody Trastuzumab, Pertuzumab etc.
  • anti-EGFR antibody Cetuximab, Panitumumab, Matuzumab, Nimotuzumab etc.
  • anti-VEGFR antibody Imatinib mesylate, Erlotinib, Gefitinib, Gefitinib, Gefitinib Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4- (4-Fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (1-pyrrolidinyl) propoxy] quinazoline (AZD- 2171), Lestaurtinib, Pazopanib, Canertinib, Tandutinib, 3- (4-Bromo-2,6-difluorobenzyloxy)
  • topoisomerase I inhibitor eg, irinote
  • 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 the concomitant drug in combination, an excellent effect 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 preparation at different time intervals in different administration routes (for example, administration of the compound of the present invention and then concomitant drugs, or administration in the reverse order), etc. It is done.
  • 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 ( Sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., and then oral or parenteral (eg, topical, Rectal and intravenous administration).
  • 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 is the same as the pharmacologically acceptable carrier that may be used for the production of the pharmaceutical of the present invention described above. Is mentioned. Further, if necessary, an appropriate amount of additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like that may be used in the production of the medicament of the present invention described above may be appropriately used. it can.
  • 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 combination agent 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 about 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 dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, Dextrin), stabilizer (eg, ascorbic acid, sodium pyrosulfite), surfactant (eg, polysorbate 80, macrogol), solubilizer (eg, glycerin, ethanol), buffer (eg, phosphoric acid and its alkali) Metal salts, citric acid and alkali metal salts thereof), isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose), pH regulators (eg, hydrochloric acid, sodium hydroxide), preservatives (eg, Ethyl paraoxybenzoate
  • a dispersant eg, Tween 80 (manufactured by
  • aqueous injections or olive oil
  • vegetable oils such as sesame oil, cottonseed oil and corn oil
  • a solubilizing agent such as propylene glycol
  • the compound of the present invention or the concomitant drug is added, for example, to an excipient (eg, lactose, sucrose, starch), a disintegrant (eg, starch, calcium carbonate), a binder (eg, starch, arabic).
  • an excipient eg, lactose, sucrose, starch
  • a disintegrant eg, starch, calcium carbonate
  • a binder eg, starch, arabic
  • 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) and pigments (eg, Bengala, titanium dioxide) 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 Dynamit Nobel, Germany)] Or vegetable oil (eg, sesame oil, soybean oil, cottonseed oil) and the like.
  • the aqueous base include polyethylene glycols and propylene glycol.
  • 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 and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferred.
  • the injection may contain benzoate and / or salicylate.
  • the injection can be 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), solubilizers (eg Eg, glycerin, ethanol), buffer (eg, phosphoric acid and its alkali metal salt, citric acid and its alkali metal salt), isotonic agent (eg, sodium chloride, potassium chloride), dispersant (eg, hydroxypropyl) Methylcellulose, dextrin), pH regulator (eg, hydrochloric acid, sodium hydroxide), preservative (eg, ethyl paraoxybenzoate, benzoic acid), solubilizer (eg, concentrated glycerin, meglumine), solubilizer (eg, propylene) Glycol, sucrose), a soothing agent (eg, glucose, benzyl alcohol) and the like can be appropriately blended.
  • additives are generally blended in a proportion usually used
  • 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 used 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 and preparation thereof
  • a sustained-release preparation comprising a core containing the compound of the present invention or a concomitant drug as desired is coated with a coating agent such as a water-insoluble substance or a swelling polymer.
  • a coating agent such as a water-insoluble substance or a swelling polymer.
  • 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
  • Methacrylic acid copolymer methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) ), Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially Hydragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / methacrylic acid trimethyl / ammonium ethyl copolymer), Eudragit NE- Curing of acrylic acid polymers such as Eudragits (Rohm Pharma Co., Ltd.) such
  • 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 sodium carboxymethylcellulose.
  • 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, lower alcohol such as water, methanol, ethanol) from the coating agent solution.
  • the sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then coating the obtained core with a film agent solution in which a water-insoluble substance or a swellable polymer is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
  • nucleus containing a drug coated with a film agent is not particularly limited, but is preferably formed in a particle shape such as a granule or a fine particle.
  • 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.
  • suitable excipients, binders, disintegrants, lubricants, stabilizers and the like are mixed with the drug, and prepared by wet extrusion granulation method, fluidized bed granulation method and the like.
  • 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 an inorganic salt thereof, and polyethylene glycol or the like as a lubricant
  • polyethylene glycol or the like polyethylene glycol or the like
  • acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
  • the nucleus may be formed by spraying a binder dissolved in an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol) on an inert carrier particle that is the center of the nucleus. 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.
  • the protective agent for example, the hydrophilic substance, the water-insoluble substance, or the like is used.
  • the protective agent is preferably a polysaccharide having polyethylene glycol or hydroxyalkyl or carboxyalkyl, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • 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 spray coating the core by, for example, a fluidized bed coating method or a pan coating method.
  • Coating of the core with a coating agent The core obtained in I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. As a result, a sustained-release preparation is produced.
  • a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent.
  • a sustained-release preparation is produced.
  • Examples of the method of coating the core with a coating agent 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), more preferably, with respect to the core (excluding the coating amount of the protective agent). 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 an ordinary coating method.
  • the coating solution is spray coated on the core by a fluidized bed coating method, a pan coating method or the like.
  • a fluidized bed coating method e.g., a fluidized bed coating method, a pan coating method or the like.
  • an antistatic agent such as talc may be mixed as necessary.
  • the immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particulate, pill, tablet, etc.).
  • oral administration agents and parenteral administration agents such as injections are used, and oral administration agents are preferred.
  • 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 hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Proprotab), partially pregelatinized starch (Asahi Kasei Co., Ltd.) Manufactured, PCS), etc., for example, using water that absorbs, swells in contact with water, or that disintegrates granules by creating a channel between the active ingredient constitu
  • 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, polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants ( For example, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (for example, Aerosil (Nippon Aerosil)), surfactants (for example, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters and poly Non-ionic surfactants such as oxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.), colorants (eg tar dyes, caramel, bengara, titanium oxide, riboflavins), essential If necessary, flavoring
  • binders for example, sucrose, gelatin, gum arabic powder, methylcellulose
  • 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 such as 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 one oral administration preparation (eg, granule, fine granule, tablet, capsule) together with a preparation excipient or the like as it is or as appropriate.
  • 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 intraoral quick disintegrating agent and preparation thereof may be a solid preparation such as a tablet, or an oral mucosal patch (film) It may be.
  • 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 derivative eg, hydroxypropyl- ⁇ -cyclodextrin
  • the like may be contained in order to facilitate absorption and increase the 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, crosslinkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose). 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. are added to increase the adhesion of the film to the mucosal lining of the oral cavity and to contain glycols such as polyethylene glycol and propylene glycol to give the film moderate elasticity.
  • 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.
  • the matrix-forming agent examples include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyllium seed proteins; gum substances such as gum arabic, guar gum, agar and xanthan; Examples include sugars, alginic acids, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such as polyvinylpyrrolidone, gelatin-gum arabic complex, and the like.
  • sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and 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.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue No. 2 and FD & C Red No. 40 from Ellis and Everard.
  • Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof.
  • Suitable pH adjusting agents 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 type, age, weight, symptom, dosage form, administration method, administration period, etc. of the compound of the present invention. For example, it is usually per 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, especially about 0 per 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. Although it is not limited, 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 the mammal 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 prolongation of life.
  • treatment with the compound of the present invention or the concomitant drug of the present invention and supportive therapy [(i) antibiotics (for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin) for the co-occurrence of various infectious diseases Administration, (ii) high calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins, (iii) morphine administration for pain relief, (iv) nausea, vomiting, loss of appetite, diarrhea, leukopenia, Combination of drugs to improve side effects such as thrombocytopenia, decreased hemoglobin concentration, hair loss, liver damage, kidney damage, DIC, fever, and (v) administration of drugs to suppress multidrug resistance of cancer, etc.) You can also.
  • antibiotics for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin
  • 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, inclusion body), subcutaneous and intramuscular injection. It is preferred to administer (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration.
  • 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.
  • N-methylbenzamide (15 g, 110 mmol) was dissolved in thionyl chloride (250 mL), heated under reflux for 2 hours, and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (290 mL), cooled to ⁇ 78 ° C., and triethylamine (56 g, 550 mmol) was added dropwise to the solution. After stirring at the same temperature for 30 minutes, a tetrahydrofuran solution (100 mL) in which benzyl 4- (hydroxyimino) piperidine-1-carboxylate (13.8 g, 55 mmol) was dissolved was added dropwise.
  • reaction solution was slowly warmed to room temperature, then further heated to reflux temperature and stirred for 18 hours. After cooling, the oil obtained by concentrating the reaction solution under reduced pressure was dissolved in ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was subjected to silica gel chromatography, and the fraction eluted with ethyl acetate was concentrated to give the title compound (12 g, 45%). Obtained as an oil.
  • N 3 -methylpyridine-3,4-diamine (570 mg, 79%) as crude crystals.
  • a mixture of this crude crystal and 4-tert-butylbenzoic acid (890 mg, 5 mmol) and polyphosphoric acid (20 g) was heated at 170 ° C. for 2 hours.
  • the reaction solution was poured into ice water, made basic with 8N sodium hydroxide, and extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.0 g, 86%) as colorless crystals.
  • Acetic anhydride (0.253 mL, 2.68 mmol) was added to a solution of the compound of Reference Example 22 (0.81 g, 2.23 mmol) and triethylamine (0.464 mL, 3.35 mmol) in THF (40 mL) under ice cooling, and the mixture was stirred at room temperature for 16 hours. Stir. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Tables 1-1 to 1-33 show the structural formulas, HPLC purity (%), mass spectrum data and yield (%) of the compounds obtained in Examples 14 to 202.
  • Tables 2-1 to 2-2 show the structural formulas and mass spectrum data of the compounds obtained in Examples 203 to 211.
  • the title compound (120 mg, 61%) was obtained as a white powder from the compound of Reference Example 2 (120 mg, 0.50 mmol) and 2-methoxybenzaldehyde (136 mg, 1.00 mmol) by the same method as in Example 214.
  • the title compound (176 mg, 35%) was obtained as a white powder from the compound of Reference Example 32 (300 mg, 1.22 mmol) and 2,5-difluorobenzaldehyde (348 mg, 2.44 mmol) by the same method as in Example 218. It was.
  • the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and extracted with ethyl acetate.
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by basic silica gel column chromatography (eluent; ethyl acetate), and recrystallized from ethyl acetate-hexane to give the title compound (60 mg, 37%) as a pale-yellow powder.
  • Example 224 In the same manner as in Example 224, the title compound (766 mg, 44%) was pale yellow from the compound of Reference Example 4 (1.0 g, 4.32 mmol) and 5-chloro-2-nitrobenzaldehyde (1.20 g, 6.49 mmol). Obtained as crystals.
  • Acetic anhydride (45 mg, 0.44 mmol) was added to a THF (10 mL) solution of the compound of Example 227 (150 mg, 0.40 mmol) and triethylamine (45 mg, 0.44 mmol), and the mixture was stirred at room temperature for 19 hours.
  • the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 232 In the same manner as in Example 232, the title was obtained from the compound of Reference Example 14 (260 mg, 1.07 mmol) and 1- (chloromethyl) -2-methoxybenzene in 50% w / w dichloromethane (335 mg, 1.07 mmol). The compound (79 mg, 17%) was obtained as a pale yellow solid.
  • Example 236 The compound of Example 236 (475 mg, 1.33 mmol) and 2N aqueous sodium hydroxide / ethanol (5 mL / 5 mL) were heated to reflux for 2 hours. The reaction solution was air-cooled and then diluted with water. The aqueous layer was washed with ethyl acetate and then neutralized with hydrochloric acid. Subsequently, the precipitate was collected by filtration and washed successively with water and diethyl ether to give the title compound (80 mg, 16%) as a white solid.
  • Example 237 The compound of Example 237 (423 mg, 1.12 mmol), 2.0M THF solution of methylamine (1.68 mL, 3.36 mmol), WSCD (322 mg, 1.68 mmol), HOBt (227 mg, 1.68 mmol), triethylamine (1.16 mL) , 8.40 mmol) and DMF (7 mL) were stirred at room temperature for 16 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the title compound (48 mg, 23%) was obtained as colorless crystals from the compound of Reference Example 18 (143 mg, 0.5 mmol) and 5-fluoro-2-methoxybenzaldehyde (92 mg, 0.6 mmol).
  • the compound of Reference Example 18 (143 mg, 0.5 mmol), 5-fluoro-2-methoxybenzaldehyde (92 mg, 0.6 mmol), sodium triacetoxyborohydride (318 mg, 1.5 mmol) and acetic acid / A mixture of THF (2 mL / 8 mL) was stirred at room temperature for 16 hours.
  • Example 239 the title compound (40 mg, 0.5 mmol) was obtained from the compound of Reference Example 18 (143 mg, 0.5 mmol) and 2,3-dihydro-1-benzofuran-7-carbaldehyde (89 mg, 0.6 mmol). 19%) was obtained as colorless crystals.
  • Example 239 the title compound (205 mg, 0.51 mmol) was obtained from the compound of Reference Example 24 (150 mg, 0.555 mmol) and 2,3-dihydro-1-benzofuran-7-carbaldehyde (164 mg, 1.11 mmol). 92%) was obtained as a light brown oil.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the title compound (202 mg, 78%) was obtained as a colorless amorphous substance from the compound of Reference Example 26 (202 mg, 0.486 mmol) and 2-methoxybenzaldehyde (0.117 mL, 0.972 mmol) by the same method as in Example 239. It was.
  • Example 212 the title compound (143 mg, 40%) was obtained from the compound of Reference Example 4 (200 mg, 0.86 mmol) and 4-chloro-2-methoxyphenyl isocyanate (191 mg, 1.0 mmol). Obtained as white crystals.
  • Acetyl chloride (0.060 mL, 0.85 mol) was added to a solution of the compound of Example 279 (70 mg, 0.17 mmol) and triethylamine (0.21 mL, 1.5 mmol) in THF (5.0 mL) under ice-cooling, and then at room temperature for 30 minutes Stir. Further triethylamine (0.21 mL, 1.5 mmol) and acetyl chloride (0.060 mL, 0.85 mol) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • the solution was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the title compound (50 mg, 30%) was obtained as pale-yellow crystals from the compound of Example 281 (150 mg, 0.43 mmol) by the same method as in Example 263. Specifically, acetyl chloride (0.061 mL, 0.86 mmol) was added to a solution of the compound of Example 281 (150 mg, 0.43 mmol) and triethylamine (0.30 mL, 2.2 mmol) in THF (5.0 mL) under ice cooling, Stir at room temperature for 1 hour.
  • Triethylamine (0.10 mL, 0.70 mmol) and acetyl chloride (0.020 mL, 0.29 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours.
  • Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Example 270 In the same manner as in Example 270, the title compound (111 mg, 69%) was prepared as pale yellow crystals from the compound of Example 282 (133 mg, 0.38 mmol) and 2-methylpropanoyl chloride (0.080 mL, 0.76 mol). Obtained.
  • Example 270 In the same manner as in Example 270, the title compound (47 mg, 29%) was obtained as pale-brown crystals from the compound of Example 281 (141 mg, 0.40 mmol) and propanoyl chloride (0.070 mL, 0.81 mol).
  • Example 270 In the same manner as in Example 270, the title compound (50 mg, 33%) was obtained as pale yellow crystals from the compound of Example 281 (127 mg, 0.36 mmol) and 2-methylpropanoyl chloride (0.076 mL, 0.73 mol). Obtained.
  • Lithium hydroxide monohydrate (67 mg, 2.8 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr.
  • Lithium hydroxide monohydrate (34 mg, 1.4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hr.
  • the reaction mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure to give 4- [5- (2,5-dimethoxybenzyl) -3-methyl-4,5,6,7-tetrahydro-3H-imidazo [4 , 5-c] pyridin-2-yl] benzoic acid was obtained as a pale yellow oil.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un dérivé hétérocyclique fusionné ayant une forte activité inhibitrice de Smo et sur l'utilisation du dérivé hétérocyclique fusionné. De façon spécifique, l'invention porte sur un composé représenté par la formule (I) (dans laquelle les symboles sont tels que définis dans la description) ou un sel de celui-ci, et un produit pharmaceutique contenant le composé ou un promédicament de celui-ci, qui est un inhibiteur de Smo ou un agent pour la prévention/traitement de cancers.
PCT/JP2009/064659 2008-08-22 2009-08-21 Dérivé hétérocyclique fusionné et son utilisation WO2010021381A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008214377 2008-08-22
JP2008-214377 2008-08-22

Publications (1)

Publication Number Publication Date
WO2010021381A1 true WO2010021381A1 (fr) 2010-02-25

Family

ID=41707255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/064659 WO2010021381A1 (fr) 2008-08-22 2009-08-21 Dérivé hétérocyclique fusionné et son utilisation

Country Status (1)

Country Link
WO (1) WO2010021381A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015086521A1 (fr) * 2013-12-09 2015-06-18 Ucb Biopharma Sprl Dérivés de tétrahydroimidazopyridine comme modulateurs de l'activité du tnf
EP3124482A4 (fr) * 2014-03-24 2017-03-22 Guangdong Zhongsheng Pharmaceutical Co., Ltd Dérivés de quinoléine comme inhibiteurs de smo
WO2017153601A1 (fr) * 2016-03-11 2017-09-14 Ac Immune Sa Composés bicycliques pour diagnostic et traitement
CN107188891A (zh) * 2017-06-29 2017-09-22 天津药明康德新药开发有限公司 一种5‑(叔丁基羰基)‑1‑甲基‑咪唑并吡啶‑7‑羧酸的合成方法
WO2019037861A1 (fr) * 2017-08-24 2019-02-28 Asceneuron S.A. Inhibiteurs de glycosidases annelés
US10266542B2 (en) 2017-03-15 2019-04-23 Mirati Therapeutics, Inc. EZH2 inhibitors
US10336775B2 (en) 2014-08-28 2019-07-02 Asceneuron Sa Glycosidase inhibitors
US10556902B2 (en) 2016-02-25 2020-02-11 Asceneuron Sa Glycosidase inhibitors
US10696668B2 (en) 2016-02-25 2020-06-30 Asceneuron Sa Acid addition salts of piperazine derivatives
US11091495B2 (en) 2018-01-31 2021-08-17 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US11261183B2 (en) 2016-02-25 2022-03-01 Asceneuron Sa Sulfoximine glycosidase inhibitors
US11612599B2 (en) 2016-02-25 2023-03-28 Asceneuron Sa Glycosidase inhibitors
US11731972B2 (en) 2018-08-22 2023-08-22 Asceneuron Sa Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors
US12016852B2 (en) 2018-08-22 2024-06-25 Asceneuron Sa Pyrrolidine glycosidase inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005507860A (ja) * 2001-07-27 2005-03-24 キュリス インコーポレイテッド ヘッジホッグシグナル伝達経路メディエーター、それに関連した組成物及び利用
JP2007535569A (ja) * 2004-04-30 2007-12-06 ジェネンテック，インコーポレイティド ヘッジホッグシグナル伝達のキノキサリン阻害剤
JP2008519044A (ja) * 2004-11-03 2008-06-05 キューリス，インコーポレーテッド ヘッジホッグ・シグナル伝達経路の伝達物質、調合物、及び、それに関連する使用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005507860A (ja) * 2001-07-27 2005-03-24 キュリス インコーポレイテッド ヘッジホッグシグナル伝達経路メディエーター、それに関連した組成物及び利用
JP2007535569A (ja) * 2004-04-30 2007-12-06 ジェネンテック，インコーポレイティド ヘッジホッグシグナル伝達のキノキサリン阻害剤
JP2008519044A (ja) * 2004-11-03 2008-06-05 キューリス，インコーポレーテッド ヘッジホッグ・シグナル伝達経路の伝達物質、調合物、及び、それに関連する使用

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105814044A (zh) * 2013-12-09 2016-07-27 Ucb生物制药私人有限公司 作为tnf活性调节剂的四氢咪唑并吡啶衍生物
JP2016539966A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのテトラヒドロイミダゾピリジン誘導体
WO2015086521A1 (fr) * 2013-12-09 2015-06-18 Ucb Biopharma Sprl Dérivés de tétrahydroimidazopyridine comme modulateurs de l'activité du tnf
US9834553B2 (en) 2013-12-09 2017-12-05 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of TNF activity
EP3124482A4 (fr) * 2014-03-24 2017-03-22 Guangdong Zhongsheng Pharmaceutical Co., Ltd Dérivés de quinoléine comme inhibiteurs de smo
US9938292B2 (en) 2014-03-24 2018-04-10 Guangdong Zhongsheng Pharmaceutical Co., Ltd Quinoline derivatives as SMO inhibitors
US10336775B2 (en) 2014-08-28 2019-07-02 Asceneuron Sa Glycosidase inhibitors
US11046712B2 (en) 2014-08-28 2021-06-29 Asceneuron Sa Glycosidase inhibitors
US10995090B2 (en) 2016-02-25 2021-05-04 Asceneuron Sa Substituted dihydrobenzofuran glycosidase inhibitors
US11591327B2 (en) 2016-02-25 2023-02-28 Asceneuron Sa Acid addition salts of piperazine derivatives
US11612599B2 (en) 2016-02-25 2023-03-28 Asceneuron Sa Glycosidase inhibitors
US11261183B2 (en) 2016-02-25 2022-03-01 Asceneuron Sa Sulfoximine glycosidase inhibitors
US10556902B2 (en) 2016-02-25 2020-02-11 Asceneuron Sa Glycosidase inhibitors
US10696668B2 (en) 2016-02-25 2020-06-30 Asceneuron Sa Acid addition salts of piperazine derivatives
KR102464274B1 (ko) 2016-03-11 2022-11-07 에이씨 이뮨 에스에이 진단 및 치료를 위한 바이사이클릭 화합물
KR20180117707A (ko) * 2016-03-11 2018-10-29 에이씨 이뮨 에스.에이. 진단 및 치료를 위한 바이사이클릭 화합물
WO2017153601A1 (fr) * 2016-03-11 2017-09-14 Ac Immune Sa Composés bicycliques pour diagnostic et traitement
EP4001277A3 (fr) * 2016-03-11 2022-09-14 AC Immune SA Composes bicycliques pour le diagnostic et le traitement
US10266542B2 (en) 2017-03-15 2019-04-23 Mirati Therapeutics, Inc. EZH2 inhibitors
CN107188891A (zh) * 2017-06-29 2017-09-22 天津药明康德新药开发有限公司 一种5‑(叔丁基羰基)‑1‑甲基‑咪唑并吡啶‑7‑羧酸的合成方法
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US11458140B2 (en) 2017-08-24 2022-10-04 Asceneuron Sa Annulated glycosidase inhibitors
WO2019037861A1 (fr) * 2017-08-24 2019-02-28 Asceneuron S.A. Inhibiteurs de glycosidases annelés
US11220509B2 (en) 2018-01-31 2022-01-11 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11485738B2 (en) 2018-01-31 2022-11-01 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11091495B2 (en) 2018-01-31 2021-08-17 Mirati Therapeutics, Inc. Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors
US11731972B2 (en) 2018-08-22 2023-08-22 Asceneuron Sa Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors
US12016852B2 (en) 2018-08-22 2024-06-25 Asceneuron Sa Pyrrolidine glycosidase inhibitors

Similar Documents

Publication Publication Date Title
WO2010021381A1 (fr) Dérivé hétérocyclique fusionné et son utilisation
JP5739334B2 (ja) 縮合複素環誘導体およびその用途
JP5238697B2 (ja) 縮合複素環誘導体およびその用途
JP5350247B2 (ja) 複素環化合物およびその用途
JP5352476B2 (ja) キナーゼ阻害剤としての二環式複素環化合物
JP4719317B2 (ja) 縮合複素環誘導体およびその用途
JP5722781B2 (ja) 縮合複素環誘導体およびその用途
CA2714181A1 (fr) Modulateurs de l'ampk
JP2012510467A (ja) 抗癌剤としてのベンゾチアゾール誘導体
EP2597095A1 (fr) Composé hétérocyclique fusionné et application associée
WO2009119776A1 (fr) Dérivé hétérocyclique condensé et son utilisation
JP5579619B2 (ja) 複素環化合物およびその用途
JP2010077109A (ja) 複素環化合物およびその用途
JP5659159B2 (ja) 縮合複素環誘導体およびその用途
JP5599802B2 (ja) 縮合複素環誘導体およびその用途
KR20180096609A (ko) 섬유증 질병의 치료 및/또는 예방을 위한 아미노나프토퀴논 화합물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09808317

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase

Ref document number: 09808317

Country of ref document: EP

Kind code of ref document: A1