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WO1999030739A1 - Remede contre la leucemie - Google Patents

Remede contre la leucemie Download PDF

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Publication number
WO1999030739A1
WO1999030739A1 PCT/JP1998/005657 JP9805657W WO9930739A1 WO 1999030739 A1 WO1999030739 A1 WO 1999030739A1 JP 9805657 W JP9805657 W JP 9805657W WO 9930739 A1 WO9930739 A1 WO 9930739A1
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group
carbon atoms
linear
branched
atom
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PCT/JP1998/005657
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English (en)
Japanese (ja)
Inventor
Yukiko Tokumitsu
Kouichi Tamoto
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Sankyo Company, Limited
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Priority to AU15077/99A priority Critical patent/AU1507799A/en
Publication of WO1999030739A1 publication Critical patent/WO1999030739A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the present invention relates to a preventive or therapeutic agent for leukemia containing an insulin sensitizer as an active ingredient, a composition for preventing or treating leukemia containing an insulin sensitizer as an active ingredient, a method for preventing or treating leukemia,
  • the present invention relates to a method for preventing or treating leukemia in which a medicament for treatment is used, or a pharmacologically effective amount of an insulin resistance improving substance is administered to a warm-blooded animal.
  • Leukemia is a disease based on the systematic and unrestricted growth of hematopoietic tissues and is regarded as a malignant tumor of hematopoietic tissues.
  • Clinically abnormal blood cells that are not normally found in peripheral blood appear, causing leukemia cells to proliferate and infiltrate into the bone marrow and other systemic organs.
  • various infections, anemia, bleeding, It is characterized by various organ disorders due to infiltration.
  • the incidence is increasing worldwide, and the major causes of leukemia are genetic factors and viral infections such as retroviruses.
  • treatments for leukemia include chemotherapy, radiation therapy, immunotherapy, and combinations thereof.
  • leukemia therapeutic agents for example, in acute leukemia, which accounts for about 80% of leukemia in Japan, antimetabolites cytarabine (Ara-C), 6-mercaptopurine (6-MP), methotrexet ( MXM), anticancer antibiotics daunorubicin (DNR), idarubicin (IDR), alkylating agent cyclophosphamide (CY), plant alkaloid vincristine (VCR), podophyllotoxin derivative etoposide (VP Alkylating agents such as busulfan (BUS) and dimustine (ACU) are used in chronic leukemia, which accounts for about 20%.
  • an insulin sensitizer has an action of improving such a condition when the action of insulin is incomplete despite the presence of endogenous insulin.
  • Compounds having various structures are known as such an insulin resistance improving substance. Examples thereof include thiazolidinedione compounds, oxazolidinedione compounds, isooxazolidinedione compounds, and oxaziazolidinedione compounds.
  • insulin sensitizers are used as preventive or therapeutic agents for diabetes, It is known that it can be used for prevention or treatment of various diseases such as diabetic complications.
  • Japanese Patent Application Laid-Open No. Sho 60-511189 U.S. Pat. No. 4,572,912, EP 1339421 A, etc. discloses 5— [4— (6 —Hydroxy-1,2,5,7,8-tetramethylchroman-12-ylmethoxy) benzyl] thiazolidin-12,4-dione (hereinafter referred to as “troglitazone”) has an activity to enhance insulin action.
  • leukemia is not disclosed as a specific disease, and there is no description or suggestion that the insulin sensitizer is useful for the prevention or treatment of leukemia.
  • the sensitivity of cancer cells to a drug may vary depending on the type of cancer, for example, a therapeutic agent for breast cancer or knee cancer is not always useful as a therapeutic agent for leukemia.
  • retinoide compounds having a thiazolidinedione structure are described in Chem. Pharm. Bull., 45 (11), 1805 (1997). Have a leukemia cell differentiation inducing activity.
  • these retinoid compounds having a thiazolidinedione structure are not included in the claims of the present application, and there is no direct description that they can be used as therapeutic agents for leukemia.
  • WO 9255,988 and WO 98,291,13 describe thiazolidinedione compounds, and these compounds are used for leukemia. It is also disclosed that it can be a therapeutic agent.
  • these conjugates have been used as agonists or activators of PPAR ⁇ (Peroxisome Prolator if Activated Receptor).
  • PPAR ⁇ Peroxisome Prolator if Activated Receptor
  • the compound of the present application The use of PPAR ⁇ is not limited to use as an agonist or activator of PPAR ⁇ .
  • the present inventors have conducted intensive studies on the pharmacological activity of the insulin sensitizer, and found that the insulin sensitizer significantly improves leukemia and is useful as a preventive or therapeutic agent for leukemia. We have completed the present invention.
  • the present invention relates to a preventive or therapeutic agent for leukemia containing an insulin sensitizer as an active ingredient, a composition for preventing or treating leukemia containing an insulin sensitizer as an active ingredient, a method for preventing or treating leukemia,
  • the present invention relates to a method for preventing or treating leukemia in which a medicament for treatment is used, or a pharmacologically effective amount of an insulin resistance improving substance is administered to a warm-blooded animal.
  • the insulin sensitizer is a thiazolidinedione compound, an iminothiazol idinone compound, a diiminothiazolidine compound, a thioxothiazol idinone compound, or an iminotriazole.
  • oxadiazolidinedione compounds more preferably thiazolidinedione compounds, iminothiazolidinone compounds and diiminothiazolidine compounds, particularly preferably thiazolidinedione compounds.
  • thiazolidinedione compounds are compounds and Okisazoriji Njion compounds, and optimally about prophylactic or therapeutic agents of leukemia containing compound is a thiazolidinedione compound as an active ingredient.
  • the thiazolidinedione compound and the like include pharmacologically acceptable salts thereof.
  • insulin sensitizer examples include the following compounds.
  • R h and a are the same or different and each represent a hydrogen atom or a T alkyl group having 1 to 5 carbon atoms,
  • R 3a is a hydrogen atom, an aliphatic acyl group having 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 6 to 8 carbon atoms, a benzoyl or naphthoyl group optionally having a substituent (a) a
  • the substituent (a) 3 is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, an amino group, a 1 to 4 carbon atoms.
  • a hetero atom composed of a nitrogen atom, an oxygen atom and a sulfur atom A 4- to 7-membered heterocyclic acyl group containing 1 to 3 heteroatoms selected from the group, a phenylacetyl group, a phenylpropionyl group, and a phenylacetyl group substituted with at least one halogen.
  • Hue - Rupuropioniru group cinnamoyl group, an alkoxycarbonyl alkylsulfonyl group or a benzyl O alkoxycarbonyl group having 2 to 7 carbon atoms,
  • R 4a and R 4 are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, or R 4a and R 5a together represent Represents an alkylenedioxy group having the number 1 to 4,
  • Y a ⁇ Pi Za are the same or different and each represents an oxygen atom or an imino group
  • na represents an integer of 1 to 3.
  • R la , R 2a , R 4a or R 5a represents an alkyl group
  • the group is a linear or branched alkyl group having 1 to 5 carbon atoms, for example, methyl, Ethynole, propyl, isopropyl, butynole, isobutynole, s-butyl, t-butynole, pentynole, 1-methylbutynole, 2-methylinobutynole, 3-methylinobutynole, 1-ethylpropyl, 2-ethylpropyl. It is preferably an alkyl group having 1 to 4 carbon atoms, and most preferably a methyl group.
  • R 3a represents an aliphatic acyl group having 1 to 6 carbon atoms
  • the group is a linear or branched aliphatic acyl group, for example, formyl, acetyl, propionyl, butyrinole, Isobutyryl, pivaloyl, linolenic, linolenic and hexanol.
  • R3a represents a cycloalkylcarbonyl group
  • the group is a group having 6 to 8 carbon atoms (for example, the cycloalkyl moiety has 5 to 7 carbon atoms), for example, cyclopentylcanolebonyl and cyclohexyl.
  • Xylcarbonyl and cycloheptylcarbonyl are examples of cycloalkylcarbonyl groups.
  • R 3a represents a heterocyclic acyl group
  • the group is a group in which a heterocyclic group is bonded to a carbonyl group.
  • the heterocyclic moiety is a 4- to 7-membered ring, preferably a 5- or 6-membered ring, and has 1 to 3, preferably 1 or 2, selected from a heteroatom group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. , But optimally has one heteroatom. If the heterocyclic moiety has three heteroatoms, preferably all are nitrogen atoms or one or two are nitrogen atoms and accordingly two or one are oxygen and / or sulfur atoms.
  • the heterocyclic moiety is preferably an aromatic ring.
  • the heterocyclic acyl group is a furoyl (preferably 2-furyl), tenyl (preferably 3-tenol), 3-pyridinecarbonyl (nicotinoyl), 4-pyridinecarbonyl (isonicotinol) group.
  • R3a represents an alkoxycarbonyl group
  • the group is a straight-chain or branched-chain alkoxycanolebonyl group having 1 to 6 alkoxy moieties, that is, having a total of 2 to 7 carbon atoms.
  • the substituent (a) a represents an alkyl group
  • the group is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, the alkyl groups exemplified as R la and R 2a Is the same as
  • the substituent (a) a represents an alkoxy group
  • the group is a linear or branched alkoxy group having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy. , Isobutoxy, s-butoxy, t-butoxy. Preferably, it is a methoxy group.
  • the substituent (a) a represents a monoalkylamino group
  • the group is a linear or branched alkylamino group having 1 to 4 carbon atoms, for example, methylamino, ethylamino, propylamino, isopropylamino.
  • it is a methylamino group.
  • the group is a linear or branched dialkylamino group in which each alkyl moiety has 1 to 4 carbon atoms, such as dimethylamino, getylamino, Dipropylamino, diisopropylamino, dibutylamino, disobutylamino, di-s-butylamino, di-t-butylamino, N-methyl-1-N-ethynoleamino, N-methyl-1-N-propylamino, N-methyl-1-N-isopropylamino Mino, N-methyl-N-butylamino, N-methinolay N-isobutylamino, N-methyl-N-s-butylamino, N-methylinolate N-t-butynoleamino, N-ethinole N-propynoleamino, N-ethinole N- Iso
  • R 4a or R 5a represents an alkoxy group
  • the group is a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, s-butoxy, t-butoxy, and pentyloxy. It is preferably an alkoxy group having 1 to 4 carbon atoms, and most preferably a methoxy group.
  • R 4a and R 5a together represent an alkylenedioxy group
  • the group is an alkylenedioxy group having 1 to 4 carbon atoms, for example, methylenedioxy, ethylenedioxy, propylenedioxy, tri Methylenedioxy and tetramethylenedioxy.
  • they are a methylenedioxy group and an ethylenedioxy group.
  • preferred compounds are shown below.
  • R2a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R3a is a hydrogen atom, an aliphatic acryl group having 1 to 4 carbon atoms, a benzoyl or naphthoyl group having no substituent, or an alkoxycarbonyl group having 2 to 4 carbon atoms.
  • R3a is a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group.
  • R3a is a hydrogen atom, an acetyl group or an ethoxycarbonyl group.
  • R 4a is an alkyl group having 1 to 4 carbon atoms.
  • R 4a is an alkyl group having 1 to 4 carbon atoms.
  • the compound wherein is a methyl group or a t_butyl group.
  • R 5a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R la in the order of (2), (3), in R 2a , in the order of (4), (5), in R 3a , in the order of (6)-(8), and in ( 9) and (10), and in R5a, (11) and (12) are ranked in favorable order. Also, select from 2 to 5 from (2)-(3), (4)-(5), (6)-(8), (9)-(10) and (1 1)-(12), Arbitrary combinations of these are also suitable, and such combinations are shown below, for example.
  • Rla is an alkyl group having 1 to 4 carbon atoms
  • R 2a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • R 3a is a hydrogen atom, an aliphatic acyl group having 1 to 4 carbon atoms, a benzoyl or naphthoyl group having no substituent Or an alkoxycarbonyl group having 2 to 4 carbon atoms,
  • R is an alkyl group having 1 to 4 carbon atoms
  • R 5a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R la is an alkyl group having 1 to 4 carbon atoms
  • R 2a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • R 3a is a hydrogen atom, an acetyl group, a benzoyl group or an ethoxycarbonyl group
  • R 4a is an alkyl group having 1 to 4 carbon atoms
  • R 5a is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • Rla is a methyl group
  • R 2a is a hydrogen atom or a methyl group
  • R 3a is a hydrogen atom, an acetyl group or an ethoxycarbonyl group; R 4a is a methyl group or a t-butyl group; A compound wherein R 5a is a hydrogen atom or a methyl group.
  • troglitazone 5- [4- (6-hydroxy2,5,7,8-tetramethylchroman-12-ylmethoxy) benzyl] thiazolidine-12,4-dione (hereinafter referred to as troglitazone),
  • n c 0, 1 or 2;
  • R c is a hydrogen atom, a methyl group or an ethyl group
  • R k is a hydrogen atom, a cycloalkyl group having 5 to 7 carbon atoms, a methyl-substituted cycloalkyl group having 6 to 8 carbon atoms, a pyridyl group, a cyenyl group, a furyl group, a naphthyl group, a p-biphenylyl group A tetrahydrobranyl group, a tetrahydrocenyl group, a tetrahydrobiranyl group, a C 6 HW 2c group [W 2c is a hydrogen atom, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 4 carbon atoms, An alkoxy group having 1 to 4 carbon atoms or an alkylthio group having 1 to 4 carbon atoms.
  • a 1 k-W le group [a 1 k is an alkyl having 1 to 6 carbon atoms A hydrogen atom, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a pyridyl group, a furyl group, a phenyl group; A tetrahydrofuryl group, a tetrahydrophenyl group, a naphthyl group, a cycloalkyl group having 5 to 7 carbon atoms, or a C 6 H 4 W2c group. ]
  • R 2C is a hydrogen atom or a methyl group
  • R 3c is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a C 6 H 4 W 2e group or a benzyl group, and — R 4C is a hydrogen atom,
  • RIC and R2c When RIC and R2c are taken together they form an alkylene group having 4 to 6 carbon atoms, and R4e are each a hydrogen atom,
  • R3c and R2e are each a hydrogen atom
  • R2C and R k are summer together, they form an alkylene group which have a 3 or 4 carbon atoms, Rlc and R4c are each hydrogen atom. ]
  • R lc or Wlc is a cycloalkyl group
  • said group is a heptyl group cyclopentyl Le, cyclohexane cyclohexyl, cyclohexylene.
  • W2c represents an alkyl group or an alkoxy group, and represents a alkoxy group, these are the same as those described above for the substituent (a) a.
  • the group is a linear or branched alkylthio group having 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s —Butylthio and t-butylthio.
  • it is a methylthio group.
  • a 1 k represents an alkylene group having 1 to 6 carbon atoms
  • the group has 1 to 6 carbon atoms.
  • a linear or branched alkylene group having two or more groups for example, methylene, methylenolemethylene, ethylene, ethylidene, propylene, isopropylidene, propylidene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene , 3-methyltrimethylene, pentamethylene, hexamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,1dimethyltetramethylene, and 2,2-dimethyltetramethylene.
  • it is a linear or branched alkylene group having 1 to 4 carbon atoms, and most preferably, a methylene group or an ethylene group.
  • R 3c represents an alkyl group having 1 to 6 carbon atoms
  • the group is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
  • Rlc and R2c together or R3C and R together form an alkylene group having 4 to 6 carbon atoms, or R2e and R3c together have 3 to 4 carbon atoms
  • the group is a linear or branched alkylene group, such as tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyl / retrimethylene, pentamethylene, Xamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene.
  • the dashed line is unjoined, The compound according to (1), wherein nc is 0 or 1.
  • R 2c , R 3c and R are hydrogen atoms
  • R k is a hydrogen atom, cyclohexyl, C 6 H ⁇ W2c (W 2e is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group.)
  • W 2e is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group.
  • Wle is a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, a cyclohexyl group or a C 6 W 2e .
  • X c is an oxygen atom
  • Rlc is a cyclohexyl group, a cyclohexylmethyl group, a benzyl group, a fluorobenzyl group, an alkyl group having 1 to 4 carbon atoms, a hydroxymethyl group, a methoxymethyl group or an ethoxyxyl group.
  • englitazone (Hereinafter, referred to as “englitazone”) or a sodium salt thereof.
  • X c is an oxygen atom
  • Rk and R2c are each a hydrogen atom
  • R lc is a hydrogen atom, a methyl group or a benzyl group
  • Aid represents a substituted or unsubstituted aromatic heterocyclic group
  • R ld represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (where the aryl moiety may be substituted or unsubstituted), or a substituted or unsubstituted aryl group;
  • R 2d and R M are the same or different and represent a hydrogen atom, or R 2d and R M together represent a bond;
  • AM represents a benzene ring having a total of up to 5 substituents
  • n d represents an integer in the range of 2 to 6.
  • A is a substituted or unsubstituted aromatic heterocyclic group
  • the group is a 5- to 7-membered aromatic containing 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom or a nitrogen atom in the ring.
  • a monocyclic aromatic heterocyclic group for example, furyl, chenyl, pyrrolyl, aze Bur, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxoxadazolyl, triazolyl, tetrazolyl, thiaziazolyl, pyriel, pyridyl, pyridazinyl, pyrimidinyl, pyrazil. It is preferably an aromatic heterocyclic group having 5 to 7 members and having at least one nitrogen atom, and optionally having another nitrogen atom, oxygen atom or sulfur atom.
  • Said groups are preferably, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiaziazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrimidinyl, . Most preferred are, for example, pyridyl, imidazolyl, oxazolyl, pyrazinyl, thiazolyl.
  • the various aromatic heterocyclic groups described above may form fused rings with other ring groups, such as indolyl, benzofurinole, benzochenyl, benzoxazolinole, benzimidazolyl, isoquinolyl, quinolyl, quinoxalyl. is there.
  • the above aromatic heterocyclic group may be unsubstituted or substituted with one or more substituents (a) d selected from the following substituents (a).
  • substituents (a) d selected from the following substituents (a).
  • substitution (a) d is selected from:
  • Halogen atom fluorine, chlorine, bromine, iodine atom
  • alkyl group having 1 to 6 carbon atoms for example, the same groups as described for R 3e above;
  • a haloalkyl group having 1 to 6 carbon atoms for example, a group in which the alkyl group described for R 3e is substituted with one or more halogen atoms, for example, fluoromethyl, chloromethyl, bromomethyl, bromomethyl, trifluoromethyl; , Trichloromethinole, 2-funoleolechinore, 2-chloroethinole, 2-bromoethenole, 2-bromoethyl, 2,2,2-triphneoleolochinole, 2,2-diphneoleolochinole, 2, 2, 2-trichloroethinole, 2, 2-dichloroethynole, 2, 2-dibromoethynole, 3-fluoropropynole, 4-chlorobutynole, 5-pentyl pentyl, 6-hexolepentyl An alkoxy group having 1 to 6 carbon atoms, wherein the group is a linear or
  • it is an alkoxy group having 1 to 4 carbon atoms, more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, most preferably a methoxy group;
  • An aliphatic acyl group having 1 to 6 carbon atoms for example, the same groups as described in R ld below;
  • Alkanesulfonyl groups having 1 to 6 carbon atoms such as methanesulfonyl, ethanesulfonyl, prono ⁇ .
  • sulfonyl Sulphonyl, butanesul honinole, isobutane sulphoninole, s-butanes sulphoninole, t-butanes sulphoninole, pentans sulphonyl, isopentans sulphoninole, pentans sulphoninole, 2-methinole butanesulphoninole , 1 — Etino Reprono ,. ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Butanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethynolebutanesulf
  • Haloalkanesulfonyl group having 1 to 6 carbon atoms such as fluoromethane snorehoninole, chloromethaneszolehoninole, bromomethanesnolehoninole, eodomethane snorehoninole, trifnoroleolomethanesulfonyl, trichloromethanesulfonyl, 2—funolenesoloethanesnorenole , 2-cloth ethanes solehoninole, 2-bromoetane sonolehoninole, 2-ryodoethanesnolehoninole, 2, 2-2 Nolehoninole, 2,2-difluoroethanesnorefonyl, 2,2,2-trichloroethane ethanenorefoni / le, 2,2-dichloroethanes / lehonino
  • alkoxycarbonyl group in which the alkoxy moiety has 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycanolebonyl, butoxycarboninole, isobutoxycanoleboninole, s-butoxycanolebonyl, t-butoxy force / Leponyl, Pentyloxycarbonyl, Isopentinocarbonyl, Neopentinoleoxycanoleboninole, 2-Methinolebutoxycanole Boninole, 1-Ethinolepropoxycanoleboninole, Hexy / Reoxycanolebon Ninole, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutyl Toxoxycarbonyl, 1,1-d
  • alkoxycanolebonyl group having 2 to 5 carbon atoms more preferably a methoxycanoleboninole, ethoxycanoleboninole, propoxycarbonyl, isopropoxycarbonyl, butoxycarbyl, or isobutoxycarbonyl group.
  • a methoxycarbonyl group Optimally a methoxycarbonyl group;
  • acylamino group having 1 to 6 carbon atoms wherein the acyl portion is an acyl group having 1 to 6 carbon atoms included in the group described in R ld ;
  • alkane sulfonylamino group having 1 to 6 carbon atoms, wherein the alkane sulfonyl moiety is a group described above;
  • Cyano group An alkylenedioxy group, for example, the same groups as those described when R4a and R5a are linked to each other to indicate an alkylenedioxy group;
  • alkylene group having 1 to 8 carbon atoms which forms a cycloalkyl group condensed with an aromatic ring or a heterocyclic ring), a a group described in 1k and higher groups such as hexamethylene and octamethylene;
  • Rid represents an alkyl group, it is preferably a group having 1 to 6 carbon atoms, and is the same group as described for R 3c above.
  • Rid represents an acyl group, for example, an aliphatic acyl group, an alkanol group having 1 to 25 carbon atoms, preferably 1 to 20 carbon atoms, more preferably 1 to 6 carbon atoms, Optimally, it has 1 to 4 carbon atoms (e.g.
  • a stearoyl group most preferably an acetyl group
  • a halogenated alkanoyl group having 2 to 6 carbon atoms particularly a halogenated acetyl group (for example, chloroacetylinole, dichloroacetyl, trichloroacetyl, trifrenoleroacetyl);
  • aromatic acyl group preferably an arylcarbonyl group, wherein the aryl moiety has 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, and more preferably 6 or 1 0, optimally 6, and the carbocyclic group is unsubstituted or has 1 to 5, preferably 1 to 3, substituents (a) d as defined above.
  • an unsubstituted group eg, benzoyl, ⁇ -naphthoyl, / 3-naphthoyl group
  • a halogenated aryl group eg, 2-bromobenzoyl, 4-cyclobenzoyl group
  • a lower alkyl-substituted arylcarbonyl group wherein the alkyl-substituted group has 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms (eg, 2, 4, 6-trimethylbenzoyl, 4-toluoyl group);
  • a lower alkoxy-substituted arylcarbonyl group wherein the alkoxy-substituted group preferably has 1 to 5 carbon atoms, more preferably 1 to 4 carbon atoms (eg, 4-anisyl group); nitro-substituted arylarylcarbonyl group (eg, 4 —Nitrobenzoyl, 2-nitrobenzoyl group);
  • Aryl-substituted arylcarbonyl group, and the aryl-substituted moiety is as described above, except that the substituted moiety is further substituted with an aryl group (for example, a 4-phenyl-2-benzoyl group) ;
  • An alkoxycarbonyl group preferably having 2 to 7 carbon atoms, more preferably having 2 to 5 carbon atoms, and an unsubstituted group (for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl group) or A halogen atom or a tri-substituted silyl group, for example, a tri (lower alkylsilyl) group (eg, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl group);
  • an unsubstituted group for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl group
  • a halogen atom or a tri-substituted silyl group for example, a tri (lower alkylsilyl) group (eg, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsily
  • alkenyloxycarbonyl group wherein the alkenyl moiety has 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms (for example, a buroxycarbonyl or aryloxycarbonyl group);
  • aryl ring is preferably substituted with one or two lower alkoxy, nitro (e.g., benzylinoleoxycanolebonyl) , 4-methoxybenzyloxycarbonyl, 3,4-dimethoxypentinoleoxycarbonyl (2-nitrobenzyloxycanolebonyl, 4-nitrobenzyloxycarbonyl));
  • R ld represents an aralkyl group, preferably an alkyl having 1 to 6 carbon atoms Is a group substituted with at least one, preferably 1 to 3, aryl (the aryl is substituted with one or more, preferably 1 to 3 selected from the substituent ⁇ ).
  • the aralkyl group has 1 to 4 carbon atoms, more preferably 1 to 3, and most preferably 1 or 2 alkyl, wherein the alkyl is 1 to 3 unsubstituted aryl.
  • Groups substituted with e.g., benzyl, phenethyl, 1-phenylethyl, 3-phenylenopineol, ⁇ -naphthinolemethinole, naphthinolemethinole, diphenyl / lemethyl, triphenylmethyl, ⁇ -naphthyldiphenylmethyl, 9-anthrylmethyl group or lower alkyl, lower alkoxy, nitro, halogen, cyano, alkylenedioxy having 1 to 3 carbon atoms, preferably methylenedioxy, or an aryl-substituted group (eg, 4— Methylbenzyl, 2, 4, 6—trimethylbenzinole, 3, 4, 5—trimethinolebenzinole, 4-methoxybenzyl, 4-meth Xyphenenolesiphenylenolemethinole, 2-nitrobenzole, 4-nitrobenzole, 4-clozenbenzole, 4-brom
  • Rid represents a substituted or unsubstituted aryl group, it is a carbocyclic aryl group having 6 to 14, preferably 6 to 10, and most preferably 6 or 10 carbon atoms.
  • the group is one aromatic ring group or two or more fused aromatic ring groups.
  • the group is unsubstituted or substituted with one or more substituents selected from the substituents (a) d.
  • substituents selected from the substituents (a) d.
  • unsubstituted aryl group examples include phenyl, 1-naphthyl, 2-naphthyl, indenyl, phenanthrenyl, and anthracenyl groups, preferably phenyl and naphthyl groups, and most preferably phenyl group.
  • Substituted aryl groups include, for example, .2- methoxypheno ⁇ , 3- methoxyphenone, 4-methoxyphenone, 2,4-dimethoxyphenone, 2,3 -dimethoxyphenone, 2, 5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2 , 3,4-trimethoxyphenyl, 2,3,5—trimethoxyphenyl 2, 3, 6-trimethoxyphenyl, 2, 4, 6-trimethoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-isopropoxyphenyl, 3- Isopropoxyphenyl, 4- _____________, 2-methinolephen, 2- 4-methinolephen, 2, 4-dimethinolephen, 2, 3-dimethinophen, two
  • AM is a benzene ring having a maximum of 5 substitutions
  • it is preferably a group selected from the above substitutions (a) d.
  • suitable compounds are shown below.
  • R 4d and R 5d are the same or different and represent a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group, or R 4d and R 5d are the same or different and are bonded to a carbon atom; R5 ⁇ ! Together with the carbon atom to which they are attached form a benzene ring, and together each of the carbon atoms denoted by R 4d and R 5d, whether substituted or unsubstituted And in the formula (a), X ⁇ > represents an oxygen atom or a sulfur atom.
  • R 6d and R 7d are the same or different and represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl or alkoxy group).
  • A is the formula ( e )
  • R 8d and R 9d are the same or different and represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl or alkoxy group), and any one of (1) to (6)
  • the compound described in one item is the same or different and represent a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl or alkoxy group.
  • Rld, R 2d, R 3d and n d is Ri as Der as defined with respect to formula (IV) (i), R 8d and R 9d are as defined with respect to formula (e) of (7).
  • mouth diglitazone (2 — [N-methyl-N- (2-pyridyl) amino] ethoxy) benzyl ⁇ thiazolidine-1, 2, 4-dione (hereinafter referred to as “mouth diglitazone”)
  • R, R5d , RM is the definition of the group represented by R 7d R8d and R 9d, in the above publications such, R 5, R 6, R 7, R 8 and R 9 It is described as.
  • R le represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms
  • R 2e represents a linear or branched alkylene group having 2 to 6 carbon atoms
  • R 3e is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, Straight-chain or branched alkylthio group having 1 to 4 carbon atoms, halogen atom, nitro group, amino group, straight-chain or branched monoalkylamino group having 1 to 4 carbon atoms, identical or different Wherein each alkyl has a linear or branched dialkylamino group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, or 7 to 12 carbon atoms Represents an aralkyl group,
  • X e also have 1 to 3 substituents (a) Ariru group or 1 to 3 substituents having 6 to 10 carbon atoms that may have a e (a) e Shows a good aromatic heterocyclic group,
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, and (ii) a linear or branched alkyl group having 1 to 4 carbon atoms.
  • a linear or branched alkoxy group (V i) a linear or branched alkylenedioxy group having 1 to 4 carbon atoms, (V ii) a carbon number of 7 to 12 carbon atoms (V iii) a linear or branched alkylthio group having 1 to 4 carbon atoms, (i X) a carbon number
  • (X i V) the same or different, each alkyl having 1 to 4 carbon atoms, a linear or branched dialkylamino group, (XV) an aralkyl group having 7 to 12 carbon atoms, (XV i) an aryl group having 6 to 10 carbon atoms which may have a substituent (b) e; (XV ii) an aryl group having 6 to 10 carbon atoms which may have a substituent (b) e 1 Ariruokishi group having zero, and the (xviii) substituents (b) ⁇ Li one thio group having 1 0 having 6 to carbon atoms which may have a e, (X ix) substituent (b) e Arylsulfonyl group having 6 to 10 carbon atoms which may have (XX) arylsulfonyl group having 6 to 10 carbon atoms which may have (b) e ; A mino group (the nitrogen atom of the amino moiety may be substitute
  • (XXV) represents an aromatic heterocyclic sulfonylamino group (the nitrogen atom of the amino moiety may be substituted with linear or branched alkyl having 1 to 6 carbon atoms).
  • the substituent (b) e is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a straight-chain or branched chain alkyl group having 1 to 4 carbon atoms.
  • Y e is an oxygen atom, a sulfur atom or a group having the formula> N— (wherein, R 4e is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a carbon atom having 1 to 6 carbon atoms) Represents a straight-chain or branched-chain acyl group having eight.
  • Z e is 2, 4-di O Kiso thiazolidine one 5-Ili Deyuru methyl, 2, 4-di O Kiso thiazolidine one 5- Irumechiru group, 2, 4-di O Kiso O hexa oxazolidine one 5 - Irumechiru group or It represents a 3,5-dioxooxadiazolidine-12-methyl group.
  • the substituted component (a) e and the substituted component (b) e each represent an alkylenedioxy group, this is the same as the case where R 4a and R 5a together represent an alkylenedioxy group. is there.
  • R 3e and the substituent (a) e represent an alkylthio group, this is the same as that described for W2e above.
  • RK R 3e the substituted component (a) e, the substituted component (b) e, and R represent an alkyl group having 1 to 6 carbon atoms, this is the same as described above for R 3e .
  • RK substitution (a) e represents an aralkyl group, or R3e, x, and the substitution ( a ) e represents an aryl group, these are the same as those described in the above.
  • R 2e represents a linear or branched alkylene group having 2 to 6 carbon atoms, this is the same as described above for a 1 k.
  • the alkyl moiety is a straight or branched chain having 1 to 6, preferably 1 to 3 carbon atoms. Alkyl.
  • the number of halogen atoms is not particularly limited except for the case where the number of substitutable positions is limited. Generally, one to three substitutions are preferred.
  • the substituent (a) e represents an acyloxy group
  • the group is a linear or branched aliphatic acyloxy group having 1 to 4 carbon atoms.
  • a formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy group isobutyryloxy group.
  • Substituent (a) e is alkylsulfonyl, aralkyloxy, aryloxy, arylthio, arylsulfonyl, arylsulfonylamino, aromatic heterocyclic oxy, aromatic heterocyclic thio, aromatic heterocyclic sulfonyl, aromatic When it is a heterocyclic sulfonylamino group, the alkyl, aralkyl, aryl, and aromatic heterocyclic moieties are the same as those described above.
  • R 4e represents an acyl group having 1 to 8 carbon atoms, it is preferably aliphatic or carbocyclic aromatic, and examples thereof are as follows.
  • an aliphatic acyl group it is preferably an alkanoyl group having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 4 carbon atoms, such as honoremil, Acetyl, propionyl, butyrinole, isobutylinole, pivaloisle, norrelyl, isovaleryl, hexanoyl, heptanyl, octanoyl; most preferably, acetyl; halogenated alkanol having 2 to 6 carbon atoms, particularly halogen.
  • Acetyl group for example, chloroacetyl, dichloroacetyl, trifluoroacetyl, trifluoroacetyl group; the alkoxy moiety has 1 to 5, preferably 1 to 3 carbon atoms, and the alkanol moiety has 2 to 6 carbon atoms.
  • an acetyl group a lower alkoxyalkanoyl group having Or an unsaturated analogous group of these groups, in particular, an alkenyl or alkynyl group having 3 to 6 carbon atoms, such as acryloyl, methacryloyl, propio-lenole, crotonyl, isocrotonyle, (E) — 2-Methyl-1-2-butenoy Group);
  • an aromatic acyl group it is preferably an arylcarbonyl group such as benzoyl, ⁇ -naphthyl,] 3-naphthoyl group; Benzoyl group; lower alkyl-substituted arylcarbonyl group, for example, 4-toluoyl group; lower alkoxy-substituted arylcarbonyl group, for example, 4-anisyl group; nitro-substituted arylcarbonyl group, for example, 412 Tolbenzoyl, 2-nitrobenzoyl group; lower alkoxycarbonyl-substituted arylcarbonyl group, for example, 2- (methoxycarbonyl) benzoyl group.
  • arylcarbonyl group such as benzoyl, ⁇ -naphthyl,] 3-naphthoyl group
  • Benzoyl group lower alkyl-substituted arylcarbonyl group, for example
  • Rle represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.
  • R 3e has a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, and 1 or 2 carbon atoms
  • the compound according to (1) which represents an alkylthio group or a halogen atom.
  • Xe is an aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents (a) e , or 1 to 3 substituents (a) e You can do it 5- to 10-membered ring with 1 to 3 nitrogen, oxygen and sulfur or sulfur atoms
  • a heteroaromatic group consisting of one or two rings
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, or (ii) a linear alkyl group having 1 to 4 carbon atoms. Or (iii) a hydroxy group, (iv) a straight or branched chain alkoxy group having 1 to 4 carbon atoms, and (V) a 1 to 4 carbon atom.
  • the substituent (b) e is a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkyl halide having 1 to 4 carbon atoms.
  • a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom or a linear or branched alkylenedioxy group having 1 to 4 carbon atoms The compound according to (1).
  • Xe has 1 to 3 substituents (a) aryl group having 6 to 10 carbon atoms which may have e , or 1 to 3 substituents (a) 6 5- to 10-membered ring having 1 to 3 nitrogen, oxygen and / or sulfur atoms which may be
  • a heteroaromatic group consisting of one or two rings
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms.
  • V i a linear or branched alkylenedioxy group having 1 to 4 carbon atoms
  • V ii an aralkyloxy group having 7 to 12 carbon atoms
  • V iii a C 1 to 4 carbon atom Linear or branched alkylthio groups having
  • a phenylsulfonylamino group optionally having e (the nitrogen atom of the amino moiety may be substituted by linear or branched alkyl having 1 to 6 carbon atoms) ), (XV ii) furyl, phenyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, ( xv iii) imidazolyl (nitrogen atoms are carbon atoms) And / or (X i X) a pyridylsulfonylamino group (where the nitrogen atom of the amino moiety is a carbon atom). And may be substituted with linear or branched alkyl having 1 to 6).
  • the substituent (b) e is a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched halo having 1 to 4 carbon atoms.
  • Genated alkyl group, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom or linear or branched alkylenedioxy group having 1 to 4 carbon atoms The compound according to (1), which represents a group.
  • X e force S 1 to 3 substituents (a) phenyl group, naphthyl group, imidazolyl group, oxazolyl group, pyridyl group, indrill group, quinolyl group which may have e Or represents an isoquinolyl group,
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms.
  • V a linear or branched alkoxy group having 1 to 4 carbon atoms
  • Vi a methylenedioxy group
  • Vii an aralkyloxy group having 7 to 12 carbon atoms
  • Viii A straight-chain or branched alkylthio group having 1 to 4 carbon atoms
  • ix a straight-chain or branched alkylsulfonyl group having 1 to 4 carbon atoms
  • X fluorine.
  • Atom chlorine atom, bromine atom,
  • X i an aralkyl group having 7 to 12 carbon atoms;
  • X ii a phenyl group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy).
  • X e is from 1-3 substituents (a) a phenyl group which may have a e, naphthyl group, an imidazolyl group, Okisazoriru group, a pyridyl group, an indolyl group, a key Noryl group or Isokinoriru group Show,
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms.
  • V a linear or branched alkoxy group having 1 to 4 carbon atoms
  • V i a methylenedioxy group, a benzyloxy group, a phenethyloxy group, a naphthylmethoxy group
  • V ii a carbon number of 1 to 4
  • V iii a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms
  • ix a fluorine atom, a chlorine atom, Bromine atom
  • X a benzyl group
  • a phenyl group (the phenyl may be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy)
  • a phenoxy group (the phenyl group) May be substituted by methyl, trifluoromethyl, methoxy, fluoro or methylenedioxy.)
  • phenylthio phenylsulfonyl, phenylsulfonylamino, N-methylphenyl Enylsulfonylamino, furyl, cheninole, oxazolinole, isoxazolyl, thiazolyl, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridylsulfonylamino, N-methylpyridylsulfony
  • Xe is a phenyl group, a naphthyl group, a pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group which may have 1 to 3 substituents (a),
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 3 carbon atoms, (ii) a trifluoromethyl group, a difluoromethyl group, or a fluoromethyl group.
  • X e is from 1-3 substituents (a) a phenyl group which may have a e, a naphthyl group, a pyridyl group, a quinolyl group or an isoquinolyl group,
  • the substituent (a) e is a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a hydroxy group, an aceethoxy group, a methoxy group, an ethoxy group, an isopropoxy group, a methylenedioxy group, a benzyloxy group, a methylthio group, Ethylthio group, methylsulfonyl group, ethylsulfonyl group, chlorine atom, benzyl group, phenyl group, phenoxy group, phenylinolethio group, phenylsulfonyl group, phenylinolesulfonylamino group, N-methylphenylsulfonylamino group
  • the compound according to (1) which represents a pyridyl group, a pyridyloxy group, a pyridylthio group, a pyri
  • X e represents 1 to 3 substituents (a) may have a e-phenylene group
  • the substituent (a) e is a methyl group, a hydroxy group, an acetoxy group, a chlorine atom, a benzyl group, a phenyl group, a phenoxy group, a phenylthio group, a phenyl group.
  • the compound according to (1) which represents a sulfonyl group, a phenylsulfonylamino group, an N-methylphenylsulfonylamino group, a pyridyl group, a pyridyloxy group, a pyridylthio group and / or a pyridylsulfonyl group.
  • Xe is a pyridyl group optionally having 1 to 3 substituents (a) e,
  • the substituent (a) e is a methoxy group, an ethoxy group, an isopropoxy group, a benzyloxy group, a methinorethio group, an ethylthio group, a methylsnolehoninole group, a ethinolesnolehoninole group, a benzinole group, or a feninole group.
  • the compound according to (1) which represents a phenyl group, a phenoxy group, a phenylinolethio group, a phenylsulfonyl group, a phenylsulfonylamino group and / or an N-methylphenylsulfonylamino group.
  • Y e is an oxygen atom, a sulfur atom or a group having the formula> N—R 4e (wherein, is a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms or A linear or branched alkynyl group having 2 to 5 carbon atoms.).
  • Rle represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms
  • R 2e represents a linear or branched alkylene group having 2 to 5 carbon atoms
  • R 3e is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, halogen Indicates an atom;
  • Xe has 1 to 3 substituents (a) aryl group having 6 to 10 carbon atoms which may have e, or 1 to 3 substituents (a) e 5- to 10-membered ring having 1 to 3 nitrogen, oxygen, and sulfur or sulfur atoms which may be
  • a heteroaromatic group consisting of one or two rings
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, or (ii) a linear alkyl group having 1 to 4 carbon atoms. Or (iii) a hydroxy group, (iv) a straight or branched chain alkoxy group having 1 to 4 carbon atoms, and (V) a 1 to 4 carbon atom.
  • V ii an aralkyloxy group having 7 to 12 carbon atoms
  • V iii a linear or branched alkylthio group having 1 to 4 carbon atoms
  • i X a carbon number of 1 to 4
  • the substituent (b) e is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a straight-chain or branched halogen group having 1 to 4 carbon atoms.
  • Ye is an oxygen atom, a sulfur atom or a group having the formula> N—R 4e (wherein is a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms or a carbon atom having 2 carbon atoms, A linear or branched alkyl group having from 5 to 5);
  • R le represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms
  • R 2e represents a linear or branched alkylene group having 2 to 5 carbon atoms
  • R 3e represents a hydrogen atom
  • X e is have Ariru group, or 1 to 3 of substituents (a) e having 1 0 having 6 to carbon atoms which may have 1 to 3 substituents (a) e 5- to 10-membered ring having 1 to 3 nitrogen, oxygen, and / or sulfur atoms
  • a heteroaromatic group consisting of one or two rings
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms.
  • V i a linear or branched alkylenedioxy group having 1 to 4 carbon atoms
  • V ii an aralkyloxy group having 7 to 12 carbon atoms
  • V iii a C 1 to 4 carbon atom Linear or branched alkylthio groups having
  • (iX) a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, (X) a fluorine atom, a chlorine atom, a bromine atom, and (Xi) a carbon atom of 7 to 12 carbon atoms.
  • a phenylsulfonylamino group optionally having e (the nitrogen atom of the amino moiety may be substituted by a linear or branched alkyl having 1 to 6 carbon atoms) ), (XV ii) a furyl group, a cyenyl group, an oxazolyl group, an isooxazolyl group, a thiazolyl group, a pyridyl group, a pyridyloxy group, a pyridylthio group, a pyridylsulfonyl group, and Or a (X i X) pyridylsulfonylamino group (where the nitrogen atom of the amino moiety has 1 carbon atom). And may be substituted with linear or branched alkyl having from 6 to 6).
  • the substituent (b) e is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a straight-chain or branched chain alkyl group having 1 to 4 carbon atoms.
  • Alkyl group, linear or branched alkyloxy group having 1 to 4 carbon atoms, halogen atom or linear or branched alkylenedioxy group having 1 to 4 carbon atoms Shows;
  • Y e represents an oxygen atom
  • Rle represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms
  • R 2e represents a linear or branched alkylene group having 2 or 3 carbon atoms
  • R 3e represents a hydrogen atom
  • X e is from 1-3 substituents (a) e a phenyl group which may have a naphthyl group, an imidazolyl group, Okisazoriru group, a pyridyl group, indolyl group, key Noryl group or Isokinoriru group,
  • substitution component (a) e is (i) a linear group having 1 to 6 carbon atoms. Or (ii) a linear or branched halogenated alkyl group having 1 to 4 carbon atoms, (iii) a hydroxy group, (iv) a 1 to 4 carbon atoms.
  • V a linear or branched alkoxy group having 1 to 4 carbon atoms, (vi) a methylenedioxy group, (V ii) an aralkyloxy group having 7 to 12 carbon atoms, (V iii) A linear or branched alkylthio group having 1 to 4 carbon atoms, (ix) a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, and (X) a fluorine atom , Chlorine atom, bromine atom,
  • Y e represents an oxygen atom
  • R le represents a hydrogen atom, a methyl group or an ethyl group
  • R2e represents an ethylene group, a trimethylene group or a methylethylene group
  • R 3e represents a hydrogen atom
  • X e is from 1-3 substituents (a) 6 a phenyl group which may have a naphthyl group, Imidazoriru group, Okisazoriru group, a pyridyl group, indolyl group, key Noryl group or Isokinoriru group,
  • the substituent (a) e is (i) a linear or branched alkyl group having 1 to 6 carbon atoms, (ii) a linear or branched alkyl group having 1 to 4 carbon atoms.
  • V a linear or branched alkoxy group having 1 to 4 carbon atoms
  • V i a methylenedioxy group, a benzyloxy group, a phenethyloxy group, a naphthylmethoxy group
  • V ii a carbon number of 1 to 4
  • V iii a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms
  • ix a fluorine atom, a chlorine atom, Bromine atom
  • Y e represents an oxygen atom
  • Z e represents a 2,4-dioxothiazolidine-5 f-methyl group; the compound according to (1).
  • R le represents a hydrogen atom, a methyl group or an ethyl group;
  • R 2e represents an ethylene group, a trimethylene group or a methylethylene group
  • R 3e represents a hydrogen atom
  • X e represents a phenyl group, a naphthyl group, a pyridyl group, an indolyl group, a quinolyl group or an isoquinolyl group which may have 1 to 3 substituents (a) e , wherein the substituent (a) e is (I) a linear or branched alkyl group having 1 to 3 carbon atoms, (ii) a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, a hydroxy group, a formyloxy group, an acetoxy group, (iii) a linear or branched alkoxy group having 1 to 3 carbon atoms, (iv) methylenedioxy, benzyloxy, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, (V ) Fluorine atom, chlorine atom, bromine atom, (vi)
  • Y e represents an oxygen atom
  • Z e represents a 2,4-dioxothiazolidine-15-ylmethyl group; the compound according to (1).
  • R le represents a hydrogen atom, a methyl group or an ethyl group
  • R2e represents an ethylene group
  • R 3e represents a hydrogen atom
  • X e represents a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group or an isoquinolyl group which may have 1 to 3 substituents (a) e ,
  • the substituent (a) e is a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a hydroxy group, an acetoxy group, a methoxy group, an ethoxy group, Isopropoxy group, methylenedioxy group, benzyloxy group, methylthio group, ethynolethio group, methylsulfonyl group, ethylsulfonyl group, chlorine atom, benzyl group, phenyl group, phenoxy group, phenylthio group, phenylsulfonyl group, phenylsulfonyl An amino group, an N-methylphenylsulfonylamino group, a pyridyl group, a pyridyloxy group, a pyridylthio group, a pyridylsulfonyl group, a pyri
  • Y e represents an oxygen atom
  • (31) represents a methyl group or an ethyl group
  • R2e represents an ethylene group
  • R 3e represents a hydrogen atom
  • X e represents a phenyl group which may have 1 to 3 substituents (a) 6 ,
  • the substituent (a) e is a methyl group, a hydroxy group, an aceethoxy group, a chlorine atom, a benzinole group, a phenyl group, a phenoxy group, a phenylthio group, a phenylsulfoninole group, a phenylsolehoninoleamino group , N-methinorefenylsulfoninoleamino, pyridyl, pyridyloxy, pyridylthio and Z or pyridylsulfonyl;
  • Y e represents an oxygen atom
  • Z e represents a 2,4-dioxothiazolidine-15-ylmethyl group; the compound according to (1).
  • (32) represents a methyl group or an ethyl group
  • R2e represents an ethylene group
  • R 3e represents a hydrogen atom
  • X s represents a pyridyl group optionally having 1 to 3 substituents (a) e,
  • the substituent (a) e is a methoxy group, an ethoxy group, an isopropoxy group, a benzyloxy group, a methylthio group, an ethylthio group, a methylsulfonyl group, A tinolesulfonyl group, a benzyl group, a phenyl group, a phenoxy group, a phenylthio group, a phenylenolesnorefinole group, a phenylszolefony / reamino group, and a Z or N-methinolephenylsulfonylamino group;
  • Y e represents an oxygen atom
  • Z e represents a 2,4-dioxothiazolidine-1-ylmethyl group; the compound according to (1).
  • R ⁇ is an optionally substituted aromatic hydrocarbon group, an optionally substituted cycloaliphatic hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted fused heterocyclic group, or formula
  • R lf is an optionally substituted aromatic hydrocarbon group, optionally substituted, cycloaliphatic hydrocarbon group, optionally substituted! /, Heterocyclic group or optionally substituted, fused complex a Hajime Tamaki
  • R 2f and R 3 f are the same or different, a hydrogen atom or a lower alkyl group
  • X f is a group represented by an oxygen atom, a sulfur atom or a secondary amino group
  • R 4f is a hydrogen atom or a lower alkyl group
  • R 5f is lower alkyl
  • P f and Q f are the same or different and are a hydrogen atom, or P f and Q f together represent a bond.
  • R f and R lf are the same as those described above for R ld .
  • R f and R lf represent a heterocyclic group or a fused heterocyclic group, they are an aromatic heterocyclic group or an aromatic fused heterocyclic group, and are the same as those described for R 1 (i .
  • R f and R lf represent a non-aromatic heterocyclic group, it has 5 to 7 carbon atoms, of which 1 to 3 are hetero atoms selected from nitrogen, oxygen and sulfur atoms.
  • At least one is a nitrogen atom, such as pyrrolidinyl, piperidinyl, piperazinyl, N-methinolepidrazenole, monoreforinyl, thiomonoreolininole, oxosazolidinyl, thiazolidinyl, diazolidinyl, oxorazonyl, thioxoranyl, thioxoranyl, thioxolanyl Group.
  • a nitrogen atom such as pyrrolidinyl, piperidinyl, piperazinyl, N-methinolepidrazenole, monoreforinyl, thiomonoreolininole, oxosazolidinyl, thiazolidinyl, diazolidinyl, oxorazonyl, thioxoranyl, thioxoranyl, thioxolanyl Group.
  • Rf and Rlf represent a cyclic aliphatic hydrocarbon group
  • they are preferably a cycloalkyl group, and more preferably a group having 3 to 8 carbon atoms.
  • they are cyclopropyl, cyclobutynole, cyclopentynole, cyclohexynole, cyclohepty / le, and cyclooctyl groups, preferably cyclopentyl and cyclohexyl groups.
  • it is a cycloalkenyl group, preferably a group having 5 to 8 carbon atoms.
  • R f and R lf may be substituted or unsubstituted. When substituted, the group may be substituted with groups commonly used in the art, for example as described above for the substituent (a) e .
  • R 2f, R 3 f, R « may exhibit R 5 f is an alkyl group, preferably 1 to 6 carbon atoms, more preferably a lower alkyl group having 1 to 4 carbon, atoms, e.g. R 3c and substitution (a) Same as described in a.
  • Rf may be substituted with a fuunyl group, a sulfur atom, an oxygen atom, and a 5- or 6-membered optionally substituted aromatic heterocyclic group containing one or two heteroatoms selected from a nitrogen atom, Or the compound according to (2), which is a condensed aromatic heterocyclic group which is obtained by condensing an aromatic heterocyclic ring and a benzene ring.
  • R 1 is selected from a fluorine group, a sulfur atom, an oxygen atom and a nitrogen atom. Or a 5- or 6-membered aromatic heterocyclic group containing two hetero atoms, or a condensed aromatic heterocyclic group obtained by condensing an aromatic complex ring and a benzene ring.
  • Rlf is a phenyl group which may be substituted, or a 5- or 6-membered optionally substituted aromatic heteroatom containing one or two hetero atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom or an atom atom.
  • R lf is a 5- or 6-membered aromatic heterocyclic group containing one or two hetero atoms selected from a sulfur atom, an oxygen atom and a nitrogen atom.
  • ⁇ represents an indole ring group, an indoline ring group, an azaindole ring group, an azaindolin ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings represent one to three substituents (a) g described later. May have,
  • Yg represents an oxygen atom or a sulfur atom
  • R8 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom A hydroxy group, a dinitro group, a substituted group (b) an amino group optionally having S (the substituted group (b) i is a straight-chain or branched chain having 1 to 8 carbon atoms) Alkyl group, linear or branched aralkyl group having 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, straight chain having 1 to 11 carbon atoms, Represents a branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.
  • the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A benzyloxy group, a halogen atom, a hydroxy group, an acetyloxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, A trifluoromethyl group, a nitro group, an amino group which may have a substituent (b) g (the substituent (b) g is a straight-chain or branched-chain having 1 to 8 carbon atoms) Alkyl groups, linear or branched aralkyl groups having 7 to 11 carbon atoms, aryl groups having 6 to 10 carbon atoms, and linear groups having 1 to 11 carbon atoms are also available.
  • an aryl group having 6 to 10 carbon atoms which may have g the substituent (c) 8 is a linear or branched alkyl group having 1 to 4 carbon atoms, C1-C4 linear or branched alkoxy group, halogen atom, hydroxy group, nitro group, phenyl A trifluoromethyl group, a substituted moiety (b) an amino group optionally having 5), or a substituted moiety (c) a linear chain having 7 to 11 carbon atoms optionally having S Represents a branched or branched aralkyl group.
  • the substituent (c) 8 is a linear or branched alkyl group having 1 to 4 carbon atoms, C1-C4 linear or branched alkoxy group, halogen atom, hydroxy group,
  • the substituent (a) S, and the substituent (c) S represent an alkyl group or an alkoxy group having 1 to 4 carbon atoms, they are the same as those described above for the substituent (a) a. The same is true.
  • substitution (a) S and the substitution (c) g represent a halogen atom, they are the same as those described for the substitution (a) a above.
  • the substituted group (b) g represents an alkyl group having 1 to 8 carbon atoms
  • the group is a linear or branched alkyl group, for example, methyl, ethyl, propyl, isopropylinole, butynole.
  • (2) represents an indole ring group, an indoline ring group, an azaindole ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings have one to three substituents (a) 8 described later. May be
  • K is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • XS represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings may have 1 to 3 substituents (a) g described below,
  • the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • the substituent (b) S is a linear or branched alkyl group having 1 to 8 carbon atoms, and a substituted or unsubstituted alkyl group having 7 to 11 carbon atoms; Linear or branched aralkyl group having 6 to 10 carbon atoms, linear or branched aliphatic acryl group having 1 to 11 carbon atoms, carbon Araliphatic acyl group having the number 8 to 12 or carbon
  • XS represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) ⁇ described below,
  • (A) 6 is linear or branched having 1 to 4 carbon atoms Branched alkyl group, linear or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, hydroxy group, acetoxy group, phenylthio group, 1 to 4 carbon atoms Linear or branched alkylthio group, trifluoromethyl group, nitro group, substituted (b) amino group which may have S (the substituted (b) g is A linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched aralkyl group having 7 to 11 carbon atoms, and 6 to 10 carbon atoms; An aryl group having 1 to 11 carbon atoms, a linear or branched alipha
  • Xg represents an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) g described below;
  • the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • Xg represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) ⁇ described below;
  • the substituent (a) g is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group.
  • the compound according to (1) which represents an ethylthio group or a phenyl group.
  • R5 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom.
  • ZS is 2,4-dioxothiazolidine-15-iridylmethyl group, 2,4-dioxothiazolidine-15-ylmethyl group or 2,4-dioxoxazozolidine-1-5—
  • ⁇ represents an oxygen atom or a sulfur atom
  • Zg is 2,4-dioxothiazolidine-1-5-idylmethyl group, 2,4-dioxothiazolidine-15-ylmethyl group, 2,4-dioxoxazolidine-15-ylmethyl group, 3,5-dioxo Oxadiazolidine-12-methyl group or N-hydroxyperidomethyl group;
  • R8 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom;
  • n 1 to 5
  • the substituent (a) 8 is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 1 to 4 carbon atoms.
  • An amino group which may have a substituent (b) ⁇ (the substituent (b) 6 is a linear or branched alkyl group having 1 to 8 carbon atoms, A linear or branched aralkyl group having 1 carbon atom, an aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic alkyl having 1 to 11 carbon atoms Represents an aromatic aliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.
  • (16) represents an indole ring group, an indoline ring group, an imidazopyridine ring group or an imidazopyrimidine ring group, and these rings each have 1 to 3 substituents to be described later.
  • (a) may have S,
  • Y8 represents an oxygen atom
  • Z g represents a 2,4-dioxothiazolidine-15-ylenylmethyl group, a 2,4-dioxothiazolidine-15-ylmethyl group or a 2,4-dioxoxazolidine-15f-methyl group;
  • Rg represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom;
  • mS represents an integer of 1 to 5
  • the substituent (a) S is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms. , Benzyloxy group, halogen atom, hydroxy group, acetoxy group, Phenylthio group, linear or branched alkylthio group having 1 to 4 carbon atoms, trifluoromethyl group, nitro group, amino group optionally substituted (b) S (The substituted (b) 8 is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched aralkyl group having 7 to 11 carbon atoms.
  • (17) represents an indole ring group, an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) g described below;
  • YS represents an oxygen atom
  • Z g represents a 2,4-dioxothiazolidine-15-yridenylmethyl group or a 2,4-dioxothiazolidine-15-ylmethyl group;
  • RS represents a hydrogen atom, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom
  • n 1 to 5
  • the substituent (a) g is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • An amino group which may have a moiety (b) S (the substituted moiety (b) 6 is a linear or branched alkyl group having 1 to 8 carbon atoms, 7 to 11 carbon atoms) Linear or branched aral with Kill group, aryl group having 6 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, aromatic fatty acid having 8 to 12 carbon atoms An aromatic acyl group or an aromatic acyl group having 7 to 11 carbon atoms.
  • substituted (c) aryl groups having 6 to 10 carbon atoms which may have S (the substituted (c) 6 has 1 to 4 carbon atoms) Linear or branched alkyl group, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom, hydroxy group, nitro group, phenyl group, triphenylenomethyl A group, a substituent (b) an amino group optionally having S), or a straight-chain having 7 to 11 carbon atoms optionally having 1 to 3 substituents (c) g;
  • the compound according to (1) which represents a branched aralkyl group.
  • XS represents an indoline ring group or an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) 6 described below;
  • Y8 represents an oxygen atom
  • Z g represents a 2,4-dioxothiazolidine-1-5-methyl group
  • Rg represents a hydrogen atom or a methoxy group
  • n 1 to 5
  • the substituent (a) S is a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • the compound according to (1) which represents a benzyloxy group, a halogen atom, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group or a phenyl group. .
  • X S represents an imidazopyridine ring group, and these rings may have 1 to 3 substituents (a) 8 described below;
  • YS represents an oxygen atom
  • Z S represents a 2,4-dioxothiazolidine-1-5-ylmethyl group
  • R8 represents a hydrogen atom
  • n 1 to 5
  • the substituted component (a) S represents a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group,
  • the compound according to (1) which represents a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group or a phenyl group.
  • X h represents a benzimidazole ring group, which may have 1 to 5 substituents (a) k described below;
  • Y h represents an oxygen atom or a sulfur atom
  • Z h is a 2,4-dioxothiazolidine-15-yridenylmethyl group, a 2,4-dioxothiazolidine-15-ylmethyl group, a 2,4-dioxoxazolidine-15-ylmethyl group, 3,5-dioxoxaziazolidine-1-ylmethyl group or N—Hydroxyperidomethyl group,
  • R 11 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom A hydroxy group, a nitro group, an amino group which may have a substituent (b) h (the substituent (b) h is a linear or branched chain having 1 to 8 carbon atoms).
  • Alkyl group, linear or branched aralkyl group having 7 to 11 carbon atoms, aryl group having 6 to 10 carbon atoms, straight chain having 1 to 11 carbon atoms Represents a branched aliphatic acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.
  • n h represents an integer of 1 to 5
  • the substituent (a) h is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A benzyloxy group, a halogen atom, a hydroxy group, an acetyloxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, ) Amino group which may have a 'group (the substituent (b) h is a linear or branched alkyl group having 1 to 8 carbon atoms; and a substituted or unsubstituted alkyl group having 7 to 11 carbon atoms).
  • substitution (a) h and substitution ( c ) h represent an alkyl group or an alkoxy group having 1 to 4 carbon atoms, they are the same as those described in the above substitution (a) 3 It is.
  • R h the substituted moiety (a) h, and the substituted moiety (b) h represent an aralkyl group, they are the same as those described above for R 1 (i ).
  • substitution (a) h, and substitution (c) h represent a halogen atom, they are the same as those described for the substitution (a) a above.
  • substituted moiety (a) h and the substituted moiety ( b ) h represent an aryl group, they are the same as those described in above.
  • Substituent (b) h is a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms or 7 to 11 carbon atoms
  • substitution (b) h represents an alkyl group having 1 to 8 carbon atoms, it is the same as that described for the substitution (b) g above.
  • Rh is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom
  • Rh is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, or a halogen atom Indicates that
  • Y h represents an oxygen atom
  • Rh represents a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom.
  • R h is a hydrogen atom, a methyl group, main butoxy group, an ethoxy group, a fluorine atom or a chlorine atom,
  • substituent (a) h is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, Benzyloxy, halogen, phenylthio, linear or branched alkylthio having 1 or 4 carbon atoms, trifluoromethyl, hydroxy, acetyl, benzyl, phenyl or phenyl (1) The compound described in (1).
  • Rh represents a hydrogen atom, a methyl group or a methoxy group.
  • (1 3) represents 1 to 5 substituents (a) a benzodimidazole ring group optionally having h,
  • substituent (a) h is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, Benzyloxy, halogen, phenylthio, linear or branched alkylthio having 1 or 4 carbon atoms, trifluoromethyl, hydroxy, acetoxy, benzyl, phenyl or phenyl Represents a group,
  • Y h represents an oxygen atom
  • Z 11 represents a 2,4-dioxoxazolidine-1-ylmethyl group
  • R h represents a hydrogen atom, a methyl group or a methoxy group
  • substitution (a) h is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group
  • the compound according to (1) which represents an ethylthio group, a hydroxy group, an acetyl group, a benzyl group or a fuzyl group.
  • Xh represents 1 to 5 substituents (a) a benzodimidazole ring group optionally having h ,
  • substituent (a) h is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, Represents a methylthio group, an ethylthio group, a hydroxy group, an acetyl group, a benzyl group or a phenyl group;
  • Yh represents an oxygen atom
  • Z h represents a 2,4-dioxothiazolidine_5-ylmethyl group
  • R h represents a hydrogen atom
  • ⁇ is 1 to 5 substituted (a) a benzimidazoyl ring group optionally having h ,
  • the substituent (a) h represents a methyl group, a methoxy group, a hydroxy group, an acetate group or a benzyl group;
  • Y h represents an oxygen atom
  • Z h represents a 2,4-dioxothiazolidine-1-ylmethyl group
  • R h represents a hydrogen atom
  • the compound according to (1) which is 5- [4-(5-acetoxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-1,2,4-dione.
  • Zi represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a pyridyl group, a furyl group, a phenyl group, or the same or different carbon atoms.
  • Zli is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • Ri and Rii are the same or different and are a hydrogen atom or a methyl group
  • n 1 is 1, 2 or 3.
  • Zi is an alkyl group having 1 to 7 carbon atoms or a Zli group or a phenyl group represented by Zi is an alkyl group having 1 to 3 carbon atoms
  • Zi represents a cycloalkyl group having 3 to 7 carbon atoms, Propinole, cyclopentinole, cyclopentyl, cyclohexinole, and cycloheptinole groups.
  • Xi is an oxygen atom
  • ⁇ ' is a nitrogen atom forming an oxazole-4-hydroxyl group
  • Z 1 is a 2-phenyl group, a 2-furyl group, a phenyl group, a substituted phenyl group or a naphthyl group;
  • Wi is> CO
  • Xi is an oxygen atom or a sulfur atom
  • Yi is a CH group forming a pyridyl 2 _yl group
  • Rij, R 2), R 3 i, and R 5 j are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, Ariru group, alkoxy group, alkoxyalkoxy group, Ariruo alkoxy group, alkanoyloxy noisy Ruo alkoxy group, ⁇ Reelcarbonyloxy group, carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, alkamoyl group, alkylaminocarbonyl group, arylaminocarbonyl group, amino group, alkylamino group, alkanoylamino Group, arylcarbonylamino group, ethylenedioxymethyl group, formyl group, cyano group, nitro group, or trihalomethyl group,
  • R fi j represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group,
  • n i represents an integer from 0 to 3
  • the dotted line indicates that the bond at that portion may be a double bond.
  • R 2 j, RKR "and R 5 j are alkoxyalkoxy, aryloxy, alkanoyloxy, arylcarbonyl, alkoxycarbonyl, aryloxycarbyl, alkyl
  • R 5 j are alkoxyalkoxy, aryloxy, alkanoyloxy, arylcarbonyl, alkoxycarbonyl, aryloxycarbyl, alkyl
  • R! J, R 2 j, R, R, and R 5 represent an alkylamino group, this is a mono- or di-alkylamino group, and is the same as that described in (a) a above. is there.
  • R l KR 2 KRK When represents a trihalomethyl group, this is a trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl group, preferably a trifluoromethyl group.
  • R2] ′, R3j, R4j and R5j are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, An alkoxy group having 1 to 8 carbon atoms, an alkoxyoxy group having 2 to 6 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, an alkanoyloxy group having 2 to 9 carbon atoms An arylcarbonyloxy group having 7 to 13 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 9 carbon atoms, an aryloxycarbonyl group having 7 to 13 carbon atoms, carbamoyl Group, alkylaminocarbonyl group having 2 to 9 carbon atoms, arylaminocarbonyl group having 7 to 13 carbon atoms, amino group, alkylamino
  • R 6 j is an alkyl group having 1 to 8 carbon atoms which may have one or more substituents selected from a hydrogen atom, halogen, nitro and cyano, or halogen, nitro
  • R R2j, RK and R 5 j are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, alkoxy group having 1 to 8 carbon atoms having 1 to 8 carbon atoms, or 2 carbon atoms
  • R 6 j represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms which may be substituted with halogen.
  • R 2 j, R y K and R 5j ′ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, 2 to 6 carbon atoms An alkoxyalkoxy group having 2 to 6 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, and an arylaminocarbonyl group having 7 to 13 carbon atoms , An amino group, an alkanoylamino group having 2 to 6 carbon atoms, an ethylenedioxymethyl group, a formyl group, a cyano group, a nitro group or a trihalomethyl group,
  • R 6j represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an aryl group having 6 to 12 carbon atoms which may be substituted with halogen.
  • R 2 KR and R 4 j are the same or different and represent a hydrogen atom or a halogen atom
  • R 5 j represents a hydrogen atom
  • R 6 j represents a hydrogen atom
  • nJ 1,
  • mixtures c such stereoisomers both encompassed by the present invention of these isomers ⁇ Pico these isomers, the general formula with an optically divided raw material (I) to (X)
  • the compound having the general formulas (I) to (X) can be optically resolved by a conventional optical resolution method or separation method, if desired.
  • the compound having the general formula (I) to (X) or a pharmaceutically acceptable salt thereof forms a solvate (for example, a hydrate), all of these are included. It is a thing.
  • the compound having the general formulas (I) to (X) or a pharmacologically acceptable salt thereof is left in the air or recrystallized, thereby absorbing water and adsorbing water.
  • hydrates may form.
  • the present invention includes such a solvate.
  • the present invention also includes all compounds that are converted into the compounds having the above general formulas (I) to (X) or pharmacologically acceptable salts thereof by metabolizing in vivo, so-called prodrugs. .
  • the insulin resistance improving substance of the present invention is useful as an agent for preventing or treating leukemia.
  • the insulin sensitizer of the present invention is administered in various forms.
  • the administration form is not particularly limited, but is determined according to various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. Examples include oral administration by tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules or capsules, and parenteral administration by injections or suppositories. In the case of injections, they are administered intravenously, alone or mixed with normal replacement fluids such as glucose and amino acids, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. It is.
  • a preferred dosage form is oral administration.
  • a wide variety of carriers conventionally known in the art can be used as tablets in the form of tablets, such as lactose, sucrose, glucose, starch, sodium chloride, urea, calcium carbonate, kaolin, crystalline cellulose, and caic acid.
  • Excipients water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder for polyvulpioridone sugar, dried starch , Sodium alginate, Agar powder, Laminaran powder, Sodium hydrogen carbonate, Calcium carbonate, Polyoxyethylene sorbitan fatty acid esters, Sodium lauryl sulfate, Stearic acid monoglyceride, Starch, Lactose and other disintegrants, Sucrose, Stearin, Cocoa batata First, hydrogenation Disintegration inhibitors such as quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, hume
  • Powder tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar.
  • various carriers conventionally known in the art can be used widely, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride, etc. Can be mentioned.
  • the liquid preparation and the suspension are preferably sterilized and isotonic with blood.
  • these liquid preparations, emulsions and suspensions they are used as diluents. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. .
  • a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary solubilizing agents, buffers, and soothing agents may be used.
  • An agent may be added. If necessary, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be added.
  • the amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and may be appropriately selected in a wide range, but is usually 1 to 70% by weight in the whole composition. / 0 , preferably 1-30% by weight.
  • the dose of the insulin sensitizer is different depending on symptoms, age, administration method and the like.
  • the lower limit is ⁇ . It is preferable to administer lOOmg (preferably 50mg) once or in several divided doses depending on the symptoms.
  • lOOmg preferably 50mg
  • human leukemia cell KU As a culture solution of human leukemia cells, an RPMI 1640 solution containing 10% of non-activated fetal bovine serum and 50 g / m1 of kanamycin was used. That is, human leukemia cell KU
  • troglitazone compound name: 5— [4— (6—hydroxy-1,2,5,7,8—tetramethylchroman).
  • the mixture was placed in a 1 ml culture medium containing (l-methoxy) benzyl] thiazolidine-1,4-dione) and cultured in a carbon dioxide incubator at 37 ° C for 96 hours.
  • the cell proliferation of human leukemia cells was determined every 24 hours by measuring the number of viable cells in a culture solution containing troglitazone and a culture solution without troglitazone by the trypan blue staining method.
  • the human leukemia cell growth inhibitory activity (inhibition rate) by troglitazone was calculated by the following formula, and the results are shown in Table 1.
  • "contact time” indicates the contact time between human leukemia cell KU812 and troglitazone.
  • Human leukemia cell proliferation inhibitory activity [1 vitritazone-added group viable cells Z untreated group viable cells] X 100
  • Acute toxicity was measured according to standard methods. That is, 3 d dY mice (male) Ritazone was orally administered at a dose of 30 Omg Z kg, and observed for 5 days, all of which survived. Similarly, the acute toxicity of Compounds C and D was determined to be SOO mg Z kg or more for oral administration.
  • a preparation containing the insulin resistance improving substance of the present invention as an active ingredient can be produced, for example, by the following method.
  • a powder is obtained by mixing 5 g of troglitazone, 8995 g of lactose and 100 g of corn starch in a blender.
  • troglitazone 15 g of lactose, 58 g of corn starch and 2 g of magnesium stearate were mixed using a V-type mixer, and then mixed into a No. 3 capsule.
  • tablets After mixing 5 g of troglitazone, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate with a blender, tablets are obtained with a tablet machine.
  • a powder is obtained by mixing 5 g of pioglitazone, 8995 g of lactose and 100 g of corn starch in a blender.

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Abstract

L'invention concerne un médicament préventif de la leucémie ou un remède contre la leucémie, contenant, en tant que principe actif, un agent améliorant la résistance insulinique.
PCT/JP1998/005657 1997-12-16 1998-12-15 Remede contre la leucemie WO1999030739A1 (fr)

Priority Applications (1)

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AU15077/99A AU1507799A (en) 1997-12-16 1998-12-15 Leukemia remedy

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JP9/345986 1997-12-16
JP34598697 1997-12-16

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Cited By (6)

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WO2001005402A1 (fr) * 1999-07-19 2001-01-25 Sankyo Company, Limited Agents preventifs et therapeutiques du cancer
WO2002051409A1 (fr) * 2000-12-22 2002-07-04 Geron Corporation Inhibiteurs de la telomerase et leurs procedes d'utilisation
WO2003082865A1 (fr) * 2002-04-01 2003-10-09 Sankyo Company, Limited Composition médicinale antitumorale
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
EP2468299A2 (fr) 2003-04-30 2012-06-27 Novartis Vaccines and Diagnostics, Inc. Compositions d'induction des réponses immunitaires
US9180118B2 (en) 2006-07-18 2015-11-10 University Of Rochester Thiadiazolidinone derivatives

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US7425557B2 (en) 1998-06-19 2008-09-16 Novartis Vaccines And Diagnostics, Inc. Inhibitors of glycogen synthase kinase 3
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AU760917B2 (en) * 1999-07-19 2003-05-22 Sankyo Company Limited Preventive and therapeutic agents for cancer
US6569877B2 (en) 1999-07-19 2003-05-27 Sankyo Company, Limited Therapeutic and prophylactic agents for neoplasms
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WO2002051409A1 (fr) * 2000-12-22 2002-07-04 Geron Corporation Inhibiteurs de la telomerase et leurs procedes d'utilisation
US6452014B1 (en) * 2000-12-22 2002-09-17 Geron Corporation Telomerase inhibitors and methods of their use
WO2003082865A1 (fr) * 2002-04-01 2003-10-09 Sankyo Company, Limited Composition médicinale antitumorale
EP2468299A2 (fr) 2003-04-30 2012-06-27 Novartis Vaccines and Diagnostics, Inc. Compositions d'induction des réponses immunitaires
US9180118B2 (en) 2006-07-18 2015-11-10 University Of Rochester Thiadiazolidinone derivatives

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