WO2012081563A1 - Dérivé de benzothiazole et d'azabenzothiazole ayant une activité d'inhibition de la lipase endothéliale - Google Patents

Dérivé de benzothiazole et d'azabenzothiazole ayant une activité d'inhibition de la lipase endothéliale Download PDF

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WO2012081563A1
WO2012081563A1 PCT/JP2011/078736 JP2011078736W WO2012081563A1 WO 2012081563 A1 WO2012081563 A1 WO 2012081563A1 JP 2011078736 W JP2011078736 W JP 2011078736W WO 2012081563 A1 WO2012081563 A1 WO 2012081563A1
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substituted
unsubstituted
compound
halogen
pharmaceutically acceptable
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Japanese (ja)
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直樹 吉川
士郎 木田
光拡 米原
麻童 中嶋
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塩野義製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound useful for a medicine, which has a vascular endothelial lipase (Endthelial Lipase, hereinafter referred to as EL) inhibitory activity.
  • EL vascular endothelial lipase
  • EL is a Triglyceride Lipase family along with Lipoprotein Lipase (hereinafter referred to as LPL) and Hepatic Lipase (hereinafter referred to as HL), and is involved in the metabolism of HDL cholesterol (hereinafter referred to as HDLc) due to its strong phospholipase activity.
  • LPL Lipoprotein Lipase
  • HL Hepatic Lipase
  • HDLc HDL cholesterol
  • Non-patent Document 1 It has long been known that a negative correlation is established between coronary artery disease (CAD) and blood HDLc level.
  • HDLc is considered to exhibit an anti-arteriosclerosis action through an antioxidant action, an anti-inflammatory action, a reverse cholesterol transfer action, and the like, and hypoHDLcemia is recognized as one of the risk factors of CAD. Therefore, an EL inhibitor becomes a CAD therapeutic agent through an increase in HDLc, and an increase in HDLc and a decrease in atherosclerotic lesion sites have been reported in pathological mice that actually knocked out EL (Non-patent Document 2). These findings indicate that EL selective inhibitors are useful as therapeutic agents in dyslipidemia and arteriosclerosis.
  • Patent Documents 1, 2 and 3 disclose various compounds having HL and / or EL inhibitory activity, but none of the oxadiazole derivatives such as the compounds of the present invention are disclosed.
  • Patent Document 4 discloses triglyceride lipase, LPL, HL, pancreatic lipase, and a compound having EL inhibitory activity, but does not disclose an oxadiazole derivative such as the compound of the present invention.
  • Patent Documents 5 to 15 disclose various compounds having EL inhibitory activity, but none of the oxadiazole derivatives such as the compounds of the present invention are disclosed.
  • Patent Document 16 describes a benzothiazole derivative having an elastase inhibitory action.
  • Patent Document 17 discloses benzothiazole derivatives and azabenzothiazole derivatives in which the 4- or 7-position of the compound of the present invention is substituted.
  • An object of the present invention is to provide an excellent EL inhibitor.
  • the present inventors have succeeded in synthesizing an excellent compound having an EL inhibitory action.
  • the present invention relates to the following.
  • Each R 12 is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkyloxy,
  • Each R 13 is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted or unsubsti
  • a pharmaceutically acceptable salt thereof, or a solvate thereof A pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 10 is represented by the formula: — (C ⁇ O) —NR 11 — (CR 12 R 13 ) n—R 14 (wherein R 11 , R 12 , R 13 , n and R 14 are as defined above (1)).
  • R 7 is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or The compound according to any one of the above (1) to (10), which is unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy, A pharmaceutically acceptable salt or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (16), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition having a vascular endothelial lipase inhibitory activity comprising the compound according to any one of (1) to (16), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the pharmaceutical composition containing the compound of the present invention can be used for pharmaceuticals, particularly dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, hypercholesterolemia, high triglyceride It is very useful as a medicament for the treatment and / or prevention of blood glucose, diabetes, obesity and / or syndrome X.
  • the compound of the present invention selectively inhibits EL and has high selectivity for HL and LPL. In addition, it is a compound having utility as a medicine.
  • a point, a point with a small clearance, or a point having a sufficiently long half-life for exhibiting a medicinal effect are included.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkyl having 1 to 6 or 1 to 4 carbon atoms for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.
  • Alkenyl means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like can be mentioned.
  • Alkynyl means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Can be mentioned. Furthermore, you may have a double bond.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Groups and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.
  • “Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the like.
  • the “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings share one carbon atom. Specific examples include spiro [3.4] octyl.
  • “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropenyl (eg, 1-cyclopropenyl), cyclobutenyl (eg, 1-cyclobutenyl), cyclopentenyl.
  • Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
  • Aryl means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1 -Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like.
  • Heteroaryl refers to monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups.
  • the “monocyclic aromatic heterocyclic group” is derived from a 5- to 8-membered aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring. And a group which may have a bond at any substitutable position.
  • the “fused aromatic heterocyclic group” has 1 to 4 5- to 8-membered aromatic rings having one or more hetero atoms in the ring which are optionally selected from an oxygen atom, a sulfur atom and a nitrogen atom. And a group optionally having a bond at any substitutable position which is condensed with the other 5- to 8-membered aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.
  • heteroaryl examples include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl).
  • Imidazolyl eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • triazolyl eg, 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl
  • tetrazolyl eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl
  • oxazolyl eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl
  • isoxazolyl eg 3-isoxazolyl, 4-isoxazolyl, -Isoxazolyl
  • thiazolyl eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • thiadiazolyl isothiazolyl (eg 3-isothiazo
  • Heterocyclyl means a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring, or cycloalkane (preferably 5-6 members), benzene ring and / or such ring
  • a non-aromatic heterocyclic group which may have a bond at any substitutable position on a ring condensed with a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring.
  • the “non-aromatic heterocyclic group” may be saturated or unsaturated as long as it is non-aromatic. A 5- to 8-membered ring is preferred.
  • Acyl refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, It means substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl.
  • alkenylcarbonyl alkenylcarbonyl
  • cycloalkylcarbonyl cycloalkenylcarbonyl
  • arylcarbonyl cycloalkenylcarbonyl
  • heteroarylcarbonyl cyclocyclylcarbonyl
  • alkyl part of “alkyloxy” and “alkyloxycarbonyl” means the above “alkyl”.
  • the alkenyl part of “alkenyloxy” means the above “alkenyl”.
  • the alkynyl part of “alkynyloxy” means the above “alkynyl”.
  • Substituted alkyl “substituted alkenyl”, “substituted alkynyl”, “substituted aryl”, “substituted heteroaryl”, “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted heterocyclyl”, “substituted alkyloxy” , “Substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkyloxycarbonyl”, “ring formed by R 12 and R 13 bonded to the same carbon atom together with the carbon atom”, “ Examples of the substituent in “substituted acyl”, “substituted carbamoyl” or “ring formed by R 11 and R 14 together with the adjacent nitrogen atom” include, for example, Halogen, hydroxy, carboxy, nitro, cyano, Substituted or unsubstituted alkyl (substitu)
  • Substituted or unsubstituted alkenyl substituted or unsubstituted alkenyl
  • substituted or unsubstituted alkynyl substituted or unsubstituted alkynyl
  • Substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, eg ethynyl
  • Substituted or unsubstituted aryl substituted or unsubstituted aryl
  • substituted or unsubstituted aryl substituted or unsubstituted aryl
  • substituted or unsubstituted aryl include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl,
  • alkylcarbamoyl eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl
  • alkylsulfonylcarbamoyl Heteroarylalkylcarbamoyl, alkyloxycarbamoyl.
  • Substituted or unsubstituted carbamoyloxy the substituent is alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl
  • Substituted or unsubstituted acyl substituted or unsubstituted acyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl.
  • alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl , Heterocyclylcarbonyl, formyl, acetyl. Substituted or unsubstituted alkylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted cycloalkylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstit
  • substituted amino or “substituted carbamoyl” is preferably hydroxy, Substituted or unsubstituted alkyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted alkenyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted aryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), Substituted or unsubstituted or unsub
  • alkylamino means the above “alkyl”.
  • aryl moiety of “aryloxy”, “arylalkylamino”, “arylsulfonylamino”, “arylsulfonyl”, “aryloxycarbonyl”, “arylsulfinyl”, “arylalkyloxy” and “arylthio” means the above “cycloalkyl”.
  • cycloalkenyl part of “cycloalkenyloxycarbonyl”, “cycloalkenylsulfonyl”, “cycloalkenylsulfinyl”, “cycloalkenyloxy” and “cycloalkenylthio” means the above “cycloalkenyl”.
  • Heteroarylsulfonylamino “heteroarylalkylcarbamoyl”, “heteroarylsulfonyl”, “heteroaryloxycarbonyl”, “heteroarylsulfonyl”, “heteroaryloxy”, “heteroarylsulfinyl” and “heteroarylthio”
  • the heteroaryl part of means the above “heteroaryl”.
  • heterocyclyl moiety of “heterocyclylcarbonylamino”, “heterocyclyloxycarbonyl”, “heterocyclylsulfonyl”, “heterocyclylsulfinyl”, “heterocyclyloxy” and “heterocyclylthio” It means “heterocyclyl”.
  • the following compounds are preferable.
  • CR 4 - a CR 4 - a.
  • R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted Of alkynyloxy.
  • Preferred is hydrogen, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. More preferred is hydrogen or substituted or unsubstituted alkyloxy.
  • R 7 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted Of alkynyloxy.
  • Preferred is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. More preferred is hydrogen, halogen, or substituted or unsubstituted alkyl.
  • R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl Substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted carbamoyl.
  • R 5 is preferably hydrogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 is preferably substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted carbamoyl.
  • R 6 is more preferably substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.
  • R 1 and R 2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. Preferably, it is hydrogen.
  • R 3 is a group represented by the formula: — (CR 8 R 9 ) m—R 10 .
  • Each R 8 is independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. Preferably, it is hydrogen.
  • Each R 9 is independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. Preferably, it is hydrogen.
  • M is an integer of 0 to 3, preferably an integer of 0 to 2, and more preferably 1.
  • R 10 is carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino or a group represented by the formula: — (C ⁇ O) —NR 11 — (CR 12 R 13 ) n—R 14 .
  • a group represented by the formula: — (C ⁇ O) —NR 11 — (CR 12 R 13 ) n—R 14 is preferable.
  • R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl. It is le. Preferably, it is hydrogen or substituted or unsubstituted alkyl. More preferably, it is hydrogen.
  • Each R 12 is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkyloxy, and each R 13 is independently hydrogen , Halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstit
  • R 12 is preferably hydrogen or substituted or unsubstituted alkyl
  • R 13 is preferably hydrogen or substituted or unsubstituted alkyl
  • R 12 and R 13 bonded to the same carbon atom are It is preferable to form a substituted or unsubstituted ring together with the carbon atom. More preferably, R 12 and R 13 bonded to the same carbon atom may be combined with the carbon atom to form a substituted or unsubstituted ring.
  • Rings formed by R 12 and R 13 bonded to the same carbon atom together with the carbon atom include 3 to 15 saturated or unsaturated hydrocarbon rings, oxygen atoms, sulfur atoms, and And / or a saturated or unsaturated heterocycle containing 1 to 4 nitrogen atoms in the hydrocarbon ring.
  • Non-aromatic rings are preferred, and examples of such rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and oxygen and sulfur atoms.
  • / or a saturated or unsaturated heterocycle containing 1 to 4 nitrogen atoms in the hydrocarbon ring Preferably, the following are mentioned.
  • N is 0 or 1, preferably 1.
  • R 14 is cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted alkyloxycarbonyl, When n is 0, R 11 and R 14 may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted ring. Preferably, it is cyano or substituted or unsubstituted alkyl. More preferably, it is cyano.
  • the ring formed by R 11 and R 14 together with the adjacent nitrogen atom may contain, in addition to the nitrogen atom, 1 to 4 oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring. Means a good 3-15 membered saturated or unsaturated heterocycle.
  • Non-aromatic rings are preferable, and such non-aromatic rings may be further bridged with an alkyl chain having 1 to 4 carbon atoms, and a cycloalkane (preferably 5 to 6 members) or a benzene ring may be condensed. . Examples of such a ring include the following.
  • Examples of preferable combinations of substituents of the compound represented by the formula (I) include the following 1) to 8).
  • X CR 4 a and, R 7 is halogen
  • R 6 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 1 and R 2 are hydrogen
  • R 3 is a group represented by the formula: — (CR 8 R 9 ) m—R 10
  • X CR 4 - a and, R 4 is hydrogen
  • Z CR 7 - in and
  • R 7 is a substituted or unsubstituted R 6 is substituted or unsubstitute
  • R 3 is a group represented by the formula: — (CR 8 R 9 ) m—R 10
  • R 10 is represented by the formula: A compound which is a group represented by — (C ⁇ O) —NR 11 — (CR 12 R 13 ) nR 14 ; 6)
  • R 3 is a group represented by the formula: — (CR 8 R
  • One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium labeled compound represented by the formula (I) can be prepared, for example, by introducing tritium into the specific compound represented by the formula (I) by a catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
  • Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and strontium salt; metal salts such as beryllium salt, magnesium salt, zinc salt and transition metal salt; ammonium salt An aliphatic amine salt such as a trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; Aralkylamine salts such as salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltols Examples include quaternary am
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Acidic amino acids such as aspartate and glutamate are included.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate,
  • Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate
  • sulfonates such as methanesulfonate, isethionate, benz
  • the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate.
  • examples of the hydrate include monohydrate, dihydrate and the like.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph.
  • a solvate for example, a hydrate etc.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
  • inhibitor means that the compound of the present invention suppresses the action of EL.
  • pharmaceutically acceptable means not prophylactically or therapeutically harmful.
  • the general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
  • the compound represented by the formula (I) can be synthesized as follows. Wherein each symbol is as defined above, and the compound represented by the formula (E-1) may be a known compound or a compound derived from a known compound by a conventional method. “Ak” means alkyl having 1 to 3 carbon atoms, and “Hal” means halogen.)
  • First Step This is a step for producing a compound represented by the formula (E-2) by halogenating a compound represented by the formula (E-1).
  • Reaction solvents include N, N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons ( Examples, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.
  • N, N-dimethylformamide or alcohols eg, methanol, ethanol, t-butanol, etc.
  • the reaction may be performed at 0 to 50 ° C. for 0.5 to 12 hours.
  • the halogenating agent include NBS.
  • Second Step In the step of reacting a compound represented by the formula (E-2) with a compound represented by the formula: (CHR 1 R 2 —CO) 2 O to produce a compound represented by the formula (E-3) is there.
  • the reaction solvent the solvent described in Step 1 can be used.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • esters eg, acetic acid Methyl, ethyl acetate, etc.
  • a base may be used or not.
  • Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal hydrides eg, sodium hydride
  • metal hydroxides eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide
  • metal carbonates eg, sodium carbonate
  • Calcium carbonate calcium carbonate
  • metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • sodium hydrogen carbonate organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) or pyridine
  • organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • pyridine e.g, acetic anhydride.
  • Step 2 This is a step for producing a compound represented by the formula (E-4) by cyclizing a compound represented by the formula (E-3).
  • the solvent the solvent described in Step 1 can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • nitriles eg, acetonitrile, etc.
  • metal hydride eg, sodium hydride, etc.
  • metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • sodium bicarbonate metal sodium, metal amide, organic amine (eg, triethylamine, diisopropyl) Ethylamine, DBU, 2,6-lutidine, etc.) or pyridine
  • metal amide e.g, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • organic amine eg, triethylamine, diisopropyl
  • Ethylamine e.g, DBU, 2,6-lutidine, etc.
  • pyridine e.g, pyridine
  • Lawson reagent, P 2 S 5 or the like may be used as a reagent.
  • the fourth step is a step for producing a compound represented by the formula (E-5) by reacting a compound represented by the formula (E-4) with a compound represented by the formula: (ak-O) 2 CO.
  • the reaction solvent the solvent described in Step 1 can be used.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, etc.
  • the base the base described in Step 2 can be used.
  • metal amide or alkyl lithium n-BuLi, sec-BuLi, tert-BuLi
  • the reaction may be performed at ⁇ 78 to 30 ° C. for 0.5 to 24 hours.
  • Examples of the compound represented by the formula: (ak-O) 2 CO include diethyl carbonate.
  • Fifth step is a step of producing a compound represented by the formula (E-6) by reacting a compound represented by the formula (E-5) with hydrazine.
  • the reaction solvent the solvent described in Step 1 can be used.
  • N, N-dimethylformamide, alcohols (eg, methanol, ethanol, t-butanol, etc.) or N-methyl-2-pyrrolidone may be used.
  • the reaction may be carried out at a temperature at which the solvent used is refluxed for 0.5 to 12 hours. When the reaction is performed using a microwave, the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • the compound represented by the formula (E-6) is reacted with the compound represented by the formula: HOOC-R 3 to produce a compound represented by the formula (E-7).
  • This step can be performed using reaction conditions known as a condensation reaction between a carboxylic acid and an amine.
  • reaction conditions known as a condensation reaction between a carboxylic acid and an amine for example, N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSCD), or the like can be used as a condensing agent.
  • 1-hydroxybenzotriazole HOBt
  • 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine HOOBt
  • N-hydroxysuccinimide HSu
  • the reaction solvent the solvent described in Step 1 can be used.
  • anhydrous dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone may be used.
  • the reaction may be carried out at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 24 hours. When the reaction is performed using a microwave, the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • Examples of the compound represented by the formula: HOOC-R 3 include 3-tert-butoxy-3-oxopropanoic acid, 4-tert-butoxy-4-oxobutanoic acid or 2- (tert-butoxycarbonylamino) acetic acid. .
  • the seventh step is a step for producing a compound represented by the formula (E-8) by dehydrating a compound represented by the formula (E-7).
  • the solvent the solvent described in Step 1 can be used.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • esters eg, acetic acid
  • T 3 P propylphosphonic anhydride
  • Burgess reagent TsCl and organic amine
  • MsCl and organic amine MsCl and organic amine
  • PPh 3 and CBr 4 PPh 3 and C 2 Cl 6 and the like
  • the reaction may be carried out at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 24 hours.
  • the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • Step 1 A step of producing a compound represented by the formula (I) by reacting a compound represented by the formula (E-8) with a compound represented by the formula: R 6 —B (OH) 2 under a palladium catalyst.
  • the solvent the solvent described in Step 1 can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the base the base described in Step 2 can be used.
  • a metal carbonate eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • an organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction is used in the presence of a palladium catalyst (eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.) and a phosphine ligand (eg PPh 3 , BINAP etc.)
  • the reaction may be performed for 0.5 to 12 hours at a temperature at which the solvent to be refluxed.
  • the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • Examples of the compound represented by the formula: R 6 —B (OH) 2 include phenylboronic acid.
  • the compound represented by the formula (E-5) can also be synthesized by the following method. (In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (E-9) may be a known compound or a compound derived from a known compound by a conventional method. “Ak” means alkyl having 1 to 3 carbon atoms, and “Hal” means halogen.)
  • Ninth step is a step of producing a compound represented by the formula (E-5) by reacting a compound represented by the formula (E-9) with a compound represented by the formula: CHR 1 R 2 -COO-ak.
  • the solvent the solvent described in Step 1 can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • ethers eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • the base the base described in Step 2 can be used.
  • metal sodium or metal amide may be used.
  • the reaction may be performed at ⁇ 78 to 30 ° C. for 0.5 to 12 hours.
  • Examples of the compound represented by the formula: CHR 1 R 2 —COO-ak include butyl acetate, ethyl acetate, and methyl acetate.
  • the various substituents of the compound of the present invention are (1) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry (2) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry II (3) RODD'S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYLIC COMPOUNDS etc.
  • the compound of the present invention has excellent EL inhibitory activity. Therefore, it can be used for the treatment or prevention of diseases involving EL, particularly diseases such as dyslipidemia, hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis and / or syndrome X. . In particular, it is useful in the treatment or prevention of hyperlipidemia, arteriosclerosis and dyslipidemia.
  • the compound used in the present invention can be administered orally or parenterally.
  • the compound used in the present invention is a usual preparation, for example, solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs. It can be used also as any dosage form.
  • the compound used in the present invention can be used as an aqueous or oily suspension injection or nasal solution.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used.
  • Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent.
  • the preparation of the compound used in the present invention is produced by a known method using well-known and readily available components.
  • the dose of the compound used in the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually about 0.05 mg to 3000 mg per day for an adult when administered orally, preferably May be administered in an amount of about 0.1 mg to 1000 mg divided if necessary. In the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per day for an adult. In administration, it can be used in combination with other therapeutic agents.
  • NBS N-bromosuccinimide
  • THF Tetrahydrofuran
  • WSCD 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
  • Lawesson's reagent (78 g, 193 mmol) was added to 400 ml of an anhydrous toluene solution of compound (G-3) (80.32 g, 321 mmol) at room temperature, and the mixture was heated to reflux for 1 hour. After confirming disappearance of the raw materials, cesium carbonate (314 g, 964 mmol) was added, and the mixture was further heated under reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate.
  • diethyl carbonate (36 ml, 297 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 1N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine in that order and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound (G-5) (71.4 g, 91%).
  • TETRAKIS TRIPHENYLPHOSPHINE
  • PALLADIUM (0) 72.9 mg, 0.063 mmol
  • PHENYLBORONIC ACID 192 mg, 1.58) mmol
  • 2M aqueous sodium carbonate solution 790 ⁇ l, 1.58 mmol
  • the reaction mixture was extracted with 1M hydrochloric acid and ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • examples of R 3 include the following substituents.
  • examples of Z include ⁇ CR 7 — or ⁇ N—.
  • examples of R 7 include hydrogen, fluorine, chloro, methyl, ethyl, cyano, trifluoromethyl, methoxy, and ethoxy.
  • examples of R 4 include hydrogen, fluorine, chloro, methyl, cyano, trifluoromethyl, methoxy, and ethoxy.
  • examples of R 5 include the following substituents.
  • examples of R 6 include the following substituents.
  • the following compounds were also synthesized and confirmed to inhibit Endothelial Lipase (EL).
  • EL Endothelial Lipase
  • the following compounds can be synthesized by appropriately combining the general synthesis methods described in the present application and the methods described in Examples, or known methods.
  • the compound of the present invention selectively inhibits EL and has high selectivity for HL and LPL.
  • the selectivity was examined by the following test.
  • Test Example 2 Evaluation method using human very low density lipoprotein (VLDL) for human HL inhibitory action 20 mM Tris-HCl buffer (pH 7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride (150 mM), An inhibitor dissolved in DMSO was added to a reaction solution composed of human VLDL (0.5 mg / ml) so as to be 10% DMSO, and then HL enzyme was added (10 ⁇ l in total). After reacting at 37 ° C.
  • VLDL very low density lipoprotein
  • free fatty acid (NEFA) produced from VLDL by HL was measured with a commercially available assay kit, and the amount of NEFA was used as an enzyme activity index.
  • enzyme activity when no inhibitor was included as a control value the inhibition rate relative to the control value at each concentration of the inhibitor was calculated, and the 50% inhibitory concentration (IC50 value) of the inhibitor was determined from the inhibition curve.
  • Test Example 4 Evaluation method using human high density lipoprotein (HDL) for mouse EL inhibitory action 20 mM Tris-HCl buffer (pH 7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride (150 mM), human The compound of the present invention dissolved in DMSO was added to a reaction solution composed of HDL (2 mg / ml) so as to be 5% DMSO, followed by addition of EL enzyme (total amount: 10 ⁇ l). After reacting at 37 ° C. for 2 hours, free fatty acid (NEFA) produced from HDL by EL was measured with a commercially available assay kit, and the amount of NEFA was used as an enzyme activity index. The inhibition rate with respect to the control value at each concentration of the compound of the present invention was calculated using the enzyme activity when no inhibitor was contained as a control value, and the 50% inhibitory concentration (IC50 value) of the compound of the present invention was determined from the inhibition curve.
  • IC50 value 50% inhibitory concentration
  • the compound of the present invention selectively inhibits EL and has high selectivity for HL and LPL.
  • the selectivity was examined by the following test. (Test Example 5) Evaluation method using mouse very low density lipoprotein (VLDL) for inhibiting mouse HL 20 mM Tris-HCl buffer (pH 7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride (150 mM), An inhibitor dissolved in DMSO was added to a reaction solution composed of human VLDL (0.5 mg / ml) so as to be 5% DMSO, and then HL enzyme was added (10 ⁇ l in total amount). After reacting at 37 ° C.
  • VLDL very low density lipoprotein
  • free fatty acid (NEFA) produced from VLDL by HL was measured with a commercially available assay kit, and the amount of NEFA was used as an enzyme activity index.
  • enzyme activity when no inhibitor was included as a control value the inhibition rate relative to the control value at each concentration of the inhibitor was calculated, and the 50% inhibitory concentration (IC50 value) of the inhibitor was determined from the inhibition curve.
  • Test Example 7 Pharmacological test of HDL-elevating action C57BL / 6J mice aged 8 to 25 weeks were divided into groups of 5 to 20 mice, and the test compound (20-200 mg / kg / day) was orally administered. The control group was orally administered with a 0.5% aqueous methylcellulose solution (10 mL / kg). Blood was collected from the tail vein 24 hours before, 3 days or 6 days after the start of administration, and serum HDL cholesterol concentration was measured using Cholestest N HDL (Daiichi Chemical Co., Ltd.). At the time of grouping, the animals were distributed so that the average values of body weight and serum HDL cholesterol level were almost equal among the test groups. The effect of the test compound was determined by a significant difference test of serum HDL cholesterol level after administration between the control group and the administration group.
  • Test Example 8 CYP3A4 Fluorescence MBI Test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compound of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate.
  • a part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer.
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ mol / L or more was designated as (+), and the case where it was 3 ⁇ mol / L or less was designated as ( ⁇ ).
  • Test Example 9 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. Calculated.
  • Test Example 10 FAT test 20 ml of Salmonella typhimurium TA98 strain, TA100 strain frozen and stored in 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and incubated at 37 ° C for 10 hours, Incubated before shaking.
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution each 12 ⁇ L and test bacterial solution 588 ⁇ L (under metabolic activation conditions, test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L of the mixture), and cultured with shaking at 37 ° C.
  • Test Example 12 Metabolic stability test A commercially available pooled human liver microsome is reacted with the compound of the present invention for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
  • the compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%.
  • the hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.
  • Test Example 13 hERG Test
  • HEK293 cells expressing human ether-a-go-related gene (hERG) channel it is important for ventricular repolarization process
  • I Kr delayed rectifier K + current
  • the cell was held at a membrane potential of ⁇ 80 mV by the whole cell patch clamp method, a leak potential of ⁇ 50 mV was applied, and then a depolarization stimulus of +40 mV was applied.
  • the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
  • Test Example 14 Powder solubility test An appropriate amount of the compound of the present invention was put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid was added to 1000 mL) and JP-2 solution were added to each container. 200 ⁇ L of 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution was added to 1.08 g of TCA to make 100 mL) Added in increments. When the entire amount was dissolved after adding the test solution, the compound of the present invention was appropriately added. After sealing and shaking at 37 ° C.
  • the compound of the present invention was quantified using HPLC by an absolute calibration curve method.
  • Test Example 16 Fluctuation Ames Test The mutagenicity of the compounds of the present invention was evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.
  • MicroF containing 110 mL Exposure medium Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (under the metabolic activation conditions, 498 ⁇ L of the test bacterial solution and S9 (mix solution of 90 ⁇ L of mix) was mixed and incubated at 37 ° C.
  • Hard gelatin capsules are manufactured using the following ingredients: Dose (mg / capsule) Active ingredient 250 Starch (dried) 200 Magnesium stearate 10 Total 460mg
  • Tablets are manufactured using the following ingredients: Dose (mg / tablet) Active ingredient 250 Cellulose (microcrystal) 400 Silicon dioxide (fume) 10 Stearic acid 5 665mg total The ingredients are mixed and compressed into tablets each weighing 665 mg.
  • Aerosol solution is prepared containing the following ingredients: weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00 Total 100.00
  • the active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to ⁇ 30 ° C. and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
  • a tablet containing 60 mg of active ingredient is prepared as follows: Active ingredient 60mg 45mg starch Microcrystalline cellulose 35mg Polyvinylpyrrolidone (10% solution in water) 4mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1mg 150mg total The active ingredients, starch, and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
  • Capsules containing 80 mg of active ingredient are prepared as follows: Active ingredient 80mg Starch 59mg Microcrystalline cellulose 59mg Magnesium stearate 2mg Total 200mg Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
  • a suppository containing 225 mg of active ingredient is prepared as follows: Active ingredient 225mg Saturated fatty acid glyceride 2000mg Total 2225mg The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
  • a suspension containing 50 mg of active ingredient is prepared as follows: Active ingredient 50mg Sodium carboxymethylcellulose 50mg Syrup 1.25ml Benzoic acid solution 0.10ml Fragrance q. v. Dye q. v. 5ml in total with purified water The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add benzoic acid solution and perfume diluted with a portion of water and stir. Then add a sufficient amount of water to the required volume.
  • the intravenous formulation is manufactured as follows: Active ingredient 100mg Saturated fatty acid glyceride 1000ml Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
  • the compound according to the present invention exhibits an EL inhibitory action. Therefore, the compound according to the present invention is very useful as a therapeutic agent for dyslipidemia, a therapeutic agent for hyperlipidemia, and a therapeutic agent for arteriosclerosis.

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Abstract

L'invention porte sur un composé représenté par la formule (I) (dans laquelle X représente =CR4- ou =N- ; Y représente -CR5= ou -N= ; Z représente =CR7- ou =N- ; R4 et R7 représentent chacun indépendamment l'atome d'hydrogène, un atome d'halogène, le groupe cyano ou similaire et lorsque X représente =CR4-, Y représente -CR5= et Z représente =CR7-, R4 et R7 ne représentent pas simultanément l'atome d'hydrogène et lorsque X représente =CR4-, Z représente =CR7- et R4 représente un atome d'halogène, R7 ne représente pas l'atome d'hydrogène ; R5 et R6 représentent chacun indépendamment l'atome d'hydrogène, un atome d'halogène, le groupe hydroxy, le groupe cyano, un groupe alkyle substitué ou non substitué ou similaire ; R1 et R2 représentent chacun indépendamment l'atome d'hydrogène, un atome d'halogène, le groupe hydroxy, le groupe cyano ou similaire ; R3 représente un groupe représenté par la formule : -(CR8R9)m-R10 ; R8 et R9 représentent chacun indépendamment l'atome d'hydrogène, un atome d'halogène ou similaire ; m représente un nombre entier de 0 à 3 ; et R10 représente le groupe carboxy, un groupe alcoxycarbonyle substitué ou non substitué ou similaire), un sel de celui-ci ou un solvate du composé ou du sel de celui-ci.
PCT/JP2011/078736 2010-12-14 2011-12-13 Dérivé de benzothiazole et d'azabenzothiazole ayant une activité d'inhibition de la lipase endothéliale WO2012081563A1 (fr)

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WO2012173099A1 (fr) * 2011-06-14 2012-12-20 塩野義製薬株式会社 Dérivé amino inhibant la lipase endothéliale
WO2014011513A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale de type benzothiazole contenant un sulfonyle
WO2014011461A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Dérivés de benzothiazole substitués par amide ou urée en tant qu'inhibiteurs de lipase endothéliale
WO2014015088A1 (fr) 2012-07-19 2014-01-23 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale à base de benzothiazole liés à une amine, l'urée ou un sulfone amide
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US8754113B2 (en) 2009-12-15 2014-06-17 Shionogi & Co., Ltd. Oxadiazole derivative having endothelial lipase inhibitory activity
WO2015105749A1 (fr) 2014-01-07 2015-07-16 Bristol-Myers Squibb Company Composés benzothiazole à liaison amide sulfone utilisés en tant qu'inhibiteurs de la lipase endothéliale

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US8754113B2 (en) 2009-12-15 2014-06-17 Shionogi & Co., Ltd. Oxadiazole derivative having endothelial lipase inhibitory activity
WO2012173099A1 (fr) * 2011-06-14 2012-12-20 塩野義製薬株式会社 Dérivé amino inhibant la lipase endothéliale
WO2014011513A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale de type benzothiazole contenant un sulfonyle
WO2014011461A1 (fr) 2012-07-09 2014-01-16 Bristol-Myers Squibb Company Dérivés de benzothiazole substitués par amide ou urée en tant qu'inhibiteurs de lipase endothéliale
US8680090B2 (en) 2012-07-09 2014-03-25 Bristol-Myers Squibb Company Sulfonyl containing benzothiazole inhibitors of endothelial lipase
US9139578B2 (en) 2012-07-09 2015-09-22 Bristol-Myers Squibb Company Amide or urea containing benzothiazole inhibitors of endothelial lipase
WO2014015088A1 (fr) 2012-07-19 2014-01-23 Bristol-Myers Squibb Company Inhibiteurs de lipase endothéliale à base de benzothiazole liés à une amine, l'urée ou un sulfone amide
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CN103664639B (zh) * 2013-11-19 2015-05-20 中国科学院广州生物医药与健康研究院 胺类化合物及其制备方法和在制备抗流感病毒药物中的应用
WO2015105749A1 (fr) 2014-01-07 2015-07-16 Bristol-Myers Squibb Company Composés benzothiazole à liaison amide sulfone utilisés en tant qu'inhibiteurs de la lipase endothéliale
US10173991B2 (en) 2014-01-07 2019-01-08 Bristol-Myers Squibb Company Sulfone amide linked benzothiazole inhibitors of endothelial lipase

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