WO2010126002A1 - Produit pharmaceutique contenant un composé sulfonamide hétérocyclique - Google Patents

Produit pharmaceutique contenant un composé sulfonamide hétérocyclique Download PDF

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WO2010126002A1
WO2010126002A1 PCT/JP2010/057362 JP2010057362W WO2010126002A1 WO 2010126002 A1 WO2010126002 A1 WO 2010126002A1 JP 2010057362 W JP2010057362 W JP 2010057362W WO 2010126002 A1 WO2010126002 A1 WO 2010126002A1
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substituted
unsubstituted
acceptable salt
pharmaceutically acceptable
solvate
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PCT/JP2010/057362
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Japanese (ja)
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晃平 西冨
一也 鹿野
一生 加藤
佑介 酒匂
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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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/64—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D415/00—Heterocyclic compounds containing the thiamine skeleton
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having an inhibitory action on amyloid ⁇ (hereinafter, A ⁇ ) production and useful as a therapeutic agent for diseases induced by A ⁇ production, secretion and / or deposition.
  • a ⁇ amyloid ⁇
  • Alzheimer's disease As for Alzheimer's disease, the number of patients as of 2008 is said to be about 6.6 million or more worldwide, and it is considered that the number of patients will surely continue to increase with aging.
  • the current treatment of Alzheimer's disease is mainly symptomatic treatment, and has not led to radical treatment, and the development of more effective drugs is expected.
  • a ⁇ which is a major pathological determinant of Alzheimer's disease, is a metabolite of amyloid precursor protein (APP), and several types of fragments such as A ⁇ 40 and A ⁇ 42 are produced depending on the cleavage position of APP. In normal individuals, two major A ⁇ s, A ⁇ 40 and A ⁇ 42, are found, but the dominant one is A ⁇ 40.
  • a ⁇ 42 is predominantly increased compared to normal, and in the neuritic plaques observed in the lesion area of Alzheimer's disease, A ⁇ 42 is present at a very high rate compared to A ⁇ 40. . It has also been reported that A ⁇ 42 accumulates early and preferentially in soft tissue plaques, whereas A ⁇ 40 is unrelated to early deposition of amyloid plaques. For this reason, A ⁇ 42 is believed to play a major role in amyloid plaque deposition in familial Alzheimer's disease patients. Thus, A ⁇ , particularly A ⁇ 42, is deeply involved in the onset and development of Alzheimer's disease, and it is considered that compounds that suppress the production of A ⁇ 42 can be effective preventive or therapeutic agents for Alzheimer's disease.
  • ⁇ -secretase inhibitors reduce the total amount of A ⁇ fragments.
  • the ⁇ -secretase inhibitor also inhibits the enzyme activity itself of ⁇ -secretase, so there is a concern about side effects.
  • a ⁇ -secretase-modifying drug does not inhibit the enzyme activity itself, selectively inhibits the production of A ⁇ 42, and has little influence on the total amount of A ⁇ , so it may be a safe drug with fewer side effects.
  • Patent Documents 1 to 14 and Non-Patent Document 1 are known as compounds having a ⁇ -secretase inhibitory action or a modifying action, but these compounds differ in structure from the compounds according to the present invention. Yes. Further, compounds structurally similar to the compounds according to the present invention are described in Patent Documents 15 to 27 and Non-Patent Document 2, all of which are different in activity from the compounds according to the present invention.
  • a compound having a amyloid ⁇ production inhibitory action particularly a ⁇ -secretase modifying action, and useful as a therapeutic agent for diseases induced by A ⁇ production, secretion or deposition, such as Alzheimer's dementia.
  • the present invention 1) Formula (Ia): Wherein X is —S— or —O—, Ring A is a benzene ring, a pyridine ring or a pyrimidine ring, R 1a , R 2a and R 3a are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted mercapto, substituted or unsubstituted alkoxycarbonyl, substituted or Unsubstituted alkenyloxycarbonyl, substituted or unsubstitute
  • R 1a , R 2a and R 3a are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, Substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted mercapto, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heterocyclic oxycarbonyl, substituted or unsubstituted acyl, Substituted or unsubstituted amino, substituted or unsubstituted carb
  • a pharmaceutical composition for modifying ⁇ -secretase which comprises a compound represented by the formula: or a pharmaceutically acceptable salt thereof or a solvate thereof,
  • L a is -SO 2 N (R 8) - or -N (R 8) SO 2 - is, above 1), 1 ') or 2) gamma-secretase decoration pharmaceutical composition according, 4)
  • Ak 1 and Ak 2 are both single bonds, L a is -SO 2 N (R 8) - is, above 3) gamma-secretase decoration pharmaceutical composition according, 5)
  • composition for 8) The pharmaceutical composition for modifying ⁇ -secretase according to any one of 1) to 5) and 1 ′) above, wherein R 1a and R 2a are both halogen, 9) The pharmaceutical composition for modifying ⁇ -secretase according to any one of 1) to 5) and 1 ′) above, wherein R 3a is substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl.
  • R 1b and R 3b are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted mercapto, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbon
  • R 2b is a substituted or unsubstituted heterocyclic group
  • L b is —SO 2 N (R 8 ) — or —N (R 8 ) SO 2 —
  • R 1b , R 3b and R 5b is synonymous with R 1a , R 3a and R 5a described in 1) above, and the other symbols are synonymous with 1) above.
  • R 2b is A compound that is pyrazol-3-yl substituted with at least methyl; A compound wherein isoxazol-5-yl substituted at the 3 position with methyl or alkoxycarbonyl and a compound which is 1,6-dihydro-6-oxopyridazin-3-yl, and R 5b is A compound which is 4,6-dimethoxypyrimidin-2-yl, A compound which is 1,6-dihydro-4-methyl-6-oxopyridazin-3-yl, A compound that is —C ( ⁇ O) NHOH, A compound that is —C ( ⁇ O) CH 2 SC ( ⁇ O) CH 3 and a compound that is —NHC ( ⁇ O) CH 3 ; except for) Or a pharmaceutically acceptable salt thereof or a solvate thereof, 13) The compound according to 12) or 12 ′) above, wherein Ak 1 and Ak 2 are both a single bond, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 2b is substituted or unsubstituted, pyrrolyl optionally condensed with another ring, substituted or unsubstituted thiazolyl optionally condensed with another ring, or substituted or unsubstituted other ring Or a pharmaceutically acceptable salt or solvate thereof according to any one of 12) to 15), 12 ′) or 13 ′), which is thienyl optionally condensed with 18) The above 12) to 17), 12 ′) or 13 ′), wherein R 5b is a substituted or unsubstituted 5-membered unsaturated heterocyclic group or a substituted or unsubstituted alkoxycarbonyl.
  • a compound or a pharmaceutically acceptable salt thereof or a solvate thereof 19) The compound according to any one of 12) to 18), 12 ′) or 13 ′), or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 1b is hydrogen or substituted or unsubstituted alkyl. object, 20) The compound according to any one of the above 12) to 19), 12 ′) or 13 ′), wherein R 3b is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • R 1c and R 2c are both bromo, R 3c is hydrogen, R 5c is substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, alkoxycarbonyl, n-propylcarbonyl, unsubstituted morpholino
  • R 1c is bromo
  • R 2c is chloro
  • R 3c is hydrogen and R 5c is 3,5-bis (1,1-dimethylethyl) 1H-pyrazol-1-yl;
  • R 1c and R 2c are both chloro and R 5c is 2- (6-benzthiazolylamino) -4-pyrimidiny
  • R 1c and R 2c are the same or different and are halogen, L c is —SO 2 N (R 8 ) — or —N (R 8 ) SO 2 —, and R 3c and R 5c are each It is synonymous with R 3a and R 5a in 1) above, and the other symbols are synonymous with 1) above.
  • a compound or a pharmaceutically acceptable salt thereof or a solvate thereof, 27) The above 21) to 26), wherein R 5c is substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted alkoxycarbonyl. 21 ′) or 22 ′) or a pharmaceutically acceptable salt thereof or a solvate thereof, 28) The compound according to any one of the above 21) to 27), 21 ′) or 22 ′), wherein R 3c is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • R 1e , R 2e and R 3e are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted mercapto, substituted or unsubstituted alkoxycarbonyl, substituted or Unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alky
  • a pharmaceutically acceptable salt thereof or a solvate thereof 41) The compound or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of the above 35) to 39), 35 ′) or 37 ′), wherein R 1e and R 2e are the same or different and are halogen. object, 42) The above 35) to 39), 35 ′) or 37 ′), wherein R 1e is substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, and R 2e and R 3e are both hydrogen.
  • Ak 1 is carbon atoms may also be substituted or unsubstituted separated by a hetero atom 1 when it is alkylene of 1-2 carbon atoms and R 8 of Ak 1 together form a ring
  • L a is -N (R 8) SO 2 - or -N (R 8) C ( ⁇ O) —
  • Ak 2 is a substituted or unsubstituted alkylene having 1 to 2 carbon atoms which may intervene with a heteroatom, the carbon atom of Ak 2 and R 8 together form a ring.
  • Ak 1 is carbon atoms may also be substituted or unsubstituted separated by a hetero atom 1 when it is alkylene of 1-2 carbon atoms and R 8 of Ak 1 together do not form a ring
  • L a is -N (R 8) SO 2 - or -N (R 8) C ( ⁇ O) —
  • Ak 2 is a substituted or unsubstituted alkylene having 1 to 2 carbon atoms which may intervene with a heteroatom, the carbon atom of Ak 2 and R 8 together form a ring.
  • the compound according to the present invention is useful as a therapeutic agent for diseases (such as Alzheimer's disease) induced by A ⁇ production, secretion or deposition.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl includes linear or branched alkyl having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 3 carbon atoms.
  • alkyl part of “dialkoxyborane” is the same as the above “alkyl”.
  • Substituted or unsubstituted alkyl “substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl”, “substituted or unsubstituted mercapto” and “substituted or unsubstituted alkylsulfonyl” It may be substituted with one or more groups selected from the group ⁇ .
  • the substituent group ⁇ is halogen, hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, alkoxycarbonylamino, mercapto, alkylthio, carbamoyl, alkylcarbamoyl, sulfamoyl, alkylsulfamoyl.
  • Cyano nitro, a carbocyclic group optionally substituted with one or more groups selected from the following substituent group ⁇ and a heterocycle optionally substituted with one or more groups selected from the substituent group ⁇ It is a group consisting of formula groups.
  • the substituent group ⁇ means alkyl, halogen, hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, alkoxycarbonylamino, mercapto, alkylthio, carbamoyl, alkylcarbamoyl, sulfamoyl, alkylsulfur.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Includes straight chain or branched alkenyl.
  • alkenyl part of “alkenyloxy”, “alkenyloxycarbonyl” and “alkenylsulfonyl” is the same as the above “alkenyl”.
  • Substituents of “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkenyloxy”, “substituted or unsubstituted alkenyloxycarbonyl” and “substituted or unsubstituted alkenylsulfonyl” are the above substituent group ⁇ One or more selected groups may be mentioned.
  • Alkynyl includes straight-chain or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms having one or more triple bonds at any position. To do. Specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are included. These may further have a double bond at an arbitrary position.
  • alkynyl part of “alkynyloxy”, “alkynyloxycarbonyl” and “alkynylsulfonyl” is the same as the above “alkynyl”.
  • substituents of “substituted or unsubstituted alkynyloxy”, “substituted or unsubstituted alkynyloxycarbonyl” and “substituted or unsubstituted alkynylsulfonyl” include one or more groups selected from the above substituent group ⁇ . It is done.
  • substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, and “substituted or unsubstituted sulfamoyl” include halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, Examples thereof include 1 to 2 groups selected from substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted carbocyclic group and substituted or unsubstituted heterocyclic group.
  • “Acyl” includes aliphatic acyl having 1 to 10 carbon atoms, carbocyclic carbonyl and heterocyclic carbonyl. Specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioroyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl, benzothiazolecarbonyl, pyrazinecarbonyl, Examples include piperidine carbonyl.
  • acylamino and “acyloxy” is the same as described above.
  • substituents of “substituted or unsubstituted acyl” and “substituted or unsubstituted acylamino” include one or more groups selected from substituent group ⁇ .
  • the ring part of carbocyclic carbonyl and heterocyclic carbonyl is substituted with one or more groups selected from alkyl, substituent group ⁇ , and alkyl substituted with one or more groups selected from substituent group ⁇ . It may be.
  • Carbocycle includes cycloalkane, cycloalkene, aromatic carbocycle, non-aromatic fused carbocycle and the like.
  • Cycloalkane is a carbocyclic ring having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 4 to 8 carbon atoms.
  • cycloalkene includes those having one or more double bonds at any position in the ring of the cycloalkane, specifically, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene. , Cyclooctene, cyclononene, cyclodecene, cyclohexadiene and the like.
  • “Aromatic carbocycle” includes benzene, naphthalene, anthracene and the like.
  • the “non-aromatic fused carbocycle” is a ring in which two or more rings selected from the above “cycloalkane”, “cycloalkene” and “aromatic carbocycle” are fused, Includes other than “ring”.
  • Carbocyclic group includes cycloalkyl, cycloalkenyl, aryl, and non-aromatic fused carbocyclic groups.
  • “Cycloalkyl” is a carbocyclic group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 4 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo Includes octyl, cyclononyl, cyclodecyl and the like.
  • Cycloalkenyl includes those having one or more double bonds at any position in the cycloalkyl ring, specifically, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclo Examples include heptynyl, cyclooctynyl, cyclononinyl, cyclodecynyl and cyclohexadienyl.
  • “Aryl” includes phenyl, naphthyl, anthryl, phenanthryl and the like, with phenyl being particularly preferred.
  • non-aromatic fused carbocyclic group is a monovalent group consisting of a ring in which two or more rings selected from the above “cycloalkane”, “cycloalkene” and a benzene ring are condensed, Includes other than “aryl”. Specific examples include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.
  • the carbocyclic moiety of “carbocyclic carbonyl”, “carbocyclic oxy”, “carbocyclic oxycarbonyl”, and “carbocyclic sulfonyl” is the same as “carbocyclic group”.
  • the aryl part of “arylalkyl”, “aryloxy”, “aryloxycarbonyl” and “arylsulfonyl” is the same as the above “aryl”.
  • Heterocycle includes a heterocycle having one or more heteroatoms arbitrarily selected from O, S and N, specifically, pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine , Triazole, triazinyl, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan and thiophene, 5-membered or 6-membered heterocycle; indole, isoindole, indazole, indolizine, indoline, iso Indoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzopyran, benzimidazole, benzotriazole, benzisoxazole, benzoxa
  • the “heterocyclic group” includes a monovalent group formed by removing a hydrogen atom from the above “heterocycle”.
  • the “heteroaryl” includes those that are aromatic cyclic groups among the above “heterocyclic groups”.
  • the heterocyclic moiety of “heterocyclic oxy”, “heterocyclic carbonyl”, “heterocyclic sulfonyl” and “heterocyclic oxycarbonyl” is the same as the above “heterocycle”.
  • the “5-membered or 6-membered unsaturated heterocyclic group” includes those having one or more unsaturated bonds among the above “heterocyclic group”.
  • heteroaryl as well as imidazolinyl, dihydropyridyl, dihydrooxazinyl, oxadiazinyl, dioxolyl, pyranyl and the like.
  • the “5-membered unsaturated heterocyclic group” includes 5-membered cyclic groups among the above “5-membered or 6-membered unsaturated heterocyclic groups”, such as pyrrolyl, imidazolyl, pyrazolyl, Examples include tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, imidazolinyl and the like.
  • the “5-membered heterocyclic group optionally condensed with another ring” includes pyrrole, imidazole, pyrazole, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, thiophene, A 5-membered unsaturated heterocyclic ring such as imidazoline or a 5-membered saturated heterocyclic ring such as oxathiolane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, And a monovalent group formed by removing a hydrogen atom from a ring condensed with one or more rings selected from the above-mentioned “heterocycle”.
  • Examples of 5-membered heterocyclic groups fused to other rings include indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, purinyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, Benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridine, triazolopyridyl, imidazothiazolyl, dihydrobenzofuryl , Tetrahydrobenzothienyl, carbazolyl, carbolinyl and the like.
  • the bond of these groups may be located on either the 5-membered heterocyclic ring side or the other condensed ring side.
  • “Substituted or unsubstituted thiazolyl optionally fused with other ring” or “Substituted or unsubstituted other ring” The same applies to the bond of “thienyl optionally condensed”.
  • it is located on the 5-membered heterocycle side.
  • Alkylene having 1 to 2 carbon atoms includes a divalent carbon chain having 1 or 2 carbon atoms. Specifically, methylene and dimethylene.
  • the alkylene part of “alkylenedioxy” includes a straight or branched carbon chain having 1 to 6 carbon atoms, specifically, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene. , Propylene and the like.
  • substituent of “substituted or unsubstituted alkylene having 1 to 2 carbon atoms which may intervene with a heteroatom” include substituent group ⁇ , oxo and the like, preferably halogen, hydroxy and the like.
  • alkylene having 1 to 2 carbon atoms intervening a hetero atom examples include, for example, —OCH 2 —, —CH 2 O—, —SCH 2 —, —CH 2 S—, —NHCH 2 —, —CH 2 NH—, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —SCH 2 CH 2 —, —CH 2 CH 2 S—, —NHCH 2 CH 2 —, —CH 2 CH 2 NH—, —CH 2 OCH 2 —, —CH 2 SCH 2 —, —CH 2 NHCH 2 — and the like
  • These may be substituted with one or more groups selected from the group consisting of the substituent group ⁇ and oxo.
  • L a is —SO 2 N (R 8 ) — or —C ( ⁇ O) N (R 8 ) —
  • Ak 1 may have a substituted or unsubstituted carbon atom of 1 to when it is 2 alkylene may be carbon atoms and R 8 of Ak 1 together form a ring
  • Ak 2 is a substituted or unsubstituted alkylene having 1 to 2 carbon atoms which may intervene with a hetero atom, the carbon atom of Ak 2 and R 8 together form a ring.
  • “It may be” includes, for example, the following cases.
  • 0-1 indicates that the repeating of the methylene group is 0 or 1
  • 0-2 indicates that the repeating of the methylene group is 0 to 2
  • 1-2 indicates that of the methylene group. Indicates that the repetition is 1 or 2.
  • the “solvate” includes, for example, solvates with organic solvents, hydrates and the like. When forming a hydrate, it may be coordinated with any number of water molecules.
  • the compounds according to the present invention include pharmaceutically acceptable salts.
  • alkali metals such as lithium, sodium or potassium
  • alkaline earth metals such as magnesium or calcium
  • ammonium salts with organic bases and amino acids
  • inorganic acids hydroochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphorus Acid or hydroiodic acid
  • organic acids acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, and salts with p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.
  • hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable. These salts can be formed by a commonly performed method.
  • the compound (Ia) according to the present invention is not limited to a specific isomer, and all possible isomers (keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, and Rotamers, etc.) and racemates.
  • one or more hydrogen, carbon or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms.
  • the compound of formula (I) includes all radiolabels of the compound of formula (I).
  • Such “radiolabeled”, “radiolabeled” and the like of the compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. . It is also useful as a pharmaceutical product.
  • isotopes that can be incorporated into the compound of formula (I) of the present invention include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, and 35 S, respectively.
  • 18 F, and 36 Cl include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • a tritium labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • This method involves reacting a compound of formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. May be.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical. See 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.
  • the compound (Ia) according to the present invention can be produced, for example, by the following method.
  • a general synthesis method of the compound of the present invention is shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. The compounds described in the examples were synthesized generally according to these, but are not particularly limited to these methods. Reaction solvents, bases, palladium catalysts, and phosphine ligands that can be used in the production of the compounds are described below. In the general synthesis methods, preferred ones are shown, but the present invention is not particularly limited thereto.
  • Reaction solvent DMF, NMP, DMA, 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.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water, and mixed solvents thereof.
  • aromatic hydrocarbons e
  • metal hydride eg, sodium hydride
  • metal hydroxide eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide
  • metal carbonate eg, sodium carbonate
  • potassium t-butoxide e.g.
  • metal alkoxide eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • sodium bicarbonate metallic sodium
  • organic amine eg, triethylamine, diisopropylethylamine, DBU
  • Pyridine 4-dimethylaminopyridine, 2,6-lutidine, etc.
  • alkyllithium n-BuLi, sec-BuLi, tert-BuLi
  • Pd catalyst used for Pd coupling Pd (PPh 3 ) 4 , PdCl 2 (dppf), PdCl 2 (PPh 3 ) 2 , Pd (OAc) 2 , Pd 2 (dba) 3 , PdCl 2 and the like.
  • Phosphine ligands PPh 3 , BINAP, Xantphos, S-Phos, X-Phos, DPPF, t-Bu 3 P, tris o-tolylphosphine and the like.
  • the compound represented by the general formula (Ia) of the present invention can be produced, for example, by the synthetic route shown below.
  • Manufacturing method A In the formula, one of D and E is SO 2 -Hal and the other is NHR 8 ; or one is COOH or CO-Hal, the other is NHR 8 ; Hal is halogen; Is the same as above
  • Compound (Ia) can be produced by reacting compound a and compound b, each of which is a known compound or a compound obtained from a known compound by a conventional method.
  • compound a is a halogenosulfonyl compound and compound b is an amine compound.
  • Compound a may be a salt such as hydrochloride or bromate.
  • the reaction solvent described in the above (1) can be used as the reaction solvent, preferably tetrahydrofuran, dichloromethane, chloroform, acetate ester, acetonitryl, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl
  • a solvent such as sulfoxide
  • the reaction may be performed at room temperature to 200 ° C. in the presence of a base such as DBU, triethylamine, or pyridine. If the reactivity is low, it can be prepared by appropriately heating.
  • the target compound (Ia) can be produced by reacting at a temperature of from 200 ° C. to 200 ° C., preferably from 130 ° C. to 150 ° C. If necessary, a quaternary ammonium salt such as tetrabutylammonium bromide is used as an additive.
  • a quaternary ammonium salt such as tetrabutylammonium bromide is used as an additive.
  • halogen chlorine, iodine and bromine are preferable.
  • As the leaving group —OSO 2 (C r F 2r + 1 ) (where r is an integer of 1 to 4) is preferable, and in particular, an OTf group (trifluoromethanesulfonic acid ester) Is preferred.
  • R 2a may include hydrogen or any suitable substituent such as alkyl, aryl, alkenyl, acyl, amino, alkoxy, sulfamoyl, carbamoyl and the like.
  • compound c and compound d can be subjected to a Suzuki coupling reaction to introduce substituent R 2a to synthesize target compound (Ia).
  • the reaction may be carried out in the presence of the phosphine ligand shown in the above (4) and the base shown in the above (2).
  • the reaction solvent those described in the above (1) can be used. For example, dioxane, DMF, DME, lower alcohol, toluene and a mixed solution thereof are preferable.
  • reaction temperature is not particularly limited, it can be carried out at room temperature to 200 ° C. If the reactivity is low, it may be appropriately heated.
  • base a solid or aqueous solution such as Na 2 CO 3 , K 3 PO 4 , K 2 CO 3 , NaOH, Cs 2 CO 3 is preferable.
  • each Y is independently a halogen or a leaving group, n is an integer of 1 to 2, and other symbols are as defined above.
  • Compound (e) is reacted with dihalide or sulfonate (f) in the presence of a base such as sodium hydride, sodium hydroxide, sodium methoxide, tert-BuLi, DBU or the like at ⁇ 78 ° C. to 100 ° C. (If) can be manufactured.
  • a base such as sodium hydride, sodium hydroxide, sodium methoxide, tert-BuLi, DBU or the like
  • Conversion of the functional group of each substituent can be performed at an appropriate stage by a known method. For example, if a compound having a formyl group is converted into a formyloxy group using a Bayer-Villiger reaction or the like and then subjected to a normal hydrolysis reaction under an acidic condition or an alkaline condition, the substituent is changed. A compound which is hydroxy is obtained. Specifically, the compound is peracid (eg peracetic acid, perbenzoic acid, metachloroperbenzoic acid, trifluoroperacetic acid) in a suitable solvent (eg 1,2-dichloroethane, chloroform, dichloromethane, carbon tetrachloride, benzene).
  • a suitable solvent eg 1,2-dichloroethane, chloroform, dichloromethane, carbon tetrachloride, benzene
  • an appropriate solvent for example, methanol, ethanol, isopropanol, dimethyl sulfoxide, diethylene glycol dimethoxyethane, tetrahydrofuran, benzene, toluene, cyclohexane, etc.
  • an appropriate solvent for example, methanol, ethanol, isopropanol, dimethyl sulfoxide, diethylene glycol dimethoxyethane, tetrahydrofuran, benzene, toluene, cyclohexane, etc.
  • a compound in which the substituent is hydroxymethyl is obtained.
  • a compound in which any substituent is formyl is subjected to a Wittig reaction (Organic Reaction, 1965, Vol. 14, p. 270), a compound in which the substituent is alkenyl is obtained. can get.
  • a compound in which any substituent is formyl is used with an oxidizing agent such as sodium chlorite, Jones reagent, or chromic anhydride, and in a solvent such as t-butanol or acetone according to the oxidizing agent, at 0 ° C. to under heating. If it is made to react for several hours, the compound whose substituent is carboxy will be obtained. If necessary, 2-methyl-2-butene, sodium dihydrogen phosphate and the like can be added to favorably proceed the reaction.
  • an oxidizing agent such as sodium chlorite, Jones reagent, or chromic anhydride
  • a compound in which any of the substituents is hydroxy is converted to a suitable solvent (for example, tetrahydrofuran, acetone, dimethyl) in the presence of a base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium hydroxide, barium hydroxide, calcium carbonate. Reaction with the corresponding alkylating agent in formamide, acetonitrile, etc.) gives compounds in which the substituent is alkoxy.
  • a suitable solvent for example, tetrahydrofuran, acetone, dimethyl
  • a base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium hydroxide, barium hydroxide, calcium carbonate.
  • a compound in which any of the substituents is carboxy is converted into an appropriate solvent (eg, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, etc.) and an appropriate activator (eg, thionyl chloride, acid halide, acid anhydride, if necessary). And a reaction with an amine compound such as ammonia or dimethylamine under heating at 0 ° C. for several minutes to several hours, a compound having a carbamoyl substituent can be obtained.
  • an appropriate solvent eg, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, etc.
  • an appropriate activator eg, thionyl chloride, acid halide, acid anhydride, if necessary
  • a suitable solvent eg, chloroform, dichloromethane, carbon tetrachloride, acetonitrile, nitromethane, acetic acid, acetic anhydride, etc.
  • a suitable solvent eg, chloroform, dichloromethane, carbon tetrachloride, acetonitrile, nitromethane, acetic acid, acetic anhydride, etc.
  • Lewis acid e.g, hydrochloric acid, phosphoric acid, etc.
  • halogenating agents for example, bromine, chlorine, iodine, sulfuryl chloride, N-bromosuccinimide, N-iodosuccinimide, etc.
  • a compound in which any substituent is nitro is reduced by using a catalytic reduction catalyst such as 10% palladium / carbon in a suitable solvent (tetrahydrofuran, ethyl acetate, methanol, etc.), whereby the substituent is amino.
  • a catalytic reduction catalyst such as 10% palladium / carbon in a suitable solvent (tetrahydrofuran, ethyl acetate, methanol, etc.), whereby the substituent is amino.
  • R 2b is a substituted or unsubstituted heterocyclic group (wherein the heterocyclic group is, for example, isoxazolyl, thiazolyl, pyrazolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, benzothienyl, indolyl, or imidazopyridyl; Group is for example unsubstituted alkyl or unsubstituted alkoxycarbonyl), R 4 is hydroxy, unsubstituted alkyl, unsubstituted alkoxy or unsubstituted alkenyloxy, R 5b represents a substituted or unsubstituted 5- or 6-membered unsaturated heterocyclic group (wherein the 5- or 6-membered unsaturated heterocyclic group is, for example, furyl, imidazolyl, isoxazolyl or oxadiazolyl).
  • the heterocyclic group is, for example, is
  • substituent is, for example, unsubstituted alkyl) or —C ( ⁇ O) R 6 , R 6 is unsubstituted alkoxy;
  • R 8 is hydrogen and p is 0 or 1;
  • Ring A is a benzene ring or a pyridine ring
  • R 1c and R 2c are the same or different and are halogen
  • R 4 is halogen, hydroxy, unsubstituted alkyl or unsubstituted alkoxy
  • R 5c is a substituted or unsubstituted 5-membered or 6-membered unsaturated heterocyclic group (wherein the 5-membered or 6-membered unsaturated heterocyclic group is, for example, oxazolyl, isoxazolyl, thienyl, pyrrolyl, pyrazolyl) , Imidazolyl or tetrazolyl, and the substituent is, for example, halogen, unsubstituted alkyl, unsubstituted alkoxycarbonyl), —C ( ⁇ O) R 6 or —NHC ( ⁇ O) R 6 , R 6 is hydroxy, unsubstituted alkoxycarbonyl), —
  • R 1d , R 2d and R 3d are substituted or unsubstituted phenyl or substituted or unsubstituted benzyl (wherein the substituent is, for example, halogen, amino or alkylamino), Two are hydrogen, R 4 is halogen, hydroxy, unsubstituted alkyl or unsubstituted alkoxy; R 5d is a substituted or unsubstituted 5-membered or 6-membered unsaturated heterocyclic group (wherein the 5-membered or 6-membered unsaturated heterocyclic group is imidazolyl, for example, Is unsubstituted alkyl) or —C ( ⁇ O) R 6 , R 6 is hydroxy or unsubstituted alkoxy; A compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 8 is hydrogen and p is 0 or 1;
  • Ring A is a benzene ring or a pyridine ring
  • R 1e , R 2e and R 3e are each independently hydrogen, halogen, substituted or unsubstituted alkyl (wherein the substituent is, for example, amino, acylamino, phenyl or halogenophenyl), substituted or unsubstituted phenyl (Wherein the substituent is, for example, a halogen) or a substituted or unsubstituted heterocyclic group (wherein the heterocyclic group is, for example, isoxazolyl, thiazolyl, pyrazolyl, furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, benzoyl) Thienyl, indolyl or imidazopyridyl, the substituent is, for example, unsubstituted alkyl or unsubstituted alkoxycarbony
  • Alk is alkyl (preferably methyl, ethyl, n-propyl, isopropyl or t-butyl), Hal is halogen (preferably fluorine or chlorine), and Alk and Hal are the same. Or may be different, and each —Alk, —O—Alk and —Hal may be substituted on —NH— constituting the ring) Or a pharmaceutically acceptable salt thereof or a solvate thereof,
  • R 4 is halogen (preferably fluorine or chlorine), alkyl (preferably methyl), alkoxy (preferably methoxy or ethoxy), halogenoalkyl (preferably trifluoromethyl) or halogenoalkoxy (preferably trifluoromethoxy).
  • R A is halogen (preferably fluorine or chlorine), alkyl (preferably methyl) or halogenoalkyl (preferably trifluoromethyl), and each R 4 and R A is the same or different.
  • Each R 4 and R A may be substituted on the —NH— constituting the ring), Or a pharmaceutically acceptable salt thereof or a solvate thereof,
  • (a, b, c) (a1, b1, c1), (a1, b1, c2), (a1, b1, c3), (a1, b1, c4), (a1, b1, c5), (a1 , b1, c6), (a1, b1, c7), (a1, b1, c8), (a1, b1, c9), (a1, b1, c10), (a1, b1, c11), (a1, b1 , c12), (a1, b1, c13), (a1, b1, c14), (a1, b1, c15), (a1, b1, c16), (a1, b1, c17), (a1, b2, c1 ), (a1, b2, c2), (a1, b2, c3), (a1, b2, c4), (a1, b2, c5), (a1, b2, c6), (a1, b2, c7),
  • the compound (Ia) according to the present invention is useful for diseases induced by production, secretion or deposition of amyloid ⁇ protein.
  • diseases induced by production, secretion or deposition of amyloid ⁇ protein For example, Alzheimer type dementia (Alzheimer's disease, Alzheimer type senile dementia etc.), Down's syndrome, memory disorder , Prion disease (Kreuzfeld-Jakob disease, etc.), mild cognitive impairment (MCI), Dutch hereditary amyloid cerebral hemorrhage, cerebral amyloid angiopathy, other degenerative dementia, vascular degenerative mixed dementia, associated with Parkinson's disease Treatment of dementia, dementia associated with progressive supranuclear paralysis, dementia associated with cortical basal ganglia degeneration, diffuse Lewy body Alzheimer's disease, age-related macular degeneration, Parkinson's disease, amyloid angiopathy and Effective for prevention and / or symptom improvement.
  • the compound (Ia) according to the present invention selectively inhibits A ⁇ 42 production, it can be a pharmaceutical with reduced side effects.
  • the compound according to the present invention has high selectivity to other enzymes, high metabolic stability, high solubility, high oral absorption, good bioavailability, good clearance, brain migration It also has advantages such as high potency, long half-life, high non-protein binding rate, low hERG channel inhibition, low CYP inhibition, and / or negative Ames test.
  • the compound (Ia) according to the present invention may be used in combination with other medicaments (for example, other Alzheimer-type dementia therapeutic agents such as acetylcholinesterase).
  • other medicaments for example, other Alzheimer-type dementia therapeutic agents such as acetylcholinesterase.
  • drugs for treating dementia such as donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, memantine, and vinpocetine.
  • the compound (Ia) according to the present invention when administered to humans, it can be administered orally as powders, granules, tablets, capsules, pills, liquids, etc., or injections, suppositories, transdermal absorption agents, inhalants Etc. can be administered parenterally.
  • excipients, binders, wetting agents, disintegrants, lubricants and the like suitable for the dosage form may be mixed with an effective amount of this compound as necessary to obtain a pharmaceutical preparation. it can.
  • the dose varies depending on the disease state, administration route, patient age, or body weight, but when administered orally to an adult, it is usually 0.1 ⁇ g to 1 g / day, preferably 0.01 to 200 mg / day. In the case of parenteral administration, it is usually 1 ⁇ g to 10 g / day, preferably 0.1 to 2 g / day.
  • Example 1 Preparation of Compound 3 4,5-dichlorothiophene-2-sulfonyl chloride (0.15 g, 0.596 mmol) and 4- (1H-imidazol-1-yl) aniline (0.114 g, 0.716 mmol) were dissolved in pyridine (3.00 ml) at room temperature. Stir overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was extracted by adding AcOEt 30 ml and water 15 ml. The organic layer was washed twice with 15 ml of brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to obtain 0.22 g of residue.
  • Example 2 Preparation of Compound 4 4,5-dichlorothiophene-2-sulfonyl chloride (0.15 g, 0.596 mmol) and 4- (isoxazol-5-yl) aniline (0.115 g, 0.716 mmol) were dissolved in pyridine (3.00 ml) overnight at room temperature. Stir. The reaction mixture was concentrated to dryness under reduced pressure. The residue was extracted by adding 30 ml of AcOEt and 15 ml of water. The organic layer was washed twice with 15 ml of water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to obtain 0.29 g of residue.
  • Example 3 Preparation of Compound 1 4,5-dichlorothiophene-2-sulfonyl chloride (0.10 g, 0.398 mmol) and 4- (thiophen-2-yl) aniline (0.084 g, 0.477 mmol) are weighed and dissolved in pyridine (2.00 ml) at room temperature. Stir overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was extracted by adding 20 ml of AcOEt and 10 ml of water. The organic layer was washed twice with 10 ml of water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to obtain 0.16 g of residue.
  • the residue was purified using silica gel chromatography (eluted with chloroform: methanol 97: 3 v / v) to give 0.12 g of residue.
  • IPA was added to the residue, and the solid was collected by filtration and washed with a small amount of IPA and hexane to obtain the desired product (0.059 g, 38.1%) as a brown powder.
  • Example 5 Preparation of Compound 10 To a solution of 4-aminobenzoic acid ethyl ester (16.5 mg, 0.10 mmol) in pyridine (1 mL) under ice-cooling, add 4,5-dichlorothiophene-2-sulfonyl chloride (30 mg, 0.12 mmoL) at room temperature. Stir for 6 hours. The reaction solution was extracted by adding AcOEt 5 ml and water 5 ml. The organic layer was washed with 5 ml of brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by preparative LCMS (Method D) to obtain the desired product (18 mg, 49%).
  • Example 7 Preparation of Compound 58 4-Bromo-N- (3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl) thiophene-2-sulfonamide (50 mg, 0.12 mmoL), 4-fluorophenylboronic acid (20 mg, 0.14 mmoL) and dichloro [1,1'-bis (di-t-butylphosphino) ferrocene] palladium (II) (4 mg, 0.06 mmoL) suspended in THF (2 mL) -2 mol / L Na2CO3aq And reacted at 130 ° C. for 30 minutes in a microwave reactor.
  • reaction solution was extracted by adding AcOEt 10 ml and water 10 ml. The organic layer was washed with 10 ml of brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by preparative LCMS (Method E) to obtain the desired product (15 mg, 29%).
  • Example 8 Preparation of Compound 56 To a solution of 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) aniline (900 mg, 4.43 mmol) in pyridine (10 mL) under ice-cooling, 4-bromothiophene-2-sulfonyl chloride ( 1.27 g, 4.87 mmoL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted by adding AcOEt 10 ml and water 10 ml. The organic layer was washed with 10 ml of brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure.
  • Test Example 1 Measurement of A ⁇ 42 Production Inhibitory Action Using Rat Primary Nerve Cultured Cells
  • Concentration-dependent effects were tested using each test compound as an evaluation item for A ⁇ 42 production concentration and cell survival activity secreted by primary cultured cerebral cortical cells.
  • Secreted A ⁇ 42 production was evaluated by ELISA.
  • Cell viability was evaluated using a reagent for measuring the number of living cells.
  • Primary cultured cerebral cortical cells were prepared from fetal 18-day-old SD rat fetuses.
  • the fetus was removed, the brain was isolated in ice-cold DMEM (Nacalai Tesque) / PBS, and the cerebral cortex was isolated under a microscope, followed by 2.5% papain (Sigma), 0.2% DNase ( The reaction solution was added with Takara Bio) at 37 ° C. for 15 minutes. The enzyme reaction was stopped with non-immobilized horse serum (Invitrogen) and centrifuged at 1,000 rpm for 5 minutes. Resuspended in DMEM and centrifuged at 1,000 rpm for 5 minutes.
  • 96 mL of Neurobasal medium (Invitrogen), 2% B-27 supplement (Invitrogen), 0.5 mM L-glutamine, and 25 ⁇ M L-glutamate were added to the pellet and triturated with a pointed Pasteur pipette and PLL coated.
  • the well plate was seeded at 1.6 ⁇ 10 5 cells / 100 ⁇ l / well, and the medium was changed after culturing at 37 ° C. and 5% CO 2 for 1 day. The compound was treated after another 6 days.
  • the DMSO solution of the test compound was diluted to a final DMSO concentration of 1% to make the final solution 200 ⁇ L per well.
  • DAPT Calbiochem
  • a ⁇ -secretase inhibitor a ⁇ -secretase inhibitor
  • the culture supernatant was collected and subjected to ELISA after appropriate dilution as an ELISA sample for A ⁇ 42 measurement.
  • the cultured cells were used for live cell count measurement.
  • Human / Rat ⁇ Amyloid (42) ELISA Kit WAKO Human / Rat ⁇ Amyloid (42) ELISA Kit WAKO (Wako Pure Chemical Industries) was used. The method was the method described in the package insert recommended by the manufacturer. For each sample, the percentage (% of control) relative to the A ⁇ 42 concentration in the culture supernatant of the subject group was calculated, and then the IC 50 value of each test compound was calculated.
  • the cell viability activity was measured using the living cell count reagent SF (Nacalai Tesque). The method was the method described in the package insert recommended by the manufacturer. For each sample, the percentage of viable cells in the control group (% of Control) was calculated and the cell viability was evaluated. As a result, no decrease in cell viability was observed. The results are shown below. Also for compounds 5, 19, 22, 23, 43, 58, 77 and 93 etc., IC 50 was 50 ⁇ M or less.
  • Test Example 2 Measurement of ⁇ -secretase activity inhibitory action of test compound
  • SHSY5Y-APPwt cells that is, the amount of C-terminal fragment ⁇ (CTF ⁇ ) serving as a substrate for ⁇ -secretase.
  • CTF ⁇ C-terminal fragment ⁇
  • the ⁇ -secretase inhibitory effect was tested in a concentration-dependent manner (three points of 1-fold, 10-fold, and 30-fold concentrations of each test compound A ⁇ 42 IC50 value).
  • the amount of CTF ⁇ production accumulated by ⁇ -secretase inhibition was evaluated by ELISA.
  • SHSY5Y-APPwt cells were established as cells stably expressing human APP695 introduced into SHSY5Y cells.
  • the cells were cultured in DMEM containing 10% FCS.
  • SHSY5Y-APPwt cells are seeded in a 6-well plate at 1.0 ⁇ 10 6 cells / well / mL DMEM.
  • the DMSO solution of the test compound was diluted with the DMEM solution so that the final concentration was doubled, and 1 mL of this diluted solution was added and mixed well with the cells to make the final DMEM solution 2 mL per well.
  • the final DMSO concentration was adjusted to 1%.
  • DAPT Calbiochem
  • a ⁇ -secretase inhibitor was used as the target compound.
  • the cultured cells were collected and dissolved in a 1% TritonX100-containing TBS buffer, and the cell extract, which was a centrifugal supernatant (14000 rpm, 4 ° C., 10 min), was subjected to protein quantification using a protein quantification kit (Pierce).
  • a diluted cell extract was used as an evaluation sample, and the amount of CTF ⁇ was quantified using ⁇ CTF ELISA Kit (IBL).
  • IBL ⁇ CTF ELISA Kit
  • the test compound having ⁇ -secretase activity inhibition increases the amount of CTF ⁇ , which is a ⁇ -secretase substrate, in a concentration-dependent manner.
  • Compound numbers 2, 3, 24, 49, 56 and 61 were evaluated.
  • the control compound ⁇ -secretase inhibitor DAPT increased the amount of ⁇ CTF in a concentration-dependent manner.
  • Compound Nos. 2, 3, 24, 49, 56 and 61 no increase or decrease in the concentration-dependent ⁇ CTF amount was observed. That is, the above compound had A ⁇ 42 production inhibitory action, but did not have ⁇ -secretase activity inhibitory action. From the above, it was found that the compound of the present invention is not a ⁇ -secretase inhibitor but a ⁇ -secretase modifying agent having A ⁇ 42 production inhibitory action.
  • CYP3A4 Fluorescence MBI Test is a test for examining the enhancement of CYP3A4 inhibition of a compound by a metabolic reaction.
  • HFC 7-hydroxytrifluoromethylcoumarin
  • 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); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • 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.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution 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 4 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), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the amount of metabolite produced is inhibited by the test compound is evaluated.
  • reaction conditions are 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; test drug concentration, 1, 5, 10, 20 ⁇ mol / L (4 point).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was collected 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, and the residual activity (%) at each concentration of the test drug solution was calculated. Used to calculate IC 50 by inverse estimation with a logistic model.
  • Test example 5 FAT test 20 ⁇ L of Salmonella typhimurium TA98, TA100 strain cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and shaken at 37 ° C. for 10 hours. Pre-cultured.
  • 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 7 Metabolic Stability Test Using a commercially available pooled human liver microsome, the target compound was reacted for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • Test example 8 For the purpose of risk assessment of ECG QT interval prolongation, HEK293 cells expressing human ether-a-go-go related gene (hERG) channel are used to play an important role in ventricular repolarization process The effect on delayed rectifier K + current (I Kr ) was investigated. Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of -80 mV using the whole cell patch clamp method, +40 mV depolarization stimulation is applied for 2 seconds and then -50 I Kr evoked when mV repolarization stimulus was applied for 2 seconds was recorded.
  • PatchXpress 7000A Axon Instruments Inc.
  • the absolute value of the maximum tail current was measured from the obtained I Kr using the analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Moreover, to calculate the inhibition rate to the maximum tail current before application test substance, as compared with the medium application group (0.1% dimethyl sulfoxide solution) to assess influence of the I Kr analyte. (Results) The inhibition rate at a compound concentration of 5 ⁇ mol / L is shown. Compound No. 51: 9.9% Compound No. 33: 0.2%
  • Test Example 9 Powder Solubility Test Put an appropriate amount of specimen in a suitable container, JP-1 solution (2.0 g sodium chloride, 7.0 mL hydrochloric acid to 1000 mL), JP-2 solution (pH 6.8 phosphate) Add 500 mL of water to 500 mL of buffer solution), and add 20 ⁇ L each of 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (add water to 1.08 g of TCA to make 100 mL). If dissolved after adding the test solution, add bulk powder as appropriate. Seal and shake at 37 ° C for 1 hour. Filter, add 100 ⁇ L of methanol to 100 ⁇ L of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. Quantify using HPLC with the absolute calibration curve method.
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (Ia) 10 mg Lactose 700 mg Corn starch 274 mg HPC-L 16 mg
  • the compound of formula (Ia) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • HPC-L low-viscosity hydroxypropylcellulose
  • aqueous solution to the powder mixture, knead, granulate (extruded granulation pore size 0.5-1mm), and dry.
  • the obtained dried granules are combed with a vibrating sieve (12/60 mesh) to obtain granules.
  • Formulation Example 2 A capsule filling granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (Ia) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg
  • the compound of formula (Ia), lactose is passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder to knead, granulate and dry. After sizing the obtained dry granules, 150 mg thereof is filled into No. 4 hard gelatin capsules.
  • Formulation Example 3 A tablet containing the following ingredients is produced.
  • the compound of formula (Ia), lactose, microcrystalline cellulose, CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.
  • Formulation Example 5 A haptic agent containing the following components is produced.
  • Ingredient Compound represented by formula (Ia) 50 mg Aqueous base (5% ethanol / 5% butylene glycol / 90% purified water) 950 mg Glycerin Kaolin
  • Polyvinyl alcohol aqueous solution Compound (Ia) is added to an aqueous base, and after ultrasonic irradiation for about 15 minutes, the solution is sufficiently stirred to obtain a solution. 5 parts of glycerin, 1 part of kaolin and 5 parts of an aqueous polyvinyl alcohol solution are uniformly mixed, and 1 part of the prepared solution is added. This is further mixed to obtain a paste, which is coated on a non-woven fabric and covered with a polyester film to form a happing agent.
  • the compound according to the present invention is useful as a therapeutic agent for diseases induced by production, secretion or deposition of amyloid ⁇ protein.

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Abstract

La présente invention concerne un composé représenté par la formule (Ia), un sel pharmaceutiquement acceptable de celui-ci, ou un solvate du composé ou du sel, qui sert comme agent de traitement de maladies induites par la production, la sécrétion et le dépôt de la protéine β amyloïde. (Dans la formule, X représente -O- ou -S- ; le cycle A représente un cycle benzénique ou équivalent ; R1a, R2a et R3a représentent chacun indépendamment un atome d'hydrogène, un atome d'halogène, un groupe alcoxycarbonyle substitué ou non, un cycle carboné substitué ou non ou équivalent ; R4 représente un atome d'halogène, un groupe hydroxy, un groupe alkyle substitué ou non ou équivalent ; R5a représente un groupe hétérocyclique insaturé à 5 ou 6 chaînons, substitué ou non, C(=O)R6 ou équivalent ; p représente un entier de 0 à 2 ; R6 représente un groupe hydroxy, un groupe alcoxy substitué ou non ou équivalent ; La représente -SO2NH-, -C(=O)NH- ou équivalents ; et Ak1 et Ak2 représentent chacun indépendamment une liaison simple ou équivalent.)
PCT/JP2010/057362 2009-04-28 2010-04-26 Produit pharmaceutique contenant un composé sulfonamide hétérocyclique WO2010126002A1 (fr)

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KR101799005B1 (ko) 2015-07-27 2017-11-17 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 설프아마이드 유도체 화합물 및 이를 포함하는 약제학적 조성물
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WO2018210314A1 (fr) * 2017-05-19 2018-11-22 厦门大学 Composé de noyau hétéroaromatique à cinq et six chaînons, son procédé de préparation, composé à usage médical et son application
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US10494355B2 (en) 2015-10-12 2019-12-03 Chong Kun Dang Pharmaceutical Corp. Oxadiazole amine derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
US10584117B2 (en) 2015-07-27 2020-03-10 Chong Kun Dang Pharmaceutical Corp. 1,3,4-oxadiazole amide derivative compound as histone deacetylase 6 inhibitor, and pharmaceutical composition containing same
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US9512118B2 (en) 2011-06-22 2016-12-06 Takeda Pharmaceutical Company Limited Crystal of fused heterocyclic compound
WO2014163162A1 (fr) * 2013-04-04 2014-10-09 武田薬品工業株式会社 Composé hétérocyclique
JPWO2014163162A1 (ja) * 2013-04-04 2017-02-16 武田薬品工業株式会社 複素環化合物
US9624184B2 (en) 2013-04-04 2017-04-18 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2017018803A1 (fr) * 2015-07-27 2017-02-02 Chong Kun Dang Pharmaceutical Corp. Composés dérivés de 1,3,4-oxadiazole sulfonamide servant d'inhibiteur de l'histone désacétylase 6, et composition pharmaceutique comprenant ceux-ci
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TWI754702B (zh) * 2016-12-28 2022-02-11 德商Ｕｃｂ製藥有限公司 （氮雜）吲哚－和苯並呋喃－３－磺醯胺類
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