WO2004048341A1 - Nouveau derive heteroaryle - Google Patents

Nouveau derive heteroaryle Download PDF

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Publication number
WO2004048341A1
WO2004048341A1 PCT/JP2003/015197 JP0315197W WO2004048341A1 WO 2004048341 A1 WO2004048341 A1 WO 2004048341A1 JP 0315197 W JP0315197 W JP 0315197W WO 2004048341 A1 WO2004048341 A1 WO 2004048341A1
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Prior art keywords
optionally substituted
compound
substituted
alkyl
salt
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PCT/JP2003/015197
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English (en)
Japanese (ja)
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Kantaro Ushiroda
Katsunori Maruta
Ryu Nagata
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Sumitomo Pharmaceuticals Co., Ltd.
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Priority to JP2005510291A priority Critical patent/JPWO2004048341A1/ja
Priority to AU2003284479A priority patent/AU2003284479A1/en
Publication of WO2004048341A1 publication Critical patent/WO2004048341A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to a novel heteroaryl derivative having an antidiabetic action or a salt thereof.
  • the present invention relates to a novel heteroaryl derivative having an antiglycaemic effect that improves insulin resistance and controls blood glucose more safely. More specifically, a novel agent that has a peroxisome proliferator-activated receptor (PPAR) ⁇ -activating action, a PPARa-activating action, a PPAR ⁇ / a-activating action, or a PPAR herring activation-regulating action. It relates to a heteroaryl derivative.
  • PPAR peroxisome proliferator-activated receptor
  • SU sulfonylprea
  • Troglitazone was first launched as a thiazolidinedione drug, but was discontinued due to severe liver damage.
  • pioglizozone is currently used in clinical settings.However, as a serious side effect was reported as heart failure due to an increase in circulating plasma volume, emergency safety information was issued in October 2000. It has been shown that attention should be paid to heart failure and edema (Japanese clinical study, Vol. 59, 2228, 2 0 0 1).
  • Oral siglisun which is used in Europe and the United States, is also reported to have side effects such as upper respiratory tract infection, anemia, edema, and weight gain. Has not yet been released.
  • P PAR has subtypes such as ⁇ ⁇ (/ 3).
  • fibrates used as therapeutic agents for hyperlipidemia such as clofibrate and fenofibrate)
  • PPAR ⁇ activator may have a good effect not only on hyperlipidemia but also on diabetes mellitus.
  • an antidiabetic agent having a pyrrole group in which the type of heterocycle is different from that of the present application is known (for example, see Japanese Patent Application Laid-Open No. 2002-121816, WO 02/085851). However, there is no report on its efficacy and safety in clinical settings. Disclosure of the invention
  • the problem to be solved by the present invention is to have an action of activating PPARa, an action of activating PPARa, an action of activating PPAR / a, or an action of regulating PPARhear activation to improve insulin resistance.
  • Supply safe and safe diabetes prevention or treatment agents It is in.
  • the present inventors have conducted intensive studies and have found that a novel heteroaryl derivative activates PPAR ⁇ , ⁇ PARr, or PPARa / a, or modulates PPAR ⁇ / a activation to improve insulin resistance. As a result, the present inventors have found that while improving the hyperglycemic state, they are excellent in safety, and are useful for the prevention and treatment of diabetes, and completed the present invention.
  • the present invention relates to the following novel heteroaryl derivatives and salts thereof.
  • R 2 and R 3 are each independently a hydrogen atom, a C, 1 group which may be substituted by a halogen atom; an alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or a halogen atom Or R 2 and R 3 may combine with each other to form an optionally substituted ring)
  • Ar 1 represents an optionally substituted arylene or an optionally substituted heteroarylene
  • Ar 2 represents an optionally substituted aryl or an optionally substituted heteroaryl
  • W 1 shows an optionally substituted C 5 alkylene, optionally substituted C 2 _ ⁇ 5 Aruke two Ren, optionally substituted C 2 - C 5 alkynylene or, - Y- W 2 one (wherein, Y represents an oxygen atom, a sulfur atom or NR,, W 2 is optionally substituted C, one C 5 alkylene, optionally substituted C 2 - Ji 5 Aruke two Ren, Represents an optionally substituted C 2 -C 5 alkynylene, and R represents a hydrogen atom, C, 1 C 4 alkyl, or optionally substituted aryl, 1 C 4 alkyl.
  • R represents a hydrogen atom, C, 1 C 4 alkyl, or optionally substituted aryl, 1 C 4 alkyl.
  • X 1 is a single bond, an oxygen atom, a sulfur atom, or
  • ⁇ ⁇ represents 1 ⁇ -alkylalkylene
  • 2 may be substituted with a halogen atom, C, _C 4 7 alkyl or may be substituted with a halogen atom (:, —. 4 alkoxy, may be substituted.)
  • Aryl, optionally substituted aryloxy, optionally substituted aryl C, —C 4 alkyloxy, formylamino, C 2 —C 6 alkanoylamino, C, 1-C 4 alkyl optionally substituted power Ruponiruokishi, C, - C 4 it may also be substituted with Al kill I O carboxymethyl Cal Poni Rua amino, C, _ C 4 alkyl optionally substituted force Rubamoiruokishi, hydroxyl, C, one c 4 alkyl Cal Poni Le Okishi, C substituted by any group selected from a halogen atom or Shiano, - C 5 ⁇ alkylene, ®C 2 - (: 5
  • a compound represented by the above (1) or a salt thereof is a compound represented by the above (1) or a salt thereof.
  • Ring Z is the formula (4)
  • a compound represented by the above (1) or a salt thereof is a compound represented by the above (1) or a salt thereof.
  • Ring Z is the formula (5)
  • a compound represented by the above (1) or a salt thereof is a compound represented by the above (1) or a salt thereof.
  • Y 1 is a C, —C 5 alkylene or (2) a C, —C 4 alkyl optionally substituted with a halogen atom, optionally substituted with a halogen atom ((: 4 alkoxy, substituted which may be Ariru, optionally substituted Ariruokishi, it may also be substituted I Ariru C, _C 4 Arukiruokishi, Horumiruamino, C 2 _C 6 Arukanoiru Amino, optionally substituted with _ ⁇ 4 alkyl O alkoxycarbonyl Oxy,-oxycarbonylamino optionally substituted with C 4 alkyl, carbamoyloxy optionally substituted with C, _C 4 alkyl, hydroxyl, alky
  • W 1 is an optionally substituted C 2 - C 5 7 Luque two alkylene in the above (1) to (9
  • a r 1 is phenylene which may be substituted, and the bonding position of A r 1 of X 1 is
  • a r 1 is phenylene which may be substituted, and the bonding position of A r 1 of X 1 is
  • a r 1 is a good phenylene which may be substituted, the bonding position of A r 1 X 1 'is a para-position to the bonding position of W 1 (1) i (1 1) Or the salt thereof.
  • W 1 is trans C 3 - (: 4 Aruke a two lens, the bonding position of Ar 1 of X 1 The meta-position to the bonding position of W 1 (1) i (9), (1 1), (1 3) noise or a salt thereof according to any misalignment.
  • W 1 is trans C 3 - (: 4 Aruke a two lens, the bonding position of A r 1 of X 1
  • W 1 is a good Ci-Cs alkylene optionally substituted, eight 1 "1 binding position of 1, the meta-position to the bonding position of W 1 (1) - (10 ) Or the compound according to any one of (13) or a salt thereof.
  • W 1 is a good Ci_C 5 alkylene optionally substituted, binding position of A r 1 X 1 ', the (1) in the para-position to the bonding position of W 1 - (10) Or the compound according to any one of (14) or a salt thereof.
  • a medicament comprising the compound according to (1) to (19) and a prodrug thereof.
  • PPAR ⁇ agonist PPARagonist or PPAR ⁇ / argonist comprising as an active ingredient the compound according to (1) to (19) and a prodrug thereof.
  • a PPARr partial agonist, an engonist, or a PPAR ⁇ activation modifier (Module-Ichiichi) comprising, as an active ingredient, the compound according to any of (1) to (19) and a prodrug thereof.
  • a hepatic gluconeogenesis inhibitor comprising the compound according to (1) to (19) and a prodrug thereof as an active ingredient.
  • An antidiabetic agent comprising the compound according to (1) to (19) and a prodrug thereof as an active ingredient.
  • a method for treating diabetes comprising the compound according to (1) to (19) and a prodrug thereof as an active ingredient.
  • Examples of the “C t —C 4 alkyl” of “C, 1 C 4 alkyl” or “C—C alkyl optionally substituted with a halogen atom” in YR include, for example, linear or branched Ci—C 4 alkyl, specifically, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, etc., and more preferably, methyl, ethyl, 1-propyl, 2-propyl Is mentioned.
  • the “C, 1. Alkyl” in R 2 and R 3 is, for example, a linear or branched C 1.
  • Alkyl specifically, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, 1-pentyl, 2-hexyl, 1-heptyl, Examples include 1-octyl, 1-nonyl, 1-decyl, and more preferably, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, and 1-pentyl. . More preferably, methyl and ethyl are mentioned.
  • alkyl examples include linear or branched Ci— ⁇ alkyl, and specific examples include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl and the like. And more preferably, methyl, ethyl, 1-propyl and 2-propyl.
  • “Ariru C, _C 4 alkyl”, or “Ariru C, one C 4 Arukiruokishi” as "C, one C 4 alkyl” is for example a straight or branched chain Flip E - Ji alkyl are mentioned, specifically Examples include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and the like, and more preferably, methyl and ethyl.
  • the “C, 1C 4 alkoxy” for Y 1 includes, for example, a linear or branched Ci—C 4 alkoxy, specifically, methoxy, ethoxy, propoxy, butoxy and the like, and more preferably. Includes methoxy and ethoxy.
  • RA r YR “optionally substituted aryl”, “optionally substituted aryloxy”, “optionally substituted aryl” —C 4 alkyloxy ”in R 2 and R 3 ,“ is set to "Ariru" of the optionally substituted ⁇ Li one also be Rusuru Honi carbamoyl "or” substituted Ariru CI- C 4 alkyl ", include for example phenyl, 1-naphthyl, 2-naphthyl and And preferably phenyl.
  • heteroaryl in A r R 2 and R 3 includes, for example, a monocyclic or bicyclic monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. And heteroaryl.
  • monocyclic 5-membered heteroaryl such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, and isooxazole
  • monocyclic 6-membered such as pyridine, pyrimidine, pyrazine, pyridazine, triazine, etc.
  • heteroaryl indole, isoindole, indolizine, indazole, purine, 4-H-quinolidine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline
  • bicyclic heteroaryls such as benzthiazole, benzoxazole, benzofuran, benzothiophene and benzimidazole, and more preferably pyridin, thiophene, indole, benzthiazole, benzoxazole, benzofuran, Benzothiophene.
  • arylene in Ar 1 include C 6 —C 10 arylene, specifically, 1,3-phenylene, 1,4-phenylene, and naphthene. Len-1,3-zil, Naphne 1,1,4-zil and the like. Preferred are 1,3-phenylene and 1,4-phenylene.
  • Heteroari one Ren” in A r for example, nitrogen atom, oxygen atom, from 1 selected arbitrarily from the group consisting of sulfur atoms 3 of the monocyclic containing hetero atoms or bicyclic into the Terrorism; Specifically, monocyclic 5-membered heteroarylenes such as thiophen-zyl, furan-zyl, and pyrroyl-zilyl, pyridine-diyl, pyrimidine-zil, pyrazine-diyl, pyridazine-diyl, and triazine-diyl-like Cyclic 6-membered heteroarylene, indole-zil, isoindyl-zyl, indolizine-zil, indazoyl-zyl, pudding-zyl, 4-H-quinolidine-dzyl, quinoline-dzyl, isoquinoline-dzyl, phthalazine And bicyclic heteroaryls such as benzy
  • Examples of the “c, _c 5 alkylene” for W 2 include straight-chain or branched-chain mono-c 5 alkylene, and specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and propane. Examples thereof include 1,2-diyl and butane-1,1,3-diyl, and more preferred examples include methylene, ethylene, trimethylene, and tetramethylene.
  • the “C, —C 5 alkylene” for Y 1 includes, for example, straight-chain or branched-chain Ci—c 5 alkylene, and specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, propane 1 1 , 2-diyl, butane-1,1,3-diyl, etc., more preferably, methylene, ethylene, trimethylene, and tetramethylene, and further preferably, methylene.
  • Examples of “c 2 _c 5 alkynylene” in, W 2 and Y 1 include straight-chain or branched C 2 _C 5 alkynylene, and specifically include ethinylene, 1-propynylene, and 3-methyl-1-alkyl. —Propynylene, 2-propynylene, and the like, more preferably, 1-propynylene.
  • C 2 —C 6 alkanoylamino for Y 1 , for example, a linear or branched C 2 —C 6 alkanoylamino can be mentioned, and more preferably acetylamino, propanoylamino, and bushinoylamino. And pentanoylamino.
  • R 2 and R 3 taken together, ring which may be substituted” as the "ring" of, heptyl cyclobutyl, cyclopentyl, hexyl, cyclohexane cyclopentane, sik clever speech corruptible, phenyl, pyridyl, naphthyl And the like, but preferably include phenyl, pyridyl, and cyclohexyl.
  • halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • "Optionally substituted by a halogen atom C, one C 4 alkyl" in Y 1 "C substituted with halo gen atom, one C 4 alkyl” is replacement in the "halogen atom in R 2, R 3 which may be C, one C 10 alkyl C substituted with "halogen atoms", - it includes C 10 alkyl ", fluorine atom, chlorine atom, alkyl of straight or branched Edakusari substituted by a bromine atom
  • Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like, more preferably trifluoromethyl and 2,2,2-trifluoroethyl.
  • Ci-C alkoxy optionally substituted with atoms
  • Y 1 a fluorine atom, a chlorine atom, a straight substituted with bromine
  • Specific examples include a chain or branched chain C 4 alkoxy, and specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy. Methoxy, 2,2,2-trifluoroethoxy.
  • the "Ariru one C 4 Arukiruokishi" in Y 1, for example, base Njiruoki shea, Fuenechiruokishi, 2 _ phenylalanine propoxy, 3-phenylpropyl propoxy, 4_ Fuenirubutokishi, 1 one naphthylmethoxy, 2-naphthylmethoxy and the like.
  • one C 4 which may O alkoxycarbonyl O carboxymethyl also be substituted with alkyl include straight or branched chain
  • Flip the E one C 4 alkoxy force Lupo two Ruokishi is ani Gerare, specifically Specific examples include methoxycarbonyloxy, ethoxycarbonyloxy, 1-propoxycarbonyloxy, 2-propoxycarbonyloxy, 1-butoxycarbonyloxy, 2-butoxycarponyloxy, and the like. More preferably, Examples include methoxycarbonyloxy, ethoxycarbonyloxy, and 11-propoxycarbonyl.
  • oxycarbonylamino optionally substituted with d—C 4 alkyl for Y 1 , for example, a linear or branched Ci—C 4 alkyloxycarbonylamino can be mentioned.
  • a linear or branched Ci—C 4 alkyloxycarbonylamino can be mentioned.
  • methoxycarbonylamino, ethoxycarbonylamino 1-propoxycarbonylamino, 2-propoxycarbonylamino, 1-butoxycarbonylamino, 2-butoxycarbonylamino and the like more preferably methoxycarbonylamino, ethoxycarbonylamino, _Propoxy force Luponylamino.
  • Y 1 as a "(one C 4 alkyl optionally substituted force Rubamoiruokishi", for example linear or branched ⁇ E one C 4 alkyl force Rubamoiruokishi is exemplified et al are specifically Are methylcarbamoyloxy, dimethylcarbamoyloxy, ethylcarbamoyloxy, getylcarbamoyloxy, 1-propyl rubamoyloxy, 2-propyl rubamoyloxy, 1-butyl carbamoyloxy, 2-butyl carbamoyloxy And more preferably, methyl carbamoyloxy, ethyl carbamoyloxy, 1-propyl rubamoyloxy.
  • the “., — 04 alkylcarbonyloxy” for Y 1 includes, for example, straight-chain or branched-chain alkylcarbonyloxy, and specific examples thereof include methylcarbonyloxy, ethoxylcarbonyl, 1-propylcarbonyloxy, 2-propylpyrucarbonyloxy, 1-butylcarbonyloxy, 2-butylcarbonyloxy, and the like, more preferably, methylcarbonyloxy, ethylcarboxy, 1-propylcarbonyl Oxy.
  • Examples of the “C 3 —C 8 alkylene having a cyclic structure” in Y 1 include those having a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group, for example, those shown below.
  • alkylsulfonylcarbamoyl for R 1 , for example, a linear or branched Ci—
  • alkyl include, specifically, methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl, 1-propylsulfonylcarbamoyl, 2-propylsulfonylcarbamoyl, 1-butylsulfonylcarbamoyl, and 2-butylsulfonylcarbamoyl.
  • methylsulfonylcarbamoyl More preferred are methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl, 1-propylsulfonylcarbamoyl, and 2-propylsulfonylcarbamoyl.
  • the “arylsulfonylcarbamoyl” for R 1 includes, for example, phenylsulfonylcarbamoyl, 1-naphthylsulfonylcarbamoyl, 2-naphthylsulfonylcarbamoyl and the like, preferably phenylsulfonylcarbamoyl.
  • aryl C, —C 4 alkyl examples include benzyl, phenyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, and the like. Preferable examples include benzyl and phenyl.
  • Ganmaupushiron Ariruokishi may be substituted in the 1 ", Ariru may be substituted in Ganmaupushiron 1 C, one C 4 Arukiruokishi", "R 2 and R 3, taken together, ring which may be substituted""Ar 2, YR 2 and Ariru substituted at R 3", "A r 2, Te Roariru R 2 and the optionally substituted in R 3 ', substituted in the" A r 1 which may be Ariren ",” Teroari one Ren also to the good have been your Keru replaced by Ar '", which may have been not good ⁇ Li one Rusuru Honi carbamoyl substitutions in the FR 1", be substituted in the "1 .
  • the “substituent” of the optionally substituted C 2 -C 5 alkynylene in W 2 includes a halogen atom, a hydroxyl group, an optionally substituted alkyl, an optionally substituted alkenyl, and a substituted Aryl, optionally substituted heteroaryl, formyloxy, alkanoyloxy, cyano, formyl, alkanol, optionally substituted alkoxy, alkoxycarbonyl group, carboxyl group, and optionally substituted alkyl Good amino, cyclic amino, alkoxyalkyl-substituted amino, alkyl-substitute
  • halogen atom an optionally substituted alkoxy, an optionally substituted alkyl, and a cyclic amino are exemplified.
  • the number of substituents may be one or more, and is preferably from 1 to 2. When there are a plurality of substituents, they may be the same or different.
  • halogen atom of the “substituent” examples include fluorine, chlorine, bromine and iodine, and more preferably fluorine and chlorine.
  • alkyl which may be substituted in the above-mentioned "substituent”
  • substituted examples include a linear or branched C i-C e alkyl which may be substituted, and specifically, methyl, ethyl, and propyl , Butyl, pentyl, 2-propyl, 2-methyl-1-propyl, 2-butyl, t-butyl, 3-methyl-2-butyl, 2-methyl-2-butyl, hexyl, trifluoromethyl, methoxy Methyl, 1-methoxy-2-ethyl, morpholinometyl and the like are more preferable, and methyl, methyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 1-pentyl and trifluoromethyl are more preferable.
  • alkenyl which may be substituted as the “substituent” include linear or branched C 2 -C 6 alkenyl, and specific examples thereof include vinyl, 2-probenyl and 1-probenyl. N-yl, 2-butenyl, 1-butenyl, and 2-methyl-1-propenyl, and more preferably 2-proenyl, 2-butenyl, and 2-methyl-1-proenyl.
  • aryl which may be substituted for the "substituent” include, for example, phenyl, p-chlorophenyl, m-chlorophenyl, o_chlorophenyl, p-fluorophenyl, m-fluorophenyl, o-fluoro Phenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, ⁇ _methylphenyl, m-methylphenyl, o_methylphenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, 0-trifluoro And more preferably phenyl, p-chlorophenyl, p-methoxyphenyl, p-methylphenyl, p-trifluoromethylphenyl.
  • Examples of the optionally substituted heteroaryl of the ⁇ substituent '' include 1 to 3 arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which may have a substituent.
  • Monocyclic or bicyclic heteroaryl containing a heteroatom is mentioned.
  • Unsubstituted heteroaryl such as drizine, indazole, purine, 4-H-quinolidine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, benzothiazole, benzoxazole, benzofuran, benzothiophene, or 2-methylthiophene, 2 —
  • Substituted heteroaryls such as furan, 2-methylpyrrol, 4-methylimidazole, 2-chloropyridine, 2-chloroindole, and 3-bromoquinoline; and more preferably Benzene, pyridine
  • alkanoyloxy of the “substituent” examples include straight-chain or branched-chain C 2 -C 6 alkanoyloxy, more preferably acetyloxy, propanoyloxy, butanoyloxy, isobutanoyloxy. Pentanoyloxy and hexanoyloxy.
  • alkanoyl of the above “substituent” examples include straight-chain or branched-chain C 2 — (: 6 alkanol, and more preferably acetyl, propanoyl, butanoyl, isobutynoyl, pentanoyl, hexanoyl. Is mentioned.
  • optionally substituted alkoxy of the “substituent” examples include, for example, an optionally substituted linear or branched mono-C 8 alkoxy. Specifically, methoxy, ethoxy, propoxy, 2- Proboxy, 2-methyl-propoxy, butoxy, pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, cyclohexylmethoxy, 1-methoxy-12-ethoxy, 1-morpholino1-2-ethoxy, 1-thiomorpholino-2-ethoxy , 1-piberidino 2-ethoxy, trifluoromethoxy, etc., and more preferably, methoxy, ethoxy, 2-propoxy, cyclopentyloxy, 1-morpholino-2-ethoxy, trifluoromethoxy.
  • a ring having a substituent and the adjacent group may be formed.
  • alkoxycarbonyl of the “substituent” examples include, for example, a linear or branched C 2 _C 6 alkoxycarbonyl group, more preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, 2 —Methyl-1-propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl.
  • Examples of the above-mentioned “substituent” which may be alkyl-substituted include, for example, a linear or branched C i -C 6 alkylamino or a linear or branched C 2 -C 2 dialkylamino. Is mentioned.
  • the linear or branched C ⁇ -C e alkylamino preferably includes methylamino, ethylamino, propylamino, 2-propylamino, and butylamino.
  • Examples of the linear or branched C 2 -C 12 dialkylamino include amino substituted with the same or different alkyl, and more preferably dimethylamino, getylamino, dipropylamino, diisopropyl. Amino, dibutylamino, ethylmethylamino, methylpropylamino, butylmethylamino, ethylbutylamino, dicyclohexylamino.
  • Examples of the cyclic amino of the ⁇ substituent '' include a 5- to 7-membered cyclic amino which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom. It may be substituted with an alkyl, a hydroxyl group or the like. Specific examples include pyrrolidino, piperidino, piperazinyl, 4-methylbiperazinyl, morpholino, thiomorpholino, and 4-hydroxypiperidino, and more preferably, morpholino and 4-hydroxypiperidino. Can be
  • alkoxyalkyl optionally substituted amino branched may be mentioned, specifically 2 —Methoxyethylamino, 2-Ethoxyethylamino, 2-Proboxyethylamino, 2-Isopropoxyethylamino, 2-Butoxyethylamino, 2-Cyclohexyloxyamino, 2-methoxy-1-methylethylamino, 2-methoxy-1-methylethylamino, and more preferably, 2-methoxyethylamino, 2-propoxyshetylamino, and 2-isopropanol.
  • Quichetilamino 2 —Methoxyethylamino, 2-Ethoxyethylamino, 2-Proboxyethylamino, 2-Isopropoxyethylamino, 2-Butoxyethylamino, 2-Cyclohexyloxyamino, 2-methoxy-1-methylethylamino, 2-methoxy-1-
  • Examples of the optionally substituted alkyl rubamoyl of the above “substituent” include linear or branched C 2 —C 6 alkylaminocarbonyl or linear or branched C 3 _C i 2 dialkyl And aminocarbonyl.
  • Examples of the straight-chain or branched-chain C 3 -C 12 dialkylaminocarbonyl include rubamoyl substituted with the same or different alkyl, and more preferably dimethylamino propylonyl, dimethylaminocarbonyl, Dipropylaminocarbonyl, diisopropylaminocarbonyl, dibutylaminocarbonyl, ethylmethylaminocarbonyl, methylpropylaminocarbonyl, butylmethylaminocarbonyl, ethylbutylaminocarbonyl, dicyclohexylaminocarbonyl. .
  • cyclic aminocarbonyl group of the “substituent” examples include a 5- to 7-membered cyclic aminocarbonyl which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom. May be further substituted with an alkyl, a hydroxyl group or the like. Specific examples include pyrrolidinocarbonyl, piperidinocarbonyl, piperazinylcarbonyl, 4-methylbiperazinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 4-hydroxypiperidinocarbonyl, and more preferably. Include morpholinocarbonyl and 4-hydroxypiperidinocarbonyl.
  • alkyl optionally substituted sulfamoyl group "substituent", eg if linear or branched C i-C 6 alkylamino sulfonyl or straight-chain or branched Flip 2 _ ⁇ 1 2 dialkyl Aminosulfonyl; More preferred are methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, 2-propylaminosulfonyl, and butylaminosulfonyl.
  • Examples of the linear or branched C 2 -C 12 dialkylaminosulfonyl include sulfamoyl substituted with the same or different alkyl, and more preferably dimethylaminosulfonyl, getylaminosulfonyl, dipropylaminosulfonyl , Diisopropylaminosulfonyl, dibutylaminosulfonyl And methylethylaminosulfonyl, methylpropylaminosulfonyl, butylmethylaminosulfonyl, ethylbutylaminosulfonyl and dicyclohexylaminosulfonyl.
  • cyclic aminosulfonyl group of the “substituent” examples include a 5- to 7-membered cyclic aminosulfonyl which may contain an oxygen atom, a sulfur atom, or a nitrogen atom as a ring-constituting atom.
  • Sulfonyl may be further substituted with alkyl, hydroxyl group and the like.
  • Specific examples include pyrrolidinosulfonyl, piperidinosulfonyl, piperazinylsulfonyl, 4-methylpiperazinylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, and 4-hydroxypiperidinosulfonyl. More preferred are morpholinosulfonyl and 4-hydroxypiberidinosulfonyl.
  • alkylsulfonyl group of the “substituent” examples include a linear or branched C i-Ce alkylsulfonyl group, and specifically, methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2 —Propylsulfonyl, 1-butylsulfonyl, 2-butylsulfonyl and the like, more preferably methylsulfonyl and 2-propylsulfonyl.
  • arylsulfonyl group of the above “substituent” examples include benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-fluorobenzenesulfonyl, p-methoxybenzenesulfonyl, p-methoxybenzenesulfonyl, and p-trifluoromethylbenzene Examples include sulfonyl, m-chlorobenzene benzenesulfonyl, and 0-chlorobenzenebenzenesulfonyl, and more preferably benzenesulfonyl, p-chlorobenzenebenzenesulfonyl, p-methoxybenzenesulfonyl, and p-trifluoromethylbenzenesulfonyl.
  • alkylsulfonyloxy of the “substituent” examples include linear or branched C i-Ce alkylsulfonyloxy, and specific examples include methylsulfonyloxy, ethylsulfonyloxy, and Propylsulfonyloxy, 2 —Propylsulfonyloxy, 1-butylsulfonyloxy, 2-butylsulfonyloxy and the like, more preferably methylsulfonyloxy and 2-propylsulfonyloxy.
  • alkylthio group as the “substituent” examples include a straight-chain or branched-chain C 6 alkylthio group. Specific examples include methylthio, ethylthio, propylthio, butylthio, pentylthio, 2-propylthio, and 2-propylthio. —Methyl_1-propylthio, 2-butylthio, t-butylthio, 3-methyl-2-butylthio, 2-methyl-2-butylthio, hexylthio, etc., more preferably, methylthio, ethylthio, and 2-propylthio. No.
  • heteroaryl derivative of the present invention when the heteroaryl derivative of the present invention has an acidic group, examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, zinc, and the like. And inorganic bases such as salts, organic bases such as triethylamine, triethanolamine, tris (hydroxymethyl) aminomethane, and amino acids.
  • examples thereof include inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate, and acetate, propionate, and succinic acid.
  • the present invention also includes a prodrug of a heteroaryl derivative represented by the formula (1). Further, the present invention also includes a heteroaryl derivative or a prodrug of the formula (1), or a hydrate of such a pharmaceutically acceptable salt thereof, or a solvate thereof such as an ethanol solvate. Refers to those which are chemically or biochemically hydrolyzed in vivo to regenerate the compound of the present invention.
  • the heteroaryl derivative of the present invention has a carboxyl
  • a compound in which the lipoxyl is converted to an appropriate ester is obtained.
  • this ester include methyl ester, ethyl ester, 1-propyl ester, 2-propyl ester, pivaloyloxymethyl ester, acetyloxymethyl ester, cyclohexyl acetyloxymethyl ester, 1-methylcycloalkyl ester
  • Examples include hexyl carbonyloxy methyl ester, ethoxy carboxy oxy-1-ethyl ester, cyclohexyl carbonyl carbonyloxy 1-ethyl ester, and the like.
  • the heteroaryl derivative of the present invention can be produced, for example, by the production method (1) described in detail below or a method analogous thereto.
  • the compounds used as the starting compounds may each be used as a salt.
  • Such salts include pharmaceutically acceptable salts.
  • heteroaryl moiety of the heteroaryl derivative of the present invention can be prepared by a method known per se, for example, The Chemistry of Heterocyclic Compounds (eg, a pyrazole derivative: Vo 1.22; an imidazole derivative: vo 1.6 parti; Triazole derivatives: vo 1.6 arti; indazole derivatives: V o 1.22; benzimidazole derivatives: V 01.
  • a pyrazole derivative Vo 1.22
  • an imidazole derivative vo 1.6 parti
  • Triazole derivatives vo 1.6 arti
  • indazole derivatives V o 1.22
  • benzimidazole derivatives V 01.
  • the heteroaryl derivative of the formula (1) can be produced by bonding at the ad portions.
  • the method for forming the bond of the a-d portion can be exemplified as in the production method (1-1-1) -1 (1-4). Note that these reactions are merely examples, and can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis. The order of bond formation of the a-d portion can be appropriately changed.
  • R 1G represents an alkoxy group such as methoxy and ethoxy, an alkylamino such as morpholine, and a hydroxyl group
  • L 1 represents a chlorine atom or bromine.
  • compound (102) can be obtained by reacting compound (100) with compound (101) in an inert solvent in the presence of a base.
  • the inert solvent include ether solvents such as ether, tetrahydrofuran (THF), and dioxane; hydrocarbon solvents such as toluene, benzene, and xylene; and halogens such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride.
  • Aprotic solvents such as fluorinated hydrocarbon solvents, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile.
  • solvents may be used by mixing two or more kinds in an appropriate ratio.
  • sodium hydride potassium hydride
  • examples include metal hydrides such as platinum, metal carbonates such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and cesium carbonate; alkylamines such as triethylamine and ethyldiisopropylamine; and metal alkoxides such as sodium methoxide.
  • the reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, preferably the range of about 0 to about the boiling point of the solvent.
  • oxidizing agent examples include organic peracids such as perbenzoic acid and perbenzoic acid, organic peroxides such as t-butyl peroxide, oxone, sodium periodate, and hydrogen peroxide.
  • the compound (104) can be obtained by using a usual deprotection technique for the compound (102). For example, it can be obtained by a hydrolysis reaction in the presence of an acid or a base.
  • Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid and the like.
  • the solvent examples include ether solvents such as ether, THF, and dioxane; aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile; and alcohol solvents such as methanol and ethanol.
  • ether solvents such as ether, THF, and dioxane
  • aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile
  • alcohol solvents such as methanol and ethanol.
  • one or more solvents and water may be mixed in an appropriate ratio and used, or may be used without a solvent.
  • the reaction temperature is selected from the range of about ⁇ 20 ° C. to around the boiling point of the solvent, and preferably from about 10 to about the boiling point of the solvent.
  • Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; and metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, and sodium hydrogencarbonate. Done in
  • aqueous solvent examples include ether solvents such as ether, THF, and dioxane; A mixed solvent of one or more solvents selected from aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile, and alcohol solvents such as methanol and ethanol, and an appropriate ratio of water. Used.
  • the reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably ranges from about -1 O: to about the boiling point of the solvent.
  • L 2 represents a chlorine atom, a bromine atom, a halogen atom such as iodine atom, a triflate Ruo b methanesulfonyl Ruo key sheet, Q 2 and Q 3 represent an organic group.
  • Compound (105), Compound (106), Compound (108), Compound (109) are, for example, Experimental Chemistry Course 19-26 (Maruzen, published in 1992), Precision Organic Synthesis (Nankodo, published in 1983) ), Compendium of Organic Synthetic Methods, Vol. 1-9 (John Wiley & Sons), Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press), Comprehensive Organic Transformations (1989, VCH Publ ishers)), etc. It can be manufactured by the method described above or a method according to it.
  • Compound (107) can be produced by reacting compound (105) with compound (106) or by reacting compound (108) with compound (109).
  • inert solvents examples include ether solvents such as THF, dioxane, and dimethoxyethane. Solvents, hydrocarbon solvents such as toluene, benzene, and xylene; aprotic solvents such as N, N-dimethylformamide, acetonitrile, and 1-methyl-2-pyrrolidinone. These solvents may be used as a mixture of two or more kinds in an appropriate ratio.
  • the base include metal carbonates such as potassium carbonate, sodium hydrogen carbonate and silver carbonate, triethylamine, ethyldiisopropylamine, N, And alkylamines such as N-dicyclohexylmethylamine.
  • transition metal catalyst examples include zero-valent palladium catalysts such as tetrakis (triphenylphosphine) palladium, bis (tri-t-butylphosphine) palladium, and palladium dibenzylidene complex; Valent palladium catalyst and the like.
  • reaction assistant can be added to this reaction as needed.
  • the reaction assistant include monodentate ligands such as triphenylphosphine and tris (o_tolyl) phosphine, diphenylphosphinopropane, and the like.
  • Bidentate ligands such as diphenylphosphinobutane and diphenylphosphinophenol and quaternary ammonium salts such as benzyltriethylammonium chloride and benzyltriethylammonium bromide may be added.
  • the reaction temperature under the transition metal catalyst is selected from the range of about 0 to about 100, and preferably the range of about 5 Ot: to about 100.
  • the compound (107) is obtained by reacting the compound (108) with the compound (109) in an inert solvent in the presence of a base.
  • the inert solvent examples include aprotic solvents such as N, N-dimethylformamide, ethyl acetate, acetonitrile, and dimethyl sulfoxide; ether solvents such as THF and dioxane; halogens such as chloroform and dichloromethane. And hydrocarbon solvents such as toluene and benzene. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the base examples include metal alkoxides such as t-butoxy potassium and sodium methoxide, potassium carbonate, and sodium carbonate. And metal carbonates such as cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, and metal hydrides such as sodium hydride.
  • the reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 0 ° C to about the boiling point of the solvent.
  • Compound (1 0 7) may be subjected to catalytic hydrogenation reaction if necessary, rw 1 by the contact Hydrogen addition reaction can experience a producing or one C 5 alkylene "which may be substituted it can.
  • the reaction can be performed in a hydrogen atmosphere, in an inert solvent, in the presence of a metal catalyst.
  • the inert solvent include alcohol solvents such as methanol and ethanol, aprotic solvents such as ethyl acetate, acetonitrile and dimethyl sulfoxide, and ether solvents such as THF and dioxane. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • Metal catalysts include platinum oxide, activated carbon with platinum, activated carbon with palladium, palladium hydroxide, palladium black, barium sulfate with palladium, calcium carbonate with palladium, Lind 1 ar catalyst, nickel nickel, rhodium carbon, and rhodium. Alumina, tris (triphenylphosphine) chloride rhodium, ruthenium carbon, bis (triphenylphosphine) dicarbonyldilute dimethyldichloride and the like can be mentioned.
  • the hydrogen pressure in a hydrogen atmosphere is selected from the range of 1 to 150 atm, preferably the range of 1 to 10 atm.
  • reaction aid can be added as necessary.
  • reaction aid for example, acids such as sulfuric acid, hydrochloric acid, perchloric acid, phosphoric acid, acetic acid, oxalic acid, and trifluoroacetic acid, and bases such as phenylethylamine and triethylamine may be added.
  • the reaction temperature is selected from the range of about 0 to about 150, preferably the range of about 20 to about 100.
  • oxidizing agent examples include chromic acids such as manganese dioxide and pyridinum chromate, oxidation with dimethyl sulfoxide in combination with oxalyl chloride, and complex oxidation of 4-methylmorpholine / tetra-n-propylammonium pearl tenate. Agents and the like.
  • the reaction temperature is selected from the range of about ⁇ 20 to about the boiling point of the solvent, preferably the range of about 0 to about the boiling point of the solvent.
  • Compound (112) can be obtained by reacting compound (110) with compound (111) in an inert solvent in the presence of a base.
  • the inert solvent examples include aprotic solvents such as N, N-dimethylformamide, ethyl acetate, acetonitrile, and dimethyl sulfoxide; ether solvents such as THF and dioxane; halogens such as chloroform and dichloromethane. And hydrocarbon solvents such as toluene and benzene. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the base examples include metal alkoxides such as t-butoxy potassium and sodium methoxide; metal carbonates such as potassium carbonate and sodium carbonate; and alkyl cations such as triethylamine and ethyldiisopropylamine. And hydrides such as amines and sodium hydride.
  • the reaction temperature is selected from the range of about ⁇ 20 to about the boiling point of the solvent, preferably the range of about ot: to about the boiling point of the solvent.
  • L 3 is an alkoxy such as methoxy and ethoxy, an alkylamino such as N-methyl-N-methoxyamino, N, N-dimethylamino and the like, and a deprotection of chloro group and the like.
  • M represents an alkali metal such as lithium, magnesium halide, zinc halide or the like
  • Q 6 represents an organic group.
  • Compound (113), compound (116) and compound (118) are, for example, Experimental Chemistry Lectures 19-26 (Maruzen, published in 1992), precision organic synthesis (Nankodo, published in 1983), Compend 1 um (Organic Synthetic Met hod s, Vo l. 1-9 (John Wiley & S on s), Compreh ensive Org anic Syn thesis, Vo l. 1-9 (1991 , Pe rg amon n Press), Comprehensive Organic Tran sfo rma ti ons (1989, VCH Pub1 ishers), etc., or a method analogous thereto. .
  • Compound (114) is prepared by treating compound (113) in an inert solvent with a base. Obtained by reacting aldehyde.
  • the inert solvent examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and xylene; and halogen solvents such as chloroform and dichloromethane. These solvents may be used by mixing two or more kinds in an appropriate ratio.
  • Examples of the base include alkylamines such as triethylamine and ethyldiisopropylamine, n-butyllithium, lithium diisopropylamide and the like.
  • the reaction temperature is selected from the range of from about 1 to about 78 when the base is treated, preferably from about ⁇ 78 to about 0, and the reaction with the aldehyde is about ⁇ 7.
  • the temperature ranges from 8 ° C to around the boiling point of the solvent, and preferably ranges from about 178 to about 50.
  • Compound (114) can also be obtained by reacting compound (116) with compound (117) in an inert solvent.
  • inert solvent examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride.
  • Compound (117) represents an organic metal compound such as aryl lithium salt and aryl magnesium halide.
  • the reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 0 ° C to about the boiling point of the solvent.
  • Compound (115) can be obtained by reacting compound (114) with an oxidizing agent in an inert solvent.
  • the inert solvent examples include halogen-based solvents such as chloroform and dichloromethane.
  • the oxidizing agent include chromic acids such as manganese dioxide, pyridinum bromide chromate, and dimethyl sulfoxide in combination with oxalyl chloride. Oxidation with sides, and complex oxidizing agents such as 4-methylmorpholine-no-tetra-n-propylammonium palmitate.
  • the reaction temperature is selected from the range of about ⁇ 78 to about the boiling point of the solvent, and preferably the range of about ⁇ 2 to about 60.
  • compound (115) is obtained by dissolving compound (118) in an inert solvent. Can also be obtained by reacting with the compound (117).
  • inert solvent examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and hexane; and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride.
  • Compound (117) represents an organic metal compound such as aryl aryl salt and aryl magnesium octalide.
  • inert solvent examples include ether solvents such as ether, THF, and dioxane; hydrocarbon solvents such as toluene, benzene, and xylene; and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride. And the like.
  • the reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 0 to about the boiling point of the solvent.
  • Compound (115) can also be obtained by reacting compound (113) with aryl aryl halide in the presence of triethylamine in pyridine, followed by alkali hydrolysis (the method described in Synthesis, 1978, 675, Alternatively, it can be produced by a method according to it.) This reaction can be carried out in a closed reaction vessel such as an autoclave if necessary.
  • the reaction temperature in the reaction between compound (115) and aryl acid halide is about 0 From 150 to 150, preferably in the range of about 0 to 110.
  • Examples of the base for the alkali hydrolysis reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, and the reaction is performed in a water-containing solvent.
  • aqueous solvent for example, a mixed solvent of one or more solvents selected from ether solvents such as ether, THF, and dioxane, and alcohol solvents such as methanol and ethanol, and an appropriate ratio of water is used.
  • the reaction temperature is selected from the range of about ⁇ 2 Ot: to about the boiling point of the solvent, and preferably about 0 to the range of about the boiling point of the solvent.
  • R 1 is “optionally substituted C 4 alkylsulfonylcarbamoyl, optionally substituted arylsulfonylcarbamoyl”
  • the compound (104) and the compound ( Compound (120) can be produced by reacting 119) in an inert solvent in the presence of a base and a dehydrating condensing agent. .
  • R 11 represents Ci—C 4 alkyl or aryl
  • Q 7 represents an organic group.
  • the inert solvent examples include: aprotic solvents such as N, N-dimethylformamide, ethyl acetate, acetonitrile, and dimethyl sulfoxide; ether solvents such as THF and dioxane; and chloroform, dichloromethane and the like. Halogen solvents and the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • Examples of the base include metal alkoxides such as potassium t-butoxide and sodium methoxide; metal carbonates such as potassium carbonate and sodium carbonate; triethylamine; Alkylamines such as rudiisopropylamine and 1,8-diazabicyclo [5,4,0] indene-1-ene.
  • Examples of the dehydrating condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) -capillium imide, N, N-bis (2-oxo-13-oxazolidinyl) phosphinic acid chloride, N, N'-carbonyldiimidazole and the like.
  • a reaction aid can be added to the reaction as required.
  • reaction assistant examples include N-hydroxybenztriazole, N, N-dimethyl-4-aminopyridine and the like.
  • R 2 and R 3 are aryl or heteroaryl
  • the other represents a C 4 alkyl which may be substituted with a hydrogen atom or a halogen atom
  • L 4 represents a hydroxyl group, an amino group, bromine, chlorine, etc.
  • the following compound (129) can be produced as follows, for example, by combining the production methods (111) and (114).
  • compound (121) can be protected by a dimethylsulfamoyl group as a protecting group, and the subsequent reaction can be performed.
  • a dimethylsulfamoyl group as a protecting group
  • the reaction can be carried out by reacting dimethylsulfamoyl chloride or the like in the presence of a base such as luamine.
  • Compound (122) can be produced by treating compound (121) with a base in an inert solvent and then reacting with arylaldehyde. This reaction is produced, for example, according to the method described in J. Chem. Soc. Perkin Trans. I, 481 (1984), Chem. Pharm. Bull., 41, 1226 (1993), or a method analogous thereto. be able to.
  • the inert solvent examples include ether solvents such as THF, halogen solvents such as dichloromethane, hydrocarbon solvents such as toluene, and the like.
  • Preferred bases include n-butyllithium and lithium diisopropylamide.
  • the reaction temperature is selected from the range of about 178 to about the boiling point of the solvent, preferably in the range of about _78: to about 0, and the reaction with the aldehyde is preferably in the range of about Ot: to about 50.
  • Compound (123) can be produced by reacting compound (122) with an oxidizing agent in an inert solvent.
  • Examples of the inert solvent include halogen solvents such as chloroform and dichloromethane, and examples of the oxidizing agent include manganese dioxide.
  • the reaction temperature ranges from about ⁇ 78 ° C. to about the boiling point of the solvent. And preferably ranges from about 20 to about 60.
  • Compound (124) can be obtained by deprotecting compound (123).
  • deprotection can be performed, for example, using a mixed solvent system of an acidic aqueous solution such as aqueous hydrochloric acid and an alcoholic solvent such as ethanol, or an ethereal solvent such as THF. It can be carried out by heating to reflux.
  • This reaction can be produced, for example, according to the method described in J. Org. Chem., 61, 4405 (1996) or a method analogous thereto.
  • the inert solvent examples include aprotic solvents such as N, N-dimethylformamide, ether solvents such as THF, and halogen solvents such as dichloromethane.
  • the base examples include, for example, potassium t-butoxy. Metal alkoxides, metal carbonates such as potassium carbonate, alkylamines such as ethyldiisopropylamine, and metal hydrides such as sodium hydride.
  • the reaction temperature ranges from about 12 to about the boiling point of the solvent. Selected from a range, preferably a range from about 0 to about 60.
  • the compound (127) can be produced by reacting the compound (127) with ⁇ -haloisobutyric acid in an inert solvent in the presence of a base.
  • the inert solvent examples include aprotic solvents such as ⁇ and ⁇ -dimethylformamide, ether solvents such as THF, and halogen solvents such as dichloromethane.
  • the base examples include t-butoxy potassium and the like.
  • the reaction temperature ranges from about 120 to about the boiling point of the solvent. And preferably ranges from about 0 to about 60.
  • compound (1 28) can be produced by using conventional deprotection techniques for compound (1 27). For example, it can be obtained by a hydrolysis reaction in the presence of an acid or a base.
  • examples of the acid include hydrochloric acid, sulfuric acid, and methanesulfonic acid.
  • examples of the solvent include ether solvents such as THF and dioxane, acetone, dimethyl sulfoxide, N, N-dimethyl, and the like.
  • examples include aprotic solvents such as formamide and acetonitrile, and alcoholic solvents such as methanol and ethanol.
  • One or more solvents and water may be mixed in an appropriate ratio and used, or may be used without a solvent. .
  • the reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 110 to about the boiling point of the solvent.
  • examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; and metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate.
  • the reaction is performed in a hydrated solvent.
  • the aqueous solvent is selected from, for example, ether solvents such as THF and dioxane, aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile, and alcohol solvents such as methanol and ethanol.
  • ether solvents such as THF and dioxane
  • aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile
  • alcohol solvents such as methanol and ethanol.
  • a mixed solvent of more than one kind of solvent and an appropriate ratio of water is used.
  • the reaction temperature is selected from the range of about 120 to about the boiling point of the solvent, and preferably the range of about 110 to the vicinity of the boiling point of the solvent.
  • the compound (125) can be produced by reacting the compound (125) with the compound (128) in an inert solvent in the presence of a palladium catalyst and a base.
  • the inert solvent examples include ether solvents such as THF and dioxane, hydrocarbon solvents such as toluene, and aprotic solvents such as N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, and acetonitrile.
  • the base examples include metal carbonates such as potassium carbonate, sodium hydrogen carbonate, and silver carbonate; alkylamines such as triethylamine, ethyldiisopropylamine, and N, N-dicyclohexylmethylamine; and palladium.
  • the catalyst examples include a zero-valent palladium catalyst such as tetrakis (triphenylphosphine) palladium complex, bis (tri-t-butylphosphine) palladium, and a divalent palladium catalyst such as palladium acetate.
  • a zero-valent palladium catalyst such as tetrakis (triphenylphosphine) palladium complex, bis (tri-t-butylphosphine) palladium
  • a divalent palladium catalyst such as palladium acetate.
  • reaction aid can be added to this reaction as needed.
  • reaction aid include phosphine ligands such as triphenylphosphine and tris (o-tolyl) phosphine, and benzyltriethylammonium chloride.
  • phosphine ligands such as triphenylphosphine and tris (o-tolyl) phosphine
  • benzyltriethylammonium chloride benzyltriethylammonium chloride.
  • a quaternary ammonium salt such as benzyltriethylammonium bromide may be added.
  • the reaction temperature is selected from the range of about 0 ° C. to about 100, preferably the range of about 50 to about 100.
  • the heteroaryl derivative or prodrug of the present invention may have asymmetry or may have a substituent having an asymmetric carbon, and such a compound has an optical isomer.
  • the compounds of the present invention include mixtures of these isomers and isolated ones. A method for obtaining such an optical isomer purely includes, for example, optical resolution.
  • the compound of the present invention or an intermediate thereof has a basic substituent
  • the compound is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, or 2-propanol, or an ether such as getyl ether).
  • an inert solvent for example, an alcohol solvent such as methanol, ethanol, or 2-propanol, or an ether such as getyl ether.
  • optically active acids eg, mandelic acid, N-benzyloxyalanine
  • monocarboxylic acids such as lactic acid, tartaric acid, dicarboxylic acids such as o-diisopropylidene tartaric acid and malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid).
  • heteroaryl derivative or prodrug of the present invention or an intermediate thereof has an acidic substituent such as dexamethasyl, optically active amines (for example, ⁇ -phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, 2-amino) It can also form salts with organic amines such as 1,2-diphenylethanol and 2-amino-1,1,1-diphenylpropanol.
  • an acidic substituent such as dexamethasyl, optically active amines (for example, ⁇ -phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, 2-amino) It can also form salts with organic amines such as 1,2-diphenylethanol and 2-amino-1,1,1-diphenylpropanol.
  • the temperature at which the salt is formed may be in the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled if necessary to improve the yield.
  • the amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, crystallize in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol, ether solvents such as ethyl ether, ester solvents such as ethyl acetate, and aromatic hydrocarbon solvents such as toluene. , Acetonitrile, etc. and their mixed solvents) An optically active salt of a purity can also be obtained. If necessary, the obtained salt can be treated with an acid or a base by a usual method to obtain a free form.
  • the heteroaryl derivative of the present invention or a salt thereof can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, and the like.
  • topical administration examples include capsules, tablets, pills, powders, cachets, suppositories, and liquid preparations.
  • injection include a sterile solution or suspension.
  • the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrixes) and the like.
  • compositions are formulated in a conventional manner, together with pharmaceutically acceptable excipients and additives.
  • Pharmaceutically acceptable excipients and additives include carriers, binders, flavors, buffers, thickeners, coloring agents, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc.
  • Can be Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cacao Butter and the like.
  • Capsules can be formulated by incorporating a compound of the present invention together with a pharmaceutically acceptable carrier.
  • the compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in a capsule without excipients. Cassiers can be produced in a similar manner.
  • Solutions for injection include solutions, suspensions, emulsions and the like.
  • an aqueous solution, water-propylene glycol solution and the like can be mentioned.
  • Solutions can also be prepared in the form of a solution of polyethylene glycol or Z and propylene glycol, which may contain water.
  • a liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water and adding a coloring agent, a flavor, a stabilizing agent, a sweetening agent, a solubilizing agent, a thickening agent and the like as needed.
  • a liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water together with a dispersant to make it viscous.
  • thickeners for example, pharmaceutically acceptable natural Or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or a known suspending agent.
  • topical preparation examples include the above-mentioned liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like.
  • the above-mentioned preparation for topical administration can be produced by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier usually used.
  • Ointments and creams are obtained, for example, by formulating an aqueous or oily base with a thickener and / or a gelling agent.
  • the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, and the like).
  • the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, honey bean, and the like.
  • Lotions may be added to an aqueous or oily base with one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, fragrances, etc. .
  • the powder is formulated with a pharmaceutically acceptable powder base.
  • the base include sugar, lactose, starch and the like.
  • Drops may be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like.
  • the topical preparation may contain, if necessary, a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, black cresol, benzalkonidum bride, and a bacterial growth inhibitor.
  • a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, black cresol, benzalkonidum bride, and a bacterial growth inhibitor.
  • the heteroaryl derivative of the present invention or a salt thereof can be administered to a diabetic patient, particularly a type 2 diabetic or non-insulin-dependent diabetic patient. Further, or the heteroaryl derivative or a salt thereof of the present invention can control the blood glucose level of a diabetic patient.
  • the dosage and frequency of administration at this time vary depending on the symptoms, age, body weight, dosage form, etc., but in the case of oral administration, usually about 1 to about 50 per day for adults.
  • the Omg range preferably from about 5 to about 10 Omg, can be administered once or in several divided doses. When administered as an injection, it can be administered in the range of about 0.1 to about 30 mg, preferably in the range of about 1 to about 100 mg, in one or several divided doses
  • Solution A H 2 ⁇
  • Solution B acetonitrile
  • Flow rate lml / min
  • Solution A 0.05% aqueous trifluoroacetic acid
  • Solution B acetonitrile containing 0.035% trifluoroacetic acid
  • N, N-Dimethyl-1H-imidazole-1-sulfonamide (1.00 g, 5.71 r. Ol) was dissolved in 30 ml of THF and stirred at -78. To this solution was added n-butyllithium (1.57M hexane solution, 3.9 ml, 6.3 mmol), and the mixture was stirred at -78 for 30 minutes. Then, a solution of 4- (trifluoromethyl) benzaldehyde (1.49 g, 8.57 mmol) in THF (5 ml) was added, and the mixture was heated to room temperature and stirred overnight.
  • the reaction solution was filtered through Celite, and the solvent in the filtrate was distilled off under reduced pressure.
  • the obtained residue was dissolved in 20 ml of THF, 50 ml of 4N diluted hydrochloric acid was added, and the mixture was heated under reflux for 4 hours. While stirring under ice-cooling, a 4 N aqueous sodium hydroxide solution was added dropwise to neutralize the mixture, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (320 mg, 23%).
  • the organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and azeotroped with hexane to obtain the title compound (368 mg, 99%).
  • Triazole (5.08 g, 73.6 recited 01) was dissolved in 80 ml of toluene, and triethylamine (9.52 ml, 68.4 mmol) and dimethylsulfamoyl chloride (10.6 ml, 73.6 mmol) were added, followed by stirring for 2 hours. The resulting precipitate is removed by filtration, and the filtrate is depressurized. Distilled off. The obtained residue was purified by silica gel column chromatography to give the title compound (4.52 g, 38%).
  • N, N-Dimethyl-1H-1,2,4-triazole-1-sulfonamide (2.00 g, 11.4 mmol) was dissolved in 60 ml of THF and stirred at -78. To this solution was added n-butyllithium (1.57 M hexane solution, 8.0 ml, 13 mmol), and the mixture was stirred at -78 for 1 hour. Then, a solution of 4_ (trifluoromethyl) benzaldehyde (2.98 g, 17.1 mmol) in THF (20 ml) was added, the temperature was raised to room temperature, and the mixture was stirred overnight.
  • the organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was dissolved in 50 ml of chloroform, and manganese dioxide (5.00 g, 5.75 described in 01) was added, followed by stirring at 60 ° C for 3 hours.
  • the reaction was cooled to room temperature and filtered through celite.
  • Example 23 the compounds of Example 24 and Example 25 were synthesized.
  • Reference Example 14-2 was synthesized in the same manner as Reference Example 14_1.
  • the organic layer was washed with an aqueous solution of sodium thiosulfate, dehydrated with a saturated saline solution, and dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
  • the obtained concentrated residue was dissolved in 50 ml of methanol, added with 240 mg of 10 palladium-hydrocarbon (50% water-containing product), and stirred at room temperature under a normal pressure hydrogen atmosphere for 1 hour.
  • the reaction solution was filtered through celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (2.30 g, 32%).
  • the organic layer was washed with water, an aqueous solution of sodium thiosulfate, and saturated saline.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.53 g, 94%).
  • the residue obtained by distilling off the solvent under reduced pressure is dissolved in 150 ml of ethanol, and 300 mg of 10% palladium-carbon (50% water-containing product) is added. Stirred. The reaction solution is filtered through celite, and the solvent in the filtrate is distilled off under reduced pressure.
  • the title compound was obtained (3.08 g, 99%).
  • Example 36 The compounds of Examples 36 to 42 were synthesized in the same manner as in Example 35.
  • Example 36 The compounds of Examples 36 to 42 were synthesized in the same manner as in Example 35.
  • the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and the obtained concentrated residue was dissolved in 3 ml of ethanol and 3 ml of 2N Add sodium hydroxide aqueous solution, and The reaction solution was neutralized with 1 N diluted hydrochloric acid, extracted with ethyl acetate, dehydrated with a saturated saline solution, and the obtained solution was concentrated to obtain the title compound (84.8 mg, 51%).
  • Example 48 The compounds of Examples 48 to 53 were synthesized in the same manner as in Example 47.
  • Example 48
  • Benzimidazole (3.54 g, 30.0 mol) was dissolved in 10 ml of pyridine, and triethylamine (13.3 g, 132 mol) was added, followed by stirring at room temperature.
  • m-anis chloride (15.3 g, 90.0 mmol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 1 hour. Further, the reaction temperature was raised to 50 and the mixture was stirred for 2 hours.
  • 150 ml of 4N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred at 60 for 3 hours. After allowing the reaction solution to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed sequentially with water, 1N diluted hydrochloric acid, and saturated saline, and dried over magnesium sulfate. After filtering off magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The title compound was obtained by recrystallization from ethyl acetate (4.60 g, 61%).
  • Tribromo-3,3-dimethyl-2-butanone (5.00 g, 27.9 ol) was dissolved in formamide (37.7 g, 83.7 bc01) and stirred at 160 for 5 hours. After the reaction solution was allowed to cool to room temperature, 100 ml of water was added, and the aqueous layer was washed with 50 ml of hexane. A 2N aqueous sodium hydroxide solution was added to the obtained aqueous layer to adjust the pH of the solution to about 10, and the solution was extracted with a black hole form. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the title compound (1.67 g, 48%).
  • Tobut-3-ene-4-tol-4-tert-butyl-1H-imidazole (53.5 mg, 0.300 mmol) was dissolved in 1 ml of pyridine, and triethylamine (91.1 mg, 0.900% ol), 4-Toluoyl chloride (139 mg, 0.900 mmol) was sequentially added, and the mixture was stirred at 60 ° C for 5 hours. After allowing the reaction solution to cool to room temperature, 5 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added with 10 ml of water, and extracted with ethyl acetate.
  • the organic layer was washed with water, 1N diluted hydrochloric acid and saturated saline, and dried over magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography. The title compound was obtained (29.4 mg, 33 mg).
  • Example 70 In the same manner as in Example 35, the compound of Example 70 was synthesized.
  • a reporter plasmid As a reporter plasmid, a plasmid in which a GAL4 protein response element UAS and a heron) 3 globin motor were inserted into a pGL3-basic vector (Promega) containing a firefly luciferase gene was used. To correct the transformation efficiency, a plasmid p) 3g a1 contro1 (Clontech) containing the 1 ac Z gene was used.
  • COS-1 cells are cultured in Dulbecco's modified Eagle's medium (DMEM) without phenol red containing 5% activated carbon and dextran-treated fetal serum (Gibco) in the presence of 5% carbon dioxide at 37. did. COS-1 cells were seeded at a density of 5 ⁇ 10 4 cells in a 24-well plate and cultured overnight. Replace the medium with 5% charcoal * dextran-treated medium without fetal serum, and use 5 ng of GAL4-PPAR ⁇ or ⁇ expression plasmid, 50 ng of reporter plasmid, pj3 ga 1 con trol per 1 ⁇ l 350 ng of DNA was transfected using Lipofectamine Plus reagent (Gibco).
  • DMEM Dulbecco's modified Eagle's medium
  • Gibco dextran-treated fetal serum
  • the medium was replaced with a medium containing 5% activated carbon / dextran-treated fetal bovine serum, and the compound of the present invention was added to a final concentration of 1 or 10 M.
  • the cells were lysed using the cell lysis solution attached to Luciferase Assay System (Promega), and the luciferase activity was measured with a luminometer using the attached luciferase measurement reagent.
  • Luciferase Assay System Promega
  • Galactosidase activity was measured using a galactosidase enzyme assay system (Promega) to correct for transformation efficiency.
  • PPAR ⁇ or argonist activity was determined by adding solvent (DMSO) as a control.
  • DMSO solvent
  • the luciferase activity of Dwell was shown as a relative activity with respect to 1.
  • 10 ⁇ ? ? VIII ⁇ -agonist activity and PPAR-agonist activity are shown.
  • Example 60 8.5 4.0
  • Example 75
  • Rats Wistar rats (male, 7 weeks old, SPF standard) were purchased from Charles River Japan and used after one week of quarantine. After an overnight fast from the day before hepatocyte preparation, it was used in the experiments.
  • Collagenase solution aCl 8g / L, KCl 0.4g / L, NaH 2 P0 4 ⁇ 2H 2 00.078g / L, Na 2 HP0 4 ⁇ 12H 2 0 0.151g / L, CaC "0.56g / L, HEPES 2.38g / L, Phenol red 0.006g / L, Collagenase 0.5g / L, Trypsin inhibitor 0.05g / L, NaHC0 3 0.35g / L of (pH 7.5) 0. fill evening was used as one filtered.
  • WE medium A liquid medium (500 ml bottle) was purchased from Gibco and used after adding 10% FBS and 2 mM glutamine.
  • the rats fasted overnight are anesthetized with Nembutal and laparotomized.
  • the abdominal vein was incised and perfusion was started.
  • collagenase perfusion was performed for 6-10 minutes.
  • the liver was excised, minced with a scalpel, and suspended in WE medium.
  • the suspension was filtered with a cell strainer, and the filtrate was centrifuged at 600 rpm for 1 minute. The supernatant was removed, suspended by adding KHS, and centrifuged again.
  • hepatocytes were diluted with KHS to 6 ⁇ 10 5 cells / ml, and seeded at 0.5 ml / well on a 24-well plate containing gelatin. Measurement of hepatic gluconeogenesis inhibitory effect>
  • the total amount was added to the drug and substrate liver cells prepared above and lml / wel 1, the supernatant was collected after 3 hours incubation at 37 / 53 ⁇ 4 C0 2 conditions. Lactic acid / pyruvic acid UOmM / lmM) was used as a substrate.
  • the glucose concentration in the collected supernatant was measured by the mutarotase-GOD method to calculate the amount of hepatic gluconeogenesis.
  • Metformin (10 mM) was used as a positive control, and the action of each drug was calculated as a relative value with the gluconeogenesis inhibition rate as 100%. Table 8 shows the results.
  • hypoglycemic effect was derived from the following formula.
  • Blood glucose lowering ffl (%, Vehicle blood glucose level (last day)-Blood glucose level of test substance administration group (last day) i ⁇ ()
  • a heteroaryl derivative or a salt thereof which is useful as a preventive or therapeutic drug for diabetes, improving insulin resistance and controlling blood sugar level more safely.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un nouvel agent thérapeutique pour les diabètes, de formule (1). Dans cette formule, l'anneau Z désigne la formule (2). Dans cette formule, Ar1 désigne un arylène éventuellement substitué, etc. ; Ar2 désigne un aryle éventuellement substitué, etc. ; W1 désigne alkylène C1-5 éventuellement substitué, etc. ; X1 désigne une liaison simple, oxygène, etc. ; Y1 désigne alkylène C1-5 éventuellement substitué, etc. : et R1 désigne carboxy, etc.
PCT/JP2003/015197 2002-11-28 2003-11-27 Nouveau derive heteroaryle WO2004048341A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
EP1647546A1 (fr) * 2003-07-15 2006-04-19 Dainippon Sumitomo Pharma Co., Ltd. Nouveau derive d'heteroaryle
WO2006075638A1 (fr) * 2005-01-14 2006-07-20 Dainippon Sumitomo Pharma Co., Ltd. Nouveau derive d'heteroaryle
US8273738B2 (en) 2006-09-05 2012-09-25 Kyowa Hakko Kirin Co., Ltd. Imidazole derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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WO2000064888A1 (fr) * 1999-04-28 2000-11-02 Aventis Pharma Deutschland Gmbh Derives diaryle acide en tant que ligands se fixant sur le recepteur ppar
WO2001038325A1 (fr) * 1999-11-10 2001-05-31 Takeda Chemical Industries, Ltd. Composes heterocycliques n a 5 elements a activite hypoglycemique et hypolipidemique
WO2002010131A1 (fr) * 2000-07-28 2002-02-07 Sumitomo Pharmaceuticals Co., Ltd. Derives du pyrrole
WO2002085851A1 (fr) * 2001-04-19 2002-10-31 Sumitomo Pharmaceuticals Company, Limited Derive de type pyrrole
JP2003171275A (ja) * 2001-12-11 2003-06-17 Sumitomo Pharmaceut Co Ltd ＰＰＡＲδアゴニスト
WO2003063861A1 (fr) * 2002-01-30 2003-08-07 Sumitomo Pharmaceuticals Co., Ltd. Inhibiteur de fibrose
JP2003238403A (ja) * 2002-02-08 2003-08-27 Sumitomo Pharmaceut Co Ltd 新規ピロール誘導体からなる肝糖新生阻害剤
JP2003292439A (ja) * 2002-02-04 2003-10-15 Sumitomo Pharmaceut Co Ltd 新規ピロール誘導体からなるｐｐａｒ活性化剤
WO2003091211A1 (fr) * 2002-03-28 2003-11-06 Sumitomo Pharmaceuticals Co., Ltd. Composes d'heteroaryle

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Publication number Priority date Publication date Assignee Title
WO2000064888A1 (fr) * 1999-04-28 2000-11-02 Aventis Pharma Deutschland Gmbh Derives diaryle acide en tant que ligands se fixant sur le recepteur ppar
WO2001038325A1 (fr) * 1999-11-10 2001-05-31 Takeda Chemical Industries, Ltd. Composes heterocycliques n a 5 elements a activite hypoglycemique et hypolipidemique
WO2002010131A1 (fr) * 2000-07-28 2002-02-07 Sumitomo Pharmaceuticals Co., Ltd. Derives du pyrrole
WO2002085851A1 (fr) * 2001-04-19 2002-10-31 Sumitomo Pharmaceuticals Company, Limited Derive de type pyrrole
JP2003171275A (ja) * 2001-12-11 2003-06-17 Sumitomo Pharmaceut Co Ltd ＰＰＡＲδアゴニスト
WO2003063861A1 (fr) * 2002-01-30 2003-08-07 Sumitomo Pharmaceuticals Co., Ltd. Inhibiteur de fibrose
JP2003292439A (ja) * 2002-02-04 2003-10-15 Sumitomo Pharmaceut Co Ltd 新規ピロール誘導体からなるｐｐａｒ活性化剤
JP2003238403A (ja) * 2002-02-08 2003-08-27 Sumitomo Pharmaceut Co Ltd 新規ピロール誘導体からなる肝糖新生阻害剤
WO2003091211A1 (fr) * 2002-03-28 2003-11-06 Sumitomo Pharmaceuticals Co., Ltd. Composes d'heteroaryle

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Publication number Priority date Publication date Assignee Title
EP1647546A1 (fr) * 2003-07-15 2006-04-19 Dainippon Sumitomo Pharma Co., Ltd. Nouveau derive d'heteroaryle
EP1647546A4 (fr) * 2003-07-15 2008-07-23 Dainippon Sumitomo Pharma Co Nouveau derive d'heteroaryle
US7425642B2 (en) 2003-07-15 2008-09-16 Dainippon Sumitomo Pharma Co. ,Ltd. Heteroaryl derivative
WO2006075638A1 (fr) * 2005-01-14 2006-07-20 Dainippon Sumitomo Pharma Co., Ltd. Nouveau derive d'heteroaryle
JPWO2006075638A1 (ja) * 2005-01-14 2008-06-12 大日本住友製薬株式会社 新規ヘテロアリール誘導体
US7781479B2 (en) 2005-01-14 2010-08-24 Dainippon Sumitomo Pharma Co., Ltd. Heteroaryl derivatives
US8273738B2 (en) 2006-09-05 2012-09-25 Kyowa Hakko Kirin Co., Ltd. Imidazole derivatives

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