WO2007126043A1 - Utilisation en tant que medicaments de derives d'un acide carboxylique porteurs de cycles thiazole - Google Patents

Utilisation en tant que medicaments de derives d'un acide carboxylique porteurs de cycles thiazole Download PDF

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WO2007126043A1
WO2007126043A1 PCT/JP2007/059151 JP2007059151W WO2007126043A1 WO 2007126043 A1 WO2007126043 A1 WO 2007126043A1 JP 2007059151 W JP2007059151 W JP 2007059151W WO 2007126043 A1 WO2007126043 A1 WO 2007126043A1
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thio
group
thiazole
ethyl
methyl
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PCT/JP2007/059151
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English (en)
Japanese (ja)
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Hiroki Tamakawa
Hiroyuki Iizuka
Kaoru Sakai
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Mitsubishi Tanabe Pharma Corporation
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Priority to JP2008513284A priority Critical patent/JP5225076B2/ja
Publication of WO2007126043A1 publication Critical patent/WO2007126043A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to a pharmaceutical comprising a carboxylic acid derivative containing a thiazole ring as an active ingredient.
  • Diabetes mellitus is a disease in which the number of patients has been rapidly increasing in recent years, and is known to be a risk factor with a high incidence of macrovascular disorders (coronary artery disease). Most diabetics have type 2 diabetes, and the cause of this is thought to be insulin secretion deficiency and insufficient insulin action associated with insulin resistance, which may be accompanied by abnormal lipid metabolism (hyperlipidemia) in addition to hyperglycemia. Many.
  • a high incidence of hyperlipidemia associated with diabetes is an increase in triglycerides (hereinafter sometimes referred to as “TG”), which is associated with HDL cholesterol (hereinafter referred to as “HDL-C”). There is also a lot of decrease in this. Both high TG and low HDL-C are considered risk factors for coronary artery disease, and correcting these factors is extremely important for controlling coronary artery disease in diabetic patients along with blood glucose control .
  • TG triglycerides
  • HDL-C HDL cholesterol
  • Peroxisome proliferator—activated receptor is a nuclear receptor that was cloned in 1990 as a receptor that responds to penoleosome proliferators, and other nuclear receptors, retinoid X receptor (RXR) and It develops heterodimers and activates various target genes as transcription factors.
  • RXR retinoid X receptor
  • fibrates which are antihyperlipidemic drugs
  • PPAR ⁇ It has been clarified that thiazolidine derivatives, which are insulin sensitizers, each act as a ligand.
  • Fibrate drugs are widely used as drugs for treating hyperlipidemia, and clofibrate, clofibrate aluminum, synfibrate, clinofibrate, etc. have been used so far. Bezafibrato (Bezato Nore SR (registered trademark), Bezalip (registered trademark)) and Fuenofibrato (Repankle, Tricore (registered trademark)), which are currently called the second generation, are widely used.
  • Fibrate drugs activate PPAR ct to activate genes involved in fatty acid metabolism (such as acyl CoA synthase, lipoprotein lipase, fatty acid transport protein) and apolipoproteins involved in TG and cholesterol metabolism. (AI, All, AV, cm) Regulates gene expression, lowers TG and LDL cholesterol (hereinafter sometimes referred to as “LDL_C”), and increases HDL-C to treat hyperlipidemia It is known to show high effectiveness.
  • LDL_C LDL cholesterol
  • lZL order (30 ⁇ mol / L or more) is weak, and the drug dosage is 134 1500 mgZday.
  • Various side effects such as gastrointestinal discomfort, gastrointestinal symptoms such as nausea, skin symptoms such as rash, hepatic dysfunction, and knee inflammation have been reported (above, Ripanpur (registered trademark) package insert).
  • Ripanpur registered trademark
  • Patent Document 1 and Non-Patent Document 2 include (phenylenoretio) acetic acid derivatives
  • Patent Document 2 and Non-Patent Document 3 include 3 phenylpropionic acid derivatives
  • Patent Document 3 and Non-Patent Documents include (phenylenoretio)
  • Patent Reference 4 includes phenoxyacetic acid derivatives
  • Patent Reference 4 includes phenoxyacetic acid derivative S
  • Patent Document 5 and Non-Patent Document 5 include 2,2 dichloroalkanecarboxylic acid derivative power
  • Patent Document 6 includes 1,3_ Although dioxane _ 2_carboxylic acid derivatives and phenoxyacetic acid derivatives have been reported in Patent Document 7, all (1, 3_thiazole _2_yl) -thioacetic acid derivatives like the compounds of the present invention are reported. There is no indication to suggest.
  • Patent Document 1 International Publication Pamphlet WO00 / 23407
  • Patent Document 2 International Publication Pamphlet WO00 / 75103
  • Patent Document 3 International Publication Pamphlet WO02 / 38553
  • Patent Document 4 International Publication Pamphlet WO02 / 28821
  • Patent Document 5 International Publication Pamphlet W096 / l 5784
  • Patent Document 6 International Publication Pamphlet WO01 / 90087
  • Patent Document 7 International Publication Pamphlet WO02 / 096894
  • Non-Patent Document 1 J. Med. Chem., 42, 3785 (1999)
  • Non-Patent Document 2 Bioorg. Med. Chem. Lett., 11, 1225 (2001)
  • Non-Patent Document 3 Bioorg. Med. Chem. Lett., 12, 333 (2002)
  • Non-Patent Document 4 J. Med. Chem., 46, 5121 (2003)
  • Non-Patent Document 5 Am. J. Physiol., 283 (3, Pt. 2), H949 (2002)
  • An object of the present invention is to provide a novel pharmaceutical use of a carboxylic acid derivative containing a thiazole ring, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the inventors of the present invention focused on the role of PPAR a in lipid metabolism for the purpose of creating a drug useful as a prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes.
  • the compound represented by the following general formula (I) has excellent plasma TG lowering action, free fatty acid lowering action, and high cholesterol diet-treated rat against male Zucker fatty rats, which are high TG model animals having insulin resistance. was found to have an effect of increasing serum HDL cholesterol, and the present invention was completed.
  • the gist of the present invention is as follows.
  • R 1 and R 2 are the same or different and represent a hydrogen atom or an alkyl group, or R 1 and R 2 are bonded to each other to form a cycloalkyl group;
  • R 3 represents a hydrogen atom or an alkyl group
  • R 4 represents a hydrogen atom, an alkyl group or an aryl group
  • n an integer of 1 to 5;
  • Y is an oxygen atom, sulfur atom, _NR 5 _, -CONR 5- , _NR 5 C ⁇ _ or — NHC ⁇ NR 5- (wherein R 5 is a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an aryl group, An aryleno alkeno group, an aryl alkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group);
  • Z represents a cycloalkyl group, an aryl group, an aryleno quinole group, an aryl alkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
  • an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, an arylalkylene group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group are Each may have a substituent.
  • n is an integer of :! to 3
  • Y is an oxygen atom, a sulfur atom, -NR 6- , _CONR 6 _, _NR 6 C ⁇ _ or-NHCONR 6 —
  • R 6 represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an arylalkyl group, an arylalkylene group, an alkyl group, A reloxyalkyl group or a heteroarylalkyl group is shown.
  • the alkyl group, the aryleno quinolole group, the aryl alkenyl group, the aryloxyalkyl group, or the heteroarylalkyl group each may have a substituent.
  • Z is a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, an aryl group which may have a substituent, an arylalkyl group or a substituent.
  • (1) or the foregoing which contains, as an active ingredient, a carboxylic acid derivative containing a thiazole ring which is a heteroaryl group or a pharmaceutically acceptable salt or hydrate or solvate thereof.
  • the prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to (2).
  • Y is an oxygen atom, sulfur atom or _NR 7 _ [wherein R 7 is a hydrogen atom, an alkyl group or —CH—W (where W is an aryl group) Or heteroaryl
  • R 8 , R 9 and R 1Q are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a haloalkyloxy group, a cyan group, a nitro group, — NR 13 R 14 , _NR 15 C ⁇ R 16 , _CONR 17 R 18 (where R 13 , R 14 , R 15 , R 16 , R 17 and R 18 may be the same or different and each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryleno group, an arylenoalkyleno group, a heteroaryl group or a heteroaryl alkyl group.
  • R 13 and R 14 , R 15 and R 16 combine with each other to form a heterocycle that may have carbon and heteroatoms.
  • -OR 19 , -C OR 2 Or — C 3 CR 21 (wherein R 19 , R 2, and R 21 each independently represents a hydrogen atom, an alkenoquinol group, a cycloalkyl group, an aryleno group, an arylalkyl group, a heteroaryl group, or a heterocycle) Represents a teloarylalkyl group);
  • R 11 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a cyano group or a nitro group;
  • R 12 represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylenorequinolene group, a heteroaryl group or a heteroarylalkyl group.
  • E 1 represents an oxygen atom, a sulfur atom or —NR 22 — (wherein R 22 represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group or a heteroarylalkyl group. Show.)
  • an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroaryl alkyl group, or a heterocycle may each have a substituent.
  • Y is an oxygen atom, a sulfur atom or _NR 23 - ⁇ wherein, R 23 is water atom, an alkyl group which may have a substituent or the following formula, ( ⁇ )
  • R 24 and R 25 are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryleno group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, or a haloalkyloxy group.
  • R- 32 (wherein R 32 represents a hydrogen atom, an alkyl group, a cycloalkyl group, a aryleno group, an arylenorequinolyl group, a heteroaryl group, or a heteroaryl group). (Indicates a teloarylalkyl group.) Show. Of the above groups, the alkyl group, cycloalkyl group, aryl group, arylenorequinolene group, heteroaryl group, heteroarylalkyl group or heterocycle may each have a substituent. Good. ⁇ Is a substituent selected from the group consisting of the following formula (IV)
  • R ⁇ RR 1u has the same meaning as described above.
  • the diabetes according to any one of (1) to (5) above, which contains, as an active ingredient, a carboxylic acid derivative containing a thiazole ring selected from: or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • a carboxylic acid derivative containing a thiazole ring selected from: or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • Y is an oxygen atom
  • Z is a carboxylic acid derivative containing a thiazole ring represented by an aryl group or a heteroaryl group, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • the prophylactic and Z or therapeutic agent for hyperlipidemia associated with diabetes according to (1) which contains a solvate as an active ingredient.
  • Y is an oxygen atom
  • ⁇ is a force containing a thiazole ring represented by an aryl group, a rubonic acid derivative or a pharmaceutically acceptable salt thereof, or a hydrate or solvent thereof.
  • Y is — NR 5a — (wherein R 5a represents an alkyl group having 4 to 10 carbon atoms), and Z includes a thiazole ring represented by a heteroaryl group.
  • Y is _NR 5b _ (wherein R 5b represents an alkyl group having 6 to 9 carbon atoms), and Z is a carboxylic acid containing a thiazole ring represented by a heteroaryl group.
  • (1) or (10) which contains an acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient. Prophylactic and / or therapeutic drugs.
  • Y is NR 5e (wherein R 5e represents an arylalkyl group or a heteroarylalkyl group), and Z represents a carbon containing a thiazole ring represented by a heteroaryl group.
  • the prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to the above (1) which contains a boric acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient .
  • Y is NR 5d — (wherein R 5d represents a heteroaryl alkyl group), and Z is a carboxylic acid derivative containing a thiazole ring represented by a heteroaryl group.
  • R 5d represents a heteroaryl alkyl group
  • Z is a carboxylic acid derivative containing a thiazole ring represented by a heteroaryl group.
  • a compound useful as a prophylactic and / or therapeutic agent for hyperlipidemia associated with diabetes can be provided.
  • a compound useful as a preventive and / or therapeutic agent for diabetic hyperlipidemia can be provided.
  • a compound useful as a prophylactic and / or therapeutic drug for hyperlipidemia can be provided
  • the alkyl group represented by R 1 and R 2 means a linear or branched alkyl having a carbon number:! To 15; for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl / Les, sec-butinoles, tert-butinoles, pentinoles, isopentinoles, neopentines / les, hexyl, heptyl, octyl, noninoles, decyl and the like.
  • methyl, ethynole, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl is used, and methyl or ethyl is more preferable.
  • the cycloalkyl group represented by R 1 and R 2 has 3 to 7 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and more preferred is cyclopropyl or cyclobutyl.
  • the alkyl group represented by [0027] R 3, preferably force the same meaning as the alkyl group in R 1, methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl, and the like, and more Preferably, methyl or ethyl is used.
  • the alkyl group represented by R 4 is a force having the same meaning as the alkyl group in R 1 , and preferably includes methylol, ethyl, propyl, isopropinole, butyl, isobutyl, sec butyl or tert_butyl, and more Preferably methyl is mentioned.
  • the aryl group represented by R 4 means an aryl group having 6 to 14 carbon atoms, such as phenyl, naphthyl, or ortho-fused bicyclic group having 8 to 10 ring atoms. And at least one ring is an aromatic ring (for example, indenyl).
  • the alkyl group represented by R 5, the force preferably is synonymous to the alkyl group for R 1 may include an alkyl group having 5-9 carbon atoms, more preferably include an alkyl group having 6-8 carbon atoms It is done.
  • cycloalkyl group represented by R 5 cycloalkyl portion is equivalent to a cycloalkyl group in R 1, the alkyl portion has a carbon number: at 1-8 straight-chain or branched-chain Meaning, for example, cyclopropylmethyl, 2 cyclobutylethyl, 3 cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like.
  • the aryl group represented by R 5 has the same meaning as the aryl group in R 4 .
  • the ⁇ reel alkyl group represented by R 5, Ariru unit is the same like the Ariru group in R 4, the alkyl portions Yogu Tatoebabe be either linear or branched with 1 to 8 carbon atoms Ninole, Benzhydryl, 1_Pheninoleetinole, 2_Phenenoleetinole, Phenolenopropynole, Phenylbutyl, Phenolpentyl, Phenolhexyl, Naphthylmethyl, Naphthylethyl and the like.
  • the R 23 a and the like Preferably, the R 23 a and the like.
  • the ⁇ reel alkenyl group represented by R 5, means that Ariru group for R 4 is bonded to the alkenyl group having 2 to 6 carbon atoms, for example 1 _ Fuenirueteyuru, 2_ phenylene Honoré Eteyunore, 1 —Fuenore 1—Propeninole, 2 Fueninore 1—Propeninole, 3 Hueninore _ 1 _Propeninole, 1 _Fueninore _ 2 _Propeninole, 2 _Fueninore _ 2_ propenore , 3 Phenol 1 Propennole, 1-Phenol 1-Butenore, 2 Phenol 1-Butenyl, 3 Phenol 2 Butenyl, 4 Phenol 2 Butenyl, 3 Phenol 2 Propeninole, 2Phenenoley 1 pentenyl, 2Phenynole 3Penteny
  • the heteroaryl group represented by R 5 includes carbon and:! To 5 to 6-membered cyclic group having 4 heteroatoms (oxygen, sulfur or nitrogen), or its power to 8 to: Ortho-fused bicyclic heteroaryls with 10 ring atoms, especially those derived from benzene derivatives or fused with propylene, trimethylene or tetramethylene groups, as well as their stable N-oxides, etc. Can be mentioned.
  • R 23 b and R 23 c are mentioned.
  • R 5 represents an aryl alkyl group, an aryl alkenyl group or a heteroaryl alkyl group, it is particularly preferably a substituent selected from the above general formula ( ⁇ ).
  • cycloalkyl group represented by Z the same meaning as the cycloalkyl group for R 1, with preference given to cyclohexyl.
  • the Ariru group represented by [0040] Z the force phenyl or the same meaning as Ariru group in R 5 naphthyl are preferred.
  • the ⁇ reel alkyl group represented by Z but is synonymous with ⁇ reel alkyl group for R 5, Le Shi preferred is benzyl or naphthylmethyl.
  • the aryl alkenyl group represented by Z is the same as the aryl alkenyl group for R 5 .
  • the ⁇ reel O alkoxyalkyl group represented by [0043] Z is synonymous with ⁇ reel O alkoxy alkyl Le group in R 5.
  • hetero ⁇ reel alkyl group represented by Z the same meanings as heteroaryl ⁇ reel alkyl Le group in R 5.
  • Z represents an aryl group or a heteroaryl group
  • a substituent selected from the above general formula ( ⁇ ⁇ ) is particularly preferable.
  • the halogen atom represented by R 8 , R 9 and R 1Q includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom and a bromine atom. .
  • the haloalkyl group represented by R 8 , R 9 and R 1Q includes an alkyl group equivalent to the alkyl group in R 1 substituted with the halogen atom, and examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, Chloromethylol, 2, 2, 2 _trifluoroethyl, pet And nantafluoretyl.
  • Examples of the haloalkyloxy group represented by R 8 , R 9 and R 1Q include an alkyloxy group in which the halogen atom is substituted, and examples thereof include trifluoromethyloxy, 2, 2, 2-trifluoro. Examples include oloethyloxy and difluoromethyloxy.
  • heterocycle represented by R 13 and R 14 or R 15 and R 16 is an oxygen atom in addition to carbon atoms as ring-constituting atoms, containing 1-3 heteroatoms selected from sulfur atom and a nitrogen atom
  • examples thereof include non-aromatic heterocyclic groups having 2 to 10 carbon atoms, such as azetidinyl, pyrrolidinyl, piperidino, piperazino, monoreforino, 1, 2, 5, 6-tetrahydropyridinole, thiomorpholino, oxothiomorpholino, Dioxothiomorpholino, 3_azaspiro [5,5] undecyl, 1,3,8_triazaspiro [4,5] decyl and the like.
  • the aryl moiety is the same as the aryl group in R 4 , and examples thereof include benzoyl and 1_naphthoyl.
  • the heteroaryl alkyl group and the heterocycle may each have 1 to 3 substituents at substitutable positions. Examples of such a substituent include an alkyl group, an alkyloxy group, a halogen atom, a haloalkyl group, a haloalkoxy group, an aryl group, and a heteroaryl group.
  • the substituents mentioned here are as defined above.
  • Pharmaceutically acceptable salts of the compound of the general formula (I) include all salts. Salts with inorganic acids such as acid or hydrobromic acid, salts with organic acids, alkali metals And a salt with an organic base or an amino acid.
  • the compound of the general formula (I) or a salt thereof is solvated (for example, hydrate) or metabolized in vivo to be converted into the carboxylic acid or salt of the general formula (I). All prodrugs or active metabolites of the above general formula (I).
  • the compound (I) of the present invention can be synthesized, for example, by the following method.
  • the production method is not limited to these.
  • the compound (I-4) can be produced, for example, by the following method (Production methods 1 and 2).
  • the bonding mode of the Y moiety is a nitrogen atom, it can be produced by the same method (Production Methods 1 and 2).
  • the general formula (I 1 1) By reacting an alcohol represented by the general formula ( ⁇ -1) (the synthesis method will be described later) and a compound having a leaving group represented by the general formula ( ⁇ -1) in the presence of a base, the general formula The ether compound represented by (I 1 1) can be obtained (step 1).
  • a compound represented by the general formula (II-2) having a leaving group on the alkyl chain is reacted with an alcohol derivative represented by the general formula (I ⁇ _ 2) in the presence of a base.
  • an ether compound represented by the general formula (1_1) can be obtained (step 2).
  • this compound can be converted to the carboxylic acid form (1_2) by deesterification (Step 3).
  • the compound ( ⁇ -1) and compound (III-12) which are raw material compounds are usually easily synthesized by a known method.
  • R 1 R 2 , n is as defined above, R 38 represents an alkyl group, Z 1 represents an aryl group, a heteroaryl group, an arylalkyl group, a heteroaryl alkyl group or a cycloalkyl group, and X 1 represents —SO R 39 ( In the formula, R 39 represents an alkyl group or an aryl group.)
  • X 2 is one OSO R 4Q (where R 4Q is an alkynole group, haloalkyl
  • Steps 1 and 2 are usually carried out in a solvent that does not adversely influence the reaction in the presence of a base.
  • a base examples include alkali metal carbonates such as potassium carbonate, sodium carbonate, and cesium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide, potassium hydroxide, sodium hydroxide, and hydroxide.
  • Alkali metal hydroxides such as lithium, metal hydrides such as potassium hydride and sodium hydride, trichinoleamine, N, N-diisopropylethylamine, N methylmorpholine, pyridine, N, N dimethylaniline, 4 Amines such as dimethylaminopyridine and 1,8 diazabicyclo [5.4.0] unde force_7-en are used.
  • the amount of the base used is preferably 1 to 5 molar equivalents relative to compound ( ⁇ _1) or compound ( ⁇ -2).
  • the reaction temperature is usually _50 to 200 ° C, preferably _10 to 100 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • Step 3 is usually performed in a water-containing solvent in the presence of an acid or a base.
  • the acid include formic acid, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid and the like.
  • the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. Used.
  • the amount of acid or base used is usually an excess amount relative to compound (I 1).
  • the amount of acid used is 2 to 100 equivalents relative to compound (1-1), and the amount of base used is 1.2 to 5 equivalents relative to compound (11).
  • the water-containing solvent for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, a mixed solvent of one or more solvents selected from dimethyl sulfoxide, acetone and the like are used.
  • R 38 is a tert_butyl group, in addition to the reaction in the water-containing solvent, it can be decomposed by acid.
  • the acid for example, formic acid, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid and the like are used.
  • the solvent may be mixed in an appropriate ratio.
  • the solvent include black mouth form, dichloromethane, Halogenated hydrocarbons such as chloroethane are used.
  • the amount of the acid used is usually an excess amount relative to compound (I 1).
  • the amount of acid used is 2 100 equivalents relative to compound (I 1).
  • the reaction temperature is usually 20 to: 150 ° C., preferably —10 100 ° C.
  • R 1 n is as defined above, R 41 represents an alkyl group or a resin, and Z 2 represents an aryl group or a heteroaryl group.
  • Step 4 is usually performed in the presence of a phosphine and an azodicarboxylic acid derivative in a solvent that does not adversely influence the reaction.
  • the phosphines include triphenylphosphine and tributylphosphine
  • examples of the azodicarboxylic acid derivative include azodicarboxylate jetyl, azodicarboxylate diisopropyl, azodicarbonyldipiperazine, and the like.
  • the amount of the phosphine and azodicarboxylic acid derivative used is preferably 15 molar equivalents relative to the compound ( ⁇ -1).
  • the reaction temperature is usually ⁇ 50 to: 150 ° C., preferably _10 100 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran, and dioxane, Halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, amides such as N and N dimethylformamide, sulfoxides such as dimethyl sulfoxide, and the like are used. These solvents may be mixed and used at an appropriate ratio.
  • Step 5 can be carried out in the same manner as in step 3 when R41 is an alkyl group.
  • R 41 is a resin
  • it can be carried out in the same manner as in Step 3, but it can usually be carried out by using an excess amount of water-containing or non-water-containing trifluoroacetic acid, which adversely affects the reaction.
  • a non-solvent may be mixed and used at an appropriate ratio.
  • Solvents that do not affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. It is done.
  • the reaction temperature is usually ⁇ 20 to: 150 ° C., preferably ⁇ 10 ° C. to 60 ° C.
  • the compounds represented by the general formula (I 6) and (1-8) in which the bonding mode of the Y moiety is an amide structure can be produced, for example, by the following method ( Manufacturing method 3, 4) 0
  • a primary ammine represented by the general formula ( ⁇ -3) (the synthesis method will be described later) and a carboxylic acid represented by the general formula (III 4) in the presence of a condensing agent or represented by the general formula (III 5)
  • a condensing agent or represented by the general formula (III 5) By reacting the resulting carboxylic acid chloride in the presence of a base, an amide compound represented by the general formula (I5) can be obtained (step 6). Subsequently, this compound can be converted to the carboxylic acid form (I 6) by deesterification (step 7).
  • the compound (III 4) and the compound ( ⁇ -5), which are starting materials and compounds, are usually easily synthesized by known methods.
  • Step 6 is usually carried out in the presence of a condensing agent that activates the carboxylic acid in a solvent that does not adversely influence the reaction when the carboxylic acid compound (III-14) is used.
  • a condensing agent for example, dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-tylcarbodiimide (EDC) or a hydrochloride thereof, 2-ethoxy-1-ethoxycarbonyl 1, 2-dihydroxyquinoline (EEDQ), carbodidiimidazole (CDI), jetyl phosphoryl cyanide, benzotriazole 1-yloxytrispyrrolidinophos hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPP) A), isobutyl chloroformate, cetyl acetyl chloride, and trimethyl acetyl chloride.
  • DCC dicyclohexy
  • condensing agents can be used alone, or N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-1,4-oxo-1,4-dihydro-1,2,2,3-benzotriazine (HOOBT), or Used in combination with additives such as 4-dimethylaminopyridine (DMAP).
  • the amount of the condensing agent and additive used is preferably 15 molar equivalents relative to compound (II-3).
  • the reaction temperature can usually be carried out at _30 80 ° C, preferably _10 50 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. , Amides such as N, N-dimethylformamide and N-methyl_2-pyridone, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be mixed and used at an appropriate ratio. When the carboxylic acid chloride compound (III 5) is used, it is usually carried out in the presence of a base in a solvent that does not adversely influence the reaction.
  • Alkali metal alkoxide such as lithium metal carbonate, sodium methoxide, sodium ethoxide, potassium tertiary butoxide
  • alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydride, sodium hydride, etc.
  • Metal hydrides triethylamine, N, N-diisopropylethylamine, N methylmorpholine, pyridine, N, N dimethylaniline, 4-dimethylaminopyridine, 1,8-diazabicyclo [5. 4.0] Wunde force—amines such as 7-en are used.
  • the amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (II-3).
  • the reaction temperature is usually _50 to 100 ° C, preferably _10 to 50 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chlorophenol, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, Amides such as N, N-dimethylformamide and N-methylol-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide are used. These solvents may be mixed and used at an appropriate ratio.
  • Step 7 can be carried out in the same manner as in step 3.
  • Step 8 can be performed according to a method similar to that of step 6.
  • Step 9 can be carried out in the same manner as in step 3.
  • the compound represented by the general formula (I 10) in which the bonding mode of the Y moiety is NH can be produced, for example, by the following method (Production Methods 5 and 6).
  • a secondary amine compound represented by the general formula (I-9) can be obtained (step 10). Furthermore, this compound can be deesterified and converted to the carboxylic acid compound (1_10) (step 11).
  • the compound ( ⁇ -1), which is a raw material compound, is usually easily synthesized by a known method.
  • Step 10 can be performed according to a method similar to that of step 1.
  • Step 11 can be performed according to a method similar to that of step 3.
  • a secondary ammine compound represented by the general formula (I-9) is obtained by reacting the amide compound represented by the general formula (I-7) synthesized in the production method 4 in the presence of a reducing agent. (Step 12). Subsequently, this compound can be converted to the carboxylic acid form (I-10) by deesterification (step 13).
  • Step 12 is usually performed in the presence of a reducing agent in a solvent that does not adversely influence the reaction.
  • a reducing agent examples include borane monotetrahydrofuran complex, borane monomethylsulfide complex, diborane, tetrabutylammonium borohydride, sodium hydrogen hydride in the presence of Lewis acid, and the like.
  • the amount of the reducing agent to be used is preferably:!-5 molar equivalents relative to compound (1-7).
  • the reaction temperature is usually from 50 to 150 ° C, preferably from 10 to 100 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. Is used. These solvents may be mixed and used at an appropriate ratio.
  • Step 13 can be performed according to a method similar to that of step 5.
  • the bonding mode of the Y moiety is —NR 42 — (wherein R 42 represents an alkyl group, an arylenorequinole group, an arylealkenyl group, an arylo group,
  • R 42 represents an alkyl group, an arylenorequinole group, an arylealkenyl group, an arylo group
  • a compound of the general formula (I-12), which represents a xyalkyl group and a heteroarylalkyl group, each of which may have a substituent, is prepared, for example, by the following method. (Manufacturing method 7-9).
  • a secondary amine represented by general formula (I-9) synthesized by production method 5 or 6 with a compound having a leaving group represented by general formula (III-17) in the presence of a base
  • a tertiary amine compound represented by the general formula (1-11) can be obtained (step 14).
  • the ketone compound represented by the general formula (III-8) and reacting in the presence of a reducing agent the tertiary amine represented by the general formula (1-11) is obtained.
  • a compound can be obtained (step 15).
  • this compound can be converted to the carboxylic acid form (I 12) by deesterification (Step 16).
  • the compound ( ⁇ -7) and compound (III-18), which are raw material compounds, are usually easily synthesized by known methods.
  • R 1 , R 2 , R 43 and R 44 may be the same or different and each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group. Or a heteroarylalkyl group; ]
  • Step 14 can be performed according to a method similar to that of step 1.
  • Step 15 is usually performed in the presence of a reducing agent in a solvent that does not adversely influence the reaction.
  • the reducing agent include sodium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride and the like.
  • the reaction temperature is generally 0 to 100 ° C.
  • Solvents that do not affect the reaction include ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, alcohols such as methanol and ethanol, and nitriles such as acetonitrile. Used. These solvents may be mixed and used at an appropriate ratio. If necessary, acidic catalysts such as acetic acid, p_toluenesulfonic acid, trifluoride Boron ⁇ Jetyl ether complex, etc.
  • Step 16 can be performed according to a method similar to that of step 5.
  • Carboxylic acid represented by general formula ( ⁇ -4) (the synthesis method will be described later) and an amine derivative represented by general formula ( ⁇ -9) are reacted in the presence of a condensing agent in the same manner as in production method 3.
  • an amide compound represented by the general formula (I-13) can be obtained (step 17).
  • a secondary amine compound represented by the general formula (I_15) can be obtained (step 19).
  • using the primary amine represented by the general formula (II-3) (the synthesis method will be described later) and the carboxylic acid derivative represented by the general formula ( ⁇ -10), the same as in Step 17 and Step 19.
  • the secondary amin compound represented by the general formula (1_15) can also be obtained by performing a simple condensation reaction or reduction reaction (steps 18 and 19). Subsequently, a compound having a leaving group represented by the general formula ( ⁇ —1) is reacted in the presence of a base to produce a tertiary amine compound represented by the general formula (I 1 1 1). Can be obtained (step 20). Finally, this compound can be converted to the carboxylic acid form (1-12) by deesterification (Step 21).
  • the compounds (III 1), (III 9) and (III 10) which are raw material compounds are usually easily synthesized by a known method.
  • Process 1 7 Process 1 8
  • R 1 , R 2 R 4 R "R 42 X 1 nm is as defined above, and R 45 represents an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a aryleno group, an arylalkyl group, a heteroaryl group, or a heteroarylalkyl group.
  • Step 17 can be performed in the same manner as step 6.
  • Step 18 can be performed in the same manner as step 6.
  • Step 19 can be performed according to a method similar to that of step 12.
  • Step 20 can be performed in the same manner as in step 1.
  • Step 21 can be performed in the same manner as step 5.
  • a secondary amine compound represented by the general formula (1-9) is obtained.
  • the carboxylic acid compound (1-12) can be obtained by the same operation as in Production Method 7 using this compound and the general formula ( ⁇ —7) or the general formula ( ⁇ —8).
  • the compounds ( ⁇ -6), (III-17), (III-8), and (12-12), which are starting materials, are generally easily synthesized by known methods.
  • R 1 , n is as defined above, and R 46 represents an alkyl group or an aryl group.
  • Steps 22 to 24 are carried out according to the methods described in non-patent literature [Tetrahedron Lett., 36, 6373 (1995) and Tetrahedron Lett., 33, 5831 (1997)].
  • a secondary amine compound represented by the general formula (I9) can be obtained by oral benzenesulfonylation, Mitsunobu reaction and de-2-nitrobenzenesulfonylation.
  • Step 22 can be carried out in the same manner as in Step 3, usually using 2 ditrobenzenesulfonyl chloride.
  • Step 23 can be performed in the same manner as in step 4.
  • Step 24 can be usually carried out in the same manner as in Step 1 using benzenethiol.
  • Step 25 can be carried out in the same manner as in step 1.
  • Step 26 can be performed according to a method similar to that of step 15.
  • Step 27 can be carried out in the same manner as in step 3.
  • the compound represented by the general formula (1-18) in which the binding mode of the Y moiety is —C0NR 42 _ (wherein R 42 is as defined above) From the secondary amine compound represented by the general formula (I 15) synthesized by the production method 8, for example, it can be produced by the following method (production method 10).
  • An amide compound represented by the general formula (I 17) can be obtained by reacting the carboxylic acid chloride represented by the formula (II I 5) in the presence of a base (step 28). Furthermore, this compound can be deesterified and converted to the carboxylic acid form (I 18) (step 29).
  • the compound (III 4) and compound (III 5) which are raw material compounds are usually easily synthesized by a known method.
  • Step 28 can be performed according to a method similar to that of step 6.
  • Step 29 can be carried out in the same manner as in step 3.
  • the compound of general formula (1-20) in which the binding mode of the Y moiety is NHCONR was synthesized by production method 8.
  • the secondary amine compound represented by the general formula (I15) can be produced by the following method (Production Method 11).
  • the urea represented by the general formula (I 19) is reacted with the secondary amine represented by the general formula (I 15) synthesized by the production method 8 and the isocyanate represented by the general formula (III 13).
  • the compound can be obtained (step 30). Furthermore, this compound can be converted to the carboxylic acid form (I 20) by deesterification (step 31).
  • the compound (III-13) which is a raw material compound is usually easily synthesized by a known method.
  • Step 30 is usually performed in a solvent that does not adversely affect the reaction.
  • Isocyanate (II) The amount of 1-13) to be used is preferably:!-5 molar equivalents relative to compound (I15).
  • the reaction temperature can usually be 30 to 100 ° C, preferably -10 to 50 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. Etc. are used. These solvents can be mixed and used at an appropriate ratio.
  • Step 31 can be carried out in the same manner as in step 3.
  • Z is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and an aryl group or heteroaryl group on the ring of the aryl group or heteroaryl group.
  • general formula (I 1-23) general formula ( ⁇ 26) and general formula (1-30) having a group are also produced by, for example, the following methods: (Manufacturing method 12-: 14).
  • Z in the general formula (I) is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and a halogen atom, trifluoromethanesulfonyloxy is present on the ring of the aryl group or heteroaryl group.
  • a compound having a leaving group such as a group [represented by general formula (1-21)] and a boron compound represented by general formula (III-14) or a tin compound represented by general formula (III-15) Is reacted in the presence of a metal catalyst to obtain a compound introduced with an aryl group or heteroaryl group represented by the general formula (I 2 2) (step 32). Further, this compound can be converted to the carboxylic acid form (I 23) by deesterification (Step 33).
  • the compounds (III 14) and (III-15), which are raw materials and compounds, are usually easily synthesized by known methods.
  • Step 32 is usually performed in the presence of a metal catalyst in a solvent that does not adversely influence the reaction.
  • a metal catalyst include zero-valent palladium, divalent palladium, and zero-valent nickel.
  • examples of the zero-valent palladium catalyst include tetrakis (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium
  • examples of the divalent palladium catalyst include palladium acetate and dichlorobis (trif. Enilphosphine) Palladium, etc.
  • Examples include 1,1,1bis (diphenylphosphino) phenolic nickel.
  • monodentate ligands such as triphenylphosphine and tris (o-tolyl) phosphine
  • bidentate ligands such as diphenylphosphinophine pan
  • diphenylphosphinobutane examples of the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal phosphates such as tripotassium phosphate.
  • a base must be used for the reaction with R 47 -Sn (R 49 ) ( ⁇ _15).
  • the amount of the metal catalyst to be used is, for example, 0.0 :! to 1 molar equivalent, preferably 0.05 to 0.5 molar equivalent, relative to compound (1_21).
  • the amount of the base to be used is, for example, 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (1-21).
  • the reaction temperature is usually 0 ° C. and can be carried out at the reflux temperature of the solvent.
  • Solvents that do not adversely affect the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N-methyl_2_pyrrolidone, methanol, Alcohols such as ethanol, water and the like are used. These solvents may be mixed and used at an appropriate ratio. Reaction with R 47 -Sn (R 49 ) (III-15)
  • R 47 -B (OR 48 ) (III—14) or R 47
  • the amount of Sn (R 49 ) (III-15) to be used is, for example :! to 5 molar equivalents relative to compound (1-21),
  • Step 33 can be performed according to a method similar to that of step 3.
  • An alcohol represented by the general formula (I 1) (the synthesis method will be described later) and an aryl alcohol or a heteroaryl alcohol having a borate ester group on Z represented by the general formula (III 16) are converted to phosphines and By reacting with an azodicarboxylic acid derivative, an ether compound represented by the general formula (I-24) can be obtained (step 34). Subsequently, by reacting a compound having a leaving group represented by the general formula (X 17) in the presence of a metal catalyst, an aryl group or a heteroaryl group represented by the general formula (1_25) It is possible to obtain a compound with introduced S (step 35). Further, this compound can be converted into a carboxylic acid form (I 1 26) by deesterification (Step 36).
  • the starting compounds ( ⁇ -16) and (III-17) are usually prepared by a known method. Easily synthesized c
  • R 2 , R 4 , R 38 , n are as defined above, Z 4 represents an aryl group or a heteroaryl group, X 4 represents a halogen atom or a trifluoromethanesulfoxyloxy group, and R 50 represents an aryl group. Or a heteroaryl group is shown. ]
  • Step 34 can be performed according to a method similar to that of step 4.
  • Step 35 can be performed according to a method similar to that of step 32.
  • Step 36 can be performed according to a method similar to that of step 3.
  • a compound having a halogen atom on Z 1 of a compound represented by general formula (1-16) synthesized by production method 9 [represented by general formula (1-27)] and general formula (III-14 ) Is reacted in the presence of a metal catalyst to obtain a compound introduced with an aryl group or heteroaryl group represented by the general formula (I28) (Step 37). ). Further, by reacting this compound with a compound having a thiol group represented by the general formula (III 12) in the presence of a base, a secondary amine compound represented by the general formula (I 29) can be obtained. Yes (step 38). Further, this compound can be converted into a carboxylic acid form (I-1 30) by deesterification (Step 39).
  • the compounds (III-12) and ( ⁇ -14), which are raw materials and compounds, are usually easily synthesized by known methods.
  • R 1 , R 2 , R 4 , R 38 , R 46 , R 47 , R 48 , n are as defined above, Z 5 represents an aryl group or a heteroaryl group, and X 5 represents A halogen atom or a trifluoromethanesulfonyl group.
  • Step 37 can be performed according to a method similar to that of step 32.
  • Step 38 can be performed according to a method similar to that of step 24.
  • Step 39 can be performed according to a method similar to that of step 3.
  • Z is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and an amino group is generally present on the ring of the aryl group or heteroaryl group.
  • the compound of the formula (1-32) can be produced by, for example, the following method in addition to the methods shown in production methods 1 to 12 (production method 15).
  • the general formula (A compound into which an amino group represented by 1-31) is introduced can be obtained (step 40). Furthermore, this compound can be deesterified and converted to the carboxylic acid compound (1-32) (step 41).
  • the compound ( ⁇ -18), which is a raw material compound, is usually easily synthesized by a known method.
  • R 51 and R 52 may be the same or different and each independently represents a hydrogen atom, Represents an alkyl group, a cycloalkyl group, or R 51 and R 52 combine with each other to form a heterocycle optionally having carbon and heteroatoms.
  • Step 40 is carried out by performing an amination reaction with reference to the method described in Non-Patent Document. Org. Chem., 65, 1158 (2000)] and the like.
  • the ability to obtain a compound can be achieved.
  • it is carried out in the presence of a metal catalyst, a metal ligand and a base in a solvent that does not adversely influence the reaction.
  • the metal catalyst include tris (dibenzylideneacetone) dipalladium, palladium acetate and the like.
  • metal ligands include 2- (di-tert-butyl phosphino) biphenyl.
  • the base include cesium carbonate, tripotassium phosphate, sodium tertiary butoxide and the like.
  • the amount of the metal catalyst to be used is, for example, 0.01 mol equivalent, preferably 0.05-0.5 mol equivalent, relative to compound (I21).
  • the amount of the base to be used is, for example, 15 molar equivalents, preferably 12 molar equivalents, relative to compound (I21).
  • the reaction temperature is usually 0 ° C to the reflux temperature of the solvent.
  • the solvent that does not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol. These solvents may be used by mixing at an appropriate ratio.
  • the amount of R 51 (R 52 ) NH (III-18) to be used is, for example, 15 molar equivalents, preferably 13 molar equivalents, relative to compound (1-21).
  • Step 41 can be carried out in the same manner as in step 3.
  • Z is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and the aryl group or heteroaryl group
  • the compound of the general formula (I34) having an alkynyl group on the ring can be produced, for example, by the following method in addition to the production methods:! To 12 (production method 16).
  • the general formula (I) By reacting a compound having a leaving group represented by the general formula (I-21) with a compound represented by the general formula (III-19) in the presence of a metal catalyst and a base, the general formula (I A compound into which an alkynyl group represented by (33) is introduced can be obtained (step 42). Furthermore, this compound can be converted to the carboxylic acid form (1_34) by deesterification (Step 43).
  • the compound (V-19) which is a raw material compound is usually easily synthesized by a known method.
  • R 2 , R 4 , R 38 , n, Y, z X 3 are as defined above, and R 53 represents an aryl group or a heteroaryl group.
  • Y 42 is a general formula by performing an alkynylation reaction with reference to the method described in the non-specific afternoon literature [Comprehensive Organic Syntnesis, Pergamon Press, New York, 3, 521 (1991)]. It is possible to obtain a compound into which an alkynyl group represented by (I 1 33) is introduced. Usually, it is carried out in the presence of a metal catalyst and a base in a solvent that does not adversely influence the reaction.
  • the metal catalyst include dichlorobis (triphenylphosphine) paradium.
  • the base include triethylamine, N, N diisopropylethylamine, N methylmorpholine, pyridine and the like.
  • a catalyst amount of copper (I) iodide As an additive, it is preferable to cover a catalyst amount of copper (I) iodide.
  • the amount of the metal catalyst to be used is, for example, 0.01 to :! molar equivalent, preferably 0.05 to 0.5 molar equivalent, relative to compound (I 21).
  • the amount of the base to be used is, for example, 1 to 50 molar equivalents, preferably 10 to 20 molar equivalents, relative to compound (1-21).
  • the reaction temperature can usually be carried out at 0 ° C. to the reflux temperature of the solvent. Examples of solvents that do not adversely affect the reaction include ethers such as tetrahydrofuran and dioxane, and amides such as N, N dimethylformamide and N methyl 2-pyrrolidone. These solvents may be mixed and used at an appropriate ratio.
  • the amount of the alkynyl compound ( ⁇ -19) to be used is, for example, 1 to 5 molar equivalents,
  • Step 43 can be carried out in the same manner as in step 3.
  • i-ketoester represented by diketene or general formula (III-20) —ketocarboxylic acid or general formula (III-21) The represented ketoamide compound can be obtained (step 44). Further, this compound and a compound having a hydrazino group represented by the general formula (III 22) are reacted to obtain a hydrazone compound, and then an appropriate dehydrating agent is used or an appropriate sulfurizing agent is used.
  • a desulfurization reaction is performed in the presence of a base via a thioamide compound to obtain a compound represented by the general formula (I 37) in which Z is a pyrazole ring (Step 45). ). Furthermore, this compound can be deesterified and converted to the carboxylic acid form (I 38) (step 46).
  • the compounds ( ⁇ -20), ( ⁇ _21), and ( ⁇ -22), which are raw material compounds, are usually easily synthesized by known methods.
  • R ⁇ RRR 6 n is as defined above, A represents a hydrogen atom or (in the formula, as defined above), R 54 represents an alkyl group or an aryl group, R 55 represents an alkyl group, and R 56 represents an alkyl group or an aryl group. ]
  • Step 44 is performed in a solvent that does not adversely influence the reaction when diketene is used as a reaction reagent.
  • the reaction temperature is usually 0 ° C to room temperature.
  • solvents that do not adversely influence the reaction include etherols such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, and amides such as N, N-dimethylformamide. These solvents may be mixed and used at an appropriate ratio.
  • a ketocarboxylic acid when a ketocarboxylic acid is used as a reaction reagent, it can be applied in the same manner as in Step 6.
  • a ketoester When a ketoester is used as a reaction reagent, it is carried out in a solvent that does not adversely influence the reaction.
  • the reaction temperature can usually be carried out at 0 ° C. to the reflux temperature of the solvent.
  • solvents that do not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene, toluene and xylene. These solvents may be mixed and used at an appropriate ratio.
  • the hydrazone step of Step 45 is usually performed in a solvent that does not adversely influence the reaction.
  • an acid or base catalyst may coexist.
  • the acid catalyst for example, acetic acid, hydrochloric acid, p-toluenesulfonic acid, etc.
  • the basic catalyst for example, sodium methoxy-piperidine or the like is used.
  • the reaction temperature can usually be applied from 0 ° C to the reflux temperature of the solvent.
  • Solvents that do not adversely affect the reaction include tetrahydrofuran, di- Ethers such as oxane, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol are used.
  • the subsequent cyclization step is usually carried out in the presence of a suitable dehydrating agent in a solvent that does not adversely influence the reaction.
  • a suitable dehydrating agent for example, phosphorus oxychloride is used.
  • the amount of the dehydrating agent to be used is preferably:! To 2 equivalents relative to compound (1-36).
  • the reaction temperature can usually be carried out at 0 ° C. to the reflux temperature of the solvent.
  • Solvents that do not adversely affect the reaction include ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene, toluene and xylene. These solvents may be mixed and used at an appropriate ratio.
  • a sulfurizing agent When a sulfurizing agent is used, it is usually carried out in the presence of a base in a solvent that does not adversely influence the reaction.
  • a sulfiding agent for example, diphosphorus pentasulfide, Lawson's reagent, or the like is used.
  • the amount of the sulfurizing agent used is preferably 1 to 2 equivalents relative to compound (1_36).
  • the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.
  • Metal hydrides such as alkali metal hydroxide, potassium hydride, sodium hydride, triethinoleamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 1 , 8-diazabicyclo [5.4.0] unde force amines.
  • the amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (1-36). Usually, it can be carried out from 0 ° C to the reflux temperature of the solvent.
  • solvents that do not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. These solvents may be mixed and used at an appropriate ratio.
  • Step 46 can be performed according to a method similar to that of step 3.
  • the secondary amine compound represented by the general formula (I-15) synthesized by the production method 8 is converted into a thiourea compound represented by the general formula (I_39) (step 47), and then the general formula (III — A thiazole compound represented by the general formula (1_40) can be obtained by reacting with a monohaloketone represented by (23) (Step 48). Further, this compound is deesterified to give a carboxylic acid form. It can be converted to (I-41) (step 49).
  • the compound (III 23) which is a raw material compound is usually easily synthesized by a known method.
  • R 2 R 4 R 41 R 42 n is as defined above, R 57 represents an alkyl group, a haloalkyl group, an aryleno group, or a heteroaryl group, X 6 represents a halogen atom, Fmoc represents 9H-fluorene-9- A rumethyloxycarbonyl group is shown. ]
  • Step 47 9H_fluorene-9-ylmethyloxycarbonylisothiocyate (Fmoc-NCS) was reacted to obtain 9H_fluorene-1-9-ylmethyloxycarbonylureaide derivative, and then with a base.
  • a cabia compound represented by the general formula (1_39) can be obtained.
  • the amount of Fmoc—NCS to be used is preferably:!-5 molar equivalents relative to compound (1-15).
  • the reaction temperature is usually 30 to: 100 ° C, preferably 10 50 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, N, N dimethylformamide, N methyl 2-pyrrolidone and the like. Amides, hexane, benzene, toluene and other hydrocarbons are used. These solvents may be mixed and used at an appropriate ratio. The subsequent base treatment step is usually performed in a solvent that does not affect the reaction.
  • bases examples include triethinoleamine, N, N-disopropylethylamine, N-methylmorpholine, morpholine, piperidine, 1,8-diazabicyclo [5.4.0] unde. Amines such as 7-en are used.
  • the amount of the base used is preferably 15 molar equivalents relative to the 9H-fluorene-9-ylmethyloxycarbonylureido derivative obtained above.
  • the reaction temperature is usually from 30 to 100 ° C, preferably 1050 ° C.
  • reaction Solvents that do not have an adverse effect include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, Amides such as N dimethylformamide and N methyl _2 pyrrolidone, sulfoxides such as dimethyl sulfoxide, alcohols such as methanol and ethanol are used. These solvents may be mixed and used at an appropriate ratio.
  • ethers such as jetyl ether, tetrahydrofuran and dioxane
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane
  • hydrocarbons such as hexane
  • N Amides such as N dimethylformamide and N methyl _2 pyrrolidone
  • Step 48 is usually performed in a solvent that does not adversely influence the reaction.
  • the amount of the a-haloketone (I ⁇ _23) to be used is preferably 1 to 5 molar equivalents relative to compound (1-39).
  • the reaction temperature is usually -30 to 200 ° C, preferably 0 to 150 ° C.
  • solvents that do not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol and isopropanol. These solvents may be mixed and used at an appropriate ratio.
  • Step 49 can be performed according to a method similar to that of step 5.
  • the compounds represented by the general formulas (II-1), (11-2), (11-3), and (II4) used in the above production method have, for example, the following thiol groups: Starting from the general formula (VI-1) or general formula (VI-1) (obtained in the raw material compound manufacturing method 1) as a starting material, it can be manufactured by the methods shown in the raw material compound manufacturing methods 2 to 5 .
  • the general formula (V (1 ) Or (VI-2) can be obtained (step 50).
  • the compound (IV), (V-1) or (V-2) which is a raw material compound is usually easily synthesized by a known method.
  • R 4 and m are as defined above, R 58 represents an alkyl group, and X 7 represents a halogen atom.] ]
  • the reaction is usually carried out under heating in a solvent that does not adversely influence the reaction.
  • the amount of dithio-rubamate (IV) used is preferably 1 to 5 molar equivalents relative to ⁇ -haloketone (V-1) or (V-2).
  • the reaction temperature is usually 30 to 200 ° C, preferably 0 to 150 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol and isopropanol. These solvents may be mixed and used at an appropriate ratio.
  • the carboxylic acid compound represented by the general formula ( ⁇ -4) is prepared from the thiazole compound represented by the general formula (VI-3) synthesized by the above production method 1 of the raw material compound, for example, by the following two methods. Can be manufactured. First, after obtaining the diester compound represented by the general formula ( ⁇ _5) by reacting the monohaloester compound represented by the general formula (VII) in the presence of a base (Step 51). ), And further, this compound is monodeesterified to convert it to a monocarboxylic acid compound ( ⁇ -4) (step 52). The second is a chain represented by the general formula (VI-3).
  • the ester compound is deesterified to obtain the carboxylic acid compound (VI-4) (step 53)
  • the ⁇ -haloester ich compound represented by the general formula (VII) is reacted in the presence of a base.
  • the haloester compound (VII) which is a raw material compound, is usually easily synthesized by a known method.
  • Step 51 is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
  • the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide, potassium hydroxide, sodium hydroxide and lithium hydroxide.
  • Metal hydrides such as alkali metal hydroxide, potassium hydride, sodium hydride, triethylamine, N, N-diisopropylethylamine, piperidine, pyrrolidine, N methylmorpholine, pyridine, N, N dimethylaniline, 1 , 8-diazabicyclo [5. 4.
  • the amount of the base to be used is preferably:!-5 molar equivalents relative to compound (VI-3).
  • the amount of a-haloester (VII) to be used is preferably 1 to 3 molar equivalents relative to compound (VI-3).
  • the reaction temperature is usually 50 to 200 ° C., preferably ⁇ 10 to 100 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N , N Amides such as dimethylformamide and N methyl 2-pyrrolidone, Sulphoxides such as dimethyl sulfoxide, Alcohols such as methanol and ethanol And the like are used. These solvents can be mixed and used at an appropriate ratio.
  • Step 52 is usually performed in a water-containing solvent in the presence of a base.
  • the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide and sodium methoxide, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. Be done.
  • the amount of the base used is usually an excess amount relative to the compound ( ⁇ _5), preferably:! To 5 equivalents.
  • the water-containing solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, a mixed solvent of one or more solvents selected from dimethyl sulfoxide and acetone, and the like.
  • the reaction temperature is usually -20 to 150 ° C, preferably -10 to 100 ° C.
  • Step 53 can be performed according to a method similar to that of step 52.
  • Step 54 can be performed according to a method similar to that of step 51.
  • the alcohol compound represented by the general formula ( ⁇ -1) is obtained by reacting the carboxylic acid compound represented by the general formula (II 4) synthesized by the above-described raw material compound production method 2 in the presence of a reducing agent. (Step 55).
  • Step 55 can be performed according to a method similar to that of step 12.
  • a sulfonic acid ester is usually obtained by reacting methanesulfurol chloride, p-toluenesulfurol chloride, trifluoromethanesulfonyl chloride, etc. in a solvent that does not adversely affect the reaction in the presence of a base.
  • the base include alkali metal carbonates such as carbonated lithium and sodium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, and the like.
  • Alkali metal hydroxides, potassium hydrides, metal hydrides such as sodium hydride, triethylamine, N, N diisopropylethylamine, N methylmorpholine, pyridine, N, N dimethylaniline, 4-dimethylamino Amines such as pyridine and 1,8 diazabicyclo [5.4.0] unde are used.
  • the amount of sulfuol ligide used is preferably 1 to 5 molar equivalents relative to compound ( ⁇ -1), and the amount of base used is preferably! To 5 molar equivalents relative to compound ( ⁇ _1). .
  • the reaction temperature is usually _50 to 200 ° C, preferably _30 to 80 ° C.
  • Solvents that do not adversely affect the reaction include ethers such as jetyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, Amides such as N, N-dimethylformamide and Nmethyl_2_pyrrolidone are used. These solvents may be mixed and used at an appropriate ratio. The sulfonic acid ester thus obtained can be converted into a halogen compound using various halogenating agents.
  • ethers such as jetyl ether, tetrahydrofuran and dioxane
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane
  • hydrocarbons such as hexane
  • Amides such as N, N-dimethylformamide and Nmethyl_2_pyr
  • solvents that do not adversely affect the reaction include alcohols such as methanol and ethanol, amides such as N, N dimethylformamide and N methyl 2 pyrrolidone, and sulfoxides such as dimethyl sulfoxide. It is.
  • the primary amine compound represented by the general formula ( ⁇ -3) can be produced from the alcohol compound represented by the general formula (II-1) synthesized by the above-described raw material compound production method 3. it can.
  • Many methods for converting an alcohol compound to a primary amine compound are known. For example, the method described in the non-special literature [Comprehensive Organic Transformation, VCH Publisners, Inc. 1989] can be referred to.
  • Step 57 is usually performed using potassium phthalimide in a solvent that does not adversely affect the reaction.
  • the amount of potassium phthalimide used is preferably 1 to 5 mole equivalents relative to compound ( ⁇ -6).
  • the reaction temperature can usually be carried out at 0 to 120 ° C.
  • Solvents that do not have influence include amides such as N, N-dimethylformamide and N-methylol-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide.
  • Step 58 is usually performed in a solvent that does not adversely influence the reaction using a hydrazine compound such as hydrazine monohydrate, methyl hydrazine, or phenyl hydrazine.
  • the amount of the hydrazine compound used is preferably 1 to 5 molar equivalents relative to the compound ( ⁇ _6).
  • the reaction temperature can usually be carried out at 0 to 120 ° C.
  • Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol.
  • the primary amine compound represented by the general formula ( ⁇ _3) is added to the above-mentioned raw material compound production method 5.
  • the manufacturing method can be achieved by the following method.
  • a compound having a nitrogen atom represented by the general formula (VI-5) introduced by reacting a ketone compound having a leaving group in the structure represented by the general formula (V_3) with phthalimide potassium. Can be obtained (step 59).
  • an ⁇ -promoketone compound represented by the general formula (VI-6) can be obtained by performing a bromination reaction of these compounds (step 60).
  • a thiazole compound represented by the general formula (VI-7) can be obtained by reacting these compounds with a dithiocarbamate represented by (IV) (step 61).
  • an ester compound represented by the general formula ( ⁇ -7) is obtained. After that (step 62), it can be converted to the primary amin compound ( ⁇ -8) by performing a deprotection reaction (step 63).
  • the starting compound (IV), (V-3) or (VII) is usually easily synthesized by a known method.
  • Step 59 can be performed according to a method similar to that of step 57.
  • Step 60 is usually performed using a suitable brominating agent in a solvent that does not adversely affect the reaction.
  • brominating agents include bromine, pyridinium bromide perb mouth amide, benzyltrimethylammonium tributamide, and phenyltrimethylammonium tribromide.
  • the amount of the brominating agent to be used is preferably 1 to 5 molar equivalents relative to compound (IV-5).
  • the reaction temperature can usually be carried out at 0 to 120 ° C.
  • solvents that do not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, and acetic acid.
  • Step 61 can be performed according to a method similar to that of step 50.
  • Step 62 can be performed according to a method similar to that of step 51.
  • Step 63 can be performed according to a method similar to that of step 58.
  • the carboxylic acid derivative containing the thiazole ring of the general formula (I) of the present invention thus produced is a known separation and purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like. By appropriately applying the above means, it can be collected as having an arbitrary purity.
  • the compound of the general formula (I) obtained in this way is, if necessary, an inorganic acid such as hydrochloric acid or hydrobromic acid, an organic acid such as trifluoroacetic acid, acetic acid, methanesulfonic acid or benzenesulfonic acid, sodium, potassium,
  • an inorganic acid such as hydrochloric acid or hydrobromic acid
  • an organic acid such as trifluoroacetic acid, acetic acid, methanesulfonic acid or benzenesulfonic acid, sodium, potassium
  • alkali metals such as calcium
  • organic bases such as dicyclohexylamine
  • amino acids such as lysine and arginine. wear.
  • Hyperlipidemia combined with diabetes refers to a case in which a diabetic patient has hyperlipidemia and may be referred to as diabetic hyperlipidemia. .
  • the pathological condition in which diabetic patients have hyperlipidemia means that TG, LDL-C, HDL-C, etc. are normal even if blood glucose levels are improved by diabetes treatment.
  • the medical conditions of the present invention can be applied to these pathological conditions for therapeutic purposes.
  • the medicament of the present invention is applied for the purpose of treatment or prevention. Is possible.
  • the WHO classification that classifies hyperlipidemia by the lipoprotein phenotype is known.
  • the phenotypes where triglycerides are elevated include type I hyperlipidemia, lib type hyperlipidemia, type III hyperlipidemia, type IV hyperlipidemia, type V hyperlipidemia, among others.
  • Those who are highly suspected of having diabetes with high serum TG and / or low HDL or who cannot rule out the possibility of diabetes are preferred targets for application of the medicament of the present invention.
  • the medicament of the present invention can also be applied to patients who belong to other categories and are diagnosed with hyperlipidemia associated with diabetes.
  • the TG value, LDL-C value, HDL-C value, etc. are within the normal value range. It can be applied for purposes.
  • the compound of the present invention can also be used as a preventive and Z or therapeutic agent for diabetes.
  • diabetes refers to a fasting blood glucose level of 126 mg / dL or higher, or a 75 g glucose tolerance test 2 hour value of 200 mg / dL.
  • Glucuria is also considered when the blood glucose level is 200 mg / dL or more as needed.
  • the compound (I) of the present invention can be administered to the same subject simultaneously with other antihyperlipidemic agents and the like, and can be administered to the same subject with a time lag.
  • Antihyperlipidemic here
  • symptomatic agents include statin compounds that are cholesterol synthetase inhibitors, squalene synthetase inhibitors, and fibrates that have a triglyceride-lowering action.
  • statin compounds that are cholesterol synthetase inhibitors, squalene synthetase inhibitors, and fibrates that have a triglyceride-lowering action.
  • the compounding ratio can be appropriately selected depending on the administration target, age and weight of the administration subject, symptoms, administration time, dosage form, administration method, combination and the like.
  • the dose of the compound (I) or a pharmacologically acceptable salt thereof varies depending on the administration route, target disease, patient symptom, body weight or age, and the compound used, and is appropriately set according to the purpose of administration. can do. In general, when administered orally to an adult, it is preferable to administer 0.:! To lOOOOmg / human / day, preferably 0.5 to 100 mg / human Z day in 1 to several times a day.
  • the compound (I) and the salt thereof of the present invention are used as the above-mentioned pharmaceuticals, they are mixed with themselves or appropriate pharmacologically acceptable carriers, excipients, diluents, etc. It can be administered orally or parenterally in the form of tablets, capsules, injections and the like. In the above preparation, an effective amount of compound (I) or a pharmacologically acceptable salt thereof is incorporated.
  • ⁇ H The chemical shift of NMR was expressed as relative delta ( ⁇ straightness in parts per million (ppm) using tetramethylsilane (TMS) as an internal standard.
  • TMS tetramethylsilane
  • the coupling constant was Hertz ( Hz), and the obvious multiplicity s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), dd (doublet of doublet), Expressed as td (triplet of doublets), brs (broad singlet), etc.
  • the force ram chromatography was carried out using silica gel made by Fuji Silysia Chemical.
  • reaction mixture was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate.
  • the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 15 [0234] ⁇ 2 _ [(2_tert_butoxy-1,1-dimethyl_2-oxoethyl) thio] _5_methyl_1,3_thiazol_4-yl ⁇ synthesized in Example 15 is used as a starting material, The title compound was obtained in the same manner as in Example 3.
  • Methyl 2 [(5 Methyl 4 ⁇ 2 [(Methylsulfonyl) oxy] ethyl) ⁇ 1 3_thiazole _2_inole) thio] propionic acid tert-butyl ester
  • Example 4 2- ⁇ [5 (Hydroxymethyl) 4-methyl-1,3-thiazol 2-yl] thio ⁇ synthesized in Example 27 Using 2-methylpropionic acid tert butyl ester as a starting material, Example 4 The title compound was obtained by carrying out the same operation as.
  • Example 34 [0301] H-NMR (CDC1, 300 MHz) ⁇ : 1.65 (6H, s), 5.25 (2H, s) 7.00— 7.13
  • Example 4 The title compound was obtained in the same manner as in Example 34, starting from ol. ⁇
  • Benzoic acid 4_ (2_ ⁇ 2 _ [(2_tert_butoxy— 1, 1-dimethyl_2_oxetyl) thio] -1,1, 3 _thiazole _ 4-yl ⁇ ethoxy) phenyl ester
  • Example 57 The intermediate synthesized in Example 57 is 2 — ⁇ [4 -1 (2 -— (4 -1 [(4 chlorobenzoyl) amino] phenoxy ⁇ ethyl) 1,3 thiazole 2 yl] thio ⁇ 2 methylpropiate
  • 4 -1 (2 -— (4 -1 [(4 chlorobenzoyl) amino] phenoxy ⁇ ethyl) 1,3 thiazole 2 yl] thio ⁇ 2 methylpropiate
  • Example 60-2 4_ (2_ ⁇ 2 _ [(2_tert_butoxy-1,1, 1-dimethyl synthesized in 2 2) oxoethyl) thio] 1,3 thiazole 4-ethanoloxy) benzoic acid and N-methylaniline as starting materials, and the title compound was obtained in the same manner as in Example 60-3 and Example 60-4.
  • Example 60-2 [0399] 4_ (2_ ⁇ 2 _ [(2_tert_butoxy-1,1, -dimethyl-2-oxoethyl) thio] _ 1,3-thiazole _4-inole ⁇ ethoxy) benzoic acid synthesized in Example 60-2
  • the title compound was obtained in the same manner as in Example 60-3 and Example 60-4 using (4 fluorophenyl) aniline as starting material.
  • Example 60-2 4 (2— ⁇ 2— [(2-tert-butoxy-1, 1-dimethyl-2-oxoethyl) thio] 1,3 thiazole 4-inole ⁇ ethoxy) benzoic acid and pendinoleamine was used as a starting material, and the title compound was obtained in the same manner as in Example 60-3 and Example 60-4.
  • Example 60-2 Synthesized in 4- (2— ⁇ 2— [(2— tert-butoxy-1, 1-dimethyl

Abstract

La présente invention concerne des composés utilisables en tant que médicaments préventifs et/ou thérapeutiques pour l'hyperlipémie diabétique. L'invention repose sur l'observation selon laquelle des composés représentés par la formule générale (I) présentent un effet de diminution des TG plasmatiques, un effet de diminution des acides gras libres et un effet d'augmentation du cholestérol des HDL du sérum sur divers paramètres de l'hyperlipémie diabétique : (I)
PCT/JP2007/059151 2006-04-27 2007-04-27 Utilisation en tant que medicaments de derives d'un acide carboxylique porteurs de cycles thiazole WO2007126043A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2008129951A1 (fr) * 2007-04-13 2008-10-30 Kowa Company, Ltd. Nouveau composé de pyrimidine à structure de dibenzylamine et médicament le comprenant
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WO2010064633A1 (fr) * 2008-12-01 2010-06-10 田辺三菱製薬株式会社 Dérivé d'acide carboxylique comportant un cycle thiazole et ses applications pharmaceutiques
US7750003B2 (en) 2006-08-24 2010-07-06 Astrazeneca Ab Compounds-943
US7750019B2 (en) 2006-08-11 2010-07-06 Kowa Company, Ltd. Pyrimidine compound having benzyl(pyridylmethyl)amine structure and medicament comprising the same
US7790737B2 (en) 2007-03-13 2010-09-07 Kowa Company, Ltd. Substituted pyrimidine compounds and their utility as CETP inhibitors
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WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
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WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN111303011A (zh) * 2018-12-12 2020-06-19 乐金显示有限公司 有机化合物、具有该化合物的发光二极管和发光装置

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002527496A (ja) * 1998-10-16 2002-08-27 グラクソ グループ リミテッド 化学化合物
JP2004513166A (ja) * 2000-11-10 2004-04-30 イーライ・リリー・アンド・カンパニー ペルオキシソーム増殖因子活性化受容体アルファアゴニスト
JP2004532266A (ja) * 2001-05-31 2004-10-21 グラクソ　グループ　リミテッド 心血管系疾患の治療に有用なチアゾールまたはオキサゾール誘導体
WO2004113331A1 (fr) * 2003-06-20 2004-12-29 Galderma Research & Development, S.N.C. Nouveaux composes qui modulent les recepteurs de type ppar$g(g) et utilisations de ceux-ci dans des compositions cosmetiques ou pharmaceutiques
WO2006049232A1 (fr) * 2004-11-04 2006-05-11 Mitsubishi Pharma Corporation Dérivé d’acide carboxylique contenant un cycle thiazole et applications pharmaceutiques dudit dérivé

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62212590A (ja) * 1986-03-14 1987-09-18 Matsushita Electric Ind Co Ltd 路面凍結警告装置
ZA9610046B (en) * 1995-12-01 1997-07-10 Ciba Geigy Process for preparing 2-chlorothiazole compounds
EP1026149A4 (fr) * 1997-10-02 2004-12-01 Sankyo Co Derives d'acide amidocarboxylique
EP1394154A4 (fr) * 2001-03-23 2005-05-18 Takeda Pharmaceutical Derive heterocyclique a cinq membres d'acide alcanoique
PL367676A1 (en) * 2001-05-29 2005-03-07 Kyoto Pharmaceutical Industries, Ltd. Novel heterocyclic derivatives and medicinal use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002527496A (ja) * 1998-10-16 2002-08-27 グラクソ グループ リミテッド 化学化合物
JP2004513166A (ja) * 2000-11-10 2004-04-30 イーライ・リリー・アンド・カンパニー ペルオキシソーム増殖因子活性化受容体アルファアゴニスト
JP2004532266A (ja) * 2001-05-31 2004-10-21 グラクソ　グループ　リミテッド 心血管系疾患の治療に有用なチアゾールまたはオキサゾール誘導体
WO2004113331A1 (fr) * 2003-06-20 2004-12-29 Galderma Research & Development, S.N.C. Nouveaux composes qui modulent les recepteurs de type ppar$g(g) et utilisations de ceux-ci dans des compositions cosmetiques ou pharmaceutiques
WO2006049232A1 (fr) * 2004-11-04 2006-05-11 Mitsubishi Pharma Corporation Dérivé d’acide carboxylique contenant un cycle thiazole et applications pharmaceutiques dudit dérivé

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7750019B2 (en) 2006-08-11 2010-07-06 Kowa Company, Ltd. Pyrimidine compound having benzyl(pyridylmethyl)amine structure and medicament comprising the same
US7750003B2 (en) 2006-08-24 2010-07-06 Astrazeneca Ab Compounds-943
US7790737B2 (en) 2007-03-13 2010-09-07 Kowa Company, Ltd. Substituted pyrimidine compounds and their utility as CETP inhibitors
US8012989B2 (en) 2007-03-13 2011-09-06 Kowa Company, Ltd. Substituted pyrimidine compounds and their utility as CETP inhibitors
WO2008129951A1 (fr) * 2007-04-13 2008-10-30 Kowa Company, Ltd. Nouveau composé de pyrimidine à structure de dibenzylamine et médicament le comprenant
US7659271B2 (en) 2007-04-13 2010-02-09 Kowa Company, Ltd. Pyrimidine compound having dibenzylamine structure and medicament comprising the same
EA017321B1 (ru) * 2007-04-13 2012-11-30 Кова Компани, Лтд. Производные n,n-дибензил-2-аминопиримидина и лекарственные средства, их содержащие
US8138183B2 (en) 2007-07-09 2012-03-20 Astrazeneca Ab Morpholino pyrimidine derivatives used in diseases linked to mTOR kinase and/or PI3K
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
KR101290868B1 (ko) 2008-12-01 2013-07-29 미쓰비시 타나베 파마 코퍼레이션 티아졸환을 포함하는 카르복실산 유도체 및 그의 의약 용도
CN102300853A (zh) * 2008-12-01 2011-12-28 田边三菱制药株式会社 含有噻唑环的羧酸衍生物及其药学用途
US8497382B2 (en) 2008-12-01 2013-07-30 Mitsubishi Tanabe Pharma Corporation Carboxylic acid derivative containing thiazole ring and pharmaceutical use thereof
JP5357894B2 (ja) * 2008-12-01 2013-12-04 田辺三菱製薬株式会社 チアゾール環を含むカルボン酸誘導体およびその医薬用途
AU2009323367B2 (en) * 2008-12-01 2013-05-23 Mitsubishi Tanabe Pharma Corporation Carboxylic acid derivative containing thiazole ring and pharmaceutical use thereof
WO2010064633A1 (fr) * 2008-12-01 2010-06-10 田辺三菱製薬株式会社 Dérivé d'acide carboxylique comportant un cycle thiazole et ses applications pharmaceutiques
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
US8252802B2 (en) 2010-06-11 2012-08-28 Astrazeneca Ab Chemical compounds
US9421213B2 (en) 2010-06-11 2016-08-23 Astrazeneca Ab Chemical compounds
US9155742B2 (en) 2010-06-11 2015-10-13 Astrazeneca Ab Chemical compounds
US8999997B2 (en) 2010-06-11 2015-04-07 Astrazeneca Ab Chemical compounds
US8552004B2 (en) 2010-06-11 2013-10-08 Astrazeneca Ab Chemical compounds
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN111303011A (zh) * 2018-12-12 2020-06-19 乐金显示有限公司 有机化合物、具有该化合物的发光二极管和发光装置
CN111303011B (zh) * 2018-12-12 2023-06-16 乐金显示有限公司 有机化合物、具有该化合物的发光二极管和发光装置

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