WO2001079197A1 - Activateurs de ppar$g(d) (peroxisome proliferator activated receptor $g(d)) - Google Patents

Activateurs de ppar$g(d) (peroxisome proliferator activated receptor $g(d)) Download PDF

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WO2001079197A1
WO2001079197A1 PCT/JP2001/002271 JP0102271W WO0179197A1 WO 2001079197 A1 WO2001079197 A1 WO 2001079197A1 JP 0102271 W JP0102271 W JP 0102271W WO 0179197 A1 WO0179197 A1 WO 0179197A1
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group
carbon atoms
bond
atom
phenyl
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PCT/JP2001/002271
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Japanese (ja)
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Shogo Sakuma
Tsuyoshi Endo
Atsushi Tendo
Toshihiro Takahashi
Shinichi Yoshida
Kunio Kobayashi
Nobutaka Mochiduki
Tomio Yamakawa
Takashi Kanda
Seiichiro Masui
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Nippon Chemiphar Co.,Ltd.
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Priority to AU2001242747A priority Critical patent/AU2001242747A1/en
Publication of WO2001079197A1 publication Critical patent/WO2001079197A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to the activation scheme 1 of peroxisome proliferator-activated receptor d.
  • Peroxisomes are organelles found in the cells of animals and plants, and their matrices contain a variety of enzymes, including lipase.
  • Peroxisome protosome peroxisome prol if erator
  • Peroxisome prol if erator is a substance that induces the growth of this phenolic isomer, a variety of substances such as antilipidemic drugs (fibrates), herbicides, and furate plasticizers. Compounds are known.
  • peroxisome proliferator A nuclear receptor activated by this peroxisome proliferator was identified by Isseman et al., And a peroxisomal proliferator-activated receptor (peroxisome proliferator or activated recept or: PPAR) was named. (Nature, 347, p645—650, 1990)
  • the above-mentioned fibrate drugs have a ligand effect on PPAR ⁇ , and a strong serum TG (triglyceride) lowering effect has been recognized in clinical practice.
  • thiazolidinedione compounds which are therapeutic agents for diabetes are known as ligands of PPARy.
  • YM—16638 (Yamanouchi Pharmaceutical) and the like are known.
  • GW-2433 is described in WO 92/10 468 for use as a preventive and therapeutic agent for atherosclerosis
  • L-165041 is described in WO 97/28115 for use as a therapeutic agent for diabetes mellitus
  • an antiobesity agent and YM-16638 is described in WO 99/04815 as having a serum cholesterol lowering effect and an LDL-cholesterol lowering effect.
  • PPAR5 ligand has been reported to promote its application as an anticancer drug and an anti-inflammatory drug (J BC, 272 (6), p3406-3410, 1997; Ce 11, 99, p 335-345, 1999). I have.
  • a compound having a structure similar to the vesazol derivative represented by the following general formula (II) of the present compound is described in WO 92/10 468 for use as a preventive and therapeutic agent for atherosclerosis
  • L-165041 is described in WO 97/28115 for use as a therapeutic agent for diabetes mellitus
  • All of the above compounds A, B, and C have a carboxyl group, a cyano group, or an ethoxy or propylthio group substituted on the right side of the benzisoxazole ring or benzofuran ring.
  • Carboxyl groups are linked via an alkylene chain.
  • the compound of the present invention is acetic acid or 2-alkylpropionic acid in which the right side of penzisoxazole is bonded by an ether or thioether bond, and has a structural difference from A, B and C described above.
  • Compound D above has a benzofuran ring bonded to the left side of the indole ring via an alkylene chain, and a thiazolyl ring-oxazole ring bonded to the left side of the benzixoxazole ring via an alkylene chain.
  • An object of the present invention is to provide a compound represented by the following general formula (I) or a penzisoxazole derivative represented by the following general formula (II), which has an activity of activating peroxisome proliferator-activated receptor 3. It is in. Disclosure of the invention
  • R 6 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms, and a alkenyl group having 2 to 8 carbon atoms, and an alkynyl group having 2 to 8 carbon atoms.
  • An arylalkyl group which may have a substituent carbon number of an aryl moiety is 6 to 10; carbon number of an alkyl moiety is 1 to 4); or a carbon atom which may have a substituent has 6 to 6 carbon atoms.
  • R 1 , R 2 and R 3 are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, An alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, and an arylalkyl group which may have a substituent (The aryl moiety has 6 to 10 carbon atoms, the alkyl moiety has 1 to 4 carbon atoms), an aryl group having 6 to 10 carbon atoms which may have a substituent, and 1 to 3 as ring-forming atoms.
  • R 7 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms,
  • Y 1 represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent
  • B 1 represents CW 1 or N
  • W 1 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a bond
  • B 2 represents CW 2 or N
  • W 2 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a bond
  • D represents ⁇ , S, NR 8 ;
  • R 8 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or an arylalkyl group which may have a substituent (the carbon number of the aryl portion is 6 to 10 and the carbon number of the alkyl portion is 1 to 10). ⁇ 4), or a bond,
  • Z represents 0 or S
  • Y 2 represents an alkylene chain having 1 to 4 carbon atoms or a bond
  • E represents a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonic group, a phosphonic group, a cyano group, or a tetrazole group.
  • R 1 , R 2 3 R 3 and R 6 is a bond, and the rest is other than a bond, and this bond is bonded to X 1 , and W 1 , W 2
  • R 8 is a bond, and the rest is other than a bond, and this bond and X 2 are bonded.
  • the present invention provides the following general formula (11):
  • R 6 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a alkenyl group having 2 to 8 carbon atoms, An alkynyl group, an arylalkyl group which may have a substituent (an aryl moiety having 6 to 10 carbon atoms and an alkyl moiety having a carbon number of 1 to 4), or a carbon atom which may have a substituent Represents an aryl group or a bond of 6 to 10;
  • R 1 , R 2 and R 3 are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, An alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, and an arylalkyl group which may have a substituent (The aryl portion has 6 to 10 carbon atoms, and the alkyl portion has 1 to 4 carbon atoms), and may have a substituent.
  • Y 1 represents an alkylene chain having 1 to 8 carbon atoms which may have a substituent
  • Z represents 0 or S
  • R 4 and R 5 represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom.
  • R 1 , R 2 , and R 6 are a bond, and the rest is other than a bond, and this bond and X 1 are bonded.
  • R 1 , R 2 , and R 6 is a bond, and the rest is other than a bond, and this bond and X 1 are bonded.
  • the present invention relates to a peroxisome proliferator-activated receptor ⁇ containing, as an active ingredient, a compound represented by the above general formula (I) or a benzisoxazole derivative represented by the above general formula (II), or a salt thereof.
  • Activator BEST MODE FOR CARRYING OUT THE INVENTION
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , RRW 1 and W 2 may be a methyl group, an ethyl group, or a propyl group.
  • the alkyl Le group R 1, R 2, R 5 R 4, R 5 and the carbon number is substituted with a halogen atom R 6 1 ⁇ 8, 1 ⁇ 3 fluorine atoms, such as chlorine atom or bromine atom
  • a halogen atom R 6 1 ⁇ 8, 1 ⁇ 3 fluorine atoms such as chlorine atom or bromine atom
  • Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a t-butyl group substituted with a halogen atom, and preferably a trifluoromethyl group, a chloromethyl group, or a 2-alkyl group.
  • Examples of the cycloalkyl group having 3 to 7 carbon atoms represented by R 1 , R 2 and R 3 include a cyclopropyl group, a cyclopentyl group and a cyclohexyl group.
  • R 1 , R 1 , R 2 and R 3 include a C 1 to C 6 alkyl group substituted by a C 3 to C 7 cycloalkyl group such as a cyclohexylmethyl group and a cyclopentylmethyl group.
  • Examples of the alkenyl group having 2 to 8 carbon atoms for R 1 , R 2 , R 3 and R 6 include a vinyl group and an aryl group.
  • R 1 , R z , R 3 R and R 8 which may have a substituent may be an arylalkyl group (C 6 to C 10 in the aryl moiety and C 1 to C 4 in the alkyl moiety).
  • An alkyl group having 1 to 6 carbon atoms methyl group, ethyl group, propyl group, etc.
  • an alkoxy group having 1 to 6 carbon atoms methoxy group, ethoxy group
  • a halogen atom fluorine atom, chlorine atom, bromine atom
  • a substituted or unsubstituted aryl group (a phenyl group or a naphthyl group), for example, a methyl group or an ethyl group, preferably a pendyl group, a benzhydryl group or a phenethyl group.
  • Examples of the aryl group having 6 to 10 carbon atoms which may have a substituent of 1, R 2 , R 3 and R 6 include an alkyl group having 1 to 6 carbon atoms (a methyl group, an ethyl group, a propyl group).
  • a phenyl group or a naphthyl group which may be mentioned, and preferably a phenyl group, a 2-chlorophenyl group, a 2-methylphenyl group, a 3-chlorophenyl group, and a 2,3-dichlorophenyl Or 2, 4-dichlorophenyl group, and the like.
  • a 5- to 8-membered heterocyclic group comprising a heteroatom selected from 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms and the remaining carbon atoms
  • These complex ring groups include an alkyl group having 1 to 6 carbon atoms (a methyl group and an ethyl group) and a carbon atom having a 1 to 6 carbon atoms.
  • 6 may have a substituent such as an alkoxy group (methoxy group, ethoxy group), a halogen atom (fluorine atom, chlorine atom), a trifluoromethyl group, or a trifluoroethyl group.
  • a substituent such as an alkoxy group (methoxy group, ethoxy group), a halogen atom (fluorine atom, chlorine atom), a trifluoromethyl group, or a trifluoroethyl group.
  • the alkylene chain having 1 to 8 carbon atoms which may have a substituent of Y 1 includes a methylene which may be substituted with a substituent such as an alkyl group having 1 to 6 carbon atoms (methyl group, ethyl group). , Ethylene and propylene.
  • Examples of the alkylene chain having 1 to 4 carbon atoms of Y 2 include methylene and ethylene.
  • Examples of the alkoxycarbonyl group having 2 to 8 carbon atoms of E include methoxycarbonyl and ethoxycarbonyl.
  • the substitution position of Z is at the 4, 5, 6 or 7 position, preferably at the 5 or 6 position.
  • a compound in which B 1 is CW 1 is preferable.
  • B 1 is CW 1 and Y 2 is A compound that is a bond is preferable.
  • Gaben isoxazole ring benzofuran II, benzothiophene II, or indole Compounds in which Y 2 is a bond and ⁇ is a carboxyl group are preferred. Further, among the compounds represented by the above general formula (I), the benzodisoxazole derivative represented by the above general formula (II) of the present invention is preferable.
  • benzisoxazole derivatives represented by the general formula (II) a benzisoxazole derivative in which A is 0 or S, and X 1 and X 2 are a bond is preferable.
  • A is 0 or S, X 1 and X 2 are a bond; 1 , R 2 and R 3 are a hydrogen atom, C1-8 alkyl group substituted by halogen atom, C1-8 alkyl group substituted by halogen atom, C3-7 cycloalkyl group substituted by C3-7 cycloalkyl group Alkyl group, alkenyl group having 2 to 8 carbon atoms, alkynyl group having 2 to 8 carbon atoms, arylalkyl group which may have a substituent (alkyl having 6 to 10 carbon atoms in the aryl portion, Preferred are an aryl group, a pyridyl group, a phenyl group, a phenyl group, a phenyl group, a fenyl group, and a benzodisoxazole derivative which is a bond, having 1 to 4) carbon
  • A is 0 or S
  • X 1 and X 2 are a bond
  • R 1 , R 2 and R 3 are a hydrogen atom, a carbon atom
  • the compound represented by the general formula (I) or the benzisoxazole derivative represented by the general formula (II) may be a pharmacologically acceptable salt, for example, a sodium salt, a potassium salt, or the like. Metal salts.
  • R represents a methyl group, the carbon number of 1 to 6 alkyl groups such as Echiru group, Q represents a leaving group such as chlorine atom, bromine atom, and R 1, R 2 5 RAX 1 , Y 1 , X 2 , Z, R 4 and R 5 are the same as above.
  • the body is obtained by diazotizing the aminopenzisoxazole derivative represented by the general formula (III) with sodium nitrite or mineral acid (sulfuric acid) under ice-cooling, and sulfuric acid if Z is an oxygen atom.
  • Z is a sulfur atom, it is obtained by heating with ethyl ethyl xanthogen tandem steam or the like and then heating.
  • the benzisoxazole derivative of the present invention represented by the general formula (VI) is represented by the general formula (V) in the presence of a base such as potassium carbonate in the compound represented by the general formula (IV). It is obtained by the action of an acetate derivative.
  • the benzisoxazole derivative of the present invention represented by the general formula (VII) can be obtained by converting the benzisoxazole derivative of the present invention represented by the general formula (VI) to lithium hydroxide, hydroxide rim, or the like. It can be obtained by subjecting it to a hydrolysis reaction in the presence. Further, the benzixoxazole derivative of the present invention can also be obtained by the following reaction scheme.
  • Tables 1 to 22 show examples of the compound of the present invention thus obtained.
  • the substitution position of Z is the 6-position, and R 2 , R 3 , X 1 , X 2 , YR 4 , R 5 and Z are those described in Table 6.
  • ⁇ ⁇ means a peroxy group.
  • Y 1 is ethylene
  • the substitution position of Z is 7-position
  • R 1 , R 3 , X 1 , X 2 , R 4 and R 5 are Those described in Table 9. [Table 9]
  • R 5 is a methyl group
  • Y 1 is ethylene
  • substitution positions of R 2 , R 3 , R 4 , ⁇ D, Z, Z, X 1 and X 2 is listed in Table 11
  • R 4 and: R 5 is a methyl group, Z is S, and the substitution positions of R 2 , R 3 , BD, Z, X 1 , Y 1 and X 2 is also to in Table 1 3. [Table 13]
  • the compound of the present invention The PPAR3 activating effect is obtained by receptor plasmid (GAL 4-hPPAR0-LBD), luciferase expression plasmid (UASx4-TK-LUC) and /?-Galactosidase ( ⁇ — GAL) After transfecting the expression plasmid with DMRI E-C and culturing for 40 hours in the presence of the compound of the present invention or L-165041, which is a comparative compound, the solubilized cells are luciferase and GAL-activated. It was determined by measuring.
  • the luciferase activity was corrected by the /?-1 GAL activity, and the relative ligand activity was calculated with the luciferase activity of the cells treated with L-165041 as 100%. (Example 10 described later)
  • the compounds of the present invention (Examples 1 to 7) exhibited a PPAR5 activating effect equivalent to or higher than that of L-165041.
  • Table 24 also shows that the compounds of the present invention described in Examples 9-11 to 9-22 also exhibited the same or higher PPAR5 activating action as compared to L-165041.
  • the compound represented by the general formula (I) of the present invention has an excellent P PARS activating action. Because it has hypoglycemic agents, lipid-lowering agents, obesity, syndrome X, hypercholesterolemia, metabolic disorders such as hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, cardiovascular disease, bulimia, Malignant tumors such as ischemic disease, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer, Alzheimer's disease, inflammatory disease, and osteoporosis (Mano H. et.Al., (2000) J. Biol. Chem.
  • the compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.
  • composition it can be manufactured into tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by usual methods in the technical field of formulation.
  • excipients include lactose, D-mannitol, crystalline cellulose, sucrose and the like
  • disintegrants include starch and calcium carboxymethylcellulose (CMC-Ca)
  • lubricants include stearin.
  • examples include magnesium acid and talc
  • examples of the binder include hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).
  • the dosage for adults is about 0.1 mg / day to 100 mg / day of the compound of the present invention, which is an active ingredient in an injection, and 100 mg / day to 100 mg / day for oral administration. Can be increased or decreased.
  • the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
  • 6-acetamido-3-methyl-1,2-benzisoxazole (1.50 g, 7.89 mmol) was dissolved in dry THF (25 mL), and then dissolved under a nitrogen atmosphere.
  • C, 2M LDA (9. OmL, 18. Ommol) was added dropwise over 10 minutes, and the mixture was further stirred under the same conditions for 10 minutes.
  • a THF solution (1.90 g, 7.89 mmol 1/4. OmL) of 4-hydroxymethyl-5-methyl-2-phenyloxazole, which was synthesized according to a conventional method, was added dropwise over 5 minutes. The mixture was stirred under the conditions for 30 minutes.
  • the precipitated crystals were separated, washed with water (40 mL), air-dried for 2 minutes, and dried under reduced pressure to obtain the title compound as white crystals (170 mg).
  • Example 7 2-C [3- [2- [5-Methyl-2-phenyl 4-thiazolyl) ethyl] — 1,2-Penzisoxazolu-6-yl] oxy] -12-Methylpropionic acid Same as in Example 1. The following intermediates and the title compound were obtained by the procedure described above.

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Abstract

L'invention concerne des dérivés de benzisoxazole représentés par la formule générale (II) et et produisant une activation de PPARδ, ou de sels de ces dérivés : (II) dans laquelle A représente O, S ou analogue ; R?1 R2 et R3¿ représentent chacun l'hydrogène, l'alkyle en C¿1-8?, le phényle éventuellement substitué, ou analogue, X1 et X2 représentent chacun O, S, une valence libre, ou analogue, Y1 est une chaîne alkylène en C1-8 éventuellement substituée, Z représente O ou S, et R?4 et R5¿ représentent chacun l'hydrogène, l'alkyle C¿1-8 ?ou analogue.
PCT/JP2001/002271 2000-04-14 2001-03-22 Activateurs de ppar$g(d) (peroxisome proliferator activated receptor $g(d)) WO2001079197A1 (fr)

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JP2000113425 2000-04-14
JP2000-113425 2000-04-14
JP2000402892A JP2001354671A (ja) 2000-04-14 2000-12-28 ペルオキシソーム増殖剤応答性受容体δの活性化剤
JP2000-402892 2000-12-28

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WO2002070011A3 (fr) * 2001-02-02 2003-04-24 Smithkline Beecham Corp Regimes therapeutiques
WO2003033493A1 (fr) * 2001-10-12 2003-04-24 Nippon Chemiphar Co.,Ltd. Activateur du recepteur $g(d) active par le proliferateur de peroxisome
WO2004037776A2 (fr) 2002-10-28 2004-05-06 Novo Nordisk A/S Nouveaux composes, leur preparation et leur utilisation
WO2004037775A1 (fr) 2002-10-28 2004-05-06 Novo Nordisk A/S Nouveaux composes traitant les maladies mediees par le ppar
WO2004071509A1 (fr) * 2003-02-12 2004-08-26 Nippon Chemiphar Co., Ltd. Promoteurs de differenciation d'oligodendrocyte
US6869975B2 (en) 2001-09-14 2005-03-22 Tularik Inc. Linked biaryl compounds
WO2005060958A1 (fr) * 2003-12-19 2005-07-07 Kalypsys, Inc. Derives de l'acide (5- (2-phenyl)-thiazol-5-ylmethoxy)-indol-1-yl) -acetique et composes associes en tant que modulateurs du recepteur ppar-delta humain pour le traitement de troubles metaboliques tels que le diabete de type 2
US7091245B2 (en) 2002-09-05 2006-08-15 Novo Novdisk A/S Compounds, their preparation and use
WO2006096564A1 (fr) * 2005-03-04 2006-09-14 Merck & Co., Inc. Composes aromatiques fusionnes ayant une activite anti-diabetique
US7129268B2 (en) 2002-10-28 2006-10-31 Novo Nordisk A/S Peroxisome proliferator activated receptor-active arylene acetic acid derivatives
WO2007004733A1 (fr) * 2005-07-06 2007-01-11 Nippon Chemiphar Co., Ltd. ACTIVATEUR DU RÉCEPTEUR ACTIVÉ PAR LES PROLIFÉRATEURS DU PEROXYSOME δ
WO2007003581A1 (fr) 2005-06-30 2007-01-11 Novo Nordisk A/S Acides phénoxyacétiques en tant qu'activateurs de rapp-delta
WO2008016175A1 (fr) * 2006-08-03 2008-02-07 Nippon Chemiphar Co., Ltd. Agent activant de récepteur activé par les proliférateurs des peroxysomes
US7648999B2 (en) 2001-08-10 2010-01-19 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-activated receptor δ
WO2010045361A1 (fr) 2008-10-17 2010-04-22 Metabolex, Inc. Procédés de réduction de petites particules denses de ldl
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
US7709528B2 (en) 2002-10-28 2010-05-04 High Point Pharmaceuticals, Llc Compounds, their preparation and use
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
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US8338458B2 (en) 2007-05-07 2012-12-25 Merck Sharp & Dohme Corp. Method of treatment using fused aromatic compounds having anti-diabetic activity
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US10456406B2 (en) 2013-09-09 2019-10-29 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
WO2022007772A1 (fr) 2020-07-10 2022-01-13 成都凡诺西生物医药科技有限公司 Dérivé de benzimidazole substitué et son utilisation
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

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UA79755C2 (en) * 2002-04-16 2007-07-25 Bayer Pharmaceuticals Corp Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation
KR100474202B1 (ko) * 2002-05-04 2005-03-08 강헌중 티아졸 유도체의 제조방법 및 이를 제조하기 위한 중간체
EP1637161A4 (fr) * 2003-04-22 2007-06-27 Astellas Pharma Inc REMEDE CONTRE DES MALADIES CEREBRALES NEURODEGENERATIVES UTILISANT UN AGONISTE DES PPAR [delta]
JP2013006769A (ja) * 2009-10-08 2013-01-10 Nippon Chemiphar Co Ltd ペルオキシソーム増殖剤活性化受容体の活性化剤

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WO1997027857A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Agents antidiabetiques
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WO2002070011A3 (fr) * 2001-02-02 2003-04-24 Smithkline Beecham Corp Regimes therapeutiques
US7648999B2 (en) 2001-08-10 2010-01-19 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-activated receptor δ
US7652045B2 (en) 2001-08-10 2010-01-26 Nippon Chemiphar, Co., Ltd. Activator of peroxisome proliferator-activated receptor δ
US7645779B2 (en) 2001-09-14 2010-01-12 Amgen Inc. Linked biaryl compounds
US6869975B2 (en) 2001-09-14 2005-03-22 Tularik Inc. Linked biaryl compounds
CN1293076C (zh) * 2001-10-12 2007-01-03 日本化学医药株式会社 过氧化物酶体增殖剂应答性受体δ的活化剂
WO2003033493A1 (fr) * 2001-10-12 2003-04-24 Nippon Chemiphar Co.,Ltd. Activateur du recepteur $g(d) active par le proliferateur de peroxisome
US7402597B2 (en) 2001-10-12 2008-07-22 Nippon Chemiphar Co., Ltd Activator of peroxisome proliferator-activated receptor δ
US7119104B2 (en) 2001-10-12 2006-10-10 Nippon Chemiphar, Co., Ltd. Activator of peroxisome proliferator-activated receptor delta
US7091245B2 (en) 2002-09-05 2006-08-15 Novo Novdisk A/S Compounds, their preparation and use
WO2004037775A1 (fr) 2002-10-28 2004-05-06 Novo Nordisk A/S Nouveaux composes traitant les maladies mediees par le ppar
US7129268B2 (en) 2002-10-28 2006-10-31 Novo Nordisk A/S Peroxisome proliferator activated receptor-active arylene acetic acid derivatives
US7709528B2 (en) 2002-10-28 2010-05-04 High Point Pharmaceuticals, Llc Compounds, their preparation and use
WO2004037776A2 (fr) 2002-10-28 2004-05-06 Novo Nordisk A/S Nouveaux composes, leur preparation et leur utilisation
WO2004071509A1 (fr) * 2003-02-12 2004-08-26 Nippon Chemiphar Co., Ltd. Promoteurs de differenciation d'oligodendrocyte
WO2005060958A1 (fr) * 2003-12-19 2005-07-07 Kalypsys, Inc. Derives de l'acide (5- (2-phenyl)-thiazol-5-ylmethoxy)-indol-1-yl) -acetique et composes associes en tant que modulateurs du recepteur ppar-delta humain pour le traitement de troubles metaboliques tels que le diabete de type 2
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US7968723B2 (en) 2004-05-05 2011-06-28 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US8053598B2 (en) 2004-05-05 2011-11-08 High Point Pharmaceuticals, Llc Compounds, their preparation and use
JP2008531729A (ja) * 2005-03-04 2008-08-14 メルク エンド カムパニー インコーポレーテッド 抗糖尿病活性を有する縮合芳香族化合物
CN102584754A (zh) * 2005-03-04 2012-07-18 默沙东公司 具有抗糖尿病活性的稠合芳香化合物
WO2006096564A1 (fr) * 2005-03-04 2006-09-14 Merck & Co., Inc. Composes aromatiques fusionnes ayant une activite anti-diabetique
JP4638512B2 (ja) * 2005-03-04 2011-02-23 メルク・シャープ・エンド・ドーム・コーポレイション 抗糖尿病活性を有する縮合芳香族化合物
US7834036B2 (en) 2005-03-04 2010-11-16 Merck Sharp & Dohme Corp Fused-aromatic compounds having anti-diabetic activity
US7943669B2 (en) 2005-06-30 2011-05-17 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
US8426473B2 (en) 2005-06-30 2013-04-23 High Point Pharnaceuticals, LLC Phenoxy acetic acids as PPAR delta activators
EP2298742A1 (fr) 2005-06-30 2011-03-23 High Point Pharmaceuticals, LLC Acides phénoxyacétiques en tant qu'activateurs PPAR delta
US8217086B2 (en) 2005-06-30 2012-07-10 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
WO2007003581A1 (fr) 2005-06-30 2007-01-11 Novo Nordisk A/S Acides phénoxyacétiques en tant qu'activateurs de rapp-delta
JPWO2007004733A1 (ja) * 2005-07-06 2009-01-29 日本ケミファ株式会社 ペルオキシソーム増殖剤活性化受容体δの活性化剤
WO2007004733A1 (fr) * 2005-07-06 2007-01-11 Nippon Chemiphar Co., Ltd. ACTIVATEUR DU RÉCEPTEUR ACTIVÉ PAR LES PROLIFÉRATEURS DU PEROXYSOME δ
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US10947180B2 (en) 2005-12-22 2021-03-16 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
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US11420929B2 (en) 2005-12-22 2022-08-23 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
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US9663481B2 (en) 2005-12-22 2017-05-30 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPARδ agonists
US10471066B2 (en) 2005-12-22 2019-11-12 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
US8362016B2 (en) 2005-12-22 2013-01-29 High Point Pharmaceuticals, Llc Phenyl propionic acids as PPAR delta activators
US9855274B2 (en) 2005-12-22 2018-01-02 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
US7943612B2 (en) 2006-03-09 2011-05-17 High Point Pharmaceuticals, Llc Compounds that modulate PPAR activity, their preparation and use
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
WO2008016175A1 (fr) * 2006-08-03 2008-02-07 Nippon Chemiphar Co., Ltd. Agent activant de récepteur activé par les proliférateurs des peroxysomes
US8338458B2 (en) 2007-05-07 2012-12-25 Merck Sharp & Dohme Corp. Method of treatment using fused aromatic compounds having anti-diabetic activity
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor
CN104672220A (zh) * 2008-04-15 2015-06-03 日本化学医药株式会社 过氧化物酶体增殖剂活化受体的活化剂
CN104672220B (zh) * 2008-04-15 2017-09-22 日本化学医药株式会社 过氧化物酶体增殖剂活化受体的活化剂
US11007162B2 (en) 2008-10-17 2021-05-18 Cymabay Therapeutics, Inc. Methods of reducing small, dense LDL particles
WO2010045361A1 (fr) 2008-10-17 2010-04-22 Metabolex, Inc. Procédés de réduction de petites particules denses de ldl
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
US10456406B2 (en) 2013-09-09 2019-10-29 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
EP3756661A1 (fr) 2013-09-09 2020-12-30 vTv Therapeutics LLC Utilisation d'un agoniste de ppar-delta pour le traitement de l'atrophie musculaire
US11096946B2 (en) 2013-09-09 2021-08-24 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
WO2022007772A1 (fr) 2020-07-10 2022-01-13 成都凡诺西生物医药科技有限公司 Dérivé de benzimidazole substitué et son utilisation
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

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