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WO2008016175A1 - Agent activant de récepteur activé par les proliférateurs des peroxysomes - Google Patents

Agent activant de récepteur activé par les proliférateurs des peroxysomes Download PDF

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WO2008016175A1
WO2008016175A1 PCT/JP2007/065471 JP2007065471W WO2008016175A1 WO 2008016175 A1 WO2008016175 A1 WO 2008016175A1 JP 2007065471 W JP2007065471 W JP 2007065471W WO 2008016175 A1 WO2008016175 A1 WO 2008016175A1
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carbon atoms
alkyl group
group
compound
acceptable salt
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PCT/JP2007/065471
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English (en)
Japanese (ja)
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Shogo Sakuma
Nobutaka Mochiduki
Masatoshi Ushioda
Rie Takahashi
Tomio Yamakawa
Seiichiro Masui
Youichi Yamagishi
Toshitake Hirai
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Nippon Chemiphar Co., Ltd.
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Priority to JP2008527823A priority Critical patent/JPWO2008016175A1/ja
Publication of WO2008016175A1 publication Critical patent/WO2008016175A1/fr

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Definitions

  • the present invention relates to an activator of peroxisome proliferator-activated receptor (PPAR).
  • PPAR peroxisome proliferator-activated receptor
  • Peroxisome proliferator-activated receptor peroxisomepro 1 iferatoractivatedr eceptor: P PAR
  • P PAR o There are three subtypes known so far, and they are called P PAR o !, PP AR ⁇ and PP AR ⁇ . It has been.
  • KR P— 29 7 (Ky orin) represented by Tesaglitazar (Astra Zeneca), Mu rag 1 itazar (BMS), non-TZD derivatives, Tesaglitazar (A stra Zeneca), etc. have been reported. These compounds have PPAR ⁇ as the main action and have been developed as antidiabetic drugs, and it has been reported that the activity of PPAR is not necessarily strong. As PP AR ⁇ selective agonist, phenoxyacetic acid type ⁇ ", C0 2 H
  • GW-50 1 51 6 (G S K) is known, and it has been reported that development is in progress as an agent for improving lipid metabolism.
  • Patent Document 1 Bio rg. Med. Chem. Lett., 1 3 (2 003) 1 5 1 7- 1 5 2 1: Non-Patent Document 3
  • Patent Document 1 includes the following formula:
  • Non-Patent Document 3 described that the P PAR ⁇ activity of the phenylpropionic acid type is about 30 times weaker than that of the phenoxyacetic acid type.
  • Patent Document 1 and Non-Patent Document 3 do not describe the specific medicinal effects of the phenylglycine type.
  • the compounds of the present invention represented by the following general formulas (I), (II) and (III) have a clear structural difference from GW-50 1 5 1 6 etc. These compounds are not described. Disclosure of the invention
  • An object of the present invention is to provide a compound represented by the following general formulas (I), (I I) and (III) having an activating action on a peroxisome proliferator-activated receptor.
  • W 1 and W 2 may be the same or different and each represents CH or a nitrogen atom
  • X represents NR 3 or CR 4 R 5 , wherein R 3 is an alkyl having 1 to 8 carbon atoms Group, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with an alkoxy group having 1 to 8 carbon atoms, and an alkyl group having 3 to 7 membered ring opening.
  • R 4 and R 5 may be the same or different and each represents a hydrogen atom or an alkynole group having 1 to 8 carbon atoms,
  • Y represents one (CR 6 R 7 ) n , where R 6 and R 7 may be the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and n represents 1 to 4 Represents an integer,
  • Z represents a carboxyl group or a tetrazolyl group
  • A is an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered ring alkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or an alkoxy having 1 to 8 carbon atoms.
  • D represents a nitrogen atom or CH
  • E represents an oxygen atom or a sulfur atom
  • R 1 and R 2 may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms.
  • R 13 represents an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom
  • ⁇ represents an integer of 1 to 4,
  • a 1 is substituted with an alkyl group having 1 to 8 carbon atoms or a halogen atom as a substituent.
  • B 1 represents an alkylene group having 2 to 4 carbon atoms
  • R 1 1 and R 12 may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a halogen atom, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom. . )
  • R 2 3 represents an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom
  • q represents an integer of 1 to 4,
  • R 2 ° represents an alkyl group having 1 to 8 carbon atoms
  • B 2 represents an alkylene chain having 2 to 4 carbon atoms
  • an alkyl group of R 2 1 and R 2 2 are the same or different and have good hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a halogen atom or halogen carbon atoms are replaced by an atom 1-8.
  • the present invention also relates to activation of a peroxisome proliferator-activated receptor (PPAR) containing a compound represented by the above general formula (I), (II) or (III) or a salt thereof as an active ingredient. It relates to the agent.
  • PPAR peroxisome proliferator-activated receptor
  • the present invention also contains a compound represented by the above general formula (I), (II) or ( ⁇ ) or a salt thereof and at least one pharmaceutically acceptable excipient.
  • the present invention relates to a pharmaceutical composition.
  • the present invention is also characterized in that a therapeutically effective amount is administered to a patient in need of the compound represented by the general formula (I), (II) or (III) or a salt thereof.
  • the present invention relates to a method for activating PPAR.
  • the present invention is also characterized in that a therapeutically effective amount is administered to a patient in need of the compound represented by the above general formula (I), (II) or (III) or a salt thereof.
  • the present invention relates to a method for treating and / or preventing diseases mediated by PPAR.
  • the disease mediated by PPAR may be hyperlipidemia, dyslipidemia, hypercholesterolemia, hyperTGemia, hypoHDLemia, hyperlipidemia and / or non-HDL Hemopathy, Hyper VLDL, Lipoprotein Abnormal, Hypoapolipoprotein AI, Atherosclerosis, Atherosclerosis, Coronary Artery, Cerebrovascular Disorder, Peripheral Vascular Disorder, Metapolic 'Syndrome, Syndrome X, Obesity including visceral fat obesity, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, fatty liver, nonalcoholic steatohepatitis , Blood plug, Alzheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, abnormal hair growth, inflammation, arthritis, asthma (V
  • the present invention also indicates that the disease mediated by PPAR is various dyslipidemias, metabolic syndrome, obesity including visceral fat obesity, atherosclerosis and related diseases or diabetes.
  • the treatment described in (Vii) above Treatment and / or prevention methods
  • the present invention also relates to the use of a compound represented by the above general formula (I), (I I) or (III) or a salt thereof for the treatment and / or prevention of a disease mediated by PPAR.
  • the disease mediated by PPAR may be hyperlipidemia, dyslipidemia, hypercholesterolemia, hyperTG, hypoHDLemia, high LDL and / or non-HDL , High V LDL, lipoprotein abnormality, hypoapolipoprotein AI, atherosclerosis, arteriosclerotic disease, coronary artery disease, cerebrovascular disorder, peripheral vascular disorder, metapolic syndrome, syndrome X, obesity including visceral fat obesity, diabetes, high blood sugar, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, fatty liver, Nonalcoholic steatohepatitis, blood clot, Alheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, abnormal hair growth, inflammation, arthritis Asthma, Regarding the use described in (X)
  • the present invention also provides that the disease mediated by PPAR is a variety of dyslipidemias, metapolitic syndromes, obesity including visceral fat obesity, atherosclerosis and related diseases or diabetes (X ).
  • the present invention relates to the invention of the P PAR is P PAR S (iv) ⁇ ( X ii). Best mode for carrying out dawn
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and the substitution that the hetero 5 or 6-membered ring of A or the benzene ring may have Base and B
  • the alkyl group having 1 to 8 carbon atoms of the substituent that the alkylene chain having 1 to 8 carbon atoms may have include a methyl group, an ethyl group, a propyl group, an isopropyl group, a ptyl group, and an i-butanol group. , T-butyl group, pentyl group or hexino group.
  • R 1 , R 2 , R 3 and A hetero 5- or 6-membered ring or a benzene ring which may have a alkenyl group having 2 to 8 carbon atoms includes a bur group or an aryl group. Can be mentioned.
  • R 1 , R 2 and A hetero 5 or 6-membered ring or benzene ring which may have a alkynyl group having 2 to 8 carbon atoms of the substituent includes propargyl group and the like
  • R 1 , R 2 and A hetero 5 or 6-membered ring or the substituent that the benzene ring may have and the carbon number of the substituent that the alkylene chain having 1 to 8 carbon atoms of B may have
  • the alkoxy group of 1 to 8 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a ptoxy group, an i-butoxy group, a tert-butoxy group, a pentynoleoxy group, and a hexyloxy group.
  • Examples of the halogen atom of the substituent that the alkylene chain of 1 to 8 carbon atoms of R 1 , R 2 and B may have include a fluorine atom, a chlorine atom, or a bromine atom.
  • R 1, R 2 , R 3 , and A hetero 5 or 6-membered ring or a benzene ring optionally substituted by a halogen atom of a substituent having 1 to 8 carbon atoms include 1 to Examples thereof include a methyl group substituted with a halogen atom such as three fluorine atoms, a chlorine atom or a bromine atom, an ethyl group, a propyl group, an isopropyl group, a butyl group or a t-butyl group, preferably trifluoromethyl.
  • a halogen atom such as three fluorine atoms, a chlorine atom or a bromine atom, an ethyl group, a propyl group, an isopropyl group, a butyl group or a t-butyl group, preferably trifluoromethyl.
  • R 1 , R 2 and A hetero 5 or 6-membered ring or 1 to 3 carbon atoms substituted with a halogen atom of the substituent which the benzene ring may have are 1 to 3 Examples thereof include a methoxy group substituted by a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, an ethoxy group, a propoxy group, an isopropyloxy group, a ptyloxy group or a t-ptyloxy group, preferably trifluoromethyl. Examples thereof include an oxy group, a chloromethylenooxy group, a 2-chloroethenoleoxy group, a 2-promochinenoleoxy group, and a 2-fluoroethyloxy group
  • Examples of the acyl group having 2 to 8 carbon atoms of R 1 R 2 and R 3 include a acetyl group or a propionyl group.
  • Examples of the aryl group having 6 to 10 carbon atoms of the substituent which the 5- or 6-membered ring of R 1 , R 2 and A or the benzene ring may have include a phenyl group.
  • the hetero 5- or 6-membered ring which may be possessed by the hetero ring of R 1 , R 2 and A or the benzene ring may be a pyridyl group or the like.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted by the alkoxy group having 1 to 8 carbon atoms of R 3 include methoxy group, ethoxy group, propoxy group, isopropoxy group, ptoxy group, i-butoxy group, t Examples include a methyl group substituted with a monobutoxy group, a pentyloxy group, a hexyloxy group, or the like, an ethyl group, a propyl group, an isopropyl group, a ptyl group, an i-butyl group, a t_butyl group, a pentyl group, or a hexyl group. .
  • a heterocycle of A 3 to 7-membered cycloalkyl of the substituent which the 5- or 6-membered ring or benzene ring may have and the substituent which the alkylene chain of B 1 to 8 carbon atoms may have Examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • R 3 and A hetero A 5- or 6-membered ring or a 1- to 8-carbon alkyl group substituted with a 3- to 7-membered ring alkyl group which may be substituted on the benzene ring includes A methyl group substituted with a cyclopropinole group, a cycloptyl group, a cyclopentyl group, a cyclohexyl group, etc., an ethyl group, a propyl group, an isopropyl group, a butyl group, i—Butyl group, t-butyl group, pentyl group or hexyl group.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted by the phenyl group of R 3 include a benzyl group and a phenethyl group.
  • Hetero of A or 5- or 6-membered ring which may have a benzene ring or an alkyl group having 1 to 8 carbon atoms substituted by 5- or 6-membered ring includes a pyridylmethyl group, etc. It is done.
  • R 1 1 ! ⁇ 1 2 ! ⁇ 1 3 and A 1 hetero 5 or 6-membered ring or alkyl having 1 to 8 carbon atoms which the benzene ring may have Examples of the group, a halogen atom, and an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom include the hetero 5 or 6 member of I 1 , R 2 , R 3 and A in the general formula (I).
  • R 2 1 , R 2 2 and R 2 3 in the general formula (III) are alkyl groups having 1 to 8 carbon atoms, halogen atoms, and alkyl groups having 1 to 8 carbon atoms substituted with halogen atoms.
  • Illustrative examples include those exemplified by the substituents that the 5-, 6-membered or benzene ring of R 1 , R 2 , R 3 and A in general formula (I) may have. The same can be mentioned.
  • alkyl group having 1 to 8 carbon atoms examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group and hexyl group.
  • R 1 and R 2 in the general formula (I), R 1 1 ! ⁇ 1 2 in the general formula (II) and R 2 1 and R 2 2 in the general formula (III) Ben is replacing There may be 1 to 3 identical or different zen rings.
  • the following compounds are preferred.
  • the compound of the present invention is preferably a compound represented by the above general formula (I) wherein W 1 and W 2 are both CH or a pharmacologically acceptable salt thereof.
  • the compound of the present invention is preferably a compound represented by the above general formula (I) wherein X is CR 4 R 5 , or a compound described in (1) above or a pharmacologically acceptable salt thereof. .
  • the compound of the present invention is preferably a compound represented by the above general formula (I) wherein X is CH 2 , or a compound described in (1) above or a pharmacologically acceptable salt thereof.
  • the compound of the present invention is preferably a compound represented by the above general formula (I) wherein X is NR 3 , or a compound described in (1) above or a pharmacologically acceptable salt thereof.
  • the compound of the present invention includes a compound represented by the above general formula (I) wherein X is N (an alkyl group having 1 to 8 carbon atoms), or a compound described in (1) above or a pharmacologically thereof Acceptable salts are preferred.
  • the compound of the present invention is preferably a compound represented by the above general formula (I) wherein X is N (methyl group), or a compound described in (1) above or a pharmacologically acceptable salt thereof. .
  • the compound of the present invention includes a compound represented by the above general formula (I) wherein Z is a carboxyl group, or a compound according to any one of the above (1) to (7) or a pharmacologically acceptable compound thereof.
  • the salts to be prepared are preferred.
  • A is substituted with an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or a halogen atom.
  • the above general formula (1) is a thiazole or oxazole which may have an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms or a hetero 5 or 6 membered ring.
  • the compound represented by I), the compound according to any one of the above (1) to (8) or a pharmacologically acceptable salt thereof is preferred.
  • the compound of the present invention includes a compound represented by the above general formula (I), wherein A is thiazole or oxazole having an alkyl group having 1 to 8 carbon atoms as a substituent, or the above (1) to (8 Or a pharmacologically acceptable salt thereof.
  • A is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or a carbon atom substituted with a halogen atom.
  • the compound of the present invention includes a compound represented by the above general formula (I), wherein A is a pyrazole having an alkyl group having 1 to 8 carbon atoms as a substituent, or the above (1) to (1)
  • the compound according to any one of (8) or a pharmacologically acceptable salt thereof is preferred.
  • the compound of the present invention includes a compound represented by the above general formula (I) wherein B is an ethylene chain, or a compound according to any one of the above (1) to (12) or a pharmacological compound thereof
  • B is an ethylene chain
  • the salts that are acceptable are preferred.
  • the compound of the present invention is a compound represented by the above general formula (I), wherein D is a nitrogen atom and E is an oxygen atom, or any one of the above (1) to (13) A compound or a pharmacologically acceptable salt thereof is preferred.
  • R 1 and R 2 may be the same or different from each other, a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 2 to 8 carbon atoms, or a carbon number 1
  • a hydrogen atom which is an azoalkoxy group of ⁇ 8, a halogen atom, an alkyl group of 1 to 8 carbon atoms substituted with a halogen atom, or an alkoxy group of 1 to 8 carbon atoms substituted with a halogen atom.
  • a compound described in any one of (1) to (14) or a pharmacologically acceptable salt thereof is a compound described in any one of (1) to (14) or a pharmacologically acceptable salt thereof.
  • R 1 and R 2 may be the same or different, and a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a halogen atom, or a carbon atom substituted with a halogen atom
  • the compound represented by the above general formula (I), which is an alkyl group of 1 to 8, or the compound described in any of the above (1) to (15) or a pharmaceutically acceptable salt thereof is preferable.
  • the compound of the present invention includes a compound represented by the above general formula (I) wherein m is 0, or the compound according to any one of the above (1) to (16) or a pharmacological compound thereof Salts that are acceptable are preferred.
  • the compound of the present invention is represented by the above general formula (II) in which the substitution position of N (R 1 3 ) ((CH 2 ) p -C0 2 H) is the 6-position of benzisoxazole. Or a pharmacologically acceptable salt thereof.
  • the compound of the present invention includes a compound represented by the above general formula (II) wherein R 13 is a methyl group, or a compound described in (18) above or a pharmacologically acceptable salt thereof. preferable.
  • the compound of the present invention includes a compound represented by the above general formula (II) wherein p is 1, or the compound described in (18) or (19) above or a pharmacologically acceptable compound thereof. Are preferred.
  • a 1 is a thiazole, oxazole or benzene ring having a C 1-8 alkyl group as a substituent or a C 1-8 alkyl group substituted with a halogen atom.
  • the compound represented by the above general formula (II), the compound described in any one of the above (18) to (20), or a pharmacologically acceptable salt thereof is preferable.
  • the compound of the present invention includes a compound represented by the above general formula (II), wherein A 1 is thiazole or oxazole having a C 1-8 alkyl group as a substituent, or the above (18) To (20) or a pharmacologically acceptable salt thereof is preferred.
  • the compound of the present invention includes R 1 2 force S, 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.
  • the compound represented by II), the compound according to any one of the above (18) to (24) or a pharmacologically acceptable salt thereof is preferred.
  • the compound of the present invention includes the above general formula (II), wherein R 13 is an alkyl group having 1 to 8 carbon atoms, p is 1, and A 1 is an alkyl group having 1 to 8 carbon atoms as a substituent.
  • Thiazole having B 1 , B 1 is an ethylene chain
  • R 11 is an alkyl group having 1 to 8 carbon atoms, a halogen atom, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom
  • R A compound which is 1 2 force S, 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 or a pharmaceutically acceptable salt thereof is preferable.
  • the compound of the present invention is preferably a compound represented by the above general formula (III), wherein R 23 is a methyl group, or a compound described in (27) or a pharmacologically acceptable salt thereof. .
  • the compound of the present invention includes a compound represented by the above general formula (III) wherein q is 1, or the compound described in (2 7) or (28) above or a pharmacologically acceptable compound thereof. Are preferred.
  • the compound of the present invention includes a compound represented by the above general formula (III), wherein B 2 is an ethylene chain, a compound described in the above (2 7) to (29), or a pharmacologically acceptable
  • B 2 is an ethylene chain
  • the salts to be prepared are preferred.
  • R 2 1 is an alkyl group having 1 to 8 carbon atoms, a halogen atom, or the general is an alkyl group of C port Gen carbon atoms are replaced by an atom 1-8
  • a compound represented by the formula (III), a compound described in the above (27) to (30) or a pharmacologically acceptable salt thereof is preferable.
  • the compound of the present invention is represented by the above general formula (III), which is an R 2 2 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. Or a compound described in the above (27) to (31) or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention represented by the above general formula (I), (II) or (III) may be a pharmacologically acceptable salt, for example, alkali metal salts such as sodium, potassium and lithium, Furthermore, organic amine salts such as lysine, arginine and THAM can be mentioned.
  • the compound of the present invention may contain an optically active substance, a cis or trans geometric isomer, etc., and any of them is included in the present invention.
  • the compound represented by the general formula (c) is represented by the general formula ( It can be obtained by reacting the compound represented by a) with the compound represented by the general formula (b) in a solvent that does not participate in the reaction such as THF in the presence of a base such as LDA.
  • the obtained compound represented by the general formula (c) and the compound represented by the general formula (d) are reacted in a solvent such as DMF in the presence of a base such as sodium hydride.
  • a base such as sodium hydride.
  • the compound can be obtained by the general formula (e).
  • the compound represented by the general formula (f) can be obtained.
  • the PPAR activation action of the compound of the present invention was measured as follows.
  • Receptor expression plasmid (p SG 5— GAL 4— h P PAR o; 0 ryor ⁇ L BD), luciferase expression plasmid (p UC 8— MH 1 00 X4— TK 1 L uc) / 3—galactosidase (p CMX— ⁇ -GAL) expression plasmid was introduced. After gene transfer using lipogenic reagent DMR IE-C, Lip 0fectamin 2000 (Invitrogen), the cells were cultured for 40 hours in the presence of the test compound. Luciferase activity in solubilized cells And / 3— Used for GAL activity measurement.
  • Example 7 As is apparent from Table 16, the compounds of the present invention described in Examples 1 to 5 exhibited an excellent PPAR ⁇ activating action. Furthermore, the compounds of the present invention described in Examples 1, 3, and 5 also showed an excellent PPAR ⁇ activation effect. It should be noted that the compounds of the present invention described in Examples 1 to 5 did not exhibit a P AR y activation action.
  • Example 6 As is clear from Table 18 as well, the compound of the present invention described in Example 6 had an excellent PPAR AR ⁇ activation action.
  • the compounds represented by the general formulas (I), (II) and (III) of the present invention have an excellent PPAR ⁇ activation action, diabetes, hypoglycemic agent, obesity, syndrome X Metabolic disorders such as hypercholesterolemia, hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, heart failure, cardiomyopathy, nonalcoholic steatohepatitis, cardiovascular disease, bulimia, ischemic disease, lung It is expected as a preventive or therapeutic agent for malignant tumors such as cancer, breast cancer, colon cancer, colon cancer, and ovarian cancer, Alzheimer's disease, and inflammatory diseases.
  • malignant tumors such as cancer, breast cancer, colon cancer, colon cancer, and ovarian cancer, Alzheimer's disease, and inflammatory diseases.
  • the compound of the present invention having PPAR ⁇ activation action is expected as a therapeutic agent for hyperlipidemia and a therapeutic agent for arteriosclerosis.
  • the compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.
  • tablets, granules, powders are used in the usual manner in the technical field of pharmaceutical preparations. It can be manufactured in dosage forms such as ⁇ 1 / Li I, capsule, suspension, injection, suppository.
  • usual excipients, disintegrating agents, binders, lubricants, dyes, diluents, etc. are used for these preparations.
  • Example Example 1 the binder include magnesium stearate and talc, and examples of the binder include hydroxypropylcellulose (HP C), gelatin, and polyvinylpyrrolidone (PVP).
  • the dose of the compound of the present invention is approximately 0.1 mg / day; LO Omg, orally 1 mg / 2000 mg / day, but may vary depending on age, symptoms, etc. can do.
  • Example Example 1 the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
  • N-methinoreglicin ethenoreestenole (71 mg, 0.1 3 mmol) is suspended in ethanol (l mL) and water (0.5 mL) and mixed with lithium hydroxide monohydrate (ll mg , 0.27 mmo 1) was added and heated to reflux for 4 hours.
  • the PPAR activation effect of the test compound was measured as follows. ⁇ ⁇ 1 cell (ATCC ⁇ Am ericantyeculturecollection)) receptor expression plasmid (p SG 5—GAL 4—h P PAR o; oror ⁇ LBD), luciferase expression plasmid (p UC 8— MH 10 0 0 X 4 -TK-L uc) and jS monogalactosidase (p CMX- ⁇ -GAL) expression plasmid (K liewer, S. A. et. A 1., (1 9 9 2) Nature, 3 5 8: 7 7 1-7 7 4) was introduced.
  • Luciferase activity is corrected by
  • Test compounds are:
  • P PAR activity The relative value of the test compound when the control drug was 10.0% was calculated, and the concentration of the test compound showing the relative value of 50% was calculated as EC 5 Q (; zM).
  • PP AR activity relative value a of the control drug 1 0 0% test compound 1 0-7 when the M: GW- 5 9 0 7 3 5 1 0- 6 M

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Abstract

Selon l'invention, un composé de formule générale (II) ci-dessous ou un sel de qualité pharmacologique dudit composé est employé en tant qu'agent activant le PPAR. (II) (Dans la formule, R13 représente un groupement alkyle comportant entre 1 et 8 atomes de carbone ou similaire ; p représente un entier compris entre 1 et 4 ; A1 représente un groupement thiazole, oxazole ou similaire portant au titre de substituant un groupement alkyle comportant entre 1 et 8 atomes de carbone ou un groupement alkyle halogéné comportant entre 1 et 8 atomes de carbone ; B1 représente une chaîne alkylène comportant entre 2 et 4 atomes de carbone ; et R11 et R12 sont éventuellement similaires ou différents l'un de l'autre et représentent un atome d'hydrogène, un groupement alkyle comportant entre 1 et 8 atomes de carbone, un atome d'halogène ou un groupement alkyle halogéné comportant entre 1 et 8 atomes de carbone.)
PCT/JP2007/065471 2006-08-03 2007-08-01 Agent activant de récepteur activé par les proliférateurs des peroxysomes WO2008016175A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2009128558A1 (fr) 2008-04-15 2009-10-22 日本ケミファ株式会社 Activateur pour récepteur activé par les proliférateurs de peroxysomes
WO2011043453A1 (fr) * 2009-10-08 2011-04-14 日本ケミファ株式会社 Activateur pour récepteur activé par les proliférateurs de peroxysomes
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
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
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
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
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

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WO2004071509A1 (fr) * 2003-02-12 2004-08-26 Nippon Chemiphar Co., Ltd. Promoteurs de differenciation d'oligodendrocyte
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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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WO1998028254A1 (fr) * 1996-12-24 1998-07-02 Nippon Chemiphar Co., Ltd. Derives d'acide propionique
JP2003503399A (ja) * 1999-06-25 2003-01-28 グラクソ グループ リミテッド チアゾールおよびオキサゾール誘導体ならびにそれらの医薬的使用
WO2001079197A1 (fr) * 2000-04-14 2001-10-25 Nippon Chemiphar Co.,Ltd. Activateurs de ppar$g(d) (peroxisome proliferator activated receptor $g(d))
WO2003033493A1 (fr) * 2001-10-12 2003-04-24 Nippon Chemiphar Co.,Ltd. Activateur du recepteur $g(d) active par le proliferateur de peroxisome
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2009128558A1 (fr) 2008-04-15 2009-10-22 日本ケミファ株式会社 Activateur pour récepteur activé par les proliférateurs de peroxysomes
EP3424917A1 (fr) 2008-04-15 2019-01-09 Nippon Chemiphar Co., Ltd. Activateur du récepteur activé par proliférateur de peroxysome
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor
WO2011043453A1 (fr) * 2009-10-08 2011-04-14 日本ケミファ株式会社 Activateur pour récepteur activé par les proliférateurs de peroxysomes
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
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
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, 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
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

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