+

WO1999011255A1 - Regulateurs du recepteur active par les agents de proliferation des peroxysomes - Google Patents

Regulateurs du recepteur active par les agents de proliferation des peroxysomes Download PDF

Info

Publication number
WO1999011255A1
WO1999011255A1 PCT/JP1998/003760 JP9803760W WO9911255A1 WO 1999011255 A1 WO1999011255 A1 WO 1999011255A1 JP 9803760 W JP9803760 W JP 9803760W WO 9911255 A1 WO9911255 A1 WO 9911255A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
acid
ylmethoxy
group
quinoline
Prior art date
Application number
PCT/JP1998/003760
Other languages
English (en)
Japanese (ja)
Inventor
Hisao Tajima
Yoshisuke Nakayama
Daikichi Fukushima
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to AU87502/98A priority Critical patent/AU8750298A/en
Publication of WO1999011255A1 publication Critical patent/WO1999011255A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups

Definitions

  • the present invention relates to a peroxisome proliferator-activated receptor modulator containing a phenyl derivative, a non-toxic salt thereof, an acid addition salt thereof, and a hydrate thereof as an active ingredient.
  • Activating receptor regulator, and general formula ( ⁇ ) (Wherein all symbols have the same meanings as described below.), A non-toxic salt thereof, a non-toxic salt thereof, an acid addition salt thereof and a hydrate thereof.
  • PPAR receptor Peroxisome Proliferator Activated Receptor
  • cDNAs have been cloned from various animal species, and several isoform genes have been found. In mammals, three species, ", ⁇ , and a" are known (J. Steroid Biochem. Molec Biol., 51, 157 (1994); Gene Expression, 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol.
  • type 7 is mainly expressed in adipose tissue, immune cells, adrenal gland, spleen, and small intestine, and "type is mainly expressed in adipose tissue, liver, and retina, and type is mainly expressed without any tissue specificity. (See Endocrinology, 137. 354-366 (1996)).
  • the thiazolidine derivatives shown below are known as therapeutic agents for non-insulin-dependent diabetes mellitus (NIDDM), and are hypoglycemic agents used to correct hyperglycemia in diabetic patients. It is also a compound that has been shown to be extremely promising as an insulin sensitizer because it is effective in correcting or improving hyperinsulinemia, improving glucose tolerance, and lowering serum lipids.
  • NIDDM non-insulin-dependent diabetes mellitus
  • Troglitazone It has also been found that one of the intracellular target proteins of these thiazolidine derivatives is the PPAR7 receptor, which increases the transcriptional activity of PPARa (Endocrinology, 137: 4189-4195 (1996); Cell). , 83: 803-812 (1995); Cell, 83: 813-
  • PPARa activators that increase the transcriptional activity of PPARa are considered to be promising as hypoglycemic agents or lipid-lowering agents. It is known that PPAR7 agonist enhances the expression of PPARa protein itself (Genes &
  • Drugs that increase the expression of the PPAR7 protein itself are also considered clinically useful.
  • the nuclear receptor PPARa is involved in adipocytes (see J. Biol. Chem., 222, 5637-5670 (1997) and Cell, 83, 803-812 (1995)) and activates it.
  • thiazolidine derivatives which can be converted promote adipocyte differentiation.
  • an antagonist (antagonist) that suppresses PPAR activity or an agent that can reduce the expression of PPAR7 protein itself is considered to be clinically useful.
  • PPARa receptor activator agonist
  • PPARa protein expression regulator which can increase the expression of protein itself are hypoglycemic agents, hypolipidemic agents, diabetes, obesity, syndrome and Metabolic disorders such as hypercholesterolemia, hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, hypertension, cardiovascular disease, bulimia, etc. It is expected to be useful as a prophylactic or therapeutic agent.
  • antagonists that suppress the transcriptional activity of the PPAR7 receptor or PPAR7 protein expression regulators that can suppress the expression of the protein itself include hypoglycemic agents, diabetes, obesity, metabolic disorders such as syndrome X, hyperlipidemia, It is expected to be useful as a prophylactic and / or therapeutic agent for arteriosclerosis, hypertension, bulimia and the like.
  • fibrate compounds for example, clofibrate
  • fibrate compounds for example, clofibrate
  • a PPAR ⁇ receptor modulator to which a fibrate compound can be activated has a lipid-lowering effect, and is useful as a preventive and / or therapeutic agent for hyperlipidemia and the like. It is expected to be.
  • LDL cholesterol and / or VLD L cholesterol It is expected to reduce LDL cholesterol and / or VLD L cholesterol, and to suppress and treat arteriosclerosis progression, and also to suppress obesity. It is a hypoglycemic agent for treating and preventing diabetes, improving hypertension, and improving the risk factor for syndrome X. It is also promising for the prevention of shading and the prevention of ischemic heart disease.
  • PPAR S is sometimes referred to as P PAR, or NUC 1 in humans.
  • P PAR a biological activity of PPAR3
  • W ⁇ 9601430 shows that hNUC IB (PPAR subtype that is one amino acid different from human NUC1) can suppress the transcriptional activity of human PPAR ⁇ and thyroid hormone receptor-1.
  • hNUC IB PPAR subtype that is one amino acid different from human NUC1
  • W0972 8149 compounds (agonists) having high affinity for ⁇ PARS protein and significantly activating P PAR ⁇ have been found, and further, those compounds have been identified as HDL ( High-density lipoprotein) It was reported to have a cholesterol increasing effect.
  • HDL High-density lipoprotein
  • agonists capable of activating PPARS are expected to have an effect of elevating HDL cholesterol, thereby suppressing the progression of arterial sclerosis and its treatment, and being applied as a lipid-lowering agent or a hypoglycemic agent. It is considered to be useful for the treatment of diabetes, the treatment of diabetes mellitus, the reduction of the risk factor of syndrome X, and the prevention of ischemic heart disease.
  • WO 9725042 describes the general formula (A)
  • OA represents 2-benzoxazolyl or 2-pyridyl
  • R 1A represents CH 2 OCH 3 or CF 3
  • solvates are described as agonists of the P PAR "type receptor and the P PAR type receptor.
  • R 1B is selected from a hydrogen atom, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl and C 3-10 cycloalkyl, and the above alkyl, alkenyl, alkynyl, And cycloalkyl may be replaced by one to three R a A ;
  • R 8B is selected from CR 6 BR 7 B, 0, NR 6 B and S (0) p B ;
  • R SB and R 7 B are each independently selected from a hydrogen atom, c 1-6 alkyl
  • BB is selected from 1) to 3) below;
  • the heterocyclic ring may be substituted at any position on the ring, and the heterocyclic ring may be substituted with 1 to 3 R a B.
  • 3) 1) is a 5- or 6-membered heterocyclic ring containing 0 to 2 double bonds and 3 heteroatoms selected from 0, S, N, and a heteroatom of 5 or 6 members
  • the heterocyclic ring may be substituted at any position of the heterocyclic ring, and the heterocyclic ring may be substituted with 1 to 3 R a B.
  • X 1 B and ⁇ 2 ⁇ are each independently a hydrogen atom, 0 H, C 15 alkyl, C 2-15 alkenyl, C 2-15: alkynyl, halogen atom, OR 3 B , OR B CF 3 , C. 5 to 10 Ariru, C. 5 to 10 Ararukiru, selected from C5 ⁇ l 0 Heteroari Le and C. 1 to 10 Ashiru, the alkyl, alkenyl, alkynyl, Ariru and to Teroariru from one to three R a B May be substituted;
  • RaB is halogen atom, Ashiru, Ariru, Heteroariru, CF 3, 0 CF 3,
  • COR 3 B C 0 2 R 3 B, CON (R 3 B) 2 , s 0 2 (R 3 B) 2 , OC ON (R 3 B), one to three of the above aryls and heteroaryls May be substituted with a halogen atom or C 1-6 alkyl;
  • YB is s (0) p B, one CH 2 -, -C (0) one, - C (0) NH-, _NRB -, one 0-, _S0 2 NH-, one NHS0 2 - is selected from,
  • Y I B is selected from 0 and C
  • ZB is selected from C0 2 R 3 B , R 3 B C0 2 3 B > CONH S0 2 Me, CONH 2 and 5_ (1H-tetrazole),
  • t B and V B each independently represent 0 or 1, 8 +: 6 is 1;
  • QB represents a saturated or unsaturated straight-chain 2 to 4 hydrocarbons, and pB is 0 to 2), or a pharmaceutically acceptable salt thereof is a compound of the PP ARS receptor It is described as a regulator.
  • W09727847, W09728115, W09728137, and W09728149 also describe that the same compound as described above is a PPARS receptor modulator.
  • AC is phenyl, which phenyl may be substituted with one or more halogen atoms, C1-6alkyl, C1-3alkoxy, C1-3fluoroalkoxy;
  • BC represents a 5- or 6-membered heterocyclic ring C1-6 alkylene containing at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the heterocyclic ring is Optionally substituted with C 1-3 alkyl;
  • a 1 represents 1 to 3 alkylenes
  • RiC represents a hydrogen atom or C13 alkyl
  • ZC is selected from one (C13 alkylene) phenyl or one NR3 CR4C. ) Or a pharmaceutically acceptable salt thereof is described to have PPAR agonist activity (the explanation of the groups in the formula was excerpted from necessary parts).
  • JP-A-61-267532 discloses a compound represented by the general formula (D)
  • a r 1 D represents a nitrogen, sulfur or oxygen heterocyclic or aromatic ring
  • a rD represents a phenyl ring or a nitrogen, oxygen or sulfur heterocycle
  • Ar D and Ar ID are H , CH 3 , lower alkyl, halo, lower alkoxy,
  • XD represents one 0 (CHR 1D) n D —
  • ZD is an alkylene chain having up to 10 carbon atoms and up to 12 total carbon atoms and 0 2 double bonds in the main chain, wherein the alkylene chain is A through an oxygen, sulfur or amino nitrogen atom. r may be linked to D,
  • R D represents one COR 4 D ;
  • 13 ⁇ 410 is 11 or (:: ⁇ represents 3 ;
  • R4D represents OR 2D ;
  • AE represents one 0—, one CH 2 —,
  • WE represents a C1-C13 alkylene group
  • R 1 E represents a hydrogen atom, a C 1 -C 4 alkyl group, a 4- to 7-membered monocyclic heterocyclic ring containing one saturated or unsaturated nitrogen atom,
  • ⁇ represents an ethylene or vinylene group
  • D ⁇ represents a group represented by 1 BE—BE
  • ZE represents a C3-C11 alkylene or alkenylene group
  • ZE and BE together represent a C3-C22 alkyl group
  • R 3 E represents a hydrogen atom, a halogen atom, C 1 -C 8 alkyl, C 1-8 alkoxy,
  • n E represents an integer of 1 to 3.
  • R IF represents a hydrogen atom, a linear or branched alkyl group or alkoxy group having 1 to 15 carbon atoms
  • R 2 F represents a hydrogen atom or a methyl group
  • R 3 F represents a carboxyl group, a carboxymethyl group, a linear or branched alkoxyl carbonyl group having 2 to 6 carbon atoms, or a linear or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms;
  • R 4 F represents a hydrogen atom, a halogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms
  • X F is one CH 2 0—CH 2 S—, one CH 2 NH—, one CH 2 NR5F—
  • R 5 F represents a linear or branched alkyl group having 1 to 4 carbon atoms.
  • 11 represents 0 1 or 2;
  • ⁇ represents a double bond ( ⁇ ⁇ or ⁇ mixture) or a single bond. It has been described that the substituted phenyl derivative represented by the formula (1), its non-toxic salt or its non-toxic acid addition salt has a leukotriene antagonism, a phospholipase inhibitory action, and a 5-reductase inhibitory action. Is an excerpt of the required part 1 " ⁇ ⁇
  • aryl G contains 0, 1, 2, 3, or 4 N atoms and has no substituent or is a monocyclic aromatic 6-membered ring system substituted with R 5 G And;
  • XG contains 0, 1, 2, 3 or 4 heteroatoms selected from N, 0, S and has no substituent or is substituted with R 1 G, R2 G, R3 G or R4G A monocyclic or polycyclic aromatic or non-aromatic 4- to 10-membered ring system,
  • R1G, R2G, 1 ⁇ 30 ⁇ 4 are independently selected from the group consisting of hydrogen, C1-10alkyl, C1-4alkoxyC0-6alkyl;
  • nG is an integer from 0 to 2
  • ZG and AG are (CH 2 ) mG , (CH 2 ) mG 0 (CH 2 ) n G ,
  • (CH 2 ) mG NR3 G (CH 2 ) nG , (CH 2 ) mG S ⁇ 2 (CH 2 ) nG , (CH 2 ) mG S (CH 2 ) n G , (CH 2 ) mG SO (CH 2 ) is independently selected from n G, wherein mG and nG are Ri integer der independently selected from 0 to 6, provided that when AG is (CH 2) mG, combined with ZG and AG " ⁇ Re
  • R 5 G is hydrogen, C 1-6 alkyl, C 0-6 alkyloxy C 0-6 alkyl, or halogen;
  • R 6G, R 7 G, R 8G, R 9G, R 10 G and R 1 1 G is hydrogen, are independently selected from C 1 to 8 AL kill,
  • R 12G is selected from hydroxy, C 1-8 alkyloxy.
  • a pharmaceutically acceptable salt thereof is a fibrinogen receptor receptor. It has been described that it has gonist activity (necessary parts were extracted for the explanation of the groups in the formula). Disclosure of the invention
  • the present inventors have conducted intensive studies to find a compound having a PPAR receptor controlling action, and as a result, have found that the compound of the present invention represented by the general formula (I) achieves the object, and completed the present invention. .
  • JP-A-61-267532, JP-A-3-261752, JP-A-60-142936 and JP-A-8-504194 has already been known in these publications, and has those actions, namely, lipoxygenase inhibitory action, leukotriene antagonistic action, phospholipase inhibitory action, 5 "-reductase inhibitory action, and fibrinogen receptor antagonist activity. Although it is also known, these facts do not anticipate a PPAR receptor regulatory action.
  • the present invention is a.
  • R 4 represents a hydrogen atom or a C 1-4 alkyl group. ) May be replaced by a group selected from ),
  • R 5 represents a hydrogen atom or a C 1-4 alkyl group. ) May be replaced by a group selected from ),
  • R 8 represents a hydrogen atom or a C 1-4 alkyl group
  • n 0 or 1
  • E 1 and E 3 shall not simultaneously represent a single bond.
  • R 6 represents a hydrogen atom or a C 1-4 alkyl group.
  • Z represents a saturated or partially saturated 5- to 7-membered carbocycle, and A is bonded only to the Cy1 ring.
  • A is a methylene group, an ethylene group, a vinylene group or one S-group having one carbon atom,
  • E 3 represents a single bond
  • E iC 3 to 57 alkylene, C 3 to 5 alkenylene, or C 3 to 5 alkynylene does not represent a ring.
  • A is a methylene group, an ethylene group, a vinylene group or one S-group having one carbon atom,
  • C 1-8 alkylene group (one carbon atom of the C 1-8 alkylene group is One S- group, -SO- group, -S0 2 - in 0- group or a NR4- group (group, - group,
  • R 4 represents a hydrogen atom or a C 1-4 alkyl group. ) May be replaced by a group selected from ),
  • R 5 represents a hydrogen atom or a C 1-4 alkyl group. ) May be replaced by a group selected from forces. ),
  • R 7 represents a hydrogen atom or a C 1-4 alkyl group, which may be replaced by a group selected from:
  • E 1 is 1) Single bond
  • n 0 or 1
  • E 1 and E 3 shall not simultaneously represent a single bond
  • alkyl, alkoxy, alkylene, alkenylene and alkynylene include straight and branched ones, and the double bond in alkenylene is a mixture of E, Z and EZ. Some are included. Also included are isomers (optical isomers) caused by the presence of asymmetric carbon atoms, such as the presence of branched alkyl, alkoxy, alkylene, alkenylene, and alkynylene groups.
  • the C 1-4 alkyl group represented by R 3, R 4, R 5, R 6, R 7, and R 8 is a methyl, ethyl, propyl, butyl, Represents their isomeric groups.
  • the C 1-8 alkyl group represented by the substituent of the carbocyclic and heterocyclic groups in the R 1 and G groups is methyl, ethyl, propyl, butyl, pentyl Hexyl, heptyl, octyl and their isomers.
  • the C 1-8 alkoxy group represented by the substituent of the carbocyclic group and the heterocyclic group in the R 1 and G groups is methoxy, ethoxy, propoxy, butoxy. Pentoxy, hexyloxy, heptyloxy, octyloxy and isomers thereof.
  • the c1-8 alkylene group represented by A, E1, or E3 is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, or octamethylene. Group and it These areomer groups are shown.
  • C 2-8 alkynylene represented by A and E 1 means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene. Groups and their isomeric groups.
  • the C 2-8 alkynylene group represented by E 1 is enylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene. And their isomeric groups.
  • the halogen atom represented by the substituent of the carbocyclic group and the heterocyclic group in the R 1 and G groups is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom .
  • the carbocyclic group represented by G represents a C3-10 monocyclic, bicyclic carbocyclic or bridged carbocyclic ring.
  • C 3-10 monocyclic, bicyclic carbocycles and bridged carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclo Hexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, dihydronaphthalene, tetrahydronaphthalene, perhydrodonaphthalene, indane (dihydroindane), perhydroindene, bicyclopentane, bicyclohexane, Bi
  • the heterocyclic group represented by G means an unsaturated group containing 1 to 3 nitrogen atoms, 1 to 2 oxygen atoms and Z or 1 sulfur atom. Represents a partially or wholly saturated 5- to 15-membered monocyclic or bicyclic heterocyclic group.
  • the groups include pyrroline, pyrrolidine, imidazoline, imidazolidin, pyrazoline, virazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, Hexahydroazepine, dihydrofuran, tetrahydrofuran, dihydrovirane, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiane (dihydrothiopyran), tetrahydrothine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole,
  • the saturated, partially saturated or unsaturated 5- to 7-membered carbon ring represented by the following formula means a ring shown below fused with a benzene ring.
  • A is a group,- ⁇ (C 1-8 alkylene) one group
  • A is preferably a C 3-7 alkylene group (where one carbon atom of the C 3-7 alkylene group is one S— group or one SO— group). , _S0 2 — group, 10 — group or 1 NR 4 — group), C 3-7 alkenylene group (one carbon atom of the above C 3-7 alkenylene is one S- group, one SO- group, - S0 2 - group, one 0-group or
  • — May be replaced by a group selected from —NR 5 — groups.
  • Or ⁇ (C l ⁇ 8 alkylene) - group (wherein C 1 to 8 1 single carbon atom one S- group in the alkylene group, one SO- group, - S0 2 - group, -O- group or - NR7- a may be replaced by a group or al selected the group),
  • yo Ri preferably, one carbon atom is one S- group, one SO- group, _ S 0 2 -. group, — 0—group or
  • C 1-5 alkylene One group (one carbon of the above C 1-5 alkylene group) The elementary atoms have been replaced by one S—, —SO—, —SO 2 —, —0— or one NR7— group. ).
  • R 2 is an C00R3.
  • El is preferably a C1-8 alkylene group or a C2-8 alkenylene group, and more preferably a C1-8 alkylene group.
  • E 2 is preferably a 10-group or a 1S-group, and more preferably a 10-group.
  • a a represents a C 3-7 alkylene group or a C 3-7 alkenylene group-other symbols have the same meanings as described above.
  • a b is 1 carbon atom one S- group C3 ⁇ 7 alkylene group (wherein C. 3 to 7 alkylene group, -SO- group, One S0 2 - group, -O- group or a NR . are replaced by a group selected from 4-group), or C. 3 to 7 alkenylene group (one carbon atom one S- group wherein C3 ⁇ 7 alkenylene group, one SO- group, - S0 2 , A 10-group or a NR4- group.), And the other symbols have the same meanings as described above.), And the general formula (Ic)
  • More preferred compounds include those represented by the general formula (I a a )
  • Specific compounds include the compounds of 1 to 10 shown below, the compounds of Tables 1 to 13, their non-toxic salts, their acid addition salts and their hydrates, and the following examples. The compounds mentioned are mentioned.
  • Me represents a methyl group
  • i-Bu represents an i-butyl group
  • n-Bu represents an n-butyl group
  • other symbols have the same meanings as described above.
  • R2 represents one C 00R3-1 group (wherein, R3-1 represents a C 1-4 alkyl group), A is a single bond, A compound representing a C 1-8 alkylene group or a C 2-8 alkenylene group, that is, a compound represented by the general formula (IA)
  • R3-1 represents a C1-4 alkyl group
  • A1 is a single bond
  • C1-8 alkylene group one carbon atom of the C1-8 alkylene group is one S_ group, one SO- group, one S0 2 -. the group may be replaced by a group selected from _0_ group or a NR4- group), or a C 2 to 8 alkenylene group (wherein C2 ⁇ 8 alkenylene group it is a single carbon atom of a - S- group, -SO- group, - S0 2 - group, one 0 Motoma other one NR 5 -. which may be substituted by a group selected from group) were expressed And the other symbols have the same meanings as described above.)
  • the compound of the present invention represented by the general formula ( ⁇ )
  • E 2 — 1 of the compound represented by the general formula (II) is a SH group or a 10H group
  • an inert organic solvent tetrohydrofuran (THF), methyl ether, methylene chloride
  • Base carbon dioxide, carbon tetrachloride, pentane, hexane, benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphamide (HMPA), etc.
  • the reaction is carried out at 0 to 80 ° C in the presence of sodium hydride, potassium carbonate, triethylamine, pyridine, sodium hydroxide, cesium carbonate, and the like.
  • E 2 — 1 of the compound represented by the general formula ( ⁇ ) is a —NHR 6 group
  • a tertiary amine such as triethylamine may be used in an inert organic solvent as described above or without a solvent as necessary. Performed in the presence at 0-80 ° C.
  • the compound of the present invention represented by the general formula (I-A) converts an ester into an acid (a saponification reaction). Can be produced.
  • the saponification reaction is known, for example,
  • Water-miscible organic solvents THF, dioxane, ethanol, methanol Or an aqueous solution of an alkali (eg, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate) in a mixed solvent thereof,
  • an alkali eg, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate
  • the ring C yc represents a saturated or partially saturated carbocycle
  • the above reaction is known as the Wittig (WMg) reaction or the Horner-Emmons reaction.
  • a base sodium hydride, sodium methoxide
  • an inert solvent ether, tetrahydrofuran, toluene, benzene, etc.
  • Toxide, sodium ethoxide, potassium t-butoxide, etc. at 0 to 80 ° C.
  • the compound represented by the general formula (I-C) can be produced by subjecting the obtained compound to the above-mentioned saponification reaction as required.
  • a compound in which A represents a group of to (C2-8 alkenylene), R2 represents a C00R3 group, and the Cy 1 ring represents a saturated or partially saturated carbocycle, that is, a compound represented by the general formula (I—D)
  • A3-1 represents a single bond or a C1-6 alkylene group, and other symbols have the same meanings as described above.
  • This reaction can be carried out in the same manner as the above-mentioned Wittig reaction or Homner-Emmons reaction. Further, the compound represented by the general formula (ID) can be produced by subjecting the obtained compound to the above-mentioned saponification reaction as required.
  • A ⁇ (C1-8 alkylene) one group (in the C1-8 alkylene group
  • One carbon atom has been replaced by a group selected from one S—, —0— or —NR 6 — group.
  • a 4 ⁇ (C 1-8 alkylene) — group (wherein one carbon atom of the C 1-8 alkylene group is —S— group, — 0— group or 1 NR 6 — Has been replaced by a group selected from the group:), or
  • A4-2 represents one SH group, 10H group, or —NHR4 group
  • A4_3 represents a 1-7 alkylene group or a C2-7 alkenylene group, and other symbols have the same meanings as described above.
  • This reaction can be carried out in the same manner as the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (II).
  • A is ⁇ (C. 1 to 8 alkylene) Single group (wherein, C. 1 to 8 1 carbon atoms one SO- group in the alkylene group or, - S 0 2 - replaced-out location by a group selected from groups ), Or
  • the compound of the present invention represented by the formula (I) can be produced by subjecting a compound represented by the general formula (IE), in which -S is present in one of A 4 groups, to an oxidation reaction.
  • the oxidation reaction is known.
  • a sulfide group is oxidized to a sulfoxide group
  • an organic solvent methylene chloride, chloroform, benzene, hexane, t-butyl alcohol, etc.
  • Agents hydrogen peroxide, sodium periodate
  • a sulfide group is converted to a sulfone group
  • an excess of an oxidizing agent eg, methylene chloride, chloroform, benzene, hexane, t-butyl alcohol
  • an organic solvent eg, methylene chloride, chloroform, benzene, hexane, t-butyl alcohol
  • A ⁇ (C l ⁇ 8 alkylene) Single group (wherein, C l ⁇ 8 1 carbon atoms one S- group alkylene group, -SO- group, - S0 2 - group, one O-group And is replaced by a group selected from the group consisting of one NR6 — group.
  • C 2-8 alkenylene ⁇ (C 2-8 alkenylene) one group (wherein one carbon atom of the C 2-8 alkenylene group is one S— group, — SO— group, — SO 2— group, 10— group or
  • C2-8 alkenylene One group (in the group, C2-8 alkenylene) Carbon atoms of - S- group, - SO- group, - S0 2 - group, - 0- group or
  • the compound of the present invention represented by the general formula (I-E) or the compound represented by the general formula (IF) is subjected to a reaction (saponification reaction) for converting a ester into an acid. It can be manufactured by
  • This reaction can be carried out in the same manner as in the saponification reaction.
  • the above reaction is known.
  • an alkali such as potassium hydroxide, sodium hydroxide, potassium carbonate, or sodium carbonate
  • an inert organic solvent such as methanol, ethanol, or dioxane
  • the reaction is carried out at 0 to 50 ° C using an aqueous solution.
  • the compound represented by the general formula (II) is a known compound, or can be produced by a known method, a method described in Japanese Patent Publication No. 60-142936 and a method described in Japanese Patent Application Laid-Open No. 3-261752, or according to them. it can.
  • the compound represented by the general formula (II) can be produced by the method represented by the following reaction schemes 1 to 6.
  • the compounds represented by the general formulas (IV), (VH) and (VIII) are known compounds or can be produced by a known method.
  • the compounds represented by the reaction step formula 7 can do.
  • the compound represented by the general formula (X) can also be produced by a known method or a method represented by the following reaction scheme 8.
  • ⁇ 2-2 represents a protected —SH group, a monovalent group, or —NHR6 group, ⁇ represents 1 to 6, q represents 0 to 5, but p + Q is 6 or less; Represents a 13-group, a 10-group, or a NR6-group,
  • J 2 one S- group, One SO- group, one S0 2 - represents a group one 0_ group or a NR6- group,
  • Al-1 represents a C 1-6 alkylene group or a C 2-6 alkenylene group
  • R9 represents one SH group, one H group, or one NHR6 group
  • A1-2 represents a C1-7 alkylene group or a C2-7 alkenylene group, r represents 0-3, s represents 1-3, but r + s is 3 or less.
  • the total number of carbon atoms represented Te (CH 2) 6 and Al one 1 Niyotsu is 7 or less.
  • the total number of carbon atoms represented by (CH 2 ) r , (CH 2 ) s and A 3 is 5 or less.
  • TMSN 3 represents trimethylsilyl azide; EDC .HC 1 is 1-ethyl
  • the reaction product is purified by conventional purification means, for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silylation gel or magnesium silicate, thin-layer chromatography, or It can be purified by a method such as column chromatography or washing and recrystallization. Purification may be performed for each reaction or after several reactions.
  • the compounds described herein are converted to salts by known methods.
  • the salt is preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium).
  • Triethylamine methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D- Glucamine and the like).
  • the compound of the present invention represented by the general formula (I) is converted into a corresponding acid addition salt by a known method.
  • the acid addition salts are preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate, Like fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate Organic acid salts.
  • the compound of the present invention or a non-toxic salt thereof described herein can be prepared by a known method. It may be converted to hydrate.
  • TK thymidine kinase
  • a response element of Ga14 protein, a basic transcription factor of yeast, and an enhancer sequence that repeats UAS four times are inserted upstream of the TK promoter to construct 4XUAS—TK—Luc.
  • the target gene was used.
  • the Enhancer sequence used (SEQ ID NO: 1) is shown below. SEQ ID NO: 1 Enhansa sequence obtained by repeating the G a 14 protein response element
  • the DNA encoding the DNA binding region of the G a14 protein, the DNA encoding the amino acid sequence from the 1st to the 147th amino acid sequence, and the DNA coding for the ligand binding region of the human PPARa or ⁇ receptor are in frame. And inserted into the PicaGene Basic Vector 2 downstream of the promoter's enhancer region. At this time, in order to localize the expressed chimeric protein in the nucleus, the amino-terminus of the ligand binding region of human P PAR "or 7 receptor is a nuclear translocation signal derived from SV40 T-antigen, A la Pro Lys.
  • LysLysArgLysValGly (SEQ ID NO: 2) is placed on the other hand, while the hemagglutinin epitope of Influenza is placed at the carboxy terminus as an epitope tag sequence for detection of the expressed protein.
  • TyrProTyrAspVa1 A DNA sequence in which a ProAspTyrAla (SEQ ID NO: 3) and a translation stop codon are arranged in this order.
  • the structural gene portion used as the binding region is described in R. Mukherjee et al. (See J. Steroid Biochem. Molec. Biol., 11, 157 (1994)), ME Green et al. (See Gene Expression, 4, 281 (1995)), Elbrecht et al. (Biochem Biophys. Res. Commun., 224, 431 (19%) or Schmidt et al. (Mol. Endocrinology , 6, 1634 (1992)) from the structural comparison of the human PPAR receptor.
  • Human PPAR ⁇ ligand binding region Ser 16- Tyr 468
  • Human PPARa ligand binding region Serl-6- Tyr 478
  • CV-1 cells used as host cells were cultured according to a conventional method. That is, fetal bovine serum (GIBCOBRL, catalog No. 26140-061) was added to Darbecco's modified Eagle's medium (DMEM) to a final concentration of 10%, and a final concentration of 50 U / m1 was added. The cells were cultured at 37 ° C. in 5% carbon dioxide gas in a medium supplemented with penicillin G and 50 gZm1 of streptomycin sulfate.
  • DMEM Darbecco's modified Eagle's medium
  • the cells were cultured at 37 ° C for 42 hours to lyse the cells, and the luciferase activity was measured according to a conventional method.
  • mice Male Sprague-Dawley (SD) rats (8 rats) were received at the age of 5 to 6 weeks (weight: 140 to 160 g), preliminarily reared for about one week, and the experiment was started. On the day of the experiment
  • the compound of the present invention represented by the general formula (I), a non-toxic salt thereof, an acid addition salt thereof, and a hydrate thereof have an action of controlling a PPAR receptor, and are provided with a hypoglycemic agent, Lipid-lowering drugs, diabetes, obesity, syndrome X, hypercholesterolemia, metabolic disorders such as hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, hypertension, cardiovascular disease, bulimia, ischemic heart disease It is expected to be useful as a prophylactic and / or therapeutic agent, etc., an HDL cholesterol-elevating agent, an agent for reducing LDL cholesterol and / or VLDL cholesterol, and an agent for reducing risk factors for diabetes and syndrome X.
  • a hypoglycemic agent Lipid-lowering drugs, diabetes, obesity, syndrome X, hypercholesterolemia, metabolic disorders such as hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, hypertension, cardiovascular disease, bulimia, ischemic heart disease It is expected to be useful as a prophy
  • the compounds of the present invention represented by the general formula (I) since the compounds of the present invention represented by the general formula (I), their non-toxic salts, their acid addition salts and their hydrates have a PPAR ⁇ agonist effect in particular, they are lipid-lowering agents.
  • Hypoglycemic agent, prophylactic or therapeutic agent for diabetes, obesity, hyperlipidemia, etc., HDL cholesterol increasing agent, LDL cholesterol and / or VLDL cholesterol reducing agent, syndrome X risk factor reducing agent It is expected to be useful as. [toxicity]
  • the toxicity of the compound of the present invention is sufficiently low, and is considered to be sufficiently safe for use as a pharmaceutical.
  • the compound of the present invention represented by the general formula (I), a non-toxic salt thereof, an acid addition salt thereof, or a hydrate thereof for the above-mentioned purpose, the compound is usually orally or non-systemically or locally. It is administered in oral form.
  • Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of 1 mg to 100 mg per adult per dose, once to several times a day.
  • the dose varies depending on various conditions, so that a dose smaller than the above-mentioned dose may be sufficient, or may be required outside the range.
  • Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • one or more active substances may be used as such, or as excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders ( Hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (calcium glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, It is mixed with a solubilizing agent (glutamic acid, aspartic acid, etc.), etc., and used in the form of a formulation according to a conventional method. Also, if necessary, coating agents (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate)
  • capsules of absorbable materials such as gelatin.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • one or more active substances are dissolved, suspended, or emulsified in a commonly used diluent (eg, purified water, ethanol, or a mixture thereof).
  • this liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent, and the like.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent before use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • a solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, or a combination thereof are used.
  • this injection contains a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. May be.
  • a sterile solid preparation for example, a lyophilized product can be produced and then used after dissolving in sterile or sterile distilled water for injection or other solvents before use.
  • compositions for parenteral administration include topical solutions, ointments, liniments, inhalants, sprays, suppositories and intravaginal preparations containing one or more active substances and prescribed in a conventional manner. Pessaries for administration, etc. are included.
  • Sprays contain, in addition to the commonly used diluents, buffers that provide isotonicity with stabilizers such as sodium bisulfite, for example, isotonic agents such as sodium chloride, sodium citrate or citrate It may be. spray The preparation of the agents is described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355. BEST MODE FOR CARRYING OUT THE INVENTION
  • the solvent in Kakko shown in TLC indicates the elution solvent or developing solvent used, and the ratio indicates the ratio.
  • the solvent in the parenthesis shown in the NMR indicates the solvent used for the measurement.
  • Example 1 3- (5-Methoxycarbonylpentyl) phenol, the compound prepared in Reference Examples 9 and 10, or a derivative equivalent thereto, and 2-quinolinemethyl chloride or a derivative equivalent thereto as in Example 1.
  • the following compound of the present invention was obtained by reacting according to the desired operation.
  • Example 2 The compound produced in Reference Example 3 or a derivative thereof was subjected to the same operation as in Reference Example 5—Example 1 to obtain the following compound.
  • Example 2 The compound produced in Reference Example 3 or a derivative thereof was subjected to the same operation as in Reference Example 5—Example 1 to obtain the following compound.
  • Example 2
  • Example 1 (1) to Example 1 (39), Example 1 (41) to Example 1 (43), Example 1 (45) to Example 1 (59) and Example 2-2 (2) By subjecting the compound produced in to the same operation as in Example 3, the following compound of the present invention was obtained. Harm Case 3 (1)
  • TLC Rf 0.58 (ethyl ether drunk);

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des régulateurs du récepteur activé par les agents de prolifération des peroxysomes renfermant pour principe actif des composés représentés par la formule générale(I), des sels non toxiques de ces derniers, des sels d'addition acides de ces derniers ou des hydrates de ces derniers: dans laquelle chaque symbole correspond à la définition donnée dans la description. En raison de leur activité de régulation du récepteur activé par les agents de prolifération des peroxysomes, les composés de la formule générale (I) sont utilisés comme hypoglycémiants, comme hypolipémiants, et comme traitements préventifs et/ou curatifs de maladies causées par des troubles du métabolisme, telles que le diabète, l'obésité, le syndrome X, l'hypercholestérolémie et l'hyperlipoprotéinémie, l'hyperlipidémie, l'artériosclérose, l'hypertension, les maladies circulatoires, l'hyperphagie, les cardiopathies ischémiques, etc.
PCT/JP1998/003760 1997-08-28 1998-08-25 Regulateurs du recepteur active par les agents de proliferation des peroxysomes WO1999011255A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU87502/98A AU8750298A (en) 1997-08-28 1998-08-25 Peroxisome proliferator-activated receptor controllers

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP9/233158 1997-08-28
JP23315897 1997-08-28
JP34882597 1997-12-18
JP9/348825 1997-12-18

Publications (1)

Publication Number Publication Date
WO1999011255A1 true WO1999011255A1 (fr) 1999-03-11

Family

ID=26530881

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/003760 WO1999011255A1 (fr) 1997-08-28 1998-08-25 Regulateurs du recepteur active par les agents de proliferation des peroxysomes

Country Status (2)

Country Link
AU (1) AU8750298A (fr)
WO (1) WO1999011255A1 (fr)

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023442A1 (fr) * 1998-10-16 2000-04-27 Ono Pharmaceutical Co., Ltd. Derives d'acide carboxylique et medicaments contenant ces derives en tant que principe actif
WO2000064888A1 (fr) * 1999-04-28 2000-11-02 Aventis Pharma Deutschland Gmbh Derives diaryle acide en tant que ligands se fixant sur le recepteur ppar
WO2001040170A1 (fr) * 1999-12-03 2001-06-07 Astrazeneca Ab Nouveaux derives phenalkyloxy-phenyle
WO2001070698A1 (fr) * 2000-03-21 2001-09-27 Mitsui Chemicals, Inc. Derives quinoline et utilisation medicinale de ceux-ci
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2002051820A1 (fr) * 2000-12-25 2002-07-04 Ono Pharmaceutical Co., Ltd. Composes derives de dihydronaphtalene et medicaments utilisant ces composes comme ingredient actif
WO2001036351A3 (fr) * 1999-11-19 2002-07-11 Corvas Int Inc Antagonistes de l'inhibiteur des activateurs du plasminogène
JP2003508516A (ja) * 1999-09-07 2003-03-04 スミスクライン・ビーチャム・コーポレイション ビトロネクチン受容体アンタゴニスト
US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
WO2004000315A1 (fr) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Acide phenylalkanoique et derives d'acide phenyloxyalkanoique en tant qu'activateurs de hppar
WO2002100341A3 (fr) * 2001-06-12 2004-07-01 Wellstat Therapeutics Corp Composes destines au traitement de troubles metaboliques
WO2004091604A1 (fr) * 2003-04-17 2004-10-28 Warner-Lambert Company Llc Composes modulant des recepteurs ppar, et leurs procedes de preparation
JP2005508308A (ja) * 2001-07-27 2005-03-31 バイエル・フアーマシユーチカルズ・コーポレーシヨン インダン酢酸誘導体および医薬としてのそれらの使用、中間体および製法
WO2005051373A1 (fr) * 2003-11-26 2005-06-09 Takeda Pharmaceutical Company Limited Agent de regulation de la fonction d'un recepteur
WO2005054213A1 (fr) * 2003-12-02 2005-06-16 Shionogi & Co., Ltd. Derive d'isoxazole presentant un effet agoniste sur le recepteur active par les proliferateurs des peroxysomes
JP2005526834A (ja) * 2002-04-16 2005-09-08 バイエル・フアーマシユーチカルズ・コーポレーシヨン インダン酢酸誘導体および薬剤としてのそれらの使用
WO2005009104A3 (fr) * 2003-07-16 2005-12-29 Ligand Pharmacueticals Inc Derives d'acide benzoique et phenylacetique utilises en tant que modulateurs des recepteurs du facteur hnf-4$g(a)
WO2006050097A1 (fr) * 2004-10-28 2006-05-11 The Institutes For Pharmaceutical Discovery, Llc Acies phenylalcanoiques substitues
JP2006517920A (ja) * 2003-02-13 2006-08-03 ウェルスタット セラピューティクス コーポレイション 代謝性障害の処置のための化合物
WO2006126514A1 (fr) 2005-05-27 2006-11-30 Shionogi & Co., Ltd. Derive d'arylacetate ayant un squelette isoxazole
US7279485B2 (en) 2002-07-09 2007-10-09 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
JP2007532625A (ja) * 2004-04-13 2007-11-15 セファロン インコーポレイティド チオ置換アリールメタンスルフィニル誘導体
WO2008020037A1 (fr) * 2006-08-16 2008-02-21 Action Medicines, S.L. Utilisation de dérivés de 2,5-dihydroxybenzène pour le traitement de l'obésité, de l'hirsutisme, de l'hypertricose et des verrues virales
US7358364B2 (en) 2003-04-30 2008-04-15 The Institute For Pharmaceutical Discovery Llc Substituted carboxylic acids
JP2008515981A (ja) * 2004-10-12 2008-05-15 デコード ジェネティクス イーエイチエフ 閉塞性動脈疾患のためのカルボン酸ペリ置換二環式化合物
JP2008526904A (ja) * 2005-01-14 2008-07-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング ヒドロキシフェノール誘導体、その調製方法、それらを含む医薬組成物、およびその治療的使用
US7442796B2 (en) * 2003-04-30 2008-10-28 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7456218B2 (en) 2003-12-25 2008-11-25 Takeda Pharmaceutical Company Limited 3-(4-benzyloxyphenyl) propanoic acid derivatives
US7572934B2 (en) 2007-04-16 2009-08-11 Amgen Inc. Substituted biphenyl GPR40 modulators
US7579479B2 (en) 1999-09-22 2009-08-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7582803B2 (en) 2005-09-14 2009-09-01 Amgen Inc. Conformationally constrained 3-(4-hydroxy-phenyl)-substituted-propanoic acids useful for treating metabolic disorders
US7585880B2 (en) 2003-12-26 2009-09-08 Takeda Pharmaceutical Company Limited Phenylpropanoic acid derivatives
US7649110B2 (en) 2004-02-27 2010-01-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
EP1559422A4 (fr) * 2002-11-08 2010-02-24 Takeda Pharmaceutical Agent de controle de la fonction recepteur
US7687526B2 (en) 2006-09-07 2010-03-30 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
US7714008B2 (en) 2006-09-07 2010-05-11 Amgen Inc. Heterocyclic GPR40 modulators
JP2010529098A (ja) * 2007-06-05 2010-08-26 ガルデルマ・リサーチ・アンド・デヴェロップメント Ｐｐａｒ型受容体の活性化剤である新規な３‐フェニルプロパン酸誘導体、その製造方法、および化粧品組成物または医薬組成物におけるその使用
US7820837B2 (en) 2003-05-30 2010-10-26 Takeda Pharmaceutical Company Limited Condensed ring compound
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
US7939528B2 (en) 2005-10-13 2011-05-10 Glaxosmithkline Llc Heterocycle compounds
US8030354B2 (en) 2007-10-10 2011-10-04 Amgen Inc. Substituted biphenyl GPR40 modulators
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
JP2012512893A (ja) * 2008-12-18 2012-06-07 メタボレックス， インコーポレイテッド Ｇｐｒ１２０受容体作動薬およびその使用
US8450522B2 (en) 2008-03-06 2013-05-28 Amgen Inc. Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders
US8541618B2 (en) 2001-07-27 2013-09-24 Bayer Healthcare Llc Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation
KR20140060242A (ko) * 2012-11-09 2014-05-19 주식회사 엘지생명과학 Gpr40 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
US8748462B2 (en) 2008-10-15 2014-06-10 Amgen Inc. Spirocyclic GPR40 modulators
KR20140104376A (ko) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
JP2017507189A (ja) * 2014-03-07 2017-03-16 ヤンセン ファーマシューティカ エヌ．ベー． Ｉｉ型糖尿病を処置するためのｇｐｒ１２０アゴニストとしてのイソチアゾール誘導体
CN110092774A (zh) * 2018-01-29 2019-08-06 中国科学院上海药物研究所 芳香丙酸类衍生物、及其制备方法和用途
CN112824394A (zh) * 2019-11-21 2021-05-21 中国科学院上海药物研究所 PPARs-FXR多靶点小分子激动剂及其制备方法和用途
WO2022053013A1 (fr) * 2020-09-10 2022-03-17 上海爱博医药科技有限公司 Composé hétérocyclique contenant de l'oxygène benzo et son application médicale
KR20220142387A (ko) * 2021-04-14 2022-10-21 주식회사 엘지화학 스핑고신-1-인산 수용체 효능제 합성을 위한 중간체의 제조방법

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02218654A (ja) * 1988-10-12 1990-08-31 Ono Pharmaceut Co Ltd 安息香酸誘導体、それらの製造方法およびそれらを含有する薬剤
EP0657422A1 (fr) * 1993-12-09 1995-06-14 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide naphtylacétique comme agonistes et antagonistes de PGEZ
EP0719760A1 (fr) * 1994-12-28 1996-07-03 Ono Pharmaceutical Co., Ltd. Dérivés d'acide naphtyloxyacétique et leur utilisation comme agonistes et antagonistes de PGE2
WO1997005091A1 (fr) * 1995-07-26 1997-02-13 Ono Pharmaceutical Co., Ltd. Derives d'acide naphtyloxyacetique et medicaments integrant ces derives comme principes actifs
WO1997027847A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Methode de traitement du diabete et d'etats pathologiques associes
WO1997028137A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Derives heterocycliques utilises comme agents contre le diabete et contre l'obesite
WO1997027857A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Agents antidiabetiques
WO1998027974A1 (fr) * 1996-12-23 1998-07-02 Merck & Co., Inc. Agents antidiabetiques

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02218654A (ja) * 1988-10-12 1990-08-31 Ono Pharmaceut Co Ltd 安息香酸誘導体、それらの製造方法およびそれらを含有する薬剤
EP0657422A1 (fr) * 1993-12-09 1995-06-14 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide naphtylacétique comme agonistes et antagonistes de PGEZ
EP0719760A1 (fr) * 1994-12-28 1996-07-03 Ono Pharmaceutical Co., Ltd. Dérivés d'acide naphtyloxyacétique et leur utilisation comme agonistes et antagonistes de PGE2
WO1997005091A1 (fr) * 1995-07-26 1997-02-13 Ono Pharmaceutical Co., Ltd. Derives d'acide naphtyloxyacetique et medicaments integrant ces derives comme principes actifs
WO1997027847A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Methode de traitement du diabete et d'etats pathologiques associes
WO1997028137A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Derives heterocycliques utilises comme agents contre le diabete et contre l'obesite
WO1997027857A1 (fr) * 1996-02-02 1997-08-07 Merck & Co., Inc. Agents antidiabetiques
WO1998027974A1 (fr) * 1996-12-23 1998-07-02 Merck & Co., Inc. Agents antidiabetiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PINEAU T., ET AL.: "ACTIVATION OF A HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR BY THE ANTITUMOR AGENT PHENYLACETATE AND ITS ANALOGS.", BIOCHEMICAL PHARMACOLOGY, ELSEVIER, US, vol. 52., no. 04., 1 January 1996 (1996-01-01), US, pages 659 - 667., XP002914757, ISSN: 0006-2952, DOI: 10.1016/0006-2952(96)00340-1 *

Cited By (125)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6821994B2 (en) 1998-10-16 2004-11-23 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivative and a pharmaceutical composition containing the derivative as active ingredient
WO2000023442A1 (fr) * 1998-10-16 2000-04-27 Ono Pharmaceutical Co., Ltd. Derives d'acide carboxylique et medicaments contenant ces derives en tant que principe actif
WO2000064888A1 (fr) * 1999-04-28 2000-11-02 Aventis Pharma Deutschland Gmbh Derives diaryle acide en tant que ligands se fixant sur le recepteur ppar
KR100709498B1 (ko) * 1999-04-28 2007-04-20 사노피-아벤티스 도이칠란트 게엠베하 Ｐｐａｒ 수용체 리간드로서의 디아릴 산 유도체
USRE40558E1 (en) 1999-04-28 2008-10-28 Sanofi-Aventis Deutschland Gmbh Therapeutic uses of di-aryl acid derivatives
US6635655B1 (en) 1999-04-28 2003-10-21 Aventis Pharma Deutschland Gmbh Therapeutic uses of di-aryl acid derivatives
JP2003508516A (ja) * 1999-09-07 2003-03-04 スミスクライン・ビーチャム・コーポレイション ビトロネクチン受容体アンタゴニスト
US7241780B2 (en) 1999-09-22 2007-07-10 Bristols-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6653314B2 (en) 1999-09-22 2003-11-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6727271B2 (en) 1999-09-22 2004-04-27 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7579479B2 (en) 1999-09-22 2009-08-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7053106B2 (en) 1999-09-22 2006-05-30 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6919358B2 (en) 1999-09-22 2005-07-19 Bristol-Meyers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7084162B2 (en) 1999-09-22 2006-08-01 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2001036351A3 (fr) * 1999-11-19 2002-07-11 Corvas Int Inc Antagonistes de l'inhibiteur des activateurs du plasminogène
US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
WO2001040170A1 (fr) * 1999-12-03 2001-06-07 Astrazeneca Ab Nouveaux derives phenalkyloxy-phenyle
US6630509B2 (en) 1999-12-03 2003-10-07 Astrazeneca Ab Phenalkyloxy-phenyl derivatives
WO2001070698A1 (fr) * 2000-03-21 2001-09-27 Mitsui Chemicals, Inc. Derives quinoline et utilisation medicinale de ceux-ci
WO2002051820A1 (fr) * 2000-12-25 2002-07-04 Ono Pharmaceutical Co., Ltd. Composes derives de dihydronaphtalene et medicaments utilisant ces composes comme ingredient actif
KR100718906B1 (ko) * 2000-12-25 2007-05-18 오노 야꾸힝 고교 가부시키가이샤 디히드로나프탈렌 유도체 화합물 및 이 화합물을 유효성분으로 하는 약제
EP1726586A1 (fr) * 2000-12-25 2006-11-29 Ono Pharmaceutical Co., Ltd. Composés dérivés de dihydronaphtalène et médicaments utilisant ces composés comme ingrédient actif
US7220864B2 (en) 2000-12-25 2007-05-22 Ono Pharmaceutical Co., Ltd. Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredient
RU2268262C2 (ru) * 2000-12-25 2006-01-20 Оно Фармасьютикал Ко., Лтд. Производные дигидронафталина и лекарственное средство, включающее указанные производные в качестве активного ингредиента
CN100357280C (zh) * 2000-12-25 2007-12-26 小野药品工业株式会社 二氢化萘衍生物及包含该衍生物作为活性成分的药物
US7547802B2 (en) 2001-06-12 2009-06-16 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
KR100959356B1 (ko) * 2001-06-12 2010-05-20 웰스테트 테라퓨틱스 코포레이션 대사 질환의 치료용 화합물
KR101009472B1 (ko) * 2001-06-12 2011-01-19 웰스테트 테라퓨틱스 코포레이션 대사 질환의 치료용 화합물
AU2007203009B2 (en) * 2001-06-12 2011-01-20 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7012071B2 (en) 2001-06-12 2006-03-14 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7041659B2 (en) 2001-06-12 2006-05-09 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US8604083B2 (en) 2001-06-12 2013-12-10 Wellstat Therapeutics Corporation Method for the treatment of metabolic disorders
US7045541B2 (en) 2001-06-12 2006-05-16 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US6924314B2 (en) 2001-06-12 2005-08-02 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US6916848B2 (en) 2001-06-12 2005-07-12 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7863475B2 (en) 2001-06-12 2011-01-04 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7101910B2 (en) 2001-06-12 2006-09-05 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US6946491B2 (en) 2001-06-12 2005-09-20 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US8552062B2 (en) 2001-06-12 2013-10-08 Wellstat Therapeutics Corporation Methods for the treatment of metabolic disorders such as diabetes
US8487000B2 (en) 2001-06-12 2013-07-16 Wellstat Therapertics Corporation Compound for the treatment of metabolic disorders
KR101059776B1 (ko) 2001-06-12 2011-08-26 웰스테트 테라퓨틱스 코포레이션 대사 질환의 치료용 화합물
US6858602B2 (en) 2001-06-12 2005-02-22 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
WO2002100341A3 (fr) * 2001-06-12 2004-07-01 Wellstat Therapeutics Corp Composes destines au traitement de troubles metaboliques
AU2002345625B2 (en) * 2001-06-12 2007-08-02 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7329782B2 (en) 2001-06-12 2008-02-12 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
CN100344616C (zh) * 2001-06-12 2007-10-24 维尔斯达医疗公司 用于治疗代谢失调的化合物
JP2005501012A (ja) * 2001-06-12 2005-01-13 ウェルスタット セラピューティクス コーポレイション 代謝障害治療用化合物
US8552203B2 (en) 2001-07-27 2013-10-08 Bayer Healthcare Llc Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation
US8541618B2 (en) 2001-07-27 2013-09-24 Bayer Healthcare Llc Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation
JP2005508308A (ja) * 2001-07-27 2005-03-31 バイエル・フアーマシユーチカルズ・コーポレーシヨン インダン酢酸誘導体および医薬としてのそれらの使用、中間体および製法
JP2005526834A (ja) * 2002-04-16 2005-09-08 バイエル・フアーマシユーチカルズ・コーポレーシヨン インダン酢酸誘導体および薬剤としてのそれらの使用
AU2003245962B2 (en) * 2002-06-19 2008-07-03 Smithkline Beecham Corporation Phenylalkanoic acid and phenyloxyalkanoic acid derivatives as hPPAR activators
WO2004000315A1 (fr) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Acide phenylalkanoique et derives d'acide phenyloxyalkanoique en tant qu'activateurs de hppar
US7279485B2 (en) 2002-07-09 2007-10-09 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
US7951793B2 (en) 2002-07-09 2011-05-31 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
US7960369B2 (en) 2002-11-08 2011-06-14 Takeda Pharmaceutical Company Limited Receptor function regulator
EP1559422A4 (fr) * 2002-11-08 2010-02-24 Takeda Pharmaceutical Agent de controle de la fonction recepteur
EP2385032A1 (fr) * 2002-11-08 2011-11-09 Takeda Pharmaceutical Company Limited Régulateur de fonction de récepteur GPR40
US7605181B2 (en) 2003-02-13 2009-10-20 Wellstat Therapeutics Orporation Method for the treatment of metabolic disorders
JP2006517920A (ja) * 2003-02-13 2006-08-03 ウェルスタット セラピューティクス コーポレイション 代謝性障害の処置のための化合物
KR101106631B1 (ko) * 2003-02-13 2012-01-20 웰스태트 테러퓨틱스 코포레이션 대사 질환의 치료용 화합물
JP2009242434A (ja) * 2003-02-13 2009-10-22 Wellstat Therapeutics Corp 代謝性障害の処置のための化合物
US7615575B2 (en) 2003-02-13 2009-11-10 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7932290B2 (en) 2003-02-13 2011-04-26 Wellstat Biologics Corporation Method for the treatment of metabolic disorders
EP2266946A3 (fr) * 2003-02-13 2012-12-12 Wellstat Therapeutics Corporation Composé pour le traitement des troubles métaboliques
NL1025961C2 (nl) * 2003-04-17 2005-02-15 Warner Lambert Co Verbindingen die ppar-activiteit moduleren en werkwijzen voor de bereiding daarvan.
WO2004091604A1 (fr) * 2003-04-17 2004-10-28 Warner-Lambert Company Llc Composes modulant des recepteurs ppar, et leurs procedes de preparation
US7442796B2 (en) * 2003-04-30 2008-10-28 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US7358364B2 (en) 2003-04-30 2008-04-15 The Institute For Pharmaceutical Discovery Llc Substituted carboxylic acids
US7749990B2 (en) 2003-04-30 2010-07-06 Wellstat Therapeutics Corporation Compositions for the treatment of metabolic disorders
US7820837B2 (en) 2003-05-30 2010-10-26 Takeda Pharmaceutical Company Limited Condensed ring compound
WO2005009104A3 (fr) * 2003-07-16 2005-12-29 Ligand Pharmacueticals Inc Derives d'acide benzoique et phenylacetique utilises en tant que modulateurs des recepteurs du facteur hnf-4$g(a)
US8008525B2 (en) 2003-11-26 2011-08-30 Takeda Pharmaceutical Company Limited Receptor function regulating agent
WO2005051373A1 (fr) * 2003-11-26 2005-06-09 Takeda Pharmaceutical Company Limited Agent de regulation de la fonction d'un recepteur
JP4922615B2 (ja) * 2003-11-26 2012-04-25 武田薬品工業株式会社 受容体機能調節剤
WO2005054213A1 (fr) * 2003-12-02 2005-06-16 Shionogi & Co., Ltd. Derive d'isoxazole presentant un effet agoniste sur le recepteur active par les proliferateurs des peroxysomes
US7456218B2 (en) 2003-12-25 2008-11-25 Takeda Pharmaceutical Company Limited 3-(4-benzyloxyphenyl) propanoic acid derivatives
US7585880B2 (en) 2003-12-26 2009-09-08 Takeda Pharmaceutical Company Limited Phenylpropanoic acid derivatives
US7816367B2 (en) 2004-02-27 2010-10-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
US7649110B2 (en) 2004-02-27 2010-01-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
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
JP2007532625A (ja) * 2004-04-13 2007-11-15 セファロン インコーポレイティド チオ置換アリールメタンスルフィニル誘導体
JP2008515981A (ja) * 2004-10-12 2008-05-15 デコード ジェネティクス イーエイチエフ 閉塞性動脈疾患のためのカルボン酸ペリ置換二環式化合物
WO2006050097A1 (fr) * 2004-10-28 2006-05-11 The Institutes For Pharmaceutical Discovery, Llc Acies phenylalcanoiques substitues
JP2008526904A (ja) * 2005-01-14 2008-07-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング ヒドロキシフェノール誘導体、その調製方法、それらを含む医薬組成物、およびその治療的使用
US7781469B2 (en) 2005-05-27 2010-08-24 Shionogi & Co., Ltd. Arylacetate derivatives having isoxazole skeleton
WO2006126514A1 (fr) 2005-05-27 2006-11-30 Shionogi & Co., Ltd. Derive d'arylacetate ayant un squelette isoxazole
US7582803B2 (en) 2005-09-14 2009-09-01 Amgen Inc. Conformationally constrained 3-(4-hydroxy-phenyl)-substituted-propanoic acids useful for treating metabolic disorders
US7939528B2 (en) 2005-10-13 2011-05-10 Glaxosmithkline Llc Heterocycle compounds
WO2008020037A1 (fr) * 2006-08-16 2008-02-21 Action Medicines, S.L. Utilisation de dérivés de 2,5-dihydroxybenzène pour le traitement de l'obésité, de l'hirsutisme, de l'hypertricose et des verrues virales
US8003648B2 (en) 2006-09-07 2011-08-23 Amgen Inc. Heterocyclic GPR40 modulators
US7687526B2 (en) 2006-09-07 2010-03-30 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
US7714008B2 (en) 2006-09-07 2010-05-11 Amgen Inc. Heterocyclic GPR40 modulators
US7572934B2 (en) 2007-04-16 2009-08-11 Amgen Inc. Substituted biphenyl GPR40 modulators
JP2010529098A (ja) * 2007-06-05 2010-08-26 ガルデルマ・リサーチ・アンド・デヴェロップメント Ｐｐａｒ型受容体の活性化剤である新規な３‐フェニルプロパン酸誘導体、その製造方法、および化粧品組成物または医薬組成物におけるその使用
US8030354B2 (en) 2007-10-10 2011-10-04 Amgen Inc. Substituted biphenyl GPR40 modulators
US8450522B2 (en) 2008-03-06 2013-05-28 Amgen Inc. Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders
US8748462B2 (en) 2008-10-15 2014-06-10 Amgen Inc. Spirocyclic GPR40 modulators
JP2012512893A (ja) * 2008-12-18 2012-06-07 メタボレックス， インコーポレイテッド Ｇｐｒ１２０受容体作動薬およびその使用
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
RU2650506C2 (ru) * 2012-11-09 2018-04-16 ЭлДжи КЕМ, ЛТД. Агонист рецептора gpr40, способы его получения и фармацевтические композиции, содержащие его в качестве активного ингредиента
KR101984629B1 (ko) * 2012-11-09 2019-05-31 주식회사 엘지화학 Gpr40 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
JP2018184454A (ja) * 2012-11-09 2018-11-22 エルジー・ケム・リミテッド Ｇｐｒ４０受容体アゴニスト、この製造方法およびこれを活性成分として含有する医薬組成物
JP2016503409A (ja) * 2012-11-09 2016-02-04 エルジー・ライフ・サイエンシーズ・リミテッドＬＧ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． Ｇｐｒ４０受容体アゴニスト、この製造方法およびこれを活性成分として含有する医薬組成物
EP2917180A4 (fr) * 2012-11-09 2016-04-27 Lg Life Sciences Ltd Agoniste du récepteur gpr40, procédés de préparation de celui-ci, et compositions pharmaceutiques contenant celui-ci en tant que substance active
AU2013341945B2 (en) * 2012-11-09 2018-07-12 Lg Chem, Ltd. GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
KR20140060242A (ko) * 2012-11-09 2014-05-19 주식회사 엘지생명과학 Gpr40 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
US9988379B2 (en) 2012-11-09 2018-06-05 Lg Chem, Ltd. GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
EP2958913A4 (fr) * 2013-02-20 2016-10-05 Lg Life Sciences Ltd Agonistes des récepteurs de la sphingosine-1-phosphate, leurs procédés de préparation, et compositions pharmaceutiques les contenant en tant que principe actif
KR101939657B1 (ko) * 2013-02-20 2019-01-17 주식회사 엘지화학 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
KR20140104376A (ko) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
RU2654483C2 (ru) * 2013-02-20 2018-05-21 ЭлДжи КЕМ, ЛТД. Агонисты рецептора сфингозин-1-фосфата, способы их получения и фармацевтические композиции, содержащие эти соединения в качестве активного средства
US9540362B2 (en) * 2013-02-20 2017-01-10 Lg Life Sciences Ltd. Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
JP2016513126A (ja) * 2013-02-20 2016-05-12 エルジー・ライフ・サイエンシーズ・リミテッドＬＧ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． スフィンゴシン−１−リン酸受容体アゴニスト、その製造方法及びそれらを活性成分として含有する医薬組成物
US20150376173A1 (en) * 2013-02-20 2015-12-31 Lg Life Sciences Ltd. Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
AU2014219575B2 (en) * 2013-02-20 2017-07-06 Lg Chem, Ltd. Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
JP2017507189A (ja) * 2014-03-07 2017-03-16 ヤンセン ファーマシューティカ エヌ．ベー． Ｉｉ型糖尿病を処置するためのｇｐｒ１２０アゴニストとしてのイソチアゾール誘導体
CN110092774A (zh) * 2018-01-29 2019-08-06 中国科学院上海药物研究所 芳香丙酸类衍生物、及其制备方法和用途
CN110092774B (zh) * 2018-01-29 2022-04-08 中国科学院上海药物研究所 芳香丙酸类衍生物、及其制备方法和用途
CN112824394A (zh) * 2019-11-21 2021-05-21 中国科学院上海药物研究所 PPARs-FXR多靶点小分子激动剂及其制备方法和用途
CN112824394B (zh) * 2019-11-21 2024-08-13 中国科学院上海药物研究所 PPARs-FXR多靶点小分子激动剂及其制备方法和用途
WO2022053013A1 (fr) * 2020-09-10 2022-03-17 上海爱博医药科技有限公司 Composé hétérocyclique contenant de l'oxygène benzo et son application médicale
KR20220142387A (ko) * 2021-04-14 2022-10-21 주식회사 엘지화학 스핑고신-1-인산 수용체 효능제 합성을 위한 중간체의 제조방법
KR102658762B1 (ko) 2021-04-14 2024-04-19 주식회사 엘지화학 스핑고신-1-인산 수용체 효능제 합성을 위한 중간체의 제조방법

Also Published As

Publication number Publication date
AU8750298A (en) 1999-03-22

Similar Documents

Publication Publication Date Title
WO1999011255A1 (fr) Regulateurs du recepteur active par les agents de proliferation des peroxysomes
JP4345230B2 (ja) カルボン酸誘導体およびその誘導体を有効成分として含有する薬剤
JP5763072B2 (ja) Ｗｎｔシグナル経路のインダゾール阻害剤およびその治療的使用
KR100927915B1 (ko) 통증 치료에 유용한 ｎ-(ｎ-설폰일아미노메틸)사이클로프로판카복사마이드 유도체
EP2154130A1 (fr) Composé de pyridone
TW591020B (en) 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
JP2001516338A (ja) マトリックスメタロプロテイナーゼ・インヒビターとしてのβ―スルホニルヒドロキサム酸
JP2002527496A (ja) 化学化合物
JP2001508796A (ja) トロンビン阻害薬
JP2001524462A (ja) マトリックスメタロプロテイナーゼインヒビターとしてのβ−スルホニルヒドロキサム酸のα−ヒドロキシ、−アミノ及びハロ誘導体
GB2276383A (en) Pharmaceutically active ring fused imidazoles
GB2277446A (en) Quinazolinones useful as endothelin antagonists
US6821994B2 (en) Carboxylic acid derivative and a pharmaceutical composition containing the derivative as active ingredient
EP0223593A2 (fr) Acides et esters phénoxyalcoylcarboxyliques, leur préparation ainsi que leur formule pharmaceutique
AU2017309751A1 (en) Sulfonamides as GPR40- and GPR120-agonists
EP1405848B1 (fr) Compose derive de tetrahydroquinoline et medicament contenant ledit compose comme principe actif
US6664281B1 (en) Carboxylic acid derivatives and drugs containing the same as the active ingredient
KR19990087484A (ko) 아미드 결합을 포함하는 신규의 황 유도체, 그의 제조방법,약물로서 그의 용도, 및 그를 함유하는 제약 조성물
WO1995005372A1 (fr) Derive de cyclopentane a activite antagoniste de l'endotheline
JP3185700B2 (ja) ペプチジルアルデヒド誘導体およびその用途
JP2002506851A (ja) カルボン酸類およびアシルスルホンアミド類、そのような化合物を含む組成物ならびに治療方法
JP3999939B2 (ja) ぺプチジルアルデヒド誘導体およびその用途
TW202440095A (zh) 三環性化合物
JP2003212831A (ja) アミノブタン酸誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载