WO1999012534A1 - Regulateurs des recepteurs actives par le proliferateur des peroxisomes - Google Patents

Regulateurs des recepteurs actives par le proliferateur des peroxisomes Download PDF

Info

Publication number
WO1999012534A1
WO1999012534A1 PCT/JP1998/003930 JP9803930W WO9912534A1 WO 1999012534 A1 WO1999012534 A1 WO 1999012534A1 JP 9803930 W JP9803930 W JP 9803930W WO 9912534 A1 WO9912534 A1 WO 9912534A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
atom
alkyl group
hydrogen atom
alkyl
Prior art date
Application number
PCT/JP1998/003930
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 AU89966/98A priority Critical patent/AU8996698A/en
Publication of WO1999012534A1 publication Critical patent/WO1999012534A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to a peroxisome proliferator-activated receptor regulator containing a compound represented by the general formula (I), a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof as an active ingredient.
  • a peroxisome proliferator-activated receptor containing a compound represented by the following formula, a non-toxic salt thereof, an acid addition salt thereof and a hydrate thereof as an active ingredient. It relates to a body control agent.
  • PPAR receptor Peroxisome Proliferator Activated Receptor
  • a type is mainly adipose tissue, immune cells, adrenal gland, spleen, small intestine It is known that the cast is mainly expressed in adipose tissue, liver, and retina, and the type 5 is expressed in a tight manner without any tissue specificity (Endocrinology, 137, 354-366 (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.
  • NIDDM non-insulin-dependent diabetes mellitus
  • it is an effective compound for correcting or improving hyperinsulinemia, improving glucose tolerance, and lowering serum lipids, and is considered to be extremely promising as an insulin sensitizer.
  • P PAR 7 receptor intracellular target proteins of these thiazolidine derivatives to increase the transcription activity of PPAR y is known (Endocrinology, 137: 4189-4195 (1996 ); Cell, 83: 803-812 (1995); Cell, 83: 813-819 (1995); J. Biol. Chem., 270: 12953-12956 (1995)). Therefore, a PPARa activator (agonist) that increases the transcriptional activity of PPARa is considered to be promising as a hypoglycemic agent and / or a lipid lowering agent. It is also known that PPAR7 agonist enhances the expression of PPARy protein itself (Genes & Development, 10: 974-984 (1996)). Drugs that increase the expression of the protein itself are also considered clinically useful.
  • the nuclear receptor PP A is involved in adipocyte differentiation (J. Biol. Chem., 272, 5637-5670 (1997) and Cell, £ 3, 803-812 (1995)), and thiazolidine derivatives capable of activating this are known to promote adipocyte differentiation. Recently, it has been reported that thiazolidine derivatives increase body fat and cause weight gain and obesity in humans (see Lance 249, 952 (1997)). Therefore, an antagonist that suppresses PPARa activity (antagonist) and a drug that can reduce the expression of PPARa protein itself are considered to be clinically useful. By the way, Science, 24: 2100-2103 (1996) introduces a compound that can suppress the activity of PPARa by phosphorylating it. Suppressing drugs may also be clinically useful.
  • PPARa receptor activator agonist
  • PPARa protein expression regulator that can increase the expression of protein itself are hypoglycemic, lipid lowering, diabetes, obesity, syndrome X, It is expected to be useful as a prophylactic and therapeutic agent for metabolic disorders such as hypercholesterolemia and hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, hypertension, cardiovascular disease, bulimia, etc. Is done.
  • antagonists that suppress the transcriptional activity of the PPARy receptor or PPARa protein expression regulators that can suppress the expression of the protein itself include hypoglycemic agents, diabetes, obesity, metabolic disorders such as syndrome X, and hyperlipidemia. Is expected to be useful as a prophylactic and / or therapeutic agent for diseases, arteriosclerosis, hypertension, bulimia, etc.
  • fibrate compounds for example, clofibrate
  • fibrate compounds for example, clofibrate
  • PPAR ⁇ receptor modulators that can be activated by fibrate compounds are considered to have lipid-lowering effects and are expected to be useful as preventive and / or therapeutic agents for hyperlipidemia, etc. .
  • PPAR ⁇ -regulators that enhance the cleavage of PPAR “receptor-activating agonist II PP AR” protein itself are useful not only as lipid-lowering agents and therapeutics for hyperlipidemia, but also as high-density drugs.
  • Cholesterol and / or ultra-low-density lipoprotein (VLDL) cholesterol are expected to increase cholesterol, to suppress the progression of atherosclerosis, to treat it, and to suppress obesity.
  • VLDL ultra-low-density lipoprotein
  • PPARS is sometimes referred to as PPAR / 3, or NUC 1 in humans.
  • PPAR / 3 As a biological activity of PPAR5, WO 9601430 shows that hNUC1B (a PPAR subtype different from human NUC1 by one amino acid) can suppress the transcriptional activity of human PPAR ⁇ and thyroid hormone receptor. ing.
  • hNUC1B a PPAR subtype different from human NUC1 by one amino acid
  • HDL High density lipoprotein
  • agonists capable of activating PPARS are expected to have an effect of increasing HDL cholesterol, thereby inhibiting the progression of arteriosclerosis and treating it, and being applied as a lipid-lowering agent or hypoglycemic agent. It is also thought to be useful for hypoglycemic agents, treatment of diabetes, reduction of the risk factor of syndrome X, and prevention of ischemic heart disease.
  • JP-A-6-184086 JP-A-6-211814 and JP-A-4-300859 (corresponding European Patent Application Publication 490820). It is described that it is useful for prevention and / or treatment of hypertension, congestive heart failure, edema disease, etc., based on angiotensin II antagonistic activity. Disclosure of the invention
  • the present inventors have conducted intensive studies to find compounds having a PPAR receptor regulating action. As a result, they have found that the compound represented by the general formula (I) achieves the object, and Was completed.
  • the present invention is a.
  • a C3-14 unit selected from a halogen atom, a C1-4 alkyl group, a C2-6 alkenyl group or a C1-4 alkoxy group, which may be substituted with one or two substituents;
  • R 15 and R 16 are Each independently represents a hydrogen atom or a C 1-4 alkyl group, or R 15 and R 16 are taken together with an adjacent nitrogen atom to form a (R 17 ) m2 group (wherein R 17 is Represents a hydrogen atom or a C1-4 alkyl group, and m2 represents an integer of 1 to 3.) 1 or 2 nitrogen atoms, one nitrogen atom and one oxygen atom, or a nitrogen atom and represents a terrorist ring acid atom total to three monocyclic 4-7 membered containing saturated of, n4 represents represents.) an integer of 1-4, or, R 12 and R 13 are adjacent Contact That such together with the nitrogen atom connexion, a nitrogen atom 1 or 2, to I Table heterocycle nitrogen atom and an oxygen atom to the saturated monocyclic 4-7 membered containing one by one.)
  • R 18 represents a hydrogen atom or a C 1-4 alkyl group; and m 3 represents an integer of 1-3.
  • (V) a halogen atom, a C1-4 alkyl group, a C2-6 alkenyl group or C1
  • R 2Q represents a hydrogen atom or a C 1-4 alkyl group.
  • (iii) represents a C 1-4 alkyleneoxy group
  • R 26 represents a hydrogen atom or a C 1-4 alkyl group
  • R 27 represents a hydrogen atom, a C 1-4 alkyl group or one CH 2 COOR 28 group (in the group And R 28 represents a hydrogen atom or a C 1-4 alkyl group.
  • n4 represents an integer of 1 to 3.
  • L is C 1 to 4 alkylene group, a halogen atom, a hydroxyl group, C L ⁇ 4 alkyl le group, C 2 to 6 alkenyl, C L ⁇ 4 alkoxy groups, one OCOR 32 group (wherein, the R 32 is the Selected from the group consisting of OCOOR 33 (wherein R 33 has the same meaning as described above) or one COOR 34 group (where R 34 has the same meaning as described above).
  • a C 1-4 alkylene group substituted with one C 3-14 monocyclic or polycyclic saturated or unsaturated carbon ring which may be substituted with 1 or 2 groups or C 2-6 Represents a alkenylene group of
  • Nono androgenic atom a hydroxyl group, C L ⁇ 4 alkyl group, C 2 to 6 alkenyl Le group, C 1 to 4 alkoxy groups, -OCOR 32 group (wherein, R 32 is the same meaning as before SL. ), One OCOOR 33 (wherein, R 33 has the same meaning as described above) or one COOR 34 group (where, R 34 has the same meaning as described above.) C 3-14 monocyclic or polycyclic saturated which may be substituted by two groups Or unsaturated carbocycle, or
  • (7) represents a 4- to 7-membered monocyclic hetero ring containing one oxygen or sulfur atom, or containing one nitrogen atom and one oxygen atom,
  • (2) represents a 5- to 7-membered lactone ring
  • R 37 is a hydrogen atom, a C14 alkyl group
  • R 43 and R 44 are each independently a hydrogen atom, a Cl-4 alkyl group, — (CH 2 ) n7 —COOR 45 group (In the group, R 45 Represents a hydrogen atom or a C 1-4 alkyl group, and 117 represents an integer of 1-4.) Or one (CH 2 ) n8 —CONR 46 R 47 group (group Wherein R 46 and R 47 each independently represent a hydrogen atom or a C 1-4 alkyl group, or R 46 and R 47 are taken together with an adjacent nitrogen atom to form-(R 48 ) m6 (Wherein, R 48 represents a hydrogen atom or a C 1-4 alkyl group, and m 6 represents an integer of 1-3.) 1 or 2 nitrogen atoms, nitrogen Represents a 4- to 7-membered monocyclic saturated hetero ring containing one atom and one oxygen atom or three nitrogen atoms and three oxygen atoms in total, and n8
  • n5 represents 0 or an integer of 1 to 4;
  • n 1 represents an integer of 1 to 4.
  • alkyl, alkenyl, alkoxy, alkylthio, and alkylene groups include straight and branched ones, and the double bond in the alkenyl group is a mixture of E, Z and EZ. Including some. It also includes isomer groups resulting from the presence of asymmetric carbon atoms, such as when a branched alkyl group is present.
  • C 2 ⁇ 6 alkenyl represented by RR 2 and R 2 9 A C 2-6 alkenyl group as a substituent on a C 3-14 carbon ring represented by R 1 and R 29 , a C 1-4 alkyl group represented by R 2 , a C 2-6 alkenyl group or C C2-6 alkenyl group as a substituent of C4-7 carbon ring substituted on C2-6 alkynyl group, and C3-4 substituted on C1-4 alkylene group represented by L
  • the C 2-6 alkenyl group as the substituent for the 14-carbon ring includes ethenyl, propenyl, butenyl, pentyl, hexenyl and isomers thereof.
  • the C 2-6 alkynyl group represented by R 1 and R 2 is ethynyl, propynyl, butynyl, pentynyl, hexyl group and their isomer groups.
  • C 1 to 4 alkylene groups represented monocyclic or polycyclic saturated or unsaturated carbon ring C3 ⁇ l 4 represented by R 1 and R 29, and by L
  • Examples of the C 3-14 monocyclic or polycyclic saturated or unsaturated carbon ring include cyclopentadiene, benzene, naphthalene, indene, azulene, fluorene, phenanthrene, anthracene, asenaphthylene, and biphenylene ring.
  • Partly or wholly saturated rings for example, cyclopentane, cyclohexane, indane or acenaphthene, etc.
  • cyclopropane, cyclobutane, adamantane rings and the like can be mentioned.
  • examples of the 4- to 7-membered monocyclic heterocycle containing one nitrogen atom or sulfur atom represented by R 1 include, for example, pyrrol, pyridine, azepine, thiophene, thiamine, chepin Rings and partially or wholly saturated rings thereof (for example, pyrroline, pyrrolidine, piperidine, thiolane, thiane, etc.) are exemplified.
  • a halogen atom represented by R 1 and R 21 a halogen atom represented by R 1 and R 29 as a substituent of a C 3-14 carbon ring, a C 1-4 represented by R 2 Alkyl group, C2-6 alkenyl group or C2-6 alkynyl group substituted with C4-7 carbocyclic substituent as halogen atom and C1-4 alkylene group represented by L ing
  • the halogen atom as a substituent on the C3-14 carbon ring is a fluorine, chlorine, bromine or iodine atom.
  • a C 1-4 alkoxy group represented by RR 21 and R 29 , a C 1-4 alkoxy group as a substituent of a C 3-14 carbon ring represented by R 1 and R 29 , C 1 to 4 alkyl groups represented by R 2, C 1 to 4 alkoxy groups as a substituent of carbocyclic ring C. 4 to 7 are replaced with C2 ⁇ 6 alkenyl group or C 2 to 6 alkynyl group, and L And a C 1-4 alkoxy group as a substituent on a C 3-14 carbon ring which is substituted on the C 1-4 alkylene group represented by methoxy, ethoxy, propoxy, butoxy and the like. Is a sexual group.
  • the heterocyclic ring of monocyclic 4-7 membered containing one oxygen atom or a sulfur atom represented by R 29, include furan, pyran, Okisepin, Chiofen, Chiain, Chepin ring Contact Examples thereof include partially or completely saturated rings (eg, oxolane, oxane, thiolane, thiane, etc.).
  • R 39, R 40, R 41 , R 42, R 43, R 44, R 45, R 46, R 47, R 48 and R 49 A C 1-4 alkyl group represented by R 1 , a C 1-4 alkyl group as a substituent of a C 3-14 carbocycle represented by R 1 and R 29 , a C 1-4 alkyl group represented by R 2 , C A C 1-4 alkyl group as a substituent on a C 4-7 carbocyclic ring which is substituted on a 2-6 alkenyl group or a C 2-6 alkynyl group, and a C 1-4 alkylene group represented by L
  • the C 1-4 alkyl group as a substituent of the C 3-14 carbocyclic ring is a methyl, ethyl, propyl, butyl group or an isomer thereof.
  • a C 3-7 cycloalkyl group represented by R 37 and a C 3-7 cycloalkyl group represented by R 29 — L— and R 3Q together with the carbon atom to which they are bonded Is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
  • examples of the 5- to 7-membered lactone ring represented by R 29 — L— and R 3 ° together with the carbon atom to which they are bonded are, for example, 4-butanolide, 5-pentanolide , 6-hexanolide and the like.
  • C 1 ⁇ 4 alkyl groups represented by R 2 the C. 4 to 7 monocyclic was saturated or of being replaced with C2 ⁇ 6 an alkenyl group, or a C. 2 to 6 alkynyl group not
  • the saturated carbocycle include cyclopentadiene, cyclopentene, cyclopentane, benzene, cyclohexadiene, cyclohexene, and cyclohexane ring.
  • the heterocyclic ring include pyrrolidine, pyrroline, pyrrolyl, piperidine, and pyridine rings.
  • the monocyclic saturated heterocycle include pyrrolidine, piperidine, perhydroazepine, imidazolidine, virazolidine, perhydrodazein (such as piperazine), perhydrodazepine, oxazolidine, Hydroxazine (morpholine, etc.), perhydrooxazepine, oxaziazolidine, perhydrooxazine diazine, perhydrooxazine diazepine, dioxazolidine, perhydrooxazine And a hydrodioxazepine
  • the C1-7 alkylene group represented by A is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, pentamethylene or isomer group thereof.
  • the C1-4 alkylene group represented by J and L is a methylene, ethylene, trimethylene, tetramethylene group or an isomer thereof.
  • the C2-6 alkenylene represented by A and L is vinylene, propenylene, butenylene, pentenylene, hexenylene, or an isomer thereof.
  • Examples of the 4- to 7-membered monocyclic unsaturated heterocyclic ring containing one sulfur atom represented by are thiophene, thiane, and chepin.
  • Examples of the 4- to 7-membered monocyclic unsaturated heterocyclic ring containing one nitrogen atom represented by are pyrrol, pyridine, azepine and the like.
  • hydroxy (C l ⁇ 4) alkyl group represented by R 2 1, hydroxymethyl, hydroxyethyl E chill, hydroxypropyl, hydroxybutyl and isomeric groups thereof.
  • the halogen atom in the halogen atom or tri Haromechiruokishi groups in trihalomethyl groups by R 2 1, is fluorine, chlorine, bromine and iodine MotoHara child.
  • the C 1-4 alkyleneoxy group represented by J is a methylenoxy, ethyleneoxy, trimethyleneoxy, tetramethyleneoxy group or an isomer thereof.
  • R 1 —A is preferably a C 1-10 alkyl group or a C 2-10 alkenyl group, more preferably a C 1-7 alkyl group.
  • X 2 is preferably an NR 2a group (wherein R 2a is a hydrogen atom, unsubstituted or substituted with a COOR 6a group (wherein, R 6a represents a hydrogen atom or a C 1-4 alkyl group). Represents an alkyl group of 1 to 4) or an oxygen atom, and is more preferably an NH group.
  • R 21a represents the same meaning as R 21. However, if it is substituted with two R 2 la group, Each R 21a group may be the same or different.
  • E is 1) a C 1-7 alkyl group, 2) a C 1-5 alkyl group substituted by a phenyl group and / or a COOR a group (wherein Ra represents a hydrogen atom or a C 1-4 alkyl group);
  • Examples of the specific compound represented by the general formula (I) used in the present invention include the compounds described in Examples and the compounds described in JP-A-6-84086 and JP-A-6-211814. included.
  • more preferred compounds include
  • the conjugated compound represented by the general formula (I) used in the present invention is disclosed in JP-A-6-84086, JP-A-6-211814 and JP-A-4-300859 (corresponding to Japanese Patent Application Publication No. 490820). It can be produced according to the method described in the specification, the method described in Examples described later, or a method analogous thereto.
  • the compound represented by the general formula (I) used in the present invention is converted into a salt by a known method.
  • the salt is preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, etc.).
  • Non-toxic caro salts with acid include inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate, or acetate, lactate, tartrate, oxalate, and fumarate.
  • Organic acid salts such as dalc oxalate and gluconate are exemplified.
  • the compounds represented by the general formula (I) and used in the present invention have an activity of controlling PPAR receptors, and have a hypoglycemic effect.
  • the compounds represented by the general formula (I) used in the present invention regulate the PPARy receptor among the above receptors Since it has an effect, hypoglycemic drugs, lipid-lowering drugs and metabolic disorders such as diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, hypertension It is expected to be useful as a prophylactic and / or therapeutic agent for cardiovascular diseases and bulimia. Furthermore, among them, usefulness as a hypoglycemic agent and a lipid lowering agent is expected.
  • the compounds used in this study have sufficiently low toxicity and are considered to be sufficiently safe for use as pharmaceuticals.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, in the range of lmg to 1000mg, once orally once or several times a day. Or parenteral (preferably intravenous) once to several times daily, in the range of lmg to 100mg per adult per day, or It is continuously administered intravenously for a period of time up to 24 hours.
  • parenteral preferably intravenous
  • the dose varies depending on various conditions, so that a dose smaller than the above dose may be sufficient, or may be required beyond the range.
  • the compound used in the present invention is administered, it is used as a solid composition, a liquid composition and other compositions for oral administration and an injection, an external preparation, a suppository and the like for parenteral administration.
  • Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrole. Ridone is mixed with magnesium metasilicate aluminate.
  • the compositions may contain any additives other than inert diluents, for example, lubricating agents such as magnesium stearate, disintegrating agents such as calcium cellulose glycolate, and stabilizing agents such as lactose. And a solubilizing agent such as glutamic acid or aspartic acid.
  • tablets or pills may be coated with a film of gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose or the like, or in two or more layers. It may be coated. Also included are capsules made of a substance which can be absorbed, such as gelatin.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such a liquid composition, one or Further active substances are contained in commonly used inert diluents (eg, purified water, ethanol).
  • compositions may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.
  • the composition contains, in addition to the inert diluent, a buffering agent that provides isotonicity with stabilizers such as sodium bisulfite, for example, isotonic agents such as sodium chloride, sodium citrate, or citric acid. It may be.
  • the method for producing the spray is described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.
  • Injections for parenteral administration of the compound used in the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (registered trademark).
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid). Good.
  • bactericides are sterilized by filtration through a bacteria-retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions, for example, sterilized or dissolved in sterile distilled water for injection or other solvents before use of the lyophilized product.
  • compositions for parenteral administration include external solutions, ointments, liniments, suppositories and vaginalis for rectal administration, which contain one or more active substances and are formulated in a conventional manner. Includes a pouch for administration.
  • Example 2 By subjecting the compound produced in Example 1 (1) to the same operation as in Example 2, a compound of the present invention having the following physical data was obtained.
  • Luciferase structural gene from pTK ⁇ (Clontech, Catalog No. 6179-1) with TK promoter (-105 / + 51) as the minimum required promoter activity.
  • Luciferase gene expression vector pTK-Luc. 4xUAS- is inserted into the upstream of the TK promoter, the response element of Ga14 protein, the basic transcription factor of yeast, and the enhancer sequence that repeats UAS four times.
  • TK-Lu was constructed and used as a reporter gene.
  • 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 amino acid sequence from position 1 to position 147 of the DNA binding region of the G a14 protein is fused with DNA encoding the ligand binding region of the human PPARa receptor in frame with the DNA encoding the amino acid sequence from position 1 to position 147.
  • Basic Vector 2 (trade name) promoter was inserted downstream of the Enhansa region.
  • the expressed chimeric protein is likely to be localized in the nucleus, and the amino-terminal of the ligand binding region of the human PPARa receptor has a nuclear translocation signal derived from SV40 T-antigen, A la Pro Lys Lys.
  • LysA rgLy s Va 1 G 1 y (SEQ ID NO: 2) is arranged, while the carboxy terminus is used as a peptide sequence for detection of the expressed protein, and the hemagglutinin epitove of Influenza, Ty rP r oTy rAs pVa l P r oAs pTy r
  • the DNA sequence was such that A la (SEQ ID NO: 3) and a translation stop codon were arranged in this order.
  • the structural gene portion used as the ligand binding region of the human PPARa receptor is described in R. Mukherjee et al. (See J. Steroid Biochem. Moke.
  • Human PP AR ⁇ ligand binding region Using DNA encoding the S er 6- ⁇ yr 4 off 8. In addition, in order to monitor the effect on basic transcription, the expression of DNA containing the DNA binding region of the Ga14 protein lacking the PPAR ligand binding region and the DNA encoding the amino acid sequence from the 1st to the 147th position The vector was also adjusted.
  • CV-1 cells used as host cells were cultured according to a conventional method. That is, fetal calf serum (GIBCOBRL, catalog No. 26140-061) was added to Darbecco's modified Eagle's medium (DMEM) to a final concentration of 10%. The cells were cultured in a medium supplemented with G and 50 gZm1 of streptomycin sulfate in 5% carbon dioxide at 37 ° C.
  • GIBCOBRL fetal calf serum
  • DMEM Darbecco's modified Eagle's medium
  • the cells are seeded in advance into 2 x 10 6 cells in a 10 cm dish, and serum is contained. After a single washing operation with no medium, 10 ml of the same medium was applied. 10 g of reporter gene, 0.5 ⁇ g of Gal4-PPAR expression vector LipofectAMINE (trade name, GIBCOBRL, catalog No. 18324-012) Mix well 50 ⁇ 1 and add to the above culture dish did. Culture was continued at 37 ° C for 5 to 6 hours, and 10 ml of a medium containing 20% of dialyzed fetal bovine serum (GIBCOBRL, catalog No. 26300-061) was added.
  • GIBCOBRL dialyzed fetal bovine serum
  • the cells were dispersed by trypsin treatment, replated at a cell density of 8000 cells / 100 ml DMEM-10% dialysed serum well in a 96-well plate, and cultured for several hours. When adhered, 100% of a DMEM-10% dialyzed serum solution of the compound used in the present invention containing twice the assay concentration was added. After culturing at 37 ° C for 42 hours, lyse the cells and measure the luciferase activity according to the standard method. Was.
  • mice After receiving C57BLKsJ-db / db mice (10 mice) at the age of 8 weeks, the animals were pre-bred for 2 weeks and the experiment was started.
  • day 0 blood was collected from the tail vein, grouped based on blood glucose level and body weight, and the compound used in the present invention was orally administered once daily for 14 consecutive days from the next day (1 O OmgZkgZday).
  • day 15 whole blood was collected from the abdominal vena cava under ether anesthesia to measure blood lipids (free fatty acid (FFA) and triglyceride (TG)). Table 2 shows the results.
  • FFA free fatty acid
  • TG triglyceride
  • the solution is sterilized in the usual way, filled into ampoules in 5 ml portions, freeze-dried in the usual way, and 100 ampoules containing 20 mg of active ingredient in one ampule I got

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le principe actif de ces régulateurs des PPAR (ou récepteurs activés par le proliférateur des péroxisomes) est constitué de composés représentés par la formule générale (I), de certains de leurs sels, ou d'hydrates des composés et de leurs sels. Dans cette formule générale, chacun des symboles est tel que défini dans la description. Ces composés font preuve d'une action régulatrice dirigée contre les PPAR. Ces composés sont donc tout désignés comme antihyperglycémiants, antihyperlipidémiants, ou comme agent préventif et/ou thérapeutique pour des affections du métabolisme telles que le diabète, l'obésité, le syndrome X, l'hypercholestérolémie et l'hyperlipoprotéinémie, l'hyperlipémie, l'artériosclérose, les affections circulatoires, la polyphagie, et les cardiopathies ischémiques.
PCT/JP1998/003930 1997-09-10 1998-09-02 Regulateurs des recepteurs actives par le proliferateur des peroxisomes WO1999012534A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU89966/98A AU8996698A (en) 1997-09-10 1998-09-02 Peroxisome proliferator-activated receptor controllers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/245101 1997-09-10
JP24510197 1997-09-10

Publications (1)

Publication Number Publication Date
WO1999012534A1 true WO1999012534A1 (fr) 1999-03-18

Family

ID=17128637

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/003930 WO1999012534A1 (fr) 1997-09-10 1998-09-02 Regulateurs des recepteurs actives par le proliferateur des peroxisomes

Country Status (2)

Country Link
AU (1) AU8996698A (fr)
WO (1) WO1999012534A1 (fr)

Cited By (7)

* 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
WO2002051799A1 (fr) * 2000-12-26 2002-07-04 Pola Chemical Industries, Inc. Dérivés de biphényle
WO2002055484A1 (fr) * 2001-01-12 2002-07-18 Takeda Chemical Industries, Ltd. Compose biaryle, procede de production de ce compose, et principe actif
WO2003062427A1 (fr) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Methode de criblage de medicaments ameliorant la resistance a l'insuline
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
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
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

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520423A2 (fr) * 1991-06-27 1992-12-30 Takeda Chemical Industries, Ltd. Composés hétérocycliques, leur fabrication et leur utilisation comme antagoniste de l'angiotensine-II
WO1993008171A1 (fr) * 1991-10-24 1993-04-29 American Home Products Corporation Pyrimidocycloalcanes en tant qu'antagonistes de l'angiotensine ii
WO1993008169A1 (fr) * 1991-10-24 1993-04-29 American Home Products Corporation Aminopyrimidines substituees utilisees comme antagonistes de l'angiotensine ii
WO1994004153A1 (fr) * 1992-08-21 1994-03-03 Fujisawa Pharmaceutical Co., Ltd. Utilisation d'antagonistes de l'angiotensine ii dans le traitement des hyperlipidemies
JPH0672985A (ja) * 1992-08-28 1994-03-15 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
JPH06184086A (ja) * 1992-12-22 1994-07-05 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
JPH06211814A (ja) * 1993-01-14 1994-08-02 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
JPH06287182A (ja) * 1993-02-05 1994-10-11 Taiho Yakuhin Kogyo Kk アルキルグリシン誘導体
EP0628313A1 (fr) * 1993-06-07 1994-12-14 Takeda Chemical Industries, Ltd. Combinaison de benzimidazoles ayant une activité antagoniste de l'angiotensine-II avec des diurétiques ou des antagonistes du calcium
EP0635263A2 (fr) * 1993-06-28 1995-01-25 American Cyanamid Company Antagonistes de l'angiotensine II (AII) comme inhibiteurs de la croissance du tissu adipeux
WO1995024901A1 (fr) * 1994-03-17 1995-09-21 Ciba-Geigy Ag Traitement de la nephropathie diabetique a l'aide de valsartan
WO1995026188A1 (fr) * 1994-03-29 1995-10-05 Merck & Co., Inc. Traitement de l'atherosclerose
JPH07316055A (ja) * 1994-05-23 1995-12-05 Nkk Corp 置換アミド基を有するピリミジン誘導体および該誘導体を有効成分として含有するアンジオテンシンｉｉ拮抗剤
JPH0841053A (ja) * 1994-07-28 1996-02-13 Nkk Corp ヘテロアリールアルキル基を有するピリミジン誘導体及 び該誘導体を有効成分として含有するアンジオテンシン ｉｉ拮抗剤
WO1996023884A2 (fr) * 1995-01-30 1996-08-08 Ligand Pharmaceuticals Incorporated Recepteurs humains actives par les proliferateurs du peroxisome
WO1996033724A2 (fr) * 1995-04-25 1996-10-31 The Salk Institute For Biological Studies MODULATEURS SELECTIFS DU RECEPTEUR η ACTIVE DE LA PROLIFERATION DES PEROXYSOMES ET TECHNIQUES D'UTILISATIONS CORRESPONDANTES
WO1996040128A2 (fr) * 1995-06-07 1996-12-19 The Salk Institute For Biological Studies Modulateurs du recepteur-gamma active de la proliferation des peroxysomes et procedes d'application
JPH0931061A (ja) * 1995-07-24 1997-02-04 Suntory Ltd ヒダントイン誘導体およびその用途
JPH09110691A (ja) * 1995-10-17 1997-04-28 Tanabe Seiyaku Co Ltd 医薬組成物
JPH09124691A (ja) * 1995-08-25 1997-05-13 Green Cross Corp:The ペプチド化合物およびそれを含有する医薬組成物

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520423A2 (fr) * 1991-06-27 1992-12-30 Takeda Chemical Industries, Ltd. Composés hétérocycliques, leur fabrication et leur utilisation comme antagoniste de l'angiotensine-II
WO1993008171A1 (fr) * 1991-10-24 1993-04-29 American Home Products Corporation Pyrimidocycloalcanes en tant qu'antagonistes de l'angiotensine ii
WO1993008169A1 (fr) * 1991-10-24 1993-04-29 American Home Products Corporation Aminopyrimidines substituees utilisees comme antagonistes de l'angiotensine ii
WO1994004153A1 (fr) * 1992-08-21 1994-03-03 Fujisawa Pharmaceutical Co., Ltd. Utilisation d'antagonistes de l'angiotensine ii dans le traitement des hyperlipidemies
JPH0672985A (ja) * 1992-08-28 1994-03-15 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
JPH06184086A (ja) * 1992-12-22 1994-07-05 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
JPH06211814A (ja) * 1993-01-14 1994-08-02 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
JPH06287182A (ja) * 1993-02-05 1994-10-11 Taiho Yakuhin Kogyo Kk アルキルグリシン誘導体
EP0628313A1 (fr) * 1993-06-07 1994-12-14 Takeda Chemical Industries, Ltd. Combinaison de benzimidazoles ayant une activité antagoniste de l'angiotensine-II avec des diurétiques ou des antagonistes du calcium
EP0635263A2 (fr) * 1993-06-28 1995-01-25 American Cyanamid Company Antagonistes de l'angiotensine II (AII) comme inhibiteurs de la croissance du tissu adipeux
WO1995024901A1 (fr) * 1994-03-17 1995-09-21 Ciba-Geigy Ag Traitement de la nephropathie diabetique a l'aide de valsartan
WO1995026188A1 (fr) * 1994-03-29 1995-10-05 Merck & Co., Inc. Traitement de l'atherosclerose
JPH07316055A (ja) * 1994-05-23 1995-12-05 Nkk Corp 置換アミド基を有するピリミジン誘導体および該誘導体を有効成分として含有するアンジオテンシンｉｉ拮抗剤
JPH0841053A (ja) * 1994-07-28 1996-02-13 Nkk Corp ヘテロアリールアルキル基を有するピリミジン誘導体及 び該誘導体を有効成分として含有するアンジオテンシン ｉｉ拮抗剤
WO1996023884A2 (fr) * 1995-01-30 1996-08-08 Ligand Pharmaceuticals Incorporated Recepteurs humains actives par les proliferateurs du peroxisome
WO1996033724A2 (fr) * 1995-04-25 1996-10-31 The Salk Institute For Biological Studies MODULATEURS SELECTIFS DU RECEPTEUR η ACTIVE DE LA PROLIFERATION DES PEROXYSOMES ET TECHNIQUES D'UTILISATIONS CORRESPONDANTES
WO1996040128A2 (fr) * 1995-06-07 1996-12-19 The Salk Institute For Biological Studies Modulateurs du recepteur-gamma active de la proliferation des peroxysomes et procedes d'application
JPH0931061A (ja) * 1995-07-24 1997-02-04 Suntory Ltd ヒダントイン誘導体およびその用途
JPH09124691A (ja) * 1995-08-25 1997-05-13 Green Cross Corp:The ペプチド化合物およびそれを含有する医薬組成物
JPH09110691A (ja) * 1995-10-17 1997-04-28 Tanabe Seiyaku Co Ltd 医薬組成物

Cited By (9)

* 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
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
WO2002051799A1 (fr) * 2000-12-26 2002-07-04 Pola Chemical Industries, Inc. Dérivés de biphényle
US7531576B2 (en) 2000-12-26 2009-05-12 Pola Chemical Industries, Inc. Biphenyl derivatives
WO2002055484A1 (fr) * 2001-01-12 2002-07-18 Takeda Chemical Industries, Ltd. Compose biaryle, procede de production de ce compose, et principe actif
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
WO2003062427A1 (fr) * 2002-01-23 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Methode de criblage de medicaments ameliorant la resistance a l'insuline
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
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

Also Published As

Publication number Publication date
AU8996698A (en) 1999-03-29

Similar Documents

Publication Publication Date Title
JP5988379B2 (ja) スフィンゴシン−１−リン酸受容体変調因子および不斉合成方法
MXPA03011448A (es) Derivados de n-arilfenilacetamida y composicion farmaceutica que los contienen.
JP6314129B2 (ja) グアニジノ安息香酸エステル化合物
US20070105959A1 (en) Cynnamyl alcohol derivative compounds and drugs containing the compounds as active ingredient
JP2019528262A (ja) Ｇｐｒ４０−アゴニストおよびｇｐｒ１２０−アゴニストとしてのスルホンアミド類
US6589969B1 (en) Carboxylic acid derivatives and drugs containing the same as the active ingredient
EP1405848B1 (fr) Compose derive de tetrahydroquinoline et medicament contenant ledit compose comme principe actif
EP1354879B1 (fr) Composes derives de dihydronaphtalene et medicaments utilisant ces composes comme ingredient actif
WO1999012534A1 (fr) Regulateurs des recepteurs actives par le proliferateur des peroxisomes
US6664281B1 (en) Carboxylic acid derivatives and drugs containing the same as the active ingredient
ES2390053T3 (es) Derivado de ácido fenilacético, procedimiento para producir el mismo y uso
RU2296760C2 (ru) Производные соединения карбоновой кислоты и средства, содержащие соединения в качестве активных ингредиентов
JP2002338555A (ja) ブタン酸誘導体
JP4062204B2 (ja) ジヒドロナフタレン誘導体化合物およびその化合物を有効成分とする薬剤
JP2004026679A (ja) ジヒドロナフタレン誘導体
JP2005119998A (ja) 縮合ベンゼン環化合物、およびその用途

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