WO2010015212A1 - 一种对δ亚型过氧化物酶增殖物激活受体具有激动作用的化合物、其制备方法和应用 - Google Patents
一种对δ亚型过氧化物酶增殖物激活受体具有激动作用的化合物、其制备方法和应用 Download PDFInfo
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- WO2010015212A1 WO2010015212A1 PCT/CN2009/073140 CN2009073140W WO2010015212A1 WO 2010015212 A1 WO2010015212 A1 WO 2010015212A1 CN 2009073140 W CN2009073140 W CN 2009073140W WO 2010015212 A1 WO2010015212 A1 WO 2010015212A1
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- trifluoromethyl
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- triazolyl
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- C07—ORGANIC CHEMISTRY
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- 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
- A61K31/4196—1,2,4-Triazoles
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
Definitions
- the present invention relates to a novel compound having agonistic effects on the ⁇ -subtype peroxidase-proliferating receptor (PPAR6), a preparation method thereof, a medicament containing the same, and its use in the treatment of cardiovascular diseases and the like.
- the invention also relates to
- NRs Nuclear receptors
- Nucleophilic receptors are activated by various physiological ligands (eg, saturated fatty acids, unsaturated fatty acids, and their metabolites and various synthetic compounds) to regulate the transcriptional system of the responding gene, thereby exhibiting physiological activity ( Kasuga, J. et al., Bioorg. Med. Chem. 2007, 75, 5177-5190).
- physiological ligands eg, saturated fatty acids, unsaturated fatty acids, and their metabolites and various synthetic compounds
- PPARs peroxisome proliferator-activated receptors
- scorpion nuclear transcription factors activated by scorpion, which are metabolic syndrome.
- An important regulator of (Guan, YJ Am. c. A ⁇ ra/, 2004, 75, 2801-2815). Therefore, PPARs are in insulin resistance, impaired glucose tolerance, type II diabetes, obesity, hyperlipidemia, hypertension, cardiovascular disease, atherosclerosis It plays an important role in the occurrence, development and prevention of diseases such as chemistry.
- PPARou PPAR6 ⁇ PPARy which regulate gene expression by binding to specific DNA sequences
- PPARa is mainly expressed in liver, heart, intestine, kidney and macrophages. When activated, it can increase fatty acid metabolism, reduce macrophage inflammatory response, P low low density lipoprotein cholesterol; ⁇ in fat cells, Expression in placental tumors and other tissues, in addition to lowering blood sugar and increasing insulin sensitivity, plays a key role in lipid metabolism, inhibition of cytokines, anti-inflammatory, immune regulation and blood pressure regulation (Kasuga, J.
- One of the objects of the present invention is to provide a compound of the formula (I) and/or a pharmaceutically acceptable salt thereof and/or Or its solvate:
- X is 0, S, N, or (CH 2 ) n , where n is 1-4, preferably X is 0, S or
- Y is 0, S or N, preferably Y is O or S;
- R is H or a C1-C9 alkyl group, preferably 1 is 11, methyl or ethyl;
- R 1, R 2 are each independently H or C1-C4 alkyl, and R 1, R 2 has at least one is H; preferably R 1, R 2 are each independently methyl, ethyl, or H;
- 11 3 is 11, C1-C9 alkyl, preferably H or C1-C4 alkyl, such as methyl, ethyl, isopropyl, more preferably methyl;
- 11 4 is 11, C1-C9 alkyl, C3-C7 cycloalkyl, phenyl or substituted phenyl, the substituent of the substituted phenyl is selected from C1-C9 alkyl, hydroxy, C1-C9 alkoxy Base, fluorenyl, C1-C9 alkylthio, trifluoromethyl, F, CI, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ; R 5 and R 6 are each independent
- the ground is H or a C1-C9 alkyl group, and when R 4 is a substituted phenyl group, the substituent is preferably 4-methoxy or 4-methyl;
- G 1 , G 4 is H alone, C1-C9 alkyl, hydroxy, C1-C9 alkoxy, fluorenyl, C1-C9 alkylthio, trifluoromethyl, F, CI, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ;
- R 5 and R 6 are each independently H or C1-C9 alkyl; preferably G 1 , G 4 is methyl or ethyl, respectively;
- G 2 , G 3 alone H, C1-C9 alkyl, hydroxy, C1-C9 alkoxy, fluorenyl, C1-C9 alkylthio, trifluoromethyl, F, CI, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ;
- R 5 and R 6 are each independently H or C 1 -C 9 alkyl; preferably G 2 , G 3 is
- G 5 , G 6 , G 8 , G 9 are H alone, C1-C9 alkyl, hydroxy, C1-C9 alkoxy, fluorenyl, C1-C9 alkylthio, trifluoromethyl, F, Cl, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ; R 5 and R 6 are each independently H or C1-C9 alkyl; preferably G 5 , G 6 , G 8 , G 9 is independently H, F, Cl, Br, methyl, ethyl or methoxy;
- 0 7 is 11, C1-C9 alkyl, hydroxy, C1-C9 alkoxy, fluorenyl, C1-C9 alkylthio, trifluoromethyl, F, CI, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ;
- R 5 and R 6 are each independently H or C1-C9 alkyl; preferably G 7 is trifluoromethyl, isopropyl, ethyl, methyl or Cl More preferably, G 7 is a trifluoromethyl group.
- Compound I ester
- Preferred compounds I (esters) of the invention include the following compounds:
- E-1 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H- 1, 2, 4-triazolyl))-benzyloxy)-phenoxy)-ethyl acetate
- E-2 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H- 1, 2, 4-triazolyl))-benzyloxy)-phenylthio)-ethyl acetate
- E-3 2-(3-Methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-) 1, 2, 4-triazolyl))-benzyloxy)-phenylthio)-ethyl acetate
- E-4" 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H- 1, 2, 4-triazolyl))-benzylthio)-phenoxy)-ethyl acetate
- E-6 2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo small(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2,4-Triazolyl))-benzyloxy)-phenoxy)-ethyl acetate
- E-6 2-(3-Methyl-4-(1-(3-(4-methyl-5-oxo small(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2,4-Triazolyl))-benzyloxy)-phenoxy)-ethyl acetate
- E-7 2-(3-Methyl-4-(1-(3-(4-methyl-5-oxo small(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2,4-Triazolyl))-benzylthio)-phenoxy)-ethyl acetate
- E-8 2-(2-Methyl-4-(3-(4-methyl-5-oxo small (4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2, 4 -Triazolyl)-methylthio)-phenoxy)-ethyl acetate
- E-10 2-(2,5-Dimethyl-4-(1-(3-(4-methyl-5-oxo-small (4-trifluoromethyl-phenyl)-4, 5-dihydro-1H) -1, 2, 4-triazolyl))-benzylthio)-phenoxy)-ethyl acetate
- E-12 2-(3-Methyl-4-(3-(4-methyl-5-oxo small (4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2, 4 -Triazolyl)-methoxy)-phenylthio)-ethyl acetate
- E-14 2-(2-Ethyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-) 1, 2, 4-triazolyl))-benzylthio)-phenoxy)-ethyl acetate
- E-15 2,2-Dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl))-4 , 5-dihydro-1H-1, 2, 4-triazolyl))-benzyloxy)-phenylthio)-ethyl acetate
- the basic condition is formed using a base, the base being an alkali metal hydroxide, including but not limited to sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.;
- reaction temperature is 0 ° C - 80 ° C, preferably 20
- the reaction time is from 1 to 12 hours, preferably from 2 to 4 hours, at °C to 40 °C.
- Preferred compounds I (acids) of the invention include the following compounds:
- A-2 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo small(4-trifluoromethyl-phenyl)-4, 5-dihydro-1 -1, 2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid
- A-3 2-(3-Methyl-4-(1-(3-(4-methyl-5-oxo small(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2,4-triazolyl))-benzyloxy)-phenylthio)-acetic acid
- A-4" 2-(2-methyl-4-(1-(3-(4-methyl-5-oxo small(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid
- A-6 2-(3-Methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-) 1, 2, 4-triazolyl))-benzyloxy)-phenoxy)-acetic acid
- A-7 2-(3-Methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-) 1, 2, 4-triazolyl))-benzylthio)-phenoxy)-acetic acid
- A-8 2-(2-Methyl-4-(3-(4-methyl-5-oxo small (4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2, 4 -triazolyl)-methylthio)-phenoxy)-acetic acid (hereinafter referred to as "A-8");
- A-10 2-(2,5-Dimethyl-4-(1-(3-(4-methyl-5-oxo-small (4-trifluoromethyl-phenyl)-4, 5-dihydro-1H) -1, 2, 4-triazolyl))-benzylthio)-phenoxy)-acetic acid
- A-12 2-(3-Methyl-4-(3-(4-methyl-5-oxo small (4-trifluoromethyl-phenyl)-4, 5-dihydro-1H-1, 2, 4 -Triazolyl)-methoxy)-phenylthio)-acetic acid (hereinafter referred to as "A-12");
- A-15 2,2-Dimethyl-2-(3-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl))-4 , 5-dihydro-1H-1, 2, 4-triazolyl))-benzyloxy)-phenylthio)-acetic acid
- A-16 2,2-Dimethyl-2-(2-methyl-4-(1-(3-(4-methyl-5-oxo-1-(4-trifluoromethyl-phenyl))-4 , 5-dihydro-1H-1, 2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid
- Particularly preferred compounds of the invention I include the following compounds:
- the pharmaceutically acceptable salt of the compound of the formula I of the present invention means an alkali metal salt or an alkaline earth metal salt. Potassium salts, sodium salts and calcium salts are preferred.
- the solvate of the compound of the formula I according to the invention means a hydrate or an organic solvate thereof, preferably water.
- Compounds and alcoholates The hydrate may include a hydrate comprising from 1 to 4 waters.
- R 3 is H or a C1-C9 alkyl group
- C1-C9 alkyl is 11, C1-C9 alkyl, C3-C7 cycloalkyl, phenyl or substituted phenyl; the substituent on the phenyl is selected from C1-C9 alkyl, hydroxy, C1-C9 alkoxy, fluorenyl, C1 -C9 alkylthio, trifluoromethyl, F, CI, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ;
- G 5 , G 6 , G 7 , G 8 , G 9 are each independently: H, C1-C9 alkyl, hydroxy, C1-C9 alkoxy, fluorenyl, C1-C9 alkylthio, trifluoromethyl, F, CI, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ; R 5 and R 6 are each independently H or C1-C9 alkyl.
- Preferred compounds III of the invention include the following compounds:
- III-2 3-(1-bromo-benzyl)-4-n-butyl-1-(4-trifluoromethyl)phenyl-1H-1, 2,4-triazole-5(4H) ketone
- Another object of the present invention is to provide a process for the preparation of a compound of formula III.
- the compound of the formula III of the present invention can be synthesized by reacting a compound of the formula VI with a chlorinating reagent or a brominating reagent: Wherein Z is CI or Br; RR 4 , G 5 -G 9 are as defined for the compound of formula m.
- the chlorinating or brominating agent can be: (1) N-bromosuccinimide (NBS) / triphenylphosphine ( Ph 3 P ); (2) dichlorosulfoxide (SOCl 2 ) or dibromo Sulfone (SOBr 2 ); (3) N-chlorosuccinimide ( NCS ) / triphenylphosphine ( Ph 3 P ); (4) carbon tetrachloride (CC1 4 ) or carbon tetrabromide (CBr) 4 ) /triphenylphosphine ( Ph 3 P ); (5) phosphorus pentachloride (PC1 5 ) or phosphorus pentabromide ( PBr 5 ); (6) trichlorooxygen brick (POCl 3 ) or tribromo-oxygen brick ( POBr 3 ); and ( 7 ) phosphorus trichloride ( PC1 3 ) or tribromide brick ( PBr 3 )o
- the solvent is dichloromethane, chloroform or carbon tetrachloride, or any mixture thereof, and the reaction temperature is from 10 ° C to 80 ° C, and the reaction time is from 2 to 8 hours.
- alcohol 16 is formed by triphenylphosphine (Ph 3 P) to form compound 111-3.
- the compound of formula III can also be reacted by reacting a compound of formula W with a chlorinating reagent or a brominating reagent.
- the solvent is chloroform or carbon tetrachloride
- the brominating reagent is N-bromosuccinimide (NBS)
- the chlorinating reagent is N-chlorosuccinimide (NCS).
- the catalyst is dibenzoyl peroxide
- the reaction temperature is 40 ° C - 80 ° C
- the reaction time is 2-8 hours.
- Z is C1 or Br; R 3 and G 5 -G 9 are as defined by the compound of the formula; G 1() - G 14 are each independently or simultaneously: H, C1-C9 alkyl, hydroxy, dC 9 alkoxy Base, fluorenyl, dC 9 alkylthio, trifluoromethyl, F, CI, Br, nitro, NR 5 R 6 , COOR 5 , NR 5 COR 6 or CONR 5 R 6 ; R 5 and R 6 are each independently Is H or C1-C9 alkyl.
- the compound of the formula (I) of the present invention is produced by the following process according to the first route or the second route: Route 1:
- X, Y, R ⁇ R ⁇ G ⁇ G 9 is as defined for the compound of formula I, R is H or C1-C9 alkyl, preferably methyl or ethyl.
- intermediate compound II is coupled with hydrazine under the action of a base to form compound I (ester).
- the base is an organic base or an inorganic base
- the inorganic base may include an alkali metal carbonate, a soluble alkaline earth metal carbonate, ammonium carbonate, or the like, or any mixture thereof, and examples thereof include sodium carbonate, potassium carbonate, and carbonic acid.
- the organic base may be triethylamine or the like;
- the solvent is selected from the group consisting of acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), Oxy hexacyclic, etc., or any mixture thereof.
- the reaction temperature is from 0 ° C to 100 ° C, preferably from 40 ° C to 80 ° C; and the reaction time is from 1 to 12 hours, preferably from 4 to 8 hours.
- the compound of formula II can be synthesized commercially or by general literature methods (for example, ML Sznaidman, Curt D. Haffner, Patric R. et al., Bioorg. Med. Chem. Lett. 2003, 13, 1517-1521; Zhi-liang wei et al., J. Org. Chem. 2003, 68, 9116-9118; Org. Syn. Coll. Vol 1, 102, 1941; Org. Syn. Coll. Vol 2, 290, 1943; Handbook of Fine Organic Chemicals and Intermediates, Science and Industry Press, edited by Xu Kexun, method described in 3-426-3-584).
- general literature methods for example, ML Sznaidman, Curt D. Haffner, Patric R. Med. Chem. Lett. 2003, 13, 1517-1521; Zhi-liang wei et al., J. Org. Chem. 2003, 68, 9116-9118; Org. Syn. Coll. Vol 1, 102, 1941; Org. Syn.
- Compounds of formula II include, but are not limited to, the following compounds:
- II-2 2-(3-methyl-4-hydroxy)-phenoxy-ethyl acetate
- II-3 2-(2-ethyl-4-hydroxy)-phenoxy-ethyl acetate
- X, Y, Z, R ⁇ R ⁇ GG 9 are as defined for the compounds of formula I, R is H or C1-C9 alkyl, preferably methyl or ethyl.
- a continuous reaction method in which a carbonate is used as a base, and the compound is first reacted with the compound IV, and then reacted with the compound V, and the intermediate is not required to be separated.
- the solvent may be, in addition to acetonitrile, tetrahydrofuran (THF), dioxane, etc., or any mixture thereof;
- carbonate in addition to potassium carbonate, sodium carbonate, cesium carbonate, ammonium carbonate or the like, or any mixture thereof may be used. Both Intermediate Compound IV and Compound V are commercially available.
- the compound I (ester) can be hydrolyzed under basic conditions to obtain a compound I (acid):
- the basic condition can be formed using a base such as, for example, a base Is an alkali metal hydroxide, including but not limited to sodium hydroxide, lithium hydroxide, potassium hydroxide, etc., or any mixture thereof;
- the reaction temperature is 0 ° C to 80 ° C, preferably 20 ° C to 40 ° C, and the reaction time is 1 to
- X, Y, Z, R ⁇ R ⁇ GG 9 are as defined for the compounds of formula I, R is H or C1-C9 alkyl, preferably methyl or ethyl.
- Another object of the present invention is to provide a pharmaceutical composition comprising the compound of the above formula (I).
- the pharmaceutical composition of the present invention containing a compound of formula I comprises a conventional excipient of the compound of formula (I) and a pharmaceutical preparation.
- excipients for such pharmaceutical preparations refer to excipients that have been approved by the medical administration and meet the standards for pharmaceutical excipients. They are divided into two categories according to their functions: one is the necessary excipients for processing pharmaceutical preparations, such as diluents, binders, glidants, suspending agents and lubricants; Excipients that are digested and absorbed by drugs in the body. These excipients include disintegrants and cosolvents. They are inactive in the human body and produce neither efficacy nor toxicity.
- the diluent may be selected from one or a mixture of any two or more of the following: starch, modified starch, sucrose, lactose monohydrate, anhydrous lactose, glucose, glucomannol, various Microcrystalline cellulose.
- the binder may be selected from one or any two or two of the following materials: Mixture of the above: hydroxypropyl methylcellulose, pregelatinized starch, povidone (polyvinylpyrrolidone), carboxymethylcellulose and its derivatives, methylcellulose, ethylcellulose, starch, sugar, etc. Preferred are hydroxypropyl methylcellulose, pregelatinized starch and povidone.
- the lubricant may be selected from one or a mixture of two or more of the following: magnesium stearate, talc, type I hydrogenated vegetable oil.
- the suspending agent may be selected from one or a mixture of two or more of the following: gelatin, pectin, gum arabic, sodium alginate, methylcellulose, ethylcellulose, hydroxy Propyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose.
- the disintegrant may be selected from one or a mixture of any two or more of the following: starch, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, calcium carboxymethylcellulose, Cross-linked povidone, cross-linked cellulose and croscarmellose sodium.
- the co-solvent may be selected from one or a mixture of two or more of the following: Sipan series, Tween series, polyethylene glycol series, soybean egg phosphamate, and the like.
- the above pharmaceutical composition may be any one of the following oral preparations: 1. a plain tablet; 2. a film coated tablet; 3. a sugar-coated tablet; 4. a casing tablet; 5. a dispersible tablet; 6. a capsule; 8, a suspension; and 9, a solution.
- Another object of the present invention is to provide a use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a disease in which treatment or prevention of ⁇ -subtype peroxisome proliferator-activated receptor (PPAR6) is required to be activated
- Diseases include: metabolic syndrome, obesity, dyslipidemia, abnormal blood glucose, insulin resistance, senile dementia or tumors.
- a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a disease in need of activating the treatment or prevention of a delta subtype peroxisome proliferator-activated receptor (PPARS), said disease selection From: one or more of metabolic syndrome, obesity, dyslipidemia, abnormal blood glucose, insulin resistance, senile dementia, or tumor.
- PPARS delta subtype peroxisome proliferator-activated receptor
- a method of treating or preventing the treatment or prevention of a disease requiring activation of a delta subtype peroxisome proliferator-activated receptor comprising administering to a patient a therapeutically or prophylactically effective amount of formula (I) a step of a compound selected from the group consisting of: metabolic syndrome, One or more of obesity, dyslipidemia, abnormal blood glucose, insulin resistance, senile dementia, or tumor.
- PPARS delta subtype peroxisome proliferator-activated receptor
- Figure 1 is a graph showing changes in body weight over time of animals, showing the effect of drugs on animal body weight and food intake; wherein the abscissa indicates the weighing time of the animal's body weight (weighed every 2 days (d), ordinate) Indicates animal body weight, the positive drug is orlistat, there are two dose groups (30mg/kg and 10mg/kg, respectively), the drugs of the invention are A3 and All, and there are also two dose groups (10mg/kg and 3.3 respectively) Mg/kg ).
- 2 is a graph showing changes in blood sugar levels of animals over time, showing the results of an oral glucose tolerance test; wherein the abscissa indicates the time of blood collection at 0 min, 30 min, 60 min, and 120 min after oral glucose administration, and the ordinate indicates the corresponding blood glucose. Value (mmol/L).
- Figure 3 is a time curve of the compounds A-3 (HS060098) and A-1 (HS060001) of the present invention; wherein the abscissa indicates the blood collection time (h) of the animal, and the ordinate indicates the plasma concentration (g/ml) in the animals of different blood collection points. . detailed description
- a C1-C9 group (alkyl, alkoxy, alkylthio, etc.) includes a group such as Cl-C2, Cl-C3, C1-C4 C1-C8 and C1-C9.
- Drug screening model includes a group such as Cl-C2, Cl-C3, C1-C4 C1-C8 and C1-C9.
- a screening model for screening nuclear receptor activators in live cells was designed using a reporter gene approach using the principle that nuclear receptor activation activates its downstream gene transcription.
- a reporter gene plasmid was constructed, and the DNA receptor sequence (NRE) of the nuclear receptor was inserted into the upstream of the luciferase gene, and the expression of the luciferase gene was regulated by nuclear receptors.
- the reporter gene plasmid and the nuclear receptor are simultaneously transferred into a cell.
- the nuclear receptor is activated, and the activated receptor can induce the luciferase gene. Expression, while luciferase production can be detected by its luminescent substrate.
- the activation intensity of the compound to the nuclear receptor can be known by observing the intensity of the luminescence.
- the experimental error caused by the number of cells inoculated and the toxicity of the compound, the GFP plasmid was also co-transfected as an internal reference.
- the luminescence values of all the test wells were corrected by the GFP value in the analysis of the experimental results.
- the test results are expressed as relative activation multiples, and the solvent control has a value of 1. The higher the value, the higher the activation capacity.
- test compound (dissolved in DMSO) was formulated into 20 mM and stored at -80.
- Hepatoma cells HepG2 (from ATCC, American Type Culture Collection) were cultured in DMEM medium containing 10% heat-inactivated fetal bovine serum (FBS, Invitogen, Grand Island, NY, USA); T-75 flask (Greiner, Germany) Cultured in an incubator containing 5% CO 2 at a temperature of 37 ° C and a relative humidity of 100%. When the cells reached 80-90% cell fusion in a culture flask, they were digested with 0.25% trypsin (containing EDTA) for 3 min, and seeded in a 96-well cell culture plate at a seeding density of 2000 cells/lOOul/well.
- FBS heat-inactivated fetal bovine serum
- T-75 flask (Greiner, Germany) Cultured in an incubator containing 5% CO 2 at a temperature of 37 ° C and a relative humidity of 100%. When the cells reached 80-90% cell fusion in a culture flask, they were digested with 0.25% try
- Cell co-transfection was performed when cells in a 96-well culture plate were grown to 50-80% confluence.
- Cell co-transfection systems include: FuGene6 transfection agent (Roche Molecular Biochemicals, Indianapolis, IN, USA ), 60 ng DNA (10 ng hRXR, lOng pCMV ⁇ lOng nuclear receptor expression plasmid RXR/PPARS, 30 ng GFP fluorescent reporter plasmid, respectively.
- the cell culture solution was immediately discarded and replaced with a newly prepared 200 ⁇ l DMEM medium (containing 10% activated carbon-treated FBS) containing the test drug, and the final concentration gradient of the test drug was ⁇ , 5 ⁇ . ⁇ ⁇ , 0.1 ⁇ , ⁇ . ⁇ ⁇ , 0.00 ⁇ ⁇ , ⁇ , 0.05 ⁇ 2-tarsolic acid (purchased from Sigma, USA) as a positive control, and the final concentration of DMSO in each well was 0.1%.
- the cells were lysed with a lysate (Celltrue Lysis buffer, Promega), centrifuged, and the supernatant was collected.
- the relative intensity of luciferase (Luciferase) was measured by reaction with a fluorescent detection kit (Promega) and reading on a fluorescence detector (Ascent Fluoroskan FL reader, Thermo Labsystems, Finland).
- a fluorescent detection kit Promega
- Fluorescence detector Absolut Fluoroskan FL reader
- On-board (Bio-tech Instruments Inc., Winooski, VT, USA) reads at 405 nm (Sauerberg, P.; Olsen, GS; Jeppesen, L.; Mogensen, JP et al" J. Med. Chem” 2007, 50 , 1495- 1503 ).
- the half effective concentration (EC 5 ) is the concentration at which the sample produces 50% pharmacological action and is one of the important indicators for measuring the pharmacological effects of the compound. In this screen, it is calculated based on the activation of the receptor at six different concentrations.
- a compound of the formula I of the present invention which has an activity of activating a PPARS receptor.
- the in vitro activity test of the compound of the formula (I) (acid) of the present invention is carried out in the following manner: The sample [the compound of the formula (I) (acid)] is dissolved and diluted to different concentrations, and then the sample is activated to a PPARS receptor according to a concentration gradient. The activity was tested to obtain a concentration/effect relationship and the corresponding semi-effective concentration (EC 5 ) value was calculated.
- In vitro activity data for the compound of formula (I) (acid) Compound No. PPAR6 EC 50 ( nM)
- the compounds of the present invention all have PPARS agonistic activity. Screening of pharmacodynamic activity of compounds in vivo
- the four compounds we selected for in vivo activity testing can lower cholesterol (TC), triglyceride (TG) and low density protein (LDL), and increase high density protein (HDL). ), it can be seen that they have a good effect of regulating blood lipids.
- TC cholesterol
- TG triglyceride
- LDL low density protein
- HDL high density protein
- compound A-3 which lowers cholesterol (TC) by up to 40%, P-low triglyceride (TG) by 65%, lowers low-density protein (LDL) by 51%, and increases high-density protein. (HDL) is up to 43%.
- Elisa showed a significant decrease in insulin; apoA-1 content was significantly increased, apoB-100 content was significantly decreased, and the ratio of apoA-1 and apoB-100 was close to that of normal animals, which was in good agreement with the results of LDLc and HDLc in hematological test results.
- the above results suggest that all the hematological test indicators and Elisa test indicators are significantly restored after the administration of A-3 drugs in hyperlipidemia animals. The therapeutic effect of this drug is much better than that of GW501516.
- mice Three-week-old male C57BL/6J mice were selected, and 15 animals were randomly selected to be fed with standard feed. The remaining animals were fed a high-fat diet and each mouse was labeled with the ear-cut method. The body weight and food intake of the mice were weighed weekly. After 15 weeks of continuous feeding (w), the average weight of the mice in the high-fat diet group was 42 g, and the standard feed group was 28 g. After successful modeling, the mice were administered in groups, and the model group was given. The drug group continued to be fed with high-fat diet for 4 weeks. The effects of the drug on blood lipids, blood sugar, body weight and food intake were observed. At the same time, the glucose tolerance test was carried out to investigate the effect of the drug on the glucose tolerance of the animals.
- the obese model animals could not return to the original concentration level within 2 hours, the glucose tolerance curve was abnormal, and the glucose tolerance decreased, while A3 and Al1 significantly improved the glucose tolerance of obese animals.
- centrifuge 14000 rpm, 5 min
- take the supernatant centrifuge (14000 rpm, 5 min)
- take the supernatant and inject.
- the time points of blood collection were: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72h.
- the peak area at each time was the average of 6 rats at the same time point. Calculate the blood concentration and plot the drug time.
- the yellow liquid was transferred to another 500 liter single-necked flask, 300 liters of dichloromethane was added, stirred, then m-chloroperoxybenzoic acid (46 g, 199.9 mmol) was added, and finally a catalytic amount of para The benzenesulfonic acid was stirred at room temperature overnight. After completion of the reaction, it was filtered, and the filter cake was washed with 100 liters of dichloromethane, and the filtrate was combined. After the filtrate was washed with saturated sodium decanoate and aqueous sodium hydrogen carbonate solution, the solvent was evaporated in vacuo to give a pale yellow liquid.
- lithium tetrahydroaluminum LiAlH 4
- 50 liters of tetrahydrofuran was added, cooled to 0 ° C, and 3 diluted with 30 liters of tetrahydrofuran was added dropwise.
- a solution of methyl-4-hydroxy-phenylthiocyanate (6.13 g, 37.1 mmol) was added. After the addition was completed, the reaction was kept for 30 minutes, and naturally allowed to warm to room temperature, and the reaction was continued for 1 hour.
- N-methylphenylacetamide 25 g, 167.7 mmol
- 250 ml of toluene was added, stirred, and heated to 80.
- Add chloroform bricks (15 liters, 180 mmol) diluted with 50 liters of toluene. After the addition, the reaction was carried out at 80 ° C - 90 ° C for 5 hours. After completion of the reaction, it was cooled to room temperature, filtered, and the cake was washed with ethyl acetate until the cake was turned to be yellow.
- N-methyl-2-phenyl-N-(4-trifluoromethyl)phenylacetamide oxime 58.6 g, 190.9 mmol
- DMAP Dimethylaminopyridine
- THF tetrahydrofuran
- CDI carbonyldiimidazole
- the reaction product was poured into a 2000 liter beaker containing 300 liters of water, and the pH was adjusted to 2-4 with 6 N hydrochloric acid, and filtered. The filter cake was washed with distilled water and dried in vacuo to give 3-benzyl-4-methyl-1-(4-trifluoromethyl)phenyl-1H-1, 2,4-triazole-5 ( 4H )
- the ketone was 56.7 g (yellow solid, yield: 89.2%).
- phenylacetic acid (16 g, 117.6 mmol) was weighed, 60 liters of methanol was added, and 5 drops of concentrated citric acid were added dropwise thereto, and the mixture was heated under reflux for 6 hours; after cooling to room temperature, it was added.
- N-butylamine (12 liters, 121.4 mmol) was heated to reflux for 3 hours. After the completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness. EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. - n-Butyl phenylacetamide 15.9 g (white flake solid, yield: 70.4%).
- the reactant was poured into a 500-liter beaker containing 100 liters of water, and the pH was adjusted to 2-4 with 6 N hydrochloric acid under stirring, and filtered. The filter cake was washed with distilled water and dried in vacuo to give 3-benzyl-4-n-butyl-1-(4-trifluoromethyl)phenyl-1H-1, 2, 4-triazole-5 ( 4H ) Ketone 6.28 g (light yellow solid, two-step yield: 29.2%).
- lithium tetrahydroaluminum LiAlH 4
- THF tetrahydrofuran
- the crude 3-methyl-4-hydroxythiophenol was dissolved in 30 liters of acetonitrile and transferred to a 250 liter single-necked flask, which was weighed into the parent bromine ⁇ -1 (2.5 g, 6.06 mmol).
- DMAP ⁇ , ⁇ -dimethylaminopyridine
- K 2 CO 3 potassium carbonate
- lithium tetrahydroaluminum LiAlH 4
- tetrahydrofuran 1.0 g, 26.3 mmol
- 3 of diluted with 20 liters of tetrahydrofuran was added dropwise.
- -Methyl-4-hydroxyphenylthiocyanate 1.38 g, 8.35 mmol
- the pale yellow liquid was transferred to a 150 liter single-necked flask, 30 liters of acetonitrile was added, stirred, and 30 liters of the parent nucleus bromide ⁇ -3 (1.3 g, 3.9 mmol) and carbonic acid clock (K 2 C0) were added. 3 ) (3.4 g, 24.6 mmol), reacted at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc (EtOAc) Yield: 91%).
- lithium tetrahydroaluminum (LiAlH 4 ) (1 g, 26.3 mmol) was weighed out, 40 liters of tetrahydrofuran was added, cooled to 0 ° C, and 20 liters of 2, 5- 2 was added dropwise.
- -Methyl-4-hydroxyphthalene-cyanic acid (1.2 g, 6.7 mmol) in tetrahydrofuran. After the addition was completed, the reaction was kept for 30 minutes, and naturally allowed to warm to room temperature, and the reaction was continued for 1 hour.
- lithium tetrahydroaluminum LiAlH 4
- tetrahydrofuran 1.0 g, 26.4 mmol
- 3 diluted with 20 liters of tetrahydrofuran was added dropwise.
- a solution of methyl-4-hydroxyphenylthiocyanate 1.38 g, 8.35 mmol was added. After the addition, the reaction was kept for 30 minutes, and naturally allowed to warm to room temperature, and the reaction was continued for 2 hours.
- lithium tetrahydrogenate LiAlH 4
- 40 liters of tetrahydrofuran was added, cooled to 0 ° C, and 20 liters of 3-ethyl- was added dropwise.
- 4-Hydroxyphenylthiocyanate 1.3 g, 7.25 mmol
- the reaction was kept for 30 minutes. Naturally rise to room temperature and continue to react for 1 hour.
- the pale yellow liquid was transferred to a 150 liter single-necked flask, 30 liters of acetonitrile was added, stirred, and 30 liters of ethyl 2-bromoisopropylate (3 liters, 20.2 mmol) and carbonic acid clock (K) were added. 2 C0 3 ) (2.0 g, 14.4 mmol), reacted at room temperature for 12 hours.
- lithium tetrahydroaluminum (LiAlH 4 ) (2.0 g, 52.7 mmol) was weighed, 40 liters of tetrahydrofuran was added, cooled to 0 ° C, and 3 diluted with 30 liters of tetrahydrofuran was added dropwise. A solution of methyl-4-hydroxyphenylthiocyanate (2.5 g, 15.13 mmol) was added. After the addition, the reaction was kept for 30 minutes, and naturally allowed to warm to room temperature, and the reaction was continued for 2 hours.
- LiAlH 4 lithium tetrahydroaluminum
- lithium tetrahydrogenate LiAlH 4
- 40 liters of tetrahydrofuran was added, cooled to 0 ° C, and 20 liters of 2, 5- 2 was added dropwise.
- -Methyl-4-hydroxyphenyl phthalocyanine (1.02 g, 5.69 mmol) in tetrahydrofuran. After the addition, the reaction was kept for 30 minutes, and naturally allowed to warm to room temperature, and the reaction was continued for 1 hour.
- Example 42 Preparation of Compound A-14 Using the compound E-14 as a starting material, a synthesis procedure similar to that of Example 29 was carried out to obtain 2-(2-ethyl-4-(1-(3-(4-methyl-5-oxo small) (4- Trifluoromethyl-phenyl)-4,5-dihydro-1H-1, 2,4-triazolyl))-benzylthio)-phenoxy)-acetic acid (A-14). White solid, yield 63.1%.
- Example 29 Using the compound E-15 as a raw material, a synthesis process similar to that of Example 29 was carried out.
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EP20090804512 EP2330098B1 (en) | 2008-08-07 | 2009-08-07 | COMPOUND WITH AGITATION EFFECT ON PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR SUBTYPE delta, AND PREPARATION METHOD AND USE THEREOF |
CN200980130124.9A CN102112452B (zh) | 2008-08-07 | 2009-08-07 | 一种对δ亚型过氧化物酶增殖物激活受体具有激动作用的化合物、其制备方法和应用 |
KR1020117005312A KR101662592B1 (ko) | 2008-08-07 | 2009-08-07 | 퍼옥시좀 증식체-활성화 수용체 하위유형 델타에 대한 흥분 효과를 가진 화합물, 이의 제조방법 및 이의 용도 |
US13/057,737 US8822519B2 (en) | 2008-08-07 | 2009-08-07 | Compound with agitation effect on peroxisome proliferator-activated receptor process for its preparation and use thereof |
JP2011521428A JP5710480B2 (ja) | 2008-08-07 | 2009-08-07 | ペルオキシソーム増殖物質活性化受容体サブタイプδに対するアゴニスト作用を有する化合物、その調製方法及びその使用 |
RU2011103231/04A RU2522450C2 (ru) | 2008-08-07 | 2009-08-07 | Соединения, оказывающие возбуждающее действие на рецептор активатора пролиферации пероксисом подтипа б, способ получения и применение указанных соединений |
BRPI0917083A BRPI0917083A2 (pt) | 2008-08-07 | 2009-08-07 | compostos com efeito de agitação no recptor de subtipo delta ativado por proliferador de peroxissomo, processo para sua preparação e uso destes |
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EP (1) | EP2330098B1 (zh) |
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KR (1) | KR101662592B1 (zh) |
CN (2) | CN101643451B (zh) |
BR (1) | BRPI0917083A2 (zh) |
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Cited By (5)
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JP2013528174A (ja) * | 2010-05-28 | 2013-07-08 | ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム | オリゴベンズアミド化合物およびそれらの使用 |
WO2015035059A1 (en) * | 2013-09-06 | 2015-03-12 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9505728B2 (en) | 2012-03-09 | 2016-11-29 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9676754B2 (en) | 2012-12-20 | 2017-06-13 | Inception 2, Inc. | Triazolone compounds and uses thereof |
WO2023024425A1 (zh) * | 2021-08-23 | 2023-03-02 | 中国药科大学 | 三氮唑酮类化合物及其医药用途 |
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CN101643451B (zh) * | 2008-08-07 | 2013-03-06 | 浙江海正药业股份有限公司 | 过氧化物酶增殖物激活受体亚型δ类激动剂化合物及其制备方法 |
CN115894379A (zh) * | 2022-01-20 | 2023-04-04 | 中国药科大学 | 海因类化合物及其医药用途 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1576964A (en) * | 1976-11-17 | 1980-10-15 | Montedison Spa | 1,2,4-triazole derivatives with an insecticide nematocide and acaricide action and their preparation |
CA1106387A (en) * | 1976-11-17 | 1981-08-04 | Montedison S.P.A. | 1,2,4-triazole intermediate derivatives |
WO2001000603A1 (en) | 1999-06-25 | 2001-01-04 | Glaxo Group Limited | Thiazole and oxazole derivatives and their pharmaceutical use |
WO2002038533A1 (de) * | 2000-11-11 | 2002-05-16 | Henkel Kommanditgesellschaft Auf Aktien | Neue kupplerkomponenten für oxidationsfärbemittel |
WO2002092590A1 (en) * | 2001-05-11 | 2002-11-21 | Glaxo Group Limited | Furan and thiophene derivatives that activate human peroxisome proliferator activated receptors |
WO2004063166A1 (en) * | 2003-01-06 | 2004-07-29 | Eli Lilly And Company | Heterocyclic ppar modulators |
WO2008103574A2 (en) * | 2007-02-23 | 2008-08-28 | Eli Lilly And Company | Peroxisome proliferator activated receptor modulators |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA82048C2 (uk) * | 2000-11-10 | 2008-03-11 | Эли Лилли Энд Компани | Агоністи альфа-рецепторів, активованих проліфератором пероксисом |
MXPA05003830A (es) * | 2002-10-11 | 2005-06-23 | Cytokinetics Inc | Compuestos, composiciones y metodos. |
EP1720860A1 (en) * | 2004-02-18 | 2006-11-15 | AstraZeneca AB | Triazole compounds and their use as metabotropic glutamate receptor antagonists |
CN101643451B (zh) * | 2008-08-07 | 2013-03-06 | 浙江海正药业股份有限公司 | 过氧化物酶增殖物激活受体亚型δ类激动剂化合物及其制备方法 |
-
2008
- 2008-08-07 CN CN2008101473100A patent/CN101643451B/zh active Active
-
2009
- 2009-08-07 CN CN200980130124.9A patent/CN102112452B/zh active Active
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1576964A (en) * | 1976-11-17 | 1980-10-15 | Montedison Spa | 1,2,4-triazole derivatives with an insecticide nematocide and acaricide action and their preparation |
CA1106387A (en) * | 1976-11-17 | 1981-08-04 | Montedison S.P.A. | 1,2,4-triazole intermediate derivatives |
WO2001000603A1 (en) | 1999-06-25 | 2001-01-04 | Glaxo Group Limited | Thiazole and oxazole derivatives and their pharmaceutical use |
WO2002038533A1 (de) * | 2000-11-11 | 2002-05-16 | Henkel Kommanditgesellschaft Auf Aktien | Neue kupplerkomponenten für oxidationsfärbemittel |
WO2002092590A1 (en) * | 2001-05-11 | 2002-11-21 | Glaxo Group Limited | Furan and thiophene derivatives that activate human peroxisome proliferator activated receptors |
WO2004063166A1 (en) * | 2003-01-06 | 2004-07-29 | Eli Lilly And Company | Heterocyclic ppar modulators |
WO2008103574A2 (en) * | 2007-02-23 | 2008-08-28 | Eli Lilly And Company | Peroxisome proliferator activated receptor modulators |
Non-Patent Citations (16)
Title |
---|
"Design, synthesis and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARa selective activators", BIOORG MED CHEM LETT., vol. 14, no. 13, 2004, pages 3507 - 11 |
"Handbook of Fine Organic Chemical Raw Materials and Intermediate", SCIENTIFIC &TECHNOLOGICAL INDUSTRY PRESS, pages: 3 - 426,3-58 |
BELLIONI, SERGIO: "Syntheses in the 1,2,4-triazolone series.", ANNALI DI CHIMICA, vol. 52, 1962, ROME, ITALY, pages 187 - 191, XP008144759 * |
BERGER, J. ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 274, no. 10, 1999, pages 6718 - 6725 |
BIOORG. MED. CHEM. LETT., vol. 13, 2003, pages 1517 |
GUAN, Y. J., AM. SOC. NEPHROL, vol. 15, 2004, pages 2801 - 2815 |
KASUGA, J. ET AL., BIOORG. MED. CHEM., vol. 15, 2007, pages 5177 - 5190 |
KASUGA, J. ET AL.: "Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists. Bioorg.", MED. CHEM., vol. 15, no. 15, 1 August 2007 (2007-08-01), pages 5177 - 5190, XP022110120 * |
M. L. SZNAIDMAN, CURT D. HAFFNER, PATRIC R. ET AL., BIOORG. MED. CHEM. LETT., vol. 13, 2003, pages 1517 - 1521 |
OLIVER, W.; JR., SHENK, J. L. ET AL., NATL. ACAD. SCI. U.S.A., vol. 98, 2001, pages 5306 - 5311 |
ORG. SYN. COLL., vol. 1, 1941, pages 102 |
ORG. SYN. COLL., vol. 2, 1943, pages 290 |
SAUERBERG, P., OLSEN, G. S., JEPPESEN, L., MOGENSEN, J. P ET AL., J. MED. CHEM., vol. 50, 2007, pages 1495 - 1503 |
See also references of EP2330098A4 * |
SZNAIDMAN, M. L. ET AL.: "Novel selective small molecule agonists for peroxisome proliferator-activated receptor6 (PPAR6)-synthesis and biological activity.", BIOORG. MED. CHEM. LETT., vol. 13, no. 9, 5 May 2003 (2003-05-05), pages 1517 - 1521, XP002995419 * |
ZHI-LIANG WEI ET AL., J. ORG. CHEM., vol. 68, 2003, pages 9116 - 9118 |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013528174A (ja) * | 2010-05-28 | 2013-07-08 | ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム | オリゴベンズアミド化合物およびそれらの使用 |
US9505728B2 (en) | 2012-03-09 | 2016-11-29 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9676754B2 (en) | 2012-12-20 | 2017-06-13 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US10568871B2 (en) | 2012-12-20 | 2020-02-25 | Tempest Therapeutics, Inc. | Triazolone compounds and uses thereof |
US11666557B2 (en) | 2012-12-20 | 2023-06-06 | Tempest Therapeutics, Inc. | Triazolone compounds and uses thereof |
WO2015035059A1 (en) * | 2013-09-06 | 2015-03-12 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9776976B2 (en) | 2013-09-06 | 2017-10-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
WO2023024425A1 (zh) * | 2021-08-23 | 2023-03-02 | 中国药科大学 | 三氮唑酮类化合物及其医药用途 |
Also Published As
Publication number | Publication date |
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BRPI0917083A2 (pt) | 2016-06-14 |
CN102112452B (zh) | 2014-05-14 |
KR101662592B1 (ko) | 2016-10-05 |
CN102112452A (zh) | 2011-06-29 |
RU2011103231A (ru) | 2012-09-20 |
KR20110074971A (ko) | 2011-07-05 |
RU2522450C2 (ru) | 2014-07-10 |
JP5710480B2 (ja) | 2015-04-30 |
CN101643451A (zh) | 2010-02-10 |
EP2330098B1 (en) | 2015-04-29 |
EP2330098A4 (en) | 2011-10-26 |
EP2330098A1 (en) | 2011-06-08 |
US20110319458A1 (en) | 2011-12-29 |
JP2011529925A (ja) | 2011-12-15 |
CN101643451B (zh) | 2013-03-06 |
US8822519B2 (en) | 2014-09-02 |
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