CN115504925B - 一类ppar激动剂、其制备方法及其作为药物的用途 - Google Patents
一类ppar激动剂、其制备方法及其作为药物的用途 Download PDFInfo
- Publication number
- CN115504925B CN115504925B CN202110694689.2A CN202110694689A CN115504925B CN 115504925 B CN115504925 B CN 115504925B CN 202110694689 A CN202110694689 A CN 202110694689A CN 115504925 B CN115504925 B CN 115504925B
- Authority
- CN
- China
- Prior art keywords
- disease
- compound
- pharmaceutically acceptable
- liver
- acceptable salt
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 229940126033 PPAR agonist Drugs 0.000 title abstract description 8
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 title abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000002159 abnormal effect Effects 0.000 claims abstract description 7
- 230000004153 glucose metabolism Effects 0.000 claims abstract description 4
- 230000037356 lipid metabolism Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 33
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 15
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 15
- 206010012601 diabetes mellitus Diseases 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
- 208000004930 Fatty Liver Diseases 0.000 claims description 5
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 5
- 208000010706 fatty liver disease Diseases 0.000 claims description 5
- 210000004185 liver Anatomy 0.000 claims description 5
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010008635 Cholestasis Diseases 0.000 claims description 2
- 208000002249 Diabetes Complications Diseases 0.000 claims description 2
- 206010012655 Diabetic complications Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 206010067125 Liver injury Diseases 0.000 claims description 2
- 208000001280 Prediabetic State Diseases 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 208000024908 graft versus host disease Diseases 0.000 claims description 2
- 231100000753 hepatic injury Toxicity 0.000 claims description 2
- 208000019423 liver disease Diseases 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 208000012268 mitochondrial disease Diseases 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 208000035475 disorder Diseases 0.000 claims 1
- 230000003612 virological effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- -1 (4-methoxyphenyl) sulfonyl Chemical group 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 238000001890 transfection Methods 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 208000001145 Metabolic Syndrome Diseases 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 7
- 230000002503 metabolic effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 102000023984 PPAR alpha Human genes 0.000 description 6
- 108010016731 PPAR gamma Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 108010015181 PPAR delta Proteins 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000001270 agonistic effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229930186217 Glycolipid Natural products 0.000 description 4
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 210000001853 liver microsome Anatomy 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000007410 oral glucose tolerance test Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 108010028924 PPAR alpha Proteins 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- JJKMIZGENPMJRC-UHFFFAOYSA-N 3-oxo-3-propan-2-yloxypropanoic acid Chemical compound CC(C)OC(=O)CC(O)=O JJKMIZGENPMJRC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- DTJVECUKADWGMO-UHFFFAOYSA-N 4-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1 DTJVECUKADWGMO-UHFFFAOYSA-N 0.000 description 1
- TUWARWGEOHQXCO-UHFFFAOYSA-N 5-methoxyindole-3-carbaldehyde Chemical compound COC1=CC=C2NC=C(C=O)C2=C1 TUWARWGEOHQXCO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010023302 HDL Cholesterol Proteins 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 241000242739 Renilla Species 0.000 description 1
- 108010052090 Renilla Luciferases Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 210000003486 adipose tissue brown Anatomy 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940125542 dual agonist Drugs 0.000 description 1
- 230000000225 effect on diabetes Effects 0.000 description 1
- 229950001279 elafibranor Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011713 fatty liver animal model Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- AFLFKFHDSCQHOL-IZZDOVSWSA-N gft505 Chemical compound C1=CC(SC)=CC=C1C(=O)\C=C\C1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1 AFLFKFHDSCQHOL-IZZDOVSWSA-N 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Emergency Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Gastroenterology & Hepatology (AREA)
- Psychiatry (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Child & Adolescent Psychology (AREA)
- Endocrinology (AREA)
- Transplantation (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一类新型PPAR激动剂、其制备方法及含有该衍生物的药物组合物作为制备预防或/和治疗葡萄糖代谢异常或/和脂质代谢异常疾病的药物用途。
Description
技术领域
本发明涉及与糖脂代谢性疾病相关的药物学领域,具体涉及一种新的PPAR激动剂、其制备方法及含有该衍生物的药物组合物作为制备治疗糖脂代谢性疾病药物中的应用。本发明中涉及的衍生物结构在该领域中具有独特性和新颖性。
背景技术
代谢综合症是以葡萄糖与脂质代谢异常为特征的常见病,伴有低密度脂蛋白升高和高密度脂蛋白胆固醇降低,其常见的病症为肥胖病、糖尿病、高血脂症、动脉粥样硬化和脂肪肝等,其中,糖尿病患者还常并发有高脂血症、心血管病、糖尿病肾病、糖尿病神经病变等疾病。
据世界卫生组织公布,目前世界范围内超过2.2亿人患糖尿病,其中,中国已成为全球糖尿病人最多的国家,超过9200万糖尿病患者,而且我国目前的糖尿病发病率还处于上升期,据估算中国目前糖尿病前期患者约为1.5亿。持续扩大的糖尿病人群已给社会带来了巨大的经济与医疗负担。世界卫生组织指出,如果不采取有效措施来应对糖尿病的发展,预计在未来10年内,仅心脏病、中风和糖尿病就将给中国带来至少5500亿美元的经济损失。因此,以糖尿病为典型的代谢综合症已成为威胁人类健康的一类严重疾病。代谢综合征可以通过饮食调节和锻炼治疗,当这些不能缓解症状时,需要进行药物治疗。在代谢综合症的药物治疗方面,目前临床使用的降糖药或降脂药等作用单一,均不同时具备较理想的改善代谢综合征各项病理指标的作用,因此,针对多个领域的改善代谢综合征药物研究正在进行,以期为代谢综合征患者带来更安全有效的新型药物。其中过氧化物酶体增殖物激活受体PPAR多重激动剂成为近来该领域的研究热点。
过氧化物酶体增殖物激活受体(peroxisome proliferator-activatedreceptor,PPAR)是调节目标基因表达的核内受体转录因子超家族成员,根据亚型结构的不同,PPAR可分为α、β(或δ)和γ三种类型,其中PPARα主要分布于肝脏及褐色脂肪中,与调节血脂水平、胰岛素抵抗即炎症反应密切相关;PPARγ主要表达于脂肪组织及免疫***,与脂肪细胞分化、机体免疫及胰岛素抵抗关系密切,是胰岛素增敏剂噻唑烷二酮类药物(troglitazone,TZDs)作用的靶分子;PPARδ主要分布于脂肪、骨骼肌、心脏和肝脏中,主要调节糖脂代谢、改善炎症反应等。现已研究证实:PPAR多重激动剂能够激活并调控相关基因表达,在脂肪形成、糖脂代谢中发挥重要作用,并能调控多种疾病包括肥胖、脂肪肝、糖尿病、高血脂等[Azadeh Matin等,J.Med.Chem.2009,52,6835-6850;Shen等,J.Nutr.2006,899-905]。PPARα/δ双重激动剂GFT505也处于非酒精性脂肪肝III期临床研究中,表现出较优异的药理活性(Bertrand Cariou等,Expert Opin.Investig.Drugs.2014,23,1441-1448)。此外,PPARα/γ/δ泛激动剂indeglitazar对于糖尿病和脂肪肝动物模型均有明显疗效,但indeglitazar体内半衰期较短,大鼠中T1/2仅1.4h,极大地限制了该化合物的临床应用(Dean R.Artis等,PNAS,2009,106,262-267)。因此,针对indeglitazar的代谢缺陷,筛选代谢更稳定的PPAR激动剂对预防或/和治疗代谢异常类疾病非常重要。
本发明涉及结构新颖的PPAR激动剂,其具有优异的PPARα/γ/δ泛激动活性和体内降糖调脂活性,且较indeglitazar具有更好的代谢稳定性。因此,所述PPAR激动剂及其可药用盐可以潜在的用于治疗或者预防糖尿病、高血脂及脂肪肝等相关代谢综合征,具有广阔的药物开发前景。
发明内容
针对现有技术存在的上述问题和未满足的临床需求,本发明的目的是提供一类代谢更稳定的PPAR激动剂及其应用,为预防或/和治疗代谢异常类疾病提供一类新的潜在药物。
本发明所述的PPAR激动剂,是含有有效量的如下所示的化合物或其可药用的盐或前药,其中所述的盐包括药学可接受的钠盐、钾盐、有机碱盐等;前药包括药学可接受的羧酸酯、酰胺等:
本发明的另一方面涉及一种药物组合物,其含有治疗有效剂量的所述化合物或其可药用的盐或前药及适当的载体、稀释剂或赋形剂。
本发明涉及的化合物或其可药用的盐或前药、及药物组合物在制备治疗过氧化物酶体增殖物激活受体介导疾病的药物中的用途。
本发明同时涉及所述化合物或其可药用的盐或前药、及其药物组合物在制备预防或/和治疗葡萄糖代谢异常或/和脂质代谢异常疾病的药物中的用途,及在制备预防或/和治疗糖尿病、肥胖症、高血脂、炎症性肠病、阿尔兹海默症、胆汁淤积性肝病、线粒体病、肝移植物抗宿主病、病毒引起的慢性肝病、酒精性肝病、药物性肝损伤、糖尿病并发症、前驱糖尿病、器官纤维化、动脉粥样硬化及脂肪肝中至少一种疾病的药物中的用途。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出各种变化均应在本申请权利要求的保护范围之内。
实施例1
3-(5-甲氧基-1-(((4-甲氧基苯基)磺酰基)-1H-吲哚-3-基)-2,2-d2-丙酸(I-1)
5-甲氧基吲哚-3-甲醛(0.5g,2.85mmol)溶于0℃的10ml无水四氢呋喃中,置于冰浴冷却至-5℃左右,分批加入氢化钠(0.075g,3.14mmol),控制内温低于0℃,冰浴搅拌0.5h后,冰浴冷却下滴加10ml无水四氢呋喃稀释的对甲氧基苯磺酰氯(0.71mg,3.42mmol),滴加过程中保持反应液内温低于0℃,滴毕,所得溶液升至室温反应4h,TLC检测反应完毕后,滴加10ml水淬灭反应,以乙酸乙酯(20ml×3)萃取,合并有机相,分别以1N的盐酸(15ml×2)洗涤,饱和碳酸氢钠水溶液(15ml×2)洗涤,饱和食盐水(15ml×2)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,柱层析(石油醚/乙酸乙酯,2∶1,v/v)纯化得白色固体0.88g,收率89.28%。取上述产物(0.5g,1.45mmol),丙二酸环(亚)异丙酯(0.27g,1.88mmol)溶于10ml四氢呋喃中,加入催化量DMAP,室温搅拌12h,TLC检测反应完毕后,将反应液倒入10ml水中,乙酸乙酯(20ml×3)萃取,合并有机相,以饱和食盐水(15ml×2)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,经重结晶(无水乙醇)得到黄色固体0.35g,收率51.28%,ESI-MS m/z:472.1[M+H]+。取上述产物(0.35g,0.74mmol)溶于的5ml甲醇中,分批加入硼氢化钠(0.056g,1.48mmol),室温反应0.5h,TLC检测反应完毕后,滴加1ml水淬灭反应,加入1N盐酸酸化(PH:5-6),以乙酸乙酯(20ml×3)萃取,合并有机相,分别以1N的盐酸(15ml×2)洗涤,饱和碳酸氢钠水溶液(15ml×2)洗涤,饱和食盐水(15ml×2)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂得白色固体0.35g,收率99.57%,ESI-MS m/z:474.1[M+H]+。
原料4(0.35g,0.74mmol)溶于4.5mL DMF中,加入D2O(0.5ml),搅拌均匀后加热至100℃反应12h,TLC检测反应完毕后,冷却至室温,将反应液倒入50ml水中,以乙酸乙酯(20ml×3)萃取,合并有机相,分别以1N的盐酸(15ml×2)洗涤,饱和碳酸氢钠水溶液(15ml×2)洗涤,饱和食盐水(15ml×2)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂得白色液体0.30g,直接用于下一步反应。取上述产物(0.3g,0.74mmol)溶于5mL甲醇中,缓慢滴加入浓硫酸(0.5ml),搅拌均匀后加热至70℃反应3h,TLC检测反应完毕后,冷却至室温,减压蒸除溶剂,加入10ml水,以乙酸乙酯(20ml×3)萃取,合并有机相,分别以饱和碳酸氢钠水溶液(15ml×2)洗涤,饱和食盐水(15ml×2)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,经柱层析(石油醚/乙酸乙酯,80∶20,v/v)得白色液体0.18g。取上述产物溶于3mL四氢呋喃,3mL甲醇和1mL水中,加入LiOH·H2O(0.1g,2.4mmol),室温反应4h,减压蒸除四氢呋喃和甲醇,冰水浴下滴加1N稀盐酸调节pH 2-3,析出白色固体,抽滤,干燥得白色粉末状固体0.17g,收率97.83%。
1H NMR(300MHz,DMSO-d6)δ7.87-7.77(m,3H),7.51(s,1H),7.10(d,J=2.5Hz,1H),7.05(d,J=8.9Hz,2H),6.95(dd,J=8.9,2.5Hz,1H),3.79(s,3H),3.77(s,3H),2.84(s,2H).13C NMR(75MHz,DMSO-d6)δ175.01,163.92,156.49,132.22,129.49,129.37,128.80,124.45,123.18,115.23,114.63,113.99,102.70,56.20,55.88,20.46.ESI-MS m/z:390.1[M-H]-.
实施例2
3-(1-(苯并呋喃-5-基磺酰基)-5-甲氧基-1H-吲哚-3-基)-2,2-d2-丙酸(I-2)
参照I-1的制备方法,得到白色固体0.25g,产率为45%。
1H NMR(300MHz,DMSO-d6)δ7.79(d,J=9.0Hz,1H),7.76(d,J=2.2Hz,1H),7.69(dd,J=8.5,2.2Hz,1H),7.49(s,1H),7.11(d,J=2.5Hz,1H),6.95(dd,J=9.0,2.5Hz,1H),6.88(d,J=8.5Hz,1H),4.60(t,J=8.8Hz,2H),3.79(s,3H),3.19(t,J=8.8Hz,2H),2.85(s,2H).13C NMR(75MHz,DMSO-d6)δ174.36,164.89,156.43,132.01,130.07,129.42,128.90,128.77,124.52,124.45,122.39,114.59,114.04,109.87,102.68,73.05,55.92,28.69,20.09.ESI-MS m/z:402.1[M-H]-.
实施例3
3-(5-甲氧基-1-(((4-(三氟甲氧基)苯基)磺酰基)-1H-吲哚-3-基)-2,2-d2-丙酸(I-3)
参照I-1的制备方法,得到白色固体0.25g,产率为43%。
1H NMR(500MHz,DMSO-d6)δ8.05(d,J=8.9Hz,2H),7.81(d,J=9.0Hz,1H),7.59-7.53(m,3H),7.13(d,J=2.6Hz,1H),6.97(dd,J=9.0,2.6Hz,1H),3.79(s,3H),2.86(s,2H).13C NMR(126MHz,DMSO-d6)δ174.32,156.77,152.44,136.03,132.24,129.80,129.36,124.44,123.52,122.09,120.14(q,J=258.9Hz),114.61,114.33,102.99,55.92,20.09.ESI-MS m/z:444.1[M-H]-.
实施例4
3-(5-环丙基-1-(((4-甲氧基苯基)磺酰基)-1H-吲哚-3-基)-2,2-d2-丙酸(I-4)
参照I-1的制备方法,得到白色固体0.51g,产率为36%。
1H NMR(500MHz,DMSO-d6)δ7.51(d,J=7.8Hz,1H),7.34(d,J=8.2Hz,1H),7.21(d,J=8.5Hz,2H),7.13-7.03(m,2H),7.02-6.93(m,1H),6.79(dd,J=8.2,1.8Hz,1H),3.46(s,3H),2.88(s,2H),1.97(tt,J=8.4,5.1Hz,1H),0.93-0.84(m,2H),0.71-0.58(m,2H).13CNMR(126MHz,DMSO-d6)δ174.78,136.67,135.23,133.32,127.49,127.38,122.83,122.67,121.34,119.76,115.19,113.33,111.59,59.68,20.65,15.82,9.20.ESI-MS m/z:400.1[M-H]-.
实施例5
3-(1-(((4-环丙基苯基)磺酰基)-5-甲氧基-1H-吲哚-3-基)-2,2-d2-丙酸(I-5)
参照I-1的制备方法,得到白色固体0.26g,产率为35%。
1H NMR(300MHz,DMSO-d6)δ7.78(d,J=9.0Hz,1H),7.73(d,J=8.5Hz,2H),7.48(s,1H),7.18(d,J=8.5Hz,2H),7.07(d,J=2.5Hz,1H),6.93(dd,J=9.0,2.5Hz,1H),3.77(s,3H),2.81(s,2H),1.90(tt,J=8.3,5.0Hz,1H),1.05-0.90(m,2H),0.75-0.60(m,2H).13CNMR(75MHz,DMSO-d6)δ175.78,156.49,151.99,134.00,132.40,129.48,127.04,126.58,124.25,124.01,114.59,113.94,102.73,55.86,21.04,15.66,11.34.ESI-MS m/z:400.1[M-H]-.
实施例6
3-(5-(甲氧基-d3)-1-((4-甲氧基苯基)磺酰基)-1H-吲哚-3-基)丙酸(I-6)
参照I-1的制备方法,得到白色固体0.17g,产率为24%。
1H NMR(300MHz,DMSO-d6)δ7.89-7.78(m,3H),7.52(s,1H),7.13(d,J=2.5Hz,1H),7.07(d,J=8.8Hz,2H),6.96(dd,J=8.8,2.5Hz,1H),3.79(s,3H),2.96(t,J=7.6Hz,2H),2.74(t,J=7.6Hz,2H).ESI-MS m/z:391.1[M-H]-.
实施例7
3-(5-甲氧基-1-((4-(甲氧基-d3)苯基)磺酰基)-1H-吲哚-3-基)丙酸(I-7)
参照I-1的制备方法,得到白色固体0.25g,产率为29%。
1H NMR(300MHz,DMSO-d6)δ7.87-7.75(m,3H),7.50(s,1H),7.15(d,J=2.5Hz,1H),7.08(d,J=8.8Hz,2H),6.95(dd,J=8.8,2.5Hz,1H),3.77(s,3H),2.95(t,J=7.6Hz,2H),2.74(t,J=7.6Hz,2H).ESI-MS m/z:391.1[M-H]-.
实施例8 本发明化合物对PPAR的激动活性测定
以下生物学测试实施例描述解释本发明。
本发明测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常用试剂。
本发明使用以下方法测定本发明化合物的PPAR激动活性:
转染:转染前,HEK293细胞以5×104/孔的密度接种至96孔板,置于37℃、5%CO2的细胞培养箱培养一天(用于PPARγ和PPARδ转染);HepG2细胞以6×104/孔的密度接种至96孔板,置于37℃、5%CO2的细胞培养箱培养一天(用于PPARα转染);分别采用FuGENE HD转染试剂(购自Roche)进行转染:25ng/well pBIND-PPARα或PPARδ或PPARγ,25ng/wellpG5Luc,及0.15μl/well FuGENE HD。
激动活性测定:转染24h后,将受试化合物加入转染后细胞孔板中,温孵18h,加入20μl细胞裂解液进行裂解及30μl萤光素酶分析试剂II(购自Promega公司),混匀,测荧光,2秒延迟,读10秒。转染效率利用内参Renilla荧光素酶活性校正。所有转染实验至少独立重复三次,每个实验组至少2个复孔。相对荧光强度=萤火虫萤光强度/肾氏萤光强度。PPAR激动活性(%)=[(X-Min)/(Max-Min)]×100%,其中X表示化合物组相对荧光强度,Min表示空白对照组相对荧光强度,Max表示10μM浓度的阳性对照化合物组相对荧光强度。实施例化合物PPARα、PPARδ及PPARδ激动活性EC50值见表1。
表1:PPARα、PPARδ及PPARγ激动活性
结论:本发明所有化合物对PPARα、PPARδ及PPARγ具有明显的激动活性,均为PPAR多重激动剂。
实施例9 本发明化合物代谢稳定性测定
将大鼠肝微粒体(0.25mg/mL)与待测化合物(500ng/mL)在0.1M PBS缓冲液(pH7.4)中于37℃下孵育5分钟,然后根据代谢稳定性试剂盒说明书添加NADPH催化生物反应,在37℃下共孵育不同时间(0,15,30和60分钟)后,使用等体积带有内标的冰甲醇终止反应,然后通过LC/MS检测上清液药物浓度并计算药物在大鼠肝微粒体中的半衰期,实验结果见表2。
表2 本发明化合物肝微粒体半衰期
结论:本发明化合物I-1至I-5对肝微粒体稳定性明显优于indeglitazar,表明本发明化合物(羧酸α位进行氘代)代谢稳定性得到极大提高;而对indeglitazar的其余潜在代谢位点进行氘代(I-6和I-7),对于肝微粒体稳定性几乎没有改善(甚至促进代谢),表明并非所有氘代化合物均可改善代谢稳定性,即本发明化合物取得了意想不到的技术效果,具备新颖性和创造性。
实施例10 本发明化合物的体内降糖调脂活性测定
8周龄ob/ob小鼠,雄性,随机分组,每组6只,空白对照组(空白溶媒:0.5%的羧甲基纤维素钠溶液),受试化合物组(20mg/kg)每天一次分别灌胃给予空白溶媒及受试化合物,连续给药15天,于给药第15天测定小鼠口服葡萄糖耐量(OGTT),实验前小鼠禁食不禁水12小时,断尾取血,测定血糖值(记为-30min)。然后分别灌胃给予空白溶媒、阳性药和受试化合物,给药30min后测定血糖值记为0min,之后立即灌胃给予3g/kg葡萄糖水溶液,并于15,30,60min测定血糖值。OGTT结果见表3。并于第16天,小鼠采血取血浆,以全自动生化分析仪测定小鼠血脂水平,结果见表4。
表3:本发明化合物对ob/ob小鼠口服糖耐量的影响(n=6)
注:*P≤0.05及**P≤0.01为相对于空白对照组的Student’s t检验结果。
ob/ob小鼠长期给药后口服糖耐量试验表明:化合物I-1、I-3、I-5能够明显改善ob/ob小鼠的口服糖耐量,表现出较好的降血糖作用。
表4:本发明化合物对ob/ob小鼠血脂水平的影响(n=6)
注:*p≤0.05为相对于空白对照组的Student’s t检验结果。
结果表明:化合物I-1、I-3、I-5能够明显改善ob/ob小鼠的高血脂水平,具有改善脂代谢作用。
实施例11
含活性剂I-1的片剂:
将活性成分、预胶化淀粉和微晶纤维素过筛,充分混合,加入聚乙烯吡咯烷酮溶液,混合,制软材,过筛,制湿颗粒,于50-60℃干燥,将羧甲基淀粉钠盐、硬脂酸镁和滑石粉过筛加入至上述颗粒中压片成型。经验证,上述组合物也具有优异的体内降糖调脂活性。
Claims (5)
1.化合物或其可药用的盐,其中所述化合物选自:
2.一种药物组合物,含有权利要求1所述的化合物或其可药用盐,及适当的载体或赋形剂。
3.权利要求1所述的化合物或其可药用的盐或权利要求2所述药物组合物在制备治疗过氧化物酶体增殖物激活受体介导疾病的药物中的用途。
4.权利要求1所述的化合物或其可药用的盐或权利要求2所述的药物组合物在制备预防或/和治疗葡萄糖代谢异常或/和脂质代谢异常疾病的药物中的用途。
5.权利要求1所述的化合物或其可药用的盐或权利要求2所述的药物组合物在制备预防或/和治疗糖尿病、肥胖症、高血脂、炎症性肠病、阿尔兹海默症、胆汁淤积性肝病、线粒体病、肝移植物抗宿主病、病毒引起的慢性肝病、酒精性肝病、药物性肝损伤、糖尿病并发症、前驱糖尿病、器官纤维化、动脉粥样硬化及脂肪肝中至少一种疾病的药物中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110694689.2A CN115504925B (zh) | 2021-06-22 | 2021-06-22 | 一类ppar激动剂、其制备方法及其作为药物的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110694689.2A CN115504925B (zh) | 2021-06-22 | 2021-06-22 | 一类ppar激动剂、其制备方法及其作为药物的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115504925A CN115504925A (zh) | 2022-12-23 |
CN115504925B true CN115504925B (zh) | 2024-03-12 |
Family
ID=84499123
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110694689.2A Active CN115504925B (zh) | 2021-06-22 | 2021-06-22 | 一类ppar激动剂、其制备方法及其作为药物的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115504925B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1845898A (zh) * | 2003-07-17 | 2006-10-11 | 普莱希科公司 | Ppar活性化合物 |
CN101304992A (zh) * | 2005-09-07 | 2008-11-12 | 普莱希科公司 | 用作ppar调节剂的1,3-二取代吲哚衍生物 |
CN101544592A (zh) * | 2002-11-28 | 2009-09-30 | 苏文生命科学有限公司 | 具有5-羟色胺受体亲和性的n-芳基磺酰-3-取代吲哚及其制备方法和含有其的药物组合物 |
CN102875441A (zh) * | 2003-07-17 | 2013-01-16 | 普莱希科公司 | Ppar活性化合物 |
CN105175309A (zh) * | 2015-10-29 | 2015-12-23 | 中国科学院上海药物研究所 | N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途 |
-
2021
- 2021-06-22 CN CN202110694689.2A patent/CN115504925B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101544592A (zh) * | 2002-11-28 | 2009-09-30 | 苏文生命科学有限公司 | 具有5-羟色胺受体亲和性的n-芳基磺酰-3-取代吲哚及其制备方法和含有其的药物组合物 |
CN1845898A (zh) * | 2003-07-17 | 2006-10-11 | 普莱希科公司 | Ppar活性化合物 |
CN102875441A (zh) * | 2003-07-17 | 2013-01-16 | 普莱希科公司 | Ppar活性化合物 |
CN101304992A (zh) * | 2005-09-07 | 2008-11-12 | 普莱希科公司 | 用作ppar调节剂的1,3-二取代吲哚衍生物 |
CN105175309A (zh) * | 2015-10-29 | 2015-12-23 | 中国科学院上海药物研究所 | N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途 |
Non-Patent Citations (1)
Title |
---|
"PPAR 激动剂的定向设计、虚拟筛选及合成";冯君等;《化学学报》;第62卷(第16期);第1544-1550页 * |
Also Published As
Publication number | Publication date |
---|---|
CN115504925A (zh) | 2022-12-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111285829B (zh) | 一类PPARγ/δ双重激动剂、其制备方法及其作为药物的用途 | |
WO2019007418A1 (zh) | Fxr受体激动剂 | |
EP3681862B1 (en) | Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia | |
EP2077846B1 (en) | Benzoxazepine compounds, their preparation and use | |
IL171269A (en) | Compounds for the treatment of metabolic disorders | |
WO2021028810A1 (en) | Sulfinic acid compounds as free fatty acid receptor agonists | |
EP4331584A1 (fr) | Derives deuteres du lanifibranor | |
KR101660936B1 (ko) | 피질 카테콜아민성 신경전달의 조절자로서의 3-페닐-3-메톡시피롤리딘 유도체 | |
CN112759515B (zh) | 一种新型FFA1和PPARα/γ/δ四重激动剂、其制备方法及其作为药物的用途 | |
JP2011527326A (ja) | パーキンソン病を治療するためのnurr−1活性化剤としてのインドール誘導体の使用 | |
CN115504925B (zh) | 一类ppar激动剂、其制备方法及其作为药物的用途 | |
CN111499591A (zh) | RORγ调节剂 | |
WO2006117743A1 (en) | Substituted aromatic compounds as antidiabetic agents | |
CN109456274B (zh) | 苯并咪唑类衍生物、其制备方法及其作为药物的用途 | |
WO2021104507A1 (zh) | 取代苯氧酰胺衍生物、应用及用于治疗帕金森病的药物 | |
CN113493374B (zh) | Sirt1受体激动剂及包含其的药物 | |
JP2754644B2 (ja) | 新規リグナン類およびリグナン類を有効成分とする5―リポキシゲナーゼ阻害剤およびアルドースリダクターゼ阻害剤 | |
CN111393372A (zh) | 一种苯并咪唑衍生物及其制备方法和用途 | |
EP3502120B1 (en) | Panaxdiol-type ginsenoside derivative, preparation method therefor and use thereof | |
EP1841748B1 (en) | Organoselenium containing compounds and their use | |
CN112480047B (zh) | 一种具有降糖调脂作用的化合物及其制剂与应用 | |
CN106146488B (zh) | 9-位取代的双功能团小檗碱衍生物的制备方法及用途 | |
WO2010034212A1 (zh) | 苯氧乙酸吡嗪酯类衍生物及其制法和用途 | |
CN110240537B (zh) | 一种茚氧乙酸类化合物及其制备方法和用途 | |
CN114874202B (zh) | 一种用于治疗阿尔茨海默症的药物及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |