CN1608056A - 羧酸衍生物化合物和包含这种化合物作为活性成分的药剂 - Google Patents
羧酸衍生物化合物和包含这种化合物作为活性成分的药剂 Download PDFInfo
- Publication number
- CN1608056A CN1608056A CNA028262646A CN02826264A CN1608056A CN 1608056 A CN1608056 A CN 1608056A CN A028262646 A CNA028262646 A CN A028262646A CN 02826264 A CN02826264 A CN 02826264A CN 1608056 A CN1608056 A CN 1608056A
- Authority
- CN
- China
- Prior art keywords
- amino
- benzyl
- oxazole
- group
- jia
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 133
- -1 Carboxylic acid derivative compounds Chemical class 0.000 title claims description 120
- 239000003795 chemical substances by application Substances 0.000 title abstract description 27
- 239000004480 active ingredient Substances 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 17
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 16
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 206010020772 Hypertension Diseases 0.000 claims abstract description 9
- 206010020710 Hyperphagia Diseases 0.000 claims abstract description 6
- 208000008589 Obesity Diseases 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 235000020824 obesity Nutrition 0.000 claims abstract description 6
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 5
- 238000008214 LDL Cholesterol Methods 0.000 claims abstract description 5
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims abstract description 5
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 177
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 75
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 75
- 239000003814 drug Substances 0.000 claims description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 40
- 231100000252 nontoxic Toxicity 0.000 claims description 25
- 230000003000 nontoxic effect Effects 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 14
- 239000005864 Sulphur Substances 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 201000001320 Atherosclerosis Diseases 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001118 alkylidene group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 5
- 208000030159 metabolic disease Diseases 0.000 claims description 5
- 235000020830 overeating Nutrition 0.000 claims description 5
- 108010069201 VLDL Cholesterol Proteins 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 44
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 abstract description 15
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 abstract description 15
- 239000003472 antidiabetic agent Substances 0.000 abstract description 14
- 229940126904 hypoglycaemic agent Drugs 0.000 abstract description 13
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 5
- 206010003210 Arteriosclerosis Diseases 0.000 abstract 1
- 239000003529 anticholesteremic agent Substances 0.000 abstract 1
- 229940127226 anticholesterol agent Drugs 0.000 abstract 1
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract 1
- 201000005577 familial hyperlipidemia Diseases 0.000 abstract 1
- 230000000055 hyoplipidemic effect Effects 0.000 abstract 1
- 230000002503 metabolic effect Effects 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 238000004809 thin layer chromatography Methods 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 238000002360 preparation method Methods 0.000 description 37
- 239000000203 mixture Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 238000000034 method Methods 0.000 description 34
- 108010028924 PPAR alpha Proteins 0.000 description 24
- 102000023984 PPAR alpha Human genes 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- 108010016731 PPAR gamma Proteins 0.000 description 21
- 102000000536 PPAR gamma Human genes 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 230000037396 body weight Effects 0.000 description 17
- 239000011159 matrix material Substances 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 16
- 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 15
- 239000013543 active substance Substances 0.000 description 15
- 239000008103 glucose Substances 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 239000000556 agonist Substances 0.000 description 11
- 150000002632 lipids Chemical class 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 108010010234 HDL Lipoproteins Proteins 0.000 description 10
- 102000015779 HDL Lipoproteins Human genes 0.000 description 10
- 108010015181 PPAR delta Proteins 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 235000013305 food Nutrition 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 230000001681 protective effect Effects 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- 239000004278 EU approved seasoning Substances 0.000 description 7
- 108010001515 Galectin 4 Proteins 0.000 description 7
- 102100039556 Galectin-4 Human genes 0.000 description 7
- 108060001084 Luciferase Proteins 0.000 description 7
- 235000011194 food seasoning agent Nutrition 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 7
- 229960001641 troglitazone Drugs 0.000 description 7
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 101000741788 Homo sapiens Peroxisome proliferator-activated receptor alpha Proteins 0.000 description 6
- 229940126033 PPAR agonist Drugs 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 230000003078 antioxidant effect Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000003750 conditioning effect Effects 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 239000003889 eye drop Substances 0.000 description 6
- 229940012356 eye drops Drugs 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 102000054223 human PPARA Human genes 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 6
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 6
- 150000003053 piperidines Chemical class 0.000 description 6
- 230000000630 rising effect Effects 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 5
- 101000741790 Homo sapiens Peroxisome proliferator-activated receptor gamma Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 5
- 206010040880 Skin irritation Diseases 0.000 description 5
- 241000534944 Thia Species 0.000 description 5
- 102000006601 Thymidine Kinase Human genes 0.000 description 5
- 108020004440 Thymidine kinase Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 238000004945 emulsification Methods 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 235000012631 food intake Nutrition 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 230000014725 late viral mRNA transcription Effects 0.000 description 5
- 230000036556 skin irritation Effects 0.000 description 5
- 231100000475 skin irritation Toxicity 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000004659 sterilization and disinfection Methods 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 229940125753 fibrate Drugs 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 238000007410 oral glucose tolerance test Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000010298 pulverizing process Methods 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000002103 transcriptional effect Effects 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UHFFFAOYSA-N 2-{[3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 3
- QMEQBOSUJUOXMX-UHFFFAOYSA-N 2h-oxadiazine Chemical compound N1OC=CC=N1 QMEQBOSUJUOXMX-UHFFFAOYSA-N 0.000 description 3
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 3
- 102000000584 Calmodulin Human genes 0.000 description 3
- 108010041952 Calmodulin Proteins 0.000 description 3
- XZFRIPGNUQRGPI-WLPVIMDJSA-N Carbacyclin Chemical compound C1\C(=C\CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 XZFRIPGNUQRGPI-WLPVIMDJSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 3
- 108010007622 LDL Lipoproteins Proteins 0.000 description 3
- 102000007330 LDL Lipoproteins Human genes 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000003288 aldose reductase inhibitor Substances 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 230000003579 anti-obesity Effects 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 3
- 229940073608 benzyl chloride Drugs 0.000 description 3
- 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 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001854 cinnolines Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 3
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 239000000865 liniment Substances 0.000 description 3
- 229940040145 liniment Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000007923 nasal drop Substances 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 229960005095 pioglitazone Drugs 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 229940118148 Aldose reductase inhibitor Drugs 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 102000012367 Beta 3 adrenoceptor Human genes 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 2
- 208000002705 Glucose Intolerance Diseases 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 102000016261 Long-Acting Insulin Human genes 0.000 description 2
- 108010092217 Long-Acting Insulin Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 2
- 229920013701 VORANOL™ Polymers 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 108040005346 beta3-adrenergic receptor activity proteins Proteins 0.000 description 2
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 2
- 229960000516 bezafibrate Drugs 0.000 description 2
- 150000004283 biguanides Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 description 2
- 229950009226 ciglitazone Drugs 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 2
- 229940043276 diisopropanolamine Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- WAAPEIZFCHNLKK-PELKAZGASA-N fidarestat Chemical compound C([C@@H](OC1=CC=C(F)C=C11)C(=O)N)[C@@]21NC(=O)NC2=O WAAPEIZFCHNLKK-PELKAZGASA-N 0.000 description 2
- 229950007256 fidarestat Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 2
- 229960000698 nateglinide Drugs 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 238000003305 oral gavage Methods 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229960002354 repaglinide Drugs 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 210000002268 wool Anatomy 0.000 description 2
- SXONDGSPUVNZLO-UHFFFAOYSA-N zenarestat Chemical compound O=C1N(CC(=O)O)C2=CC(Cl)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F SXONDGSPUVNZLO-UHFFFAOYSA-N 0.000 description 2
- 229950006343 zenarestat Drugs 0.000 description 2
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 description 1
- ODJQFZXHKPCJMD-UHFFFAOYSA-N 1,2,3,3a,4,5,6,7,8,8a-decahydroazulene Chemical compound C1CCCCC2CCCC21 ODJQFZXHKPCJMD-UHFFFAOYSA-N 0.000 description 1
- PIHAUZGWAXLKCA-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydro-1,8-naphthyridine Chemical compound N1CCCC2CCCNC21 PIHAUZGWAXLKCA-UHFFFAOYSA-N 0.000 description 1
- VKJHANNFFHMLBB-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydrocinnoline Chemical class N1NCCC2CCCCC21 VKJHANNFFHMLBB-UHFFFAOYSA-N 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- HZNXIPDYYIWDNM-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinazoline Chemical compound N1CNCC2CCCCC21 HZNXIPDYYIWDNM-UHFFFAOYSA-N 0.000 description 1
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 description 1
- MDEXMBGPIZUUBI-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoxaline Chemical compound N1CCNC2CCCCC21 MDEXMBGPIZUUBI-UHFFFAOYSA-N 0.000 description 1
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 1
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 1
- HORKYAIEVBUXGM-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoxaline Chemical compound C1=CC=C2NCCNC2=C1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 description 1
- UUZJJNBYJDFQHL-UHFFFAOYSA-N 1,2,3-triazolidine Chemical compound C1CNNN1 UUZJJNBYJDFQHL-UHFFFAOYSA-N 0.000 description 1
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 description 1
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- XXBQLHATYQHJQC-UHFFFAOYSA-N 1,2-dihydroquinoxaline Chemical compound C1=CC=C2N=CCNC2=C1 XXBQLHATYQHJQC-UHFFFAOYSA-N 0.000 description 1
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 1
- HGQBCKVFVUCIML-UHFFFAOYSA-N 1,3,3a,4,5,6,7,7a-octahydro-2-benzofuran Chemical compound C1CCCC2COCC21 HGQBCKVFVUCIML-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- GWYPDXLJACEENP-UHFFFAOYSA-N 1,3-cycloheptadiene Chemical compound C1CC=CC=CC1 GWYPDXLJACEENP-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- KEAYDQMHQHNAIG-UHFFFAOYSA-N 1-sulfanylpyrazolidine Chemical compound SN1CCCN1 KEAYDQMHQHNAIG-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 description 1
- OGHHATWOTABYKY-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1,3-benzothiazole Chemical compound C1CCCC2SCNC21 OGHHATWOTABYKY-UHFFFAOYSA-N 0.000 description 1
- XLRZZUUFKAXBGZ-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1,3-benzoxazole Chemical compound C1CCCC2OCNC21 XLRZZUUFKAXBGZ-UHFFFAOYSA-N 0.000 description 1
- LVJPACZOEKXFAY-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indazole Chemical compound C1CCCC2CNNC21 LVJPACZOEKXFAY-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 1
- YTQQIHUQLOZOJI-UHFFFAOYSA-N 2,3-dihydro-1,2-thiazole Chemical compound C1NSC=C1 YTQQIHUQLOZOJI-UHFFFAOYSA-N 0.000 description 1
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 1
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- IZEOXCXHDBQQAP-UHFFFAOYSA-N 2,3-dihydrothiazepine Chemical compound C1NSC=CC=C1 IZEOXCXHDBQQAP-UHFFFAOYSA-N 0.000 description 1
- WEEMDRWIKYCTQM-UHFFFAOYSA-N 2,6-dimethoxybenzenecarbothioamide Chemical compound COC1=CC=CC(OC)=C1C(N)=S WEEMDRWIKYCTQM-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- LUACLLSCZRRTIH-UPHRSURJSA-N 2-[[4-[(z)-4-[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]but-2-enoxy]phenyl]methyl]-1,2,4-oxadiazolidine-3,5-dione Chemical compound O1C(=O)NC(=O)N1CC(C=C1)=CC=C1OC\C=C/COC(C=C1)=CC=C1CN1C(=O)NC(=O)O1 LUACLLSCZRRTIH-UPHRSURJSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- QGLVWTFUWVTDEQ-UHFFFAOYSA-N 2-chloro-3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1Cl QGLVWTFUWVTDEQ-UHFFFAOYSA-N 0.000 description 1
- XULHFMYCBKQGEE-UHFFFAOYSA-N 2-hexyl-1-Decanol Chemical compound CCCCCCCCC(CO)CCCCCC XULHFMYCBKQGEE-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- FSUYMKXZLQOFQY-UHFFFAOYSA-N 3,4-dihydro-1,2-benzodithiine Chemical compound C1=CC=C2SSCCC2=C1 FSUYMKXZLQOFQY-UHFFFAOYSA-N 0.000 description 1
- IDUSJBBWEKNWAK-UHFFFAOYSA-N 3,4-dihydro-2h-1,2-benzothiazine Chemical compound C1=CC=C2SNCCC2=C1 IDUSJBBWEKNWAK-UHFFFAOYSA-N 0.000 description 1
- NWWJFMCCTZLKNT-UHFFFAOYSA-N 3,4-dihydro-2h-thiazine Chemical compound C1CC=CSN1 NWWJFMCCTZLKNT-UHFFFAOYSA-N 0.000 description 1
- ATVJJNGVPSKBGO-UHFFFAOYSA-N 3,4-dihydro-2h-thiopyran Chemical compound C1CSC=CC1 ATVJJNGVPSKBGO-UHFFFAOYSA-N 0.000 description 1
- JAFJNSQISURLCX-UHFFFAOYSA-N 3-(methoxymethoxy)benzaldehyde Chemical compound COCOC1=CC=CC(C=O)=C1 JAFJNSQISURLCX-UHFFFAOYSA-N 0.000 description 1
- WHGMHGPIJZTKTI-UHFFFAOYSA-N 3h-1,2-benzodithiole Chemical compound C1=CC=C2CSSC2=C1 WHGMHGPIJZTKTI-UHFFFAOYSA-N 0.000 description 1
- LGSOKZOQANLOEU-UHFFFAOYSA-N 4-[2-(2,4-dioxo-1,3-thiazolidin-5-yl)ethoxy]benzonitrile Chemical compound S1C(=O)NC(=O)C1CCOC1=CC=C(C#N)C=C1 LGSOKZOQANLOEU-UHFFFAOYSA-N 0.000 description 1
- QBQLYIISSRXYKL-UHFFFAOYSA-N 4-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,2-oxazolidine-3,5-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCOC(C=C1)=CC=C1CC1C(=O)NOC1=O QBQLYIISSRXYKL-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-Chloronicotinic acid Chemical class OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 description 1
- HWRFTOWHSBECMR-UHFFFAOYSA-N 6-n-[(4-aminophenyl)methyl]-2-n-[[3-(trifluoromethyl)phenyl]methyl]-7h-purine-2,6-diamine Chemical compound C1=CC(N)=CC=C1CNC1=NC(NCC=2C=C(C=CC=2)C(F)(F)F)=NC2=C1NC=N2 HWRFTOWHSBECMR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000003916 Arrestin Human genes 0.000 description 1
- 108090000328 Arrestin Proteins 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WZIHCQIGSYEQNQ-UHFFFAOYSA-N C(CC)(=O)N.[Cl] Chemical compound C(CC)(=O)N.[Cl] WZIHCQIGSYEQNQ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- NTURVSFTOYPGON-UHFFFAOYSA-N Dihydroquinazoline Chemical compound C1=CC=C2C=NCNC2=C1 NTURVSFTOYPGON-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- HVLSXIKZNLPZJJ-TXZCQADKSA-N HA peptide Chemical compound C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HVLSXIKZNLPZJJ-TXZCQADKSA-N 0.000 description 1
- 108010023302 HDL Cholesterol Proteins 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 244000285963 Kluyveromyces fragilis Species 0.000 description 1
- 235000014663 Kluyveromyces fragilis Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001582888 Lobus Species 0.000 description 1
- SJNZALDHDUYDBU-IHRRRGAJSA-N Lys-Arg-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(O)=O SJNZALDHDUYDBU-IHRRRGAJSA-N 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 229910001051 Magnalium Inorganic materials 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 241001508687 Mustela erminea Species 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- XDMCWZFLLGVIID-SXPRBRBTSA-N O-(3-O-D-galactosyl-N-acetyl-beta-D-galactosaminyl)-L-serine Chemical compound CC(=O)N[C@H]1[C@H](OC[C@H]([NH3+])C([O-])=O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 XDMCWZFLLGVIID-SXPRBRBTSA-N 0.000 description 1
- OKXZIVVGJRNSKN-UHFFFAOYSA-N O1N=CC=C1.O1C=NC=C1.S1C=CC=CC=C1 Chemical compound O1N=CC=C1.O1C=NC=C1.S1C=CC=CC=C1 OKXZIVVGJRNSKN-UHFFFAOYSA-N 0.000 description 1
- MTBSFYGHHCAQIY-UHFFFAOYSA-N O1NC=CC=C1.O1N=NC=C1 Chemical compound O1NC=CC=C1.O1N=NC=C1 MTBSFYGHHCAQIY-UHFFFAOYSA-N 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108010044210 PPAR-beta Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- GABWQNJCELJRRW-UHFFFAOYSA-N S1NCCC1.S1N=CC=C1 Chemical compound S1NCCC1.S1N=CC=C1 GABWQNJCELJRRW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000779819 Syncarpia glomulifera Species 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- IOUPEELXVYPCPG-UHFFFAOYSA-N Valylglycine Chemical compound CC(C)C(N)C(=O)NCC(O)=O IOUPEELXVYPCPG-UHFFFAOYSA-N 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- DMKQGDNBFLQYSV-UHFFFAOYSA-N [O].C(CCC)OC(CCCCCC)(OCCCCCC)OCCCCC Chemical compound [O].C(CCC)OC(CCCCCC)(OCCCCCC)OCCCCC DMKQGDNBFLQYSV-UHFFFAOYSA-N 0.000 description 1
- ZRXADTFMGYNRKV-UHFFFAOYSA-N [S].C1=CC=CC2=CC=CC=C21 Chemical class [S].C1=CC=CC2=CC=CC=C21 ZRXADTFMGYNRKV-UHFFFAOYSA-N 0.000 description 1
- KKLWSPPIRBIEOV-UHFFFAOYSA-N [n'-(n'-butylcarbamimidoyl)carbamimidoyl]azanium;chloride Chemical compound Cl.CCCCN=C(N)N=C(N)N KKLWSPPIRBIEOV-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000011358 absorbing material Substances 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- IHTYTYHXCRAMAV-UHFFFAOYSA-N acetic acid;dihydrochloride Chemical compound Cl.Cl.CC(O)=O IHTYTYHXCRAMAV-UHFFFAOYSA-N 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229940092738 beeswax Drugs 0.000 description 1
- JKOSHCYVZPCHSJ-UHFFFAOYSA-N benzene;toluene Chemical compound C1=CC=CC=C1.C1=CC=CC=C1.CC1=CC=CC=C1 JKOSHCYVZPCHSJ-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 108700010039 chimeric receptor Proteins 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- LMGZGXSXHCMSAA-UHFFFAOYSA-N cyclodecane Chemical compound C1CCCCCCCCC1 LMGZGXSXHCMSAA-UHFFFAOYSA-N 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- GPTJTTCOVDDHER-UHFFFAOYSA-N cyclononane Chemical compound C1CCCCCCCC1 GPTJTTCOVDDHER-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 description 1
- 239000004913 cyclooctene Substances 0.000 description 1
- HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 0.000 description 1
- 229960003263 cyclopentamine Drugs 0.000 description 1
- 150000001941 cyclopentenes Chemical class 0.000 description 1
- 125000004980 cyclopropylene group Chemical group 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- QPJORFLSOJAUNL-UHFFFAOYSA-N dibenzo[a,d][7]annulene Chemical compound C1=CC2=CC=CC=C2CC2=CC=CC=C21 QPJORFLSOJAUNL-UHFFFAOYSA-N 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- INTMMHZKGCDQGT-UHFFFAOYSA-N diethyldiazene Chemical compound CCN=NCC INTMMHZKGCDQGT-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 229950010170 epalrestat Drugs 0.000 description 1
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- BEGBSFPALGFMJI-UHFFFAOYSA-N ethene;sodium Chemical group [Na].C=C BEGBSFPALGFMJI-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- JZXVIASGAMNRDD-UHFFFAOYSA-N ethyl 2-(prop-2-enylamino)acetate Chemical compound CCOC(=O)CNCC=C JZXVIASGAMNRDD-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000001610 euglycemic effect Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- BOVGTQGAOIONJV-UHFFFAOYSA-N gliclazide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CC2CCCC2C1 BOVGTQGAOIONJV-UHFFFAOYSA-N 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N hexanedioic acid Natural products OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical class C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- KPXFIETUTLCJAC-UHFFFAOYSA-N isocyanic acid;naphthalene Chemical compound N=C=O.C1=CC=CC2=CC=CC=C21 KPXFIETUTLCJAC-UHFFFAOYSA-N 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OJVSEHLMRCLAFY-UHFFFAOYSA-N methyl propanoate;hydrochloride Chemical compound Cl.CCC(=O)OC OJVSEHLMRCLAFY-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- FYFFGSSZFBZTAH-UHFFFAOYSA-N methylaminomethanetriol Chemical compound CNC(O)(O)O FYFFGSSZFBZTAH-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 238000010397 one-hybrid screening Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- RYDICHIKLKVOEJ-UHFFFAOYSA-N oxadiazepine Chemical compound O1C=CC=CN=N1 RYDICHIKLKVOEJ-UHFFFAOYSA-N 0.000 description 1
- IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- 150000007978 oxazole derivatives Chemical class 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- GUVXZFRDPCKWEM-UHFFFAOYSA-N pentalene Chemical compound C1=CC2=CC=CC2=C1 GUVXZFRDPCKWEM-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 210000002824 peroxisome Anatomy 0.000 description 1
- 239000002508 peroxisome proliferator activated receptor antagonist Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical compound C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001739 pinus spp. Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- LUPNKHXLFSSUGS-UHFFFAOYSA-M sodium;2,2-dichloroacetate Chemical compound [Na+].[O-]C(=O)C(Cl)Cl LUPNKHXLFSSUGS-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- BXVYJQULAWJPSR-UHFFFAOYSA-N thiadiazepine Chemical compound S1C=CC=CN=N1 BXVYJQULAWJPSR-UHFFFAOYSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 1
- PGAZQSBUJDVGIX-UHFFFAOYSA-N thiazepane Chemical compound C1CCNSCC1 PGAZQSBUJDVGIX-UHFFFAOYSA-N 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229940036248 turpentine Drugs 0.000 description 1
- 238000010396 two-hybrid screening Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- 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
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- 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
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Child & Adolescent Psychology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
通式(I)的化合物或其盐,其中每个符号如说明书所定义,以及包含其作为活性成分的激活受体调节剂的过氧化物酶体增殖子。由于式(I)的化合物具有调节过氧化物酶体增殖子激活受体的活性,因而式(I)化合物可用作降血糖药、降压药、用于预防和/或治疗与代谢紊乱有关的疾病诸如糖尿病、肥胖、X综合症、高胆固醇血症和高脂蛋白血症等,高脂血症,动脉粥样硬化症,高血压,循环疾病,过度饱食,缺血性心脏病等的药剂,升高HDL胆固醇药,降低LDL胆固醇和/或VLDL胆固醇药,减轻糖尿病或X综合症危险因子的药剂。
Description
技术领域
本发明涉及羧酸衍生物化合物。
更具体地说,本发明涉及
(1)式(I)代表的羧酸衍生物化合物,或其无毒盐
(其中所有符号均具有下述的相同含义)。
(2)其制备方法,和
(3)包含其作为活性成分的药剂。
背景技术
最近,在研究有关脂肪细胞分化中的标记基因表达的转录因子中,过氧化物酶体增殖物激活受体(下文中简写为PPAR)成为研究热点,它是一种核内受体。从多种动物克隆出PPAR的cDNA,并发现多个同种型基因,特别是在哺乳动物中已知有三种同种型(α、δ、γ)(参见J.Steroid Biochem.Molec.Biol.,
51,157(1994);Gene Expression.,
4,281(1995);Biochem Biophys.Res.Commun.,
224,431(1996);Mol.Endocrinology.,
6,1634(1992))。PPARγ同种型主要在脂肪组织、免疫细胞、肾上腺、脾、小肠中表达。PPARα同种型主要在脂肪组织、肝、视网膜中表达,PPARδ同种型广泛表达而没有组织的特异性(参见Endocrinology.,
137,354(1996))。
另一方面,已知下列噻唑烷衍生物可作为治疗非胰岛素依赖型糖尿病(NIDDM)的药剂,并为用于改善糖尿病患者高血糖的降血糖药。它们对改善高胰岛素血症、葡萄糖耐量和血清脂类降低是有效的,并因此被认为是很有希望的治疗抗胰岛素的药剂。
吡格列酮(pioglitazone) 环格列酮(ciglitazone)
BRL49653 曲格列酮(troglitazone)
在这些噻唑烷衍生物单元中的一种目标蛋白恰好是PPARγ,其被分解使得这些衍生物提高了PPARγ的转录活性(参见Endocrinology.,
137,4189(1996);Cell,
83,803(1995);Cell,
83,813(1995);J.Biol.Chem.,
270,12953(1995))。因此,认为能提高其转录活性的PPARγ激活剂是有望成为降血糖药和/或降脂药。此外,由于已知PPARγ激动剂能促进PPARγ蛋白质自身的表达(Genes & Development,
10,974(1996)),因此认为能提高PPARγ蛋白质自身的表达的药剂以及PPARγ激活药剂在临床上也有用。
PPARγ与脂肪细胞分化有关(参见J.Biol.Chem.,
272,5637(1997)和Cell,
83,803(1995))。已知可激活这种受体的噻唑烷衍生物能促进脂肪细胞分化。最近报道了噻唑烷衍生物能增加脂肪质量并导致人体增重而且变得肥胖(参见Lancet.,
349,952(1997))。因此,还认为能抑制PPARγ活性的拮抗剂和能减少PPARγ蛋白质自身表达的药剂也可在临床上应用。另一方面,报道了能使PPARγ蛋白质磷酸化并降低其活性的化合物(Science,
274,2100(1996))。这表明不结合到PPARγ蛋白质上作为配体但能抑制其活性的药剂也可在临床上应用。
鉴于此,PPARγ激活剂(激动剂)和PPARγ调节剂因其能提高蛋白质自身表达的表达而被期望用作降血糖药、降脂药,和预防和/或治疗与代谢紊乱有关的疾病如糖尿病、肥胖、X综合症、高胆固醇血症和高脂蛋白血症等,高脂血症,动脉粥样硬化症,高血压,循环疾病和过度饱食等的药剂。
另一方面,能抑制PPARγ转录活性的拮抗剂或能抑制蛋白质自身表达的PPARγ调节剂均被期望可用作降血糖药和用于预防和/或治疗与代谢紊乱有关的疾病如糖尿病、肥胖、X综合症等,高脂血症,动脉粥样硬化症,高血压和过度饱食等的药剂。
已知下面的贝特类(fibrate)化合物(如氯贝特)可作为降脂药。
氯贝特
而且,它还可以分解使得贝特类化合物的单元中的一种目标蛋白为PPARα(参见Nature,
347,645(1990);J.Steroid Biochem.Molec.Biol.,51,157(1994);Biochemistry,
32,5598(1993))。从这些事实来看,认为可用贝特类化合物激活的PPARα调节剂具有降脂效果,因此它们可望用作预防和/或治疗高脂血症等的药剂。
此外,最近在WO9736579的说明书中报道了PPARα具有抗肥胖活性。另外,还报道了通过PPARα的激活诱发高密度脂蛋白(HDL)胆固醇水平的升高,低密度脂蛋白(LDL)胆固醇、特低密度脂蛋白(VLDL)胆固醇和甘油三酯水平的降低(J.Lipid Res.,
39,17(1998))。还报道了通过给药一种贝特类化合物苯扎贝特(bezafibrate)改善血液中脂肪酸的组成、抗高血压和抗胰岛素(Diabetes,
46,348(1997))。因此,能激活PPARα的拮抗剂和能促进PPARα蛋白质自身表达的PPARα调节剂可用作降脂药和治疗高脂血症的药剂,并有望具有升高HDL胆固醇水平的效果、降低LDL胆固醇和/或VLDL胆固醇水平的效果、抑制动脉粥样硬化症发展和抗肥胖的效果。因此,认为它们是作为降血糖药治疗和/或预防糖尿病、改善高血压、减轻X综合症危险因子和预防缺血性冠心病发生的有前途的药剂。
另一方面,很少发现关于能大大激活PPARδ的配体或与PPARδ有关的生物活性方面的报道。
PPARδ有时被称为PPARβ,或对于人类其还被称为NUCl。直到现在,就PPARδ的活性而言,只在WO9601430的说明书中公开了hNUClB(其结构在一个氨基酸上不同于人类NUCl的PPAR亚型)抑制人类PPARα和甲状腺激素受体的转录活性。最近,在W09728149的说明书中,报道发现了对PPARδ蛋白质具有高亲和性并能有效激活PPARδ的化合物(即激动剂),并且它们具有升高的HDL(高密度脂蛋白)胆固醇水平的活性。因此,有望能激活PPARδ的激动剂具有升高HDL胆固醇水平的效果,并因此它们有望能用于抑制动脉粥样硬化症发展及其治疗、它作为降脂药和降血糖药用于高脂血症治疗、它作为降血糖药用于糖尿病治疗、用于减轻X综合症危险因子和用于预防缺血性心脏病发生。
背景技术
在WO01/21602的说明书中,描述了以式(A)表示的氧杂和噻唑衍生物:
(其中XA为1、2、3或4,mA为1或2,n为1或2,QA为C或N,AA为O或S,ZA为O或键,R1A为氢原子或烷基,XA为CH或N,R2A为H、烷基等,R2aA、R2bA和R2cA为氢原子、烷基、烷氧基、卤原子、氨基或取代氨基(取代氨基为用一个或二个取代基取代的氨基,取代基可相同或不同,如烷基、芳基、芳烷基、杂芳基、杂芳烷基、环杂烷基、环杂烷基烷基、环烷基、环烷基烷基、卤代烷基、羟烷基、烷氧基烷基、硫代烷基。另外,氨基取代基可与连接其上的氮原子一起形成1-吡咯烷基、1-哌啶基、1-氮杂基、4-吗啉基、4-硫代吗啉基、1-哌嗪基、4-烷基-1-哌嗪基、4-芳基烷基-1-哌嗪基、4-二芳基烷基-1-哌嗪基、1-吡咯烷基、1-哌啶基或1-氮杂基(可用烷基、烷氧基、烷硫基、卤、三氟甲基、羟基任意取代),R3A为H、烷基、芳基烷基等,Y为CO2R4A(R4A为氢原子、烷基等)等)和其药物可接受的盐用作抗糖尿病的和抗肥胖的药剂。
发明公开
为了发现具有PPAR调节活性的化合物,本发明人进行了广泛研究,结果发现可使用式(I)代表的化合物实现这些目的,并因此完成了本发明。
本发明涉及:
(1)式(I)代表的羧酸衍生物化合物或其无毒盐,
(其中X和Y各自独立地为C1-4亚烷基,
Z为-O-或-S-,
R1、R2、R3和R4各自独立地为氢原子或C1-8烷基,
R5为C2-8烯基,
A为-O-或-S-,
D为D1、D2、D3、D4或D5,
D1为C1-8烷基,
环1为饱和3-7元单杂芳基,其含有一个氮原子和任意的另外一个选自氧、硫和氮原子的杂原子,
D3为
环2为
(1)任意地部分或完全饱和的C3-10单-或双-碳环芳基,或
(2)任意地部分或完全饱和的3-10节单-或双-杂芳基,其含有1-4个选自氧、氮和硫原子的杂原子,
D4为
R6为(1)氢原子、(2)C1-8烷基、(3)C1-8烷氧基、(4)CF3、(5)OCF3、(6)卤原子、(7)硝基或(8)NR7R8,
R7或R8为氢原子或C1-8烷基,或
R7和R8和与它们连接的氮原子一起形成饱和3-7员单杂芳基,其含有一个氮原子和任意的另外一个选自氧、硫和氮原子的杂原子,并且饱和杂芳基可任意用C1-8烷基取代,
E为CH或氮原子,并且
m为1-3的整数。)
(2)其制备方法,和
(3)包含其作为活性成分的药剂。
在本说明书中,C1-8烷基是指甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基或其异构基团。
在本说明书中,C2-8烯基是指乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基或其异构基团。
在本说明书中,C1-8烷氧基是指甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、庚氧基、辛氧基或其异构基团。
在本说明书中,C1-4亚烷基是指亚甲基、1,2-亚乙基、1,3-亚丙基、四亚甲基或其异构基团。
在本说明书中,卤素为氯、溴、氟或碘。
在本说明书中,环1代表的含有一个氮原子和任意另外一个选自氧、硫和氮原子的杂原子的饱和3-7节单杂芳基为,例如氮丙啶、氮杂环丁烷、吡咯烷、咪唑烷、吡唑烷、哌啶、哌嗪、全氢嘧啶、全氢哒嗪、全氢氮杂、全氢二氮杂、四氢噁唑(噁唑烷)、四氢异噁唑(异噁唑烷)、四氢噻唑(噻唑烷)、四氢异噻唑(异噻唑烷)、四氢噁嗪、全氢氧杂氮杂、四氢噻嗪、全氢硫杂氮杂(perhydrothiazepine)、吗啉、硫代吗啉等。
在本说明书中,含有一个氮原子和任意另外一个选自氧、硫和氮原子的杂原子的饱和3-6元单杂芳基由R6和R7代表的与和其相连的氮原子一起是,例如氮丙啶、氮杂环丁烷、吡咯烷、咪唑烷、吡唑烷、哌啶、哌嗪、全氢嘧啶、全氢哒嗪、四氢噁唑(噁唑烷)、四氢异噁唑(异噁唑)、四氢噻唑(噻唑烷)、四氢异噻唑(异噻唑烷)、四氢噁嗪、四氢噻嗪、吗啉、硫代吗啉等。
在本说明书中,部分或全部任意饱和的C3-10单或双碳环芳基为,例如环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环壬烷、环癸烷、环丙烯、环丁烯、环戊烯、环己烯、环庚烯、环辛烯、环戊二烯、环己二烯、环庚二烯、环辛二烯、苯、并环戊二烯、甘菊环、全氢甘菊环、全氢并环戊二烯、茚、全氢茚、茚满、萘、四氢萘或全氢萘等。
在本说明书中,在环2代表的含有1-4个选自氧、氮或硫原子的杂原子的部分或全部任意饱和的3-10节单或双杂芳基中,含有1-4个选自氧、氮或硫原子的杂原子的3-10节单或双杂芳基是指,例如吡咯、咪唑、三唑、四唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、氮杂、二氮杂、呋喃、吡喃、氧杂庚因(oxepine)、噻吩、thiaine、硫杂庚因(thiepine)、噁唑、异噁唑、噻唑、异噻唑、呋咱、噁二唑、噁嗪、噁二嗪、氧氮杂(oxazepine)、氧二氮杂(oxadiazepine)、噻二唑、噻嗪、噻二嗪、硫氮杂(thiazepine)、硫二氮杂(thiadiazepine)、吲哚、异吲哚、中氮茚、苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、二硫萘、吲唑、喹啉、异喹啉、喹嗪、嘌呤、2,3-二氮杂萘、蝶啶、1,5-二氮杂萘、喹喔啉、喹唑啉、噌啉、苯并噁唑、苯并噻唑、苯并咪唑、色烯、苯并呋咱、苯并噻二唑、苯并三唑等。
另外,含有1-4个选自氧、氮或硫原子的杂原子的部分或全部饱和的3-10元单或双杂芳基指氮丙啶、氮杂环丁烷、吡咯啉、吡咯烷、咪唑啉、咪唑烷、三唑啉、三唑烷、四唑啉、四唑烷、吡唑啉、吡唑烷、二氢吡啶、四氢吡啶、哌啶、二氢吡嗪、四氢吡嗪、哌嗪、二氢嘧啶、四氢嘧啶、全氢嘧啶、二氢哒嗪、四氢哒嗪、全氢哒嗪、二氢氮杂、四氢氮杂、全氢氮杂、二氢二氮杂、四氢二氮杂、全氢二氮杂、环氧乙烷、氧杂环丁烷、二氢呋喃、四氢呋喃、二氢吡喃、四氢吡喃、二氢氧杂庚因、四氢氧杂庚因、全氢氧杂庚因、硫杂丙环、硫杂环丁烷(thietane)、二氢噻吩、四氢噻吩、dihydrothiaine(二氢噻喃)、tetrahydrothiaine(四氢噻喃)、二氢硫杂庚因、四氢硫杂庚因、全氢硫杂庚因、二氢噁唑、四氢噁唑(噁唑烷)、二氢异噁唑、四氢异噁唑(异噁唑烷)、二氢噻唑、四氢噻唑(噻唑烷)、二氢异噻唑、四氢异噻唑(异噻唑烷)、二氢呋咱、四氢呋咱、二氢噁二唑、四氢噁二唑(噁二唑烷)、二氢噁嗪(dihydrooxazine)、四氢噁嗪、二氢噁二嗪、四氢噁二嗪、二氢氧氮杂、四氢氧氮杂、全氢氧氮杂、二氢氧二氮杂、四氢氧二氮杂、全氢氧二氮杂、二氢噻二唑、四氢噻二唑(噻二唑烷)、二氢噻嗪、四氢噻嗪、二氢噻二嗪、四氢噻二嗪、二氢硫氮杂(dihydrothiazepine)、四氢硫氮杂、全氢硫氮杂、二氢硫二氮杂、四氢硫二氮杂、全氢硫二氮杂、吗啉、硫代吗啉、氧硫杂环己烷、二氢吲哚、异二氢吲哚、二氢苯并呋喃、全氢苯并呋喃、二氢异苯并呋喃、全氢异苯并呋喃、二氢苯并噻吩、全氢苯并噻吩、二氢异苯并噻吩、全氢异苯并噻吩、二氢吲唑、全氢吲唑、二氢喹啉、四氢喹啉、全氢喹啉、二氢异喹啉、四氢异喹啉、全氢异喹啉、二氢2,3-二氮杂萘、四氢2,3-二氮杂萘、全氢2,3-二氮杂萘、二氢1,5-二氮杂萘、四氢1,5-二氮杂萘、全氢1,5-二氮杂萘、二氢喹喔啉、四氢喹喔啉、全氢喹喔啉、二氢喹唑啉、四氢喹唑啉、全氢喹唑啉、二氢噌啉、四氢噌啉、全氢噌啉、苯并氧硫杂环己烷、二氢苯并噁嗪、二氢苯并噻嗪、吡嗪并吗啉、二氢苯并噁唑、全氢苯并噁唑、二氢苯并噻唑、全氢苯并噻唑、二氢苯并咪唑、全氢苯并咪唑、二氧戊环、二噁烷、二硫戊环、二噻烷、二噁茚满、苯并二噁烷、色满、苯并二硫戊环、苯并二噻烷等。
除非另外指明,本发明中包括所有的异构体。例如,烷基、烷氧基和亚烷基包括直链或支链基团。另外,本发明中还包括双键上的异构体、环、稠环(E-、Z-、顺式、反式异构体)、非对称碳原子产生的异构体(R-、S-、α-、β-异构体、对映异构体、非对映异构体)、旋光性异构体(D-、L-、d-、I-异构体)、色谱分离产生的极性化合物(高极性化合物、低极性化合物)、平衡化合物、旋转异构体、其任意比例的混合物和外消旋混合物。
根据本发明,除非另外指明,这些内容对本领域那些技术人员来说是显而易见的,符号
表示其绑于片(sheet)的相对侧(即α-构型),符号表示其绑于片(sheet)的正侧(即β-构型),符号
表示它为α-、β-或其混合物,符号
表示它为α-构型和β-构型的混合物。
可通过已知方法将本发明的化合物转变为无毒盐。
无毒盐优选为药物可接受的和可溶于水的。
无毒盐是指,例如碱金属(钾、钠、锂等)盐、碱土金属(钙、镁等)盐、铵盐(四甲基铵、四丁基铵等)、有机胺(三乙胺、甲胺、二甲胺、环戊胺、苄胺、苯乙胺、哌啶、单乙醇胺、二乙醇胺、三(羟甲基)甲胺、赖氨酸、精氨酸、N-甲基-D-葡糖胺等)盐、酸加成盐(无机酸盐(盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、硝酸盐等)、有机酸盐(乙酸盐、三氟乙酸盐、乳酸盐、酒石酸盐、草酸盐、富马酸盐、马来酸盐、苯甲酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、羟乙磺酸盐、葡糖醛酸盐、葡糖酸盐等)等。
此外,本发明还包括本发明化合物及其上述碱(土)金属盐、铵盐、有机胺盐和酸性盐的溶剂化物。
溶剂化物优选为无毒的和可溶于水的。适宜的溶剂化物是指例如水、醇溶剂(乙醇等)等这类溶剂化物。
在本发明中,PPAR调节剂包括PPARα、γ、δ、α+γ、α+δ、γ+δ和α+γ+δ的所有调节剂。优选调节形式为PPARα调节剂、PPARγ调节剂、PPARδ调节剂、PPARα+γ调节剂、PPARα+δ调节剂,更优选PPARα+γ调节剂。
PPAR调节剂还包括PPAR激动剂和PPAR拮抗剂。PPAR调节剂优选为PPAR激动剂,更优选为PPARα激动剂、PPARγ激动剂、PPARδ激动剂、PPARα+γ激动剂或PPARα+δ激动剂,尤其优选PPARα+γ激动剂。
在本说明书中,R5优选为丙烯基,并更优选为烯丙基。
在本说明书中,X优选为C1-2亚烷基(亚甲基、亚乙基),并更优选为亚甲基。
在本说明书中,Y优选为C1-2亚烷基(亚甲基、亚乙基),并更优选为亚乙基。
在本说明书中,Z优选为-O-或-S-,并更优选为-O-。
在本说明书中,A优选为-O-或-S-,并更优选为-O-。
在本说明书中,D优选为D1、D2、D3或D4,并更优选为D3或D4,最优选为D4。
在式(I)代表的化合物中,优选的化合物为:式(I-A)代表的化合物
(其中所有符号均具有如上所述相同含义),式(I-B)代表的化合物
(其中所有符号均具有如上所述相同含义),式(I-C)代表的化合物
(其中所有符号均具有如上所述相同含义),式(I-D)代表的化合物
(其中所有符号均具有如上所述相同含义)和式(I-E)代表的化合物
(其中所有符号均具有如上所述相同含义)。
本发明的具体化合物包括表1-5所示化合物、实施例中描述的化合物及它们的无毒盐。
在每个表中,Me代表甲基,Et代表乙基,Pr代表丙基,i-Pr代表异丙基,t-Bu代表叔丁基,其它符号具有如上所述相同含义。
表1
No. D1 A Z | No. D1 A Z |
1 Me -O- -O-2 Et -O- -O-3 Pr -O- -O-4 i-Pr -O- -O-5 t-Bu -O- -O-6 Me -O- -S-7 Et -O- -S-8 Pr -O- -S-9 i-Pr -O- -S-10 t-Bu -O- -S- | 11 Me -S- -O-12 Et -S- -O-13 Pr -S- -O-14 i-Pr -S- -O-15 t-Bu -S- -O-16 Me -S- -S-17 Et -S- -S-18 Pr -S- -S-19 i-Pr -S- -S-20 t-Bu -S- -S- |
表2
表3
表4
表5
[本发明化合物的制备方法]
(1)在式(I)代表的本发明的化合物中一种其中R1代表C1-8烷基的化合物即式
(IA)代表的化合物
(其中R1-1代表C1-8烷基,其它符号具有如上所述含义)。
可通过使式(II)代表的化合物与式(III)代表的化合物反应
(式(II)中R9代表离去基团(卤原子、甲磺酰氧基或甲苯磺酰氧基等),D6与D含义相同,条件是在必要时能保护D6代表的基团中的氨基,其它符号具有如上所述含义)
(式(III)中R10代表OH或SH,其它符号具有如上所述含义),如有必要,然后再进行保护基团的去保护反应,而进行
这类反应是已知的。例如,可在有碱(氢化钠、碳酸钾、三乙胺、吡啶、碘化钠、碳酸铯等)的存在下在有机溶剂(如四氢呋喃(THF)、二乙醚、二氯甲烷、氯仿、四氯化碳、戊烷、己烷、苯、甲苯、二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、六甲基磷酰胺(HMPA)等)中于0-80℃下进行反应。
可通过以下方法进行保护基团的去保护反应。
氨基保护基团的去保护反应是熟知的,例子包括:
(1)酸性条件下的去保护反应,或
(2)通过氢解作用的去保护反应等。
下面具体描述这些方法。
(1)可在例如有机溶剂(二氯甲烷、氯仿、二噁烷、乙酸乙酯、苯甲醚、甲醇、乙醇、异丙醇等)中或没有溶剂或其水溶液中使用有机酸(乙酸、三氟乙酸、甲磺酸等)或无机酸(盐酸、硫酸等)或其混合物(溴化氢/乙酸等)于0-100℃下进行酸性条件下的去保护反应。
(2)可在例如有催化剂(如钯-碳、钯黑、氢氧化钯、氧化铂、阮内镍等)存在下在溶剂(醚类(四氢呋喃、二噁烷、二甲氧基乙烷、二乙醚等)、醇类(如甲醇、乙醇等)、苯类(如苯、甲苯等)、酮类(如丙酮、甲基乙基酮等)、腈类(如乙腈等)、酰胺类(如二甲基甲酰胺等)、水、乙酸乙酯、乙酸、或这些溶剂中二种或多种的混合溶剂等)中于常压或强制压力下在有氢气氛下或有甲酸铵存在下于0-200℃通过氢解作用而进行去保护反应。
氨基保护基团包括例如苄氧羰基、叔丁氧羰基、三氟乙酰基、9-芴基甲氧羰基等。
对氨基保护基团没有特殊限制于上述,也可以使用其它基团。只要它们能被容易并可选择性地除去即可。例如,可使用T.W.Greene,ProtectiveGroups in Organic Synthesis,3rd Ed.,Wiley,New York,1999中描述的那些。
通过去保护反应的选择使用可容易地制备本发明的目的化合物,本领域的任一熟练技术人员都能容易地理解这一点。
(2)在式(I)代表的本发明的化合物中,一种其中R1代表C1-8烷基和Z代表-O-的化合物即式(IB)代表的化合物
(其中所有符号均具有如上所述含义)。可通过使式(IV)代表的化合物反应
(其中所有符号均具有如上所述含义)与式(III-1)代表的化合物反应
(其中所有符号均具有如上所述含义),如有必要,然后再进行保护基团的去保护反应,而进行制备。
这类反应是已知的。例如,可在有偶氮化合物(二乙基偶氮二羧酸酯、二异丙基偶氮二羧酸酯、1,1′-(偶氮二羰基)二哌啶、1,1′-偶氮双(N,N-二甲基甲酰胺)等)和膦化合物(三苯基膦、三丁基膦、三甲基膦等)的存在下在有机溶剂(二氯甲烷、二乙醚、四氢呋喃、乙腈、苯、甲苯等)中于0-60℃下通过与相应的醇化合物反应而进行。
可按照上述方法进行保护基团的去保护反应。
(3)在式(I)代表的本发明的化合物中,一种其中R1代表氢的化合物即式(IC)代表的化合物
(其中所有符号均具有如上所述含义)。可通过使式(IA)或(IB)代表的上述化合物进行水解反应而制备。
所述水解反应是已知的。例如,(1)在与水相容的有机溶剂(四氢呋喃、二噁烷、乙醇、甲醇等)或其混合溶剂中使用碱(氢氧化钾、氢氧化钠、氢氧化锂、碳酸钾、碳酸钠等)的水溶液而进行,或(2)在链烷醇(甲醇、乙醇等)中使用上述碱在无水条件下进行反应。通常可在0-100℃下进行这些反应。
式(II)和(IV)代表的化合物为已知化合物或可通过已知方法或实施例中描述的方法而容易地制备。
例如,在式(IV)的化合物中,2-(5-甲基-2-苯噁唑-4-基)乙醇可通过J.Med.Chem.,
35,1853-1864(1992)中描述的方法而制备。
例如,在式(IV)的化合物中,2-(5-甲基-2-(吗啉-4-基)噁唑-4-基)乙醇可通过J.Med.Chem.,
41,5037-5054(1998)中描述的方法制备。
例如,可按照下面的反应示意图1所示方法制备式(III)代表的化合物。
在反应示意图1中,R11代表羟基的保护基团,X1代表C1-3亚烷基,其它符号含义同上所述。
反应流程1
在反应流程1中,式(V)和(VII)代表的用作原料的化合物为已知化合物或可通过已知方法而容易地制备。
在这里描述的每个反应中,可通过常规纯化方法如常压或减压下的蒸馏、高性能液相色谱法、薄层色谱法或使用硅胶或硅酸镁的柱色谱法、洗涤和重结晶来纯化反应产物。可在每步反应中或完成几个反应后进行纯化。
[药理活性]
已通过下列试验证实了本发明式(I)的化合物具有PPAR调节活性。PPARα激动活性和PPARγ激动活性的测试:
(1)使用人类PPARα或γ制备荧光素酶分析中的材料
通过基因工程技术中的基本方法和酵母单杂交或双杂交系统中的常规方法进行全部操作。
作为受胸腺嘧啶核苷激酶(TK)启动子控制的荧光素酶基因表达载体,从PicaGene Basic Vector2(商标,Toyo Ink Inc.,目录号309-04821)中切除荧光素酶结构基因,在TK启动子(-105/+51)的控制下制备荧光素酶基因表达载体pTK-Luc.,作为来自具有TK启动子的pTKβ(Chrontech Inc.,目录号6179-1)的最小基本启动子活性。在TK启动子上游,插入四倍的重复UAS序列,其为Gal4蛋白的响应要素,一种酵母中的基本转录因子,以构建4×UAS-TK-Luc.作为报导(reporter)基因。下面是使用的增强子序列(SEQ ID NO:1)。SEQ ID NO:1:重复Gal4反应元件4次的增强子序列。
5’-T(CGACGGAGTACTGTCCTCCG)×4 AGCT-3’
如下文所述制备表达嵌合(chimeric)受体蛋白的载体,其中在酵母Gal4蛋白的羧基末端,融合DNA结合区到人的PPARα或γ的配体结合区。也就是说,使用PicaGene Basic Vector2(商标,Toyo Ink Inc.,目录号309-04821)作为基本表达载体,将结构基因交换成嵌合受体蛋白,而启动子和增强子区域保持原样。
DNA编码由Gal4 DNA结合区域(binding domain)组成的融合蛋白时,与框架中人PPARα或γ的配体结合区域连接的第1-147个氨基酸序列被插入到PicaGene Basic Vector2(商标,Toyo Ink Inc.,目录号309-04821)中的启动子/增强子的下游。这里,DNA按下排序:在人类PPARα或γ的配体结合区域的氨基末端,添加源自SV-40T-抗原的核转位信号:Ala Pro Lys Lys Lys ArgLys Val Gly(SEQ ID NO:2)以制成在核内定位的融合蛋白。另一方面,在其羧基末端,流感血凝素抗原决定基:Tyr Pro Tyr Asp Val Pro Asp Tyr Ala(SEQID NO:3)和翻译终止密码子按这种顺序加入,以检测被表达的融合蛋白标记的抗原决定基序列。
根据R.Mukherjee等人(参见J.Steroid Biochem.Molec.Biol.,
51,157(1994))、M.E.Green等人(参见Gene Expression.,
4,281(1995))、A.Elbrecht等人(参见Biochem Biophys.Res.Commun.,
224,431(1996))或A.Schmidt等人(参见Mol.Endocrinology.,
6,1634(1992))文献中描述的人类PPAR结构的比较,用作人类PPARα或γ配体结合区域的部分结构基因为编码下列肽的DNA:
人类PPARα配体结合区域:Ser167-Tyr468
人类PPARγ配体结合区域:Ser176-Tyr478
(每个人类PPARγ1配体结合区域和人类PPARγ2配体结合区域为彼此相同的序列Ser204-Tyr506)。
为测定转录基础水平,还制备了含有在PPAR配体结合区域缺失的Gal4蛋白的DNA结合区域的表达载体,其只能编码Gal4蛋白中的第1-第147的氨基酸序列。
(2)使用人类PPARα或γ的荧光素酶分析
通过常规技术培养用作宿主细胞的CV-1细胞。也就是说,使用补充有10%胎牛血清(GIBCO BRL Inc.,目录号26140-061)50U/ml的青霉素G和50μg/ml的链霉素硫酸盐的Dulbecco改性Eagle培养液(DMEM)中、在5%二氧化碳气体气氛和37℃下培养CV-1细胞。
在10cm盘中接种2×106个细胞,并用没有血清的培养液冲洗一次,接着向其中加入培养液(10ml)。充分混合报导基因(10μg)、Gal4-PPAR表达载体(0.5μg)和50μl LipofectAMINE(GIBRO BRL Inc.,目录号18324-012)并加入到培养物中以将这些DNA引入到宿主细胞。将其在37℃下培养5-6小时,并向其中加入10ml含有20%透析胎牛血清(GIBRO BRL Inc.,目录号26300-061)的培养液,然后在37℃下培养过夜。用胰蛋白酶分散细胞,并将它们再接种在96孔板上,密度为8000个细胞/100ml DMEM-10%透析血清/孔。培养几小时后,当细胞附着到塑料器皿上时,接着向其中加入100μl含有本发明化合物的DMEM-10%透析血清,其浓度为其终浓度的2倍高。在37℃下沉降培养物42小时,并根据生产者指示溶解细胞以测定荧光素酶活性。
对于PPARα激动活性,本发明化合物(10μM)的相对活性示于表6,条件是在以carbacyclin(10μM)作为阳性对照化合物时定义荧光素酶活性为1.0,carbacyclin能大大激活荧光素酶基因转录为PPARα(参见Eur.J.Biochem.,233,242(1996);Genes & Development,
10,974(1996))。
对于PPARγ激动活性,本发明化合物(10μM)的相对活性示于表7,条件是在以曲格列酮(troglitazone)(10μM)作为阳性对照化合物时定义荧光素酶活性为1.0,曲格列酮能大大激活荧光素酶基因转录为PPARγ(参见Cell,
83,863(1995);Endocrinology,
137,4189(1996)和J.Med.Chem.,
39,665(1996)),并已开始作为降血糖药。
此外,各种化合物分析均进行三次,以检验其再现性并确认剂量相关的活性。
表6
化合物号 | 对阳性对照化合物的相对活性(carbacyclin=1) |
实施例2 | 0.9 |
表7
化合物号 | 对阳性对照化合物的相对活性(曲格列酮=1) |
实施例2 | 11.5 |
例如,可通过以下方法测定本发明化合物的降血糖和降脂效果。
降血糖和降脂效果(1):
在分开的笼内各自预先喂养雄性8周龄KKAy/Ta Jcl小鼠(每组5只小鼠)大约一周,并供应丸状食物和随时来自供水瓶的自来水。使小鼠适应后转变到粉碎的食物保持3天。在试验第一天(0天)测量小鼠体重。使用毛细管从尾静脉中采集血样,以测量血浆葡萄糖浓度。根据血浆葡萄糖浓度,使用分层(stratified)随机选择法将小鼠分成若干组(每组5只小鼠)。在次日上午测量小鼠体重,并从次日起连续六天给与它们含有0.03%(w/w)、0.01%(w/w)或0.003%(w/w)本发明化合物的食品混合物的复合物或只给粉碎食物。在第四和第七天上午,测定它们的体重和食物摄取量以计算平均给药剂量。在第六天上午,从尾静脉采集血样,测量葡萄糖和甘油三酯(TG)水平。在第七天测量完体重后,在用醚麻醉条件下从腹部大静脉采集血样,使用商业上可得到的试剂盒测定血浆胰岛素、未酯化的脂肪酸(NEFA)、谷草转氨酶(GOT)和三磷酸鸟苷(GPT)的水平。然后,取出肝脏并称量。从肝脏的左叶制备总RNA,并使用Northern印迹法测量双功能蛋白的基因表达水平。实际上,在对照组(仅粉碎食物)和复合物处理组(含有0.03%、0.01%或0.003%化合物的粉碎食物)之间没有明显的食物摄取量差异。在含0.03%化合物的给定食物组中,计算出的剂量约为40mg/kg/天。
从喂养良好的KKAy/Ta小鼠中的血浆葡萄糖、血浆胰岛素、NEFA或TG水平的改善效果来看,表明其可作为预防和/或治疗糖尿病、高脂血症、动脉粥样硬化症等的药剂。这种效果似乎可通过PPARγ引起体内激活。另外,肝脏重量的增加和HD mRNA表达的增加似乎依赖于PPARα体内激活。降血糖和降脂效果(2):
在分开的笼内各自预先喂养雄性8周龄Zucker fa/fa大鼠(株:Crj-[ZUC]-fa/fa)和用来作为对照的健康Zucker lean大鼠(株:Crj-[ZUC]-lean)大约二周,并供应丸状食物和随时来自自动水供应装置的自来水。在治疗前连续5天,使大鼠适应口头管饲法给药。在这期间,观察它们的全身情况,并将10周龄的健康大鼠用于试验。在试验第一天(天0)上午测量每只大鼠体重,并使用毛细管从尾静脉中采集血样,以测量血浆葡萄糖浓度、TG、NEFA浓度和HbA1c。根据HbA1c和体重,使用分层(stratified)随机选择法将大鼠分成每组包括5只动物的组。另外,任意置换大鼠以防止组间其它参数平均值的偏差。从分组后的一天起每个上午测量每只动物的体重。根据给药日测量的体重计算给药量,并每天一次进行口头管饲法给药本发明的化合物或单独的赋形剂(0.5%甲基纤维素),连续13天。对健康动物(lean大鼠)只给与赋形剂。
在1、4、7、10和13天的上午测量食物消耗量,计算平均食物摄取量。在第七天,使用毛细管从尾静脉中采集血样,以测量血浆葡萄糖、TG、NEFA浓度和HbA1c。并在第十四天,进行口服葡萄糖耐量试验(OGTT),以评价对葡萄糖不耐性的改善效果。在前一天(13天)对大鼠禁食以进行OGTT。在次日(14天)采集血样后,每次口服给药2g/5mg/kg量的40%葡萄糖溶液。输入60分钟和120分钟后,使用毛细管从尾静脉内采集血样,测定血浆葡萄糖水平。
在15天的OGTT和给药本发明的化合物后,使动物进食。在第十六天上午测完体重后,在用醚麻醉条件下从腹部腔静脉中采集血样,测定血浆葡萄糖、血浆胰岛素、TG、NEFA、GOT和GPT水平。另外,割除肝脏并称重。
从喂养良好的Zucker fa/fa大鼠中的血浆葡萄糖、血浆胰岛素、TG、NEFA水平或HbA1c的改善效果来看,表明其可作为预防和/或治疗糖尿病、高脂血症、动脉粥样硬化症等的药剂。另外,OGTT过程中空腹血浆葡萄糖的减少效果和葡萄糖不耐性的改善效果表明,其可作为预防和/或治疗糖尿病的药剂。这些效果似乎通过PPARγ引起体内激活。另外还表明,肝脏重量的增加依赖于PPARα体内激活。
降血糖和降脂效果(3):
对准备全面内科检查的雄性3-4年龄猕猴(平均体重:大约3kg)进行内科检查,并使其适应每天一次供应大约100g丸状食物和随时从自动供水装置中供应自来水,各自在分开的猴笼内呆一个月以上。此后,动物改成在1小时内进食。另外,预喂养动物14天。在治疗前的14天和7天时,测量体重,然后从后肢隐静脉内采集血样,以测量血液学的(红细胞、血细胞比容、血红蛋白、血小板和白细胞)和生物化学的(GOT、GPT、碱性磷酸酶、蛋白总量、血脲氮、肌酸酐、肌酸酐激酶、总胆红素、葡萄糖、总胆固醇、HDL、LDL和TG)参数。另外,在适应期和预喂养期观察动物的全身状态,并使用健康动物用于试验。此外,每天测量食物消耗量。
根据适应期最后一天测量的体重,使用分层(stratified)随机选择法将动物分为若干组(每组三只动物)。在第1、3、7、10和14天的上午测量体重。根据最近的体重计算给药的量,并口管饲法给药本发明的化合物(3-100mg/kg/天)或单独的赋形剂(稀释溶液),每天一次,连续14天。在治疗后的1、7和14天,在给药本发明的化合物前采集血样,以测定上述血液学的和生物化学的参数。其证实血糖未因本发明的化合物而变化。在开始治疗三周前和14天后,在口管饲给药1、2和4小时后以及在提供食物1、2和3小时后,从后肢隐静脉或前臂静脉中采集血样,以测定血浆葡萄糖和TG。
从被禁食的猴中血浆TG水平的改善效果看,表明其可作为预防和/或治疗高脂血症和动脉粥样硬化症等的药剂。这些效果似乎通过PPARα引起体内激活。这还从对进食后TG增加的抑制效果中观察到。另外,可从其它生物化学参数中来评估化合物是否有毒性危险。
[毒性]
本发明式(I)代表的化合物的毒性非常低,因此认为化合物用作药物是足够安全的。
工业适用性
[药物应用]
由于本发明式(I)代表的化合物及其无毒盐具有PPAR调节活性,因而有望将其用作降血糖药,降脂药,预防和/或治疗与代谢紊乱有关的疾病如糖尿病、肥胖、X综合症、高胆固醇血症和高脂蛋白血症等,高脂血症,动脉粥样硬化症,高血压,循环疾病,过度饱食,缺血性心脏病等的药剂,升高HDL胆固醇药,降低LDL胆固醇和/或VLDL胆固醇药,以及减轻糖尿病或X综合症危险因子的药剂。
另外,由于本发明式(I)代表的化合物及其无毒盐具有PPARα激动剂和/或PPARγ激动剂作用,因而有望将其用作降血糖药,降脂药,预防和/或治疗与代谢紊乱有关的疾病如糖尿病、肥胖、X综合症、高胆固醇血症和高脂蛋白血症等,高脂血症,动脉粥样硬化症,高血压,循环疾病和过度饱食等的药剂,升高HDL胆固醇作用,降低LDL胆固醇和/或VLDL胆固醇作用,抑制动脉粥样硬化症发展及其治疗,和对肥胖的抑制作用。还期望它们作为降血糖药用于治疗和/或预防糖尿病、用于改善高血压、用于减轻X综合症危险因子,并作为预防缺血性心脏病发生的药。
在本发明中,式(I)代表的化合物可和其它药物组合给药而用于以下目的:1)补充和/或增强预防和/或治疗效果,2)改善化合物的动力学和吸收并降低剂量,和/或3)减轻化合物的副作用。
式(I)代表的化合物可与其它药物组合作为包含这些成分的一种药物产品而给药,或可分别给药。当进行独立给药时,可同时给药,也可延迟给药。延迟给药包括在其它药物前给药式(I)代表的化合物的方法,或与此相反;它们可按照相同或不同的途径给药。
上述组合对任何一种疾病都有效,并补充和/或增强了式(I)代表的化合物的治疗和/或预防效果。
对于补充和/或增强式(I)代表的化合物的效果或增强治疗糖尿病并发症效果的其它药物,例如有磺酰脲类降血糖药、双胍制剂、α-葡萄糖苷酶抑制剂、速效胰岛素分泌促进剂、胰岛素制剂、PPAR激动剂、没有PPAR激动活性的胰岛素致敏剂、β-3肾上腺素受体激活剂、醛糖还原酶抑制剂或二肽基肽酶IV抑制剂等。
磺酰脲类药的例子包括醋磺环己脲、优降糖、甲磺吡脲、氯磺丙脲、氯丙酰胺、妥拉磺脲、甲苯磺丁脲和格列美脲等。
双胍制剂的例子包括盐酸丁二胍和盐酸二甲双胍等。
a-葡萄糖苷酶抑制剂的例子包括阿卡波糖和优格列波糖等。
速效胰岛素分泌促进剂的例子包括那格列奈(nateglinide)和瑞格列奈(repaglinide)等。
PPAR激动剂的例子包括吡格列酮、曲格列酮、罗格列酮和JTT-501等。
没有PPAR激动活性的胰岛素增敏剂的例子包括ONO-5816和YM-440等。
β-3肾上腺素受体激活剂的例子包括AJ9677、L750355和CP331648等。
醛糖还原酶抑制剂的例子包括依帕司他、非达司他(fidarestat)和折那司他(zenarestat)等。
对式(I)代表的化合物和其它药物的重量比没有特殊限制。
可组合给药任意的二种或多种其它药物。
用于补偿和/或增强式(I)代表的化合物的预防和/或治疗效果的其它药物的实例不仅包括迄今已被发现的那些,而且还包括根据上述机理将被发现的那些。
当使用本发明式(I)代表的化合物或组合式(I)代表的化合物和其它药物的伴随药物用于上述目的时,通常通过口服途径或肠胃外途径全身或局部地给药。
根据例如年龄、体重、症状、所需治疗效果、给药途径和治疗持续时间决定给药剂量。对于成年人,每人的剂量通常为:口服给药时1ng-100mg,最多每天几次;肠胃外给药时,0.1ng-10mg,最多每天几次,或从静脉在每天1-24小时内连续给药。
如上所述,使用的剂量取决于各种条件。因此,存在可使用低于或高于上述指定范围的剂量的情况。
当使用本发明式(I)代表的化合物或组合式(I)代表的化合物和其它药物的伴随药物用于上述目的时,通常通过口服途径或肠胃外途径全身地或局部地给药。在医学治疗时,希望选择最有效的给药途径。
根据例如年龄、体重、症状、所需治疗效果、给药途径和治疗持续时间决定给药剂量。对于成年人,每人的剂量通常为:口服给药时1ng-100mg,最多每天几次;肠胃外给药时,0.1ng-10mg,最多每天几次,或从静脉在每天1-24小时内连续给药。
如上所述,使用的剂量取决于各种条件。因此,存在可使用低于或高于上述指定范围的剂量的情况。
本发明式(I)代表的化合物或组合式(I)代表的化合物和其它药物的伴随药物可以组合物的形式给药,例如内服固体制剂和内服液体制剂,分别用于口服给药或注射,外用制剂或栓剂,分别用于肠胃外给药。
用于口服内用的固体制剂的实例包括片剂、丸剂、胶囊、粉剂、颗粒剂等。胶囊包括硬胶囊和软胶囊。
通过常规使用的配制方法制备这类内服固体制剂,通过使用一种或多种这种活性物质,或使用其与赋形剂(乳糖、甘露醇、葡萄糖、微晶纤维素、淀粉等)、粘合剂(羟丙基纤维素、聚乙烯吡咯烷酮、偏硅酸铝镁等)、崩解剂(纤维素乙二醇酸钙等)、润滑剂(硬脂酸镁等)、稳定剂和溶解助剂(谷氨酸、天冬氨酸等)的混合物。如果需要,可用包衣剂(蔗糖、明胶、羟丙基纤维素、邻苯二甲酸羟丙基甲基纤维素酯等)包衣。可包衣二层或多层。此外,由可吸收物质如明胶制成的胶囊也包括在其范围内。
用于口服的内服液体制剂的实例包括药物上可接受的溶液、混悬液、乳剂、糖浆、酏剂等。通过在常规使用的稀释剂(纯水、乙醇、其混合物等)中溶解、悬浮或乳化一种或多种活性物质来制备这类液体制剂。除了这些液体形式外,还可包括一些添加剂,如润湿剂、悬浮剂、乳化剂、甜味剂、调味剂、芳香剂、防腐剂或缓冲剂等。
用于肠胃外给药的注射剂包括溶液、悬浮液、乳剂和使用前进行溶解或悬浮的固体注射剂。通过在溶剂中溶解、悬浮或乳化一种或多种活性物质来使用这类注射剂。作为溶剂,可使用例如注射剂用蒸馏水、生理盐水、植物油、醇如丙二醇、聚乙二醇或乙醇及其混合物。注射剂还可包含稳定剂、溶解助剂(谷氨酸、天冬氨酸、Polysorbate 80(注册商标)等)、悬浮剂、乳化剂、抚慰剂、缓冲剂、防腐剂等。可通过在最后步骤杀菌或使用杀菌方法来生产这类注射剂。或者,也可生产无菌固体产品如冻干产品并在使用前杀菌或溶解到注射用无菌蒸馏水或另一溶剂中。
外用的肠胃外给药制剂的剂型包括软膏、冻胶、霜、热敷剂、贴片、擦剂、雾化剂、吸入剂、喷雾剂、滴眼剂、滴鼻剂等。这类制剂含有一种或多种活性物质,并按照常用配方用公知方法来制备。
软膏可按照公知配方或常用配方来制备。例如,它们可通过在基质中粉碎或融化一种或多种活性物质来制备。软膏基质选自公知的那些或常用的那些。例如,可使用选自以下物质的一种基质或其二种或多种的混合物:高脂肪酸或高脂肪酸酯(己二酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、己二酸酯、肉豆蔻酸酯、棕榈酸酯、硬脂酸酯、油酸酯等)、蜡(蜂蜡、鲸蜡、地蜡等)、表面活性剂(聚氧乙烯烷基醚磷酸酯等)、高级醇(鲸蜡醇、硬脂醇、鲸蜡硬脂醇等)、硅油(二甲基聚硅氧烷等)、烃(亲水凡士林、白凡士林、精制羊毛脂、液体石蜡等)、乙二醇类(乙二醇、二乙二醇、丙二醇、聚乙二醇、大粒凝胶(macrogol)等)、植物油(蓖麻油、橄榄油、芝麻油、松节油等)、动物油(貂油、羊毛油、角鲨烷、角鲨烯等)、水、吸收促进剂和皮肤刺激抑制剂。软膏还可包含湿润剂、防腐剂、稳定剂、抗氧化剂、调味剂等。
凝胶可按照公知配方或常用配方来制备。例如,它们通过在基质中融化一种或多种活性物质而制备。凝胶基质成分选自公知的那些或常用的那些。例如,可使用选自以下物质中的一种基质或其二种或多种的混合物::低级醇(乙醇、异丙醇等)、胶凝剂(羧甲基纤维素、羟乙基纤维素、羟丙基纤维素、乙基纤维素等)、中和剂(三乙醇胺、二异丙醇胺等)、表面活性剂(聚乙二醇单硬脂酸酯等)、树胶、水、吸收促进剂和皮肤刺激抑制剂。凝胶还可包含防腐剂、抗氧化剂、调味剂等。
霜可按照公知配方或常用配方来制备。例如,它们可通过在基质中融化或乳化一种或多种活性物质来制备。霜的基质选自公知的那些或常用的那些。例如,可使用选自以下物质中的一种基质或其二种或多种的混合物:高脂肪酸酯、低级醇、烃、多元醇(丙二醇、1,3-丁二醇等)、高级醇(2-己基癸醇、鲸蜡醇等)、乳化剂(聚氧乙烯烷基醚、脂肪酸酯等)、水、吸收促进剂和皮肤刺激抑制剂。霜还可包含防腐剂、抗氧化剂、调味剂等。
热敷剂可按照公知配方或常用配方来制备。例如,它们可通过在基质中融化一种或多种活性物质,捏和,然后将捏和的物质施加并铺展在基质上而制备。热敷剂基质选自公知的那些或常用的那些。例如,可使用选自以下物质的一种基质或其二种或多种的混合物:增稠剂(聚丙烯酸、聚乙烯吡咯烷酮、阿拉伯树胶、淀粉、明胶、甲基纤维素等)、润湿剂(脲、甘油、丙二醇等)、填充剂(高岭土、氧化锌、滑石、钙、镁等)、水、溶解助剂、粘合剂和皮肤刺激抑制剂。热敷剂还可包含防腐剂、抗氧化剂、调味剂等。
贴片可按照公知配方或常用配方来制备。例如,它们可通过在基质中融化一种或多种活性物质,然后施加并铺展在基质上而制备。贴片基质选自公知的那些或常用的那些。例如,可使用选自以下物质中的一种基质或其二种或多种的混合物:聚合物基质、脂肪及油、高级脂肪酸、粘合剂和皮肤刺激抑制剂。贴片还可包含防腐剂、抗氧化剂、调味剂等。
擦剂可按照公知配方或常用配方来制备。例如,它们可通过在一种或多种选自下列物质的介质中溶解、悬浮或乳化一种或多种活性物质来制备:水、醇(乙醇、聚乙二醇等)、高级脂肪酸、甘油、肥皂、乳化剂、悬浮剂等。擦剂还可包含防腐剂、抗氧化剂、调味剂等。
除常用的稀释剂外,雾化剂、吸入剂和喷雾剂可包含稳定剂如亚硫酸氢钠、用于提供等渗性的缓冲剂,例如等渗剂如氯化钠、柠檬酸钠或柠檬酸。用于制造喷雾剂的方法详细描述于例如美国专利2868691和美国专利3095355中。此外,它还使用气溶胶剂。
在给药滴鼻剂时,其通常使用滴鼻剂专用器械或定量喷雾器在鼻内以包含药物的液体或粉末的形式进行喷射。
用于肠胃外给药的滴眼剂可为液体、混悬液、乳化液、使用时溶于溶剂的液体或软膏的形式。
可通过任何已知的方法制备这些滴眼剂。例如,在溶剂中溶解、悬浮或乳化一种或多种活性物质。对于这类滴眼剂用溶剂,可单独或组合使用无菌纯水、生理盐水和任何其它水溶性或非水溶性溶剂(如植物油)。滴眼剂可含有一种或多种可选自以下物质的溶剂:等渗剂(如氯化钠、浓的甘油)、缓冲剂(如磷酸钠、乙酸钠)、表面活性剂(如Polysolvate80(商品名)、硬脂酸-40-聚烃氧基酯、聚氧乙烯硬化蓖麻油)、稳定剂(柠檬酸钠、乙二胺四乙酸钠)、防腐剂(如氯苄烷胺(benzalconium chloride),对羟基苯甲酸酯类(paraben))等。在最后步骤中滴眼剂杀菌或通过无菌方法来制备。可选地,可使无菌固体药剂如预先制备好的冻干产品无菌地或在使用前溶解于注射用无菌蒸馏水或其它溶剂中。
用于肠胃外给药的吸入剂包括气溶胶、粉末吸入剂和液体吸入剂。这类吸入剂可以是在使用前溶于或悬浮于水或另外适当介质中的形式。
可按照公知的方法制备吸入剂。
例如,根据需要,可通过适当选择防腐剂(氯苄烷胺、对羟基苯甲酸酯等)、着色剂、缓冲剂(磷酸钠、乙酸钠等)、等渗剂(氯化钠、浓甘油等)、增稠剂(羧乙烯聚合物等)、吸收促进剂等来制备吸入剂液体制剂。
粉末吸入剂可根据需要,通过适当选择润滑剂(硬脂酸、它的盐等)、粘合剂(淀粉、糊精等)、赋形剂(乳糖、纤维素等)、着色剂、防腐剂(氯苄烷胺、对羟基苯甲酸酯类等)、吸收促进剂等来制备。
当给药以液体吸入剂时,通常使用喷雾器(雾化器、喷雾器)。当使用粉末吸入剂时,通常使用用于粉剂的吸入给药的器械。
其它肠胃外给药组合物包括栓剂和阴道给药用阴道栓剂,其包含一种或多种活性物质,并按照常用配方制备。
实施本发明的最佳方式
下面根据参考例和实施例详细解释本发明,但本发明不限于此。
括号内的溶剂表示在色谱分离或薄层色谱(TLC)法中的展开或淋洗溶剂以及以体积表示的所用溶剂比。核磁共振(NMR)中括号内的溶剂表示测试用溶剂。MOMO代表甲氧甲氧基基团。
参考例1:
3-甲氧甲氧基苯甲醛
在0℃下向3-羟基苯甲醛(1.0g)的四氢呋喃(25mL)溶液中加入氢化钠(374mg),并在0℃下搅拌混合物20分钟。向反应混合物中加入甲氧基甲基氯(0.92mL),在室温下搅拌30分钟。将反应混合物倒入冷水中,并用乙酸乙酯萃取。用盐水洗涤有机层,在无水硫酸镁上干燥并浓缩。通过在硅胶(己烷∶乙酸乙酯=8∶1→5∶1)上用柱色谱法纯化残余物,得到具有以下物理数据的标题化合物(1.36g)。
TLC:Rf0.69(己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ9.98(s,1H),7.62-7.40(m,3H),7.30(m,1H),5.24(s,2H),3.50(s,3H)。
参考例2:
3-甲氧甲氧基苯甲醇
在0℃下向氢化铝锂(178mg)的四氢呋喃(15mL)悬浮液中滴入参考例1中制备的化合物(1.30g)的四氢呋喃(24mL)溶液,并在0℃下搅拌混合物20分钟。将饱和硫酸钠水溶液滴加入反应混合物中,然后向其中加入醚。在无水硫酸镁上干燥反应混合物并浓缩,得到具有以下物理数据的粗制标题化合物(1.39g)。没有纯化就在下面反应中使用得到的化合物。
TLC:Rf0.25(己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ7.28(dd,J=7.8,7.8Hz,1H),7.10-6.92(m,3H),5.19(s,2H),4.67(brd,J=3.0Hz,2H),3.48(s,3H)。
参考例3:
2-(N-烯丙基-N-(3-甲氧甲氧基苄基)氨基)乙酸乙酯
在0℃下向参考例2中制备的化合物的四氢呋喃(16mL)溶液中加入三乙胺(2.0mL)和甲苯磺酰基氯(0.72mL),并在0℃下搅拌混合物40分钟。将乙醇(0.23mL)加入反应混合物中,并在0℃下搅拌20分钟。将乙腈(5.0mL)、碳酸钾(2.16g)和N-烯丙基甘氨酸乙酯(1.68g)的乙腈(18mL)溶液加入到反应混合物中,并在75℃下搅拌40分钟。将反应混合物冷却至室温,然后倒入冷水中并用乙酸乙酯萃取。用盐水洗涤有机层,在无水硫酸镁上干燥并浓缩。通过在硅胶上的柱色谱法纯化残余物(己烷∶乙酸乙酯=8∶1→6∶1),得到具有以下物理数据的标题化合物(1.84g)。
TLC:Rf0.40(己烷∶乙酸乙酯=5∶1);
NMR(CDCl3):δ7.23(dd,J=7.8,7.8Hz,1H),7.08-6.90(m,3H),5.88(ddt,J=16.8,10.2,6.6Hz,1H),5.28-5.10(m,2H),5.17(s,2H),4.16(q,J=7.2Hz,2H),3.77(s,2H),3.48(s,3H),3.32(s,2H),3.28(d,J=6.6Hz,2H),1.27(t,J=7.2Hz,3H)。
参考例4:
2-(N-烯丙基-N-(3-羟基苄基)氨基)乙酸乙酯
向参考例3中制备的化合物(1.80g)的乙醇(6.1mL)溶液中加入4N氯化氢-二噁烷溶液(3.1mL),并在室温下搅拌混合物过夜。将反应混合物倒入冷的饱和碳酸氢钠水溶液中,并用乙酸乙酯萃取。用盐水洗涤有机层,用无水硫酸镁干燥并浓缩,得到具有以下物理数据的标题所示化合物(1.61g)。
TLC:Rf0.39(己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ7.17(dd,J=7.8,7.8Hz,1H),6.94-6.84(m,2H),6.73(m,1H),5.87(ddt,J=16.8,10.2,6.6Hz,1H),5.28-5.10(m,2H),4.15(q,J=6.9Hz,2H),3.73(s,2H),3.31(s,2H),3.26(d,J=6.6Hz,2H),1.26(t,J=6.9Hz,3H)。
参考例5:
6-(全氢氮杂-1-基)烟酸
在140℃下和氩气气氛中搅拌6-氯代烟酸(5.0g)和全氢氮杂(7.16mL)的二甲苯(20ml)悬浮液30小时。将反应混合物冷却至室温,用己烷稀释并过滤。将不溶物质溶于乙酸乙酯中。依次用水和盐水洗涤有机层,在无水硫酸镁上干燥并浓缩,得到具有以下物理数据的标题化合物(3.19g)。
TLC:Rf0.21(氯仿∶甲醇=9∶1)。
参考例6:
3-甲氧基羰基-2-(6-(全氢氮杂-1-基)吡啶-3-基羰基氨基)丙酸苄酯
向参考例5中制备的化合物(3.19g)和3-氨基-3-苄氧羰基丙酸甲酯氢氯化物(4.38g)的无水二甲基甲酰胺(40mL)溶液中加入1-乙基-3-(3-二甲基氨丙基)碳化二亚胺(3.34g)和三乙胺(4.45mL),在室温下搅拌混合物15小时。用水稀释反应混合物并用乙酸乙酯萃取。依次用水和盐水洗涤有机层,在无水硫酸镁上干燥并浓缩。通过在硅胶的柱色谱法(己烷∶乙酸乙酯=3∶1)纯化残余物,得到具有以下物理数据的标题化合物(2.94g)。
TLC:Rf0.77(氯仿∶甲醇=9∶1)。
参考例7:
3-甲氧羰基-2-(6-(全氢氮杂-1-基)吡啶-3-基羰基氨)丙酸
向10%钯-碳(300mg,50%湿气)的乙醇(10mL)悬浮液中加入参考例6中制备的化合物(2.94g)的乙醇(15mL)溶液,并在室温下和氢气气氛中搅拌混合物2小时。过滤反应混合物并浓缩,得到具有以下物理数据的标题化合物。
TLC:Rf0.10(氯仿∶甲醇=9∶1)。
参考例8:
3-乙酰基-3-(6-(全氢氮杂-1)吡啶基-3-基羰基氨萘)丙酸甲酯
向参考例7中制备的化合物和4-二甲基氨基吡啶(40mg)的无水吡啶(10mL)溶液中加入醋酐(1.26mL),并在80℃下搅拌混合物15小时。将反应混合物冷却至室温并浓缩,得到具有以下物理数据的标题化合物。
TLC:Rf0.20(己烷∶乙酸乙酯=1∶1)。
参考例9:
2-(2-(6-全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙酸甲酯
向参考例8中制备的化合物的醋酐(20mL)溶液中加入浓硫酸(2mL),在90℃下搅拌混合物2小时。将反应混合物冷却至室温,用饱和碳酸钾水溶液中和,并用乙酸乙酯萃取。依次用水和盐水洗涤有机层,用无水硫酸镁干燥并浓缩。通过在硅胶上的柱色谱法纯化残余物(己烷∶乙酸乙酯=2∶1),得到具有以下物理数据的标题化合物(1.44g)。
TLC:Rf0.44(己烷∶乙酸乙酯=1∶1);
NMR(CDCl3):δ8.71(d,J=2.4Hz,1H),7.96(dd,J=9.0,2.4Hz,1H),6.50(d,J=9.0Hz,1H),3.72(s,3H),3.67(dd,J=6.0,5.7Hz,4H),3.54(s,2H),2.33(s,3H),1.83-1.77(m,4H),1.60-1.52(m,4H)。
参考例10:
2-(2-(6-(全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙醇
在氩气气氛下,在0℃下向氢化铝锂(166mg)的无水四氢呋喃(10mL)悬浮液中滴加入参考例9中制备的化合物(1.44g)的无水四氢呋喃(10mL)溶液,并在室温下搅拌混合物2小时。将反应混合物冷却至0℃。向反应混合物中滴加甲醇(1.0mL),并搅拌15分钟。用二异丙醚稀释反应混合物。将饱和碳酸钠水溶液(10mL)加入到稀释液中,在室温下搅拌1小时。通过层叠在硫酸钠上的过滤器过滤反应混合物。用二异丙醚洗涤不溶物质。浓缩合并的有机层得到具有以下物理数据的标题化合物(1.20g)。
TLC:Rf0.45(乙酸乙酯);
NMR(CDCl3):δ8.72(d,J=2.4Hz,1H),7.94(dd,J=9.0,2.4Hz,1H),6.51(d,J=9.0Hz,1H),3.94-3.87(m,2H),3.68(dd,J=6.3,5.7Hz,4H),3.47-3.40(m,1H),2.69(t,J=6.0Hz,2H),2.30(s,3H),1.83-1.77(m,4H),1.62-1.52(m,4H)。
实施例1:
2-(N-烯丙基-N-(3-(2-(2-(6-(全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
在氩气气氛下,在室温下向参考例10中制备的化合物(500mg)和参考例4中制备的化合物(623mg)的无水二氯甲烷溶液(30mL)中加入三苯基膦(656mg)和1,1’-(偶氮二羰基)二哌啶(631mg),并搅拌混合物18小时。浓缩反应混合物,并用二乙醚稀释残余物并过滤。依次用2N氢氧化钠水溶液、水和盐水洗涤滤出物,在无水硫酸镁上干燥并浓缩。通过在硅胶上的柱色谱法纯化残余物(己烷∶乙酸乙酯=4∶1),得到具有以下物理数据的本发明化合物(777mg)。
TLC:Rf0.47(己烷∶乙酸乙酯=1∶1);
NMR(CDCl3):δ8.71(d,J=2.4Hz,1H),7.96(dd,J=9.0,2.4Hz,1H),7.20(dd,J=7.8,7.5Hz,1H),6.92-6.88(m,2H),6.82-6.77(m,1H),6.50(d,J=9.0Hz,1H),5.94-5.80(m,1H),5.23-5.12(m,2H),4.22(t,J=6.9Hz,2H),4.14(q,J=6.9Hz,2H),3.76(s,2H),3.68(dd,J=6.3,5.7Hz,4H),3.30(s,2H),3.27(d,J=6.6Hz,2H),2.95(t,J=6.9Hz,2H),2.34(s,3H),1.83-1.77(m,4H),1.58-1.52(m,4H),1.24(t,J=6.9Hz,3H)。
实施例1(1)-实施例1(17):
通过实施例1所述的相同过程,使用相应的醇衍生物代替参考例11中制备的化合物和参考例5中制备的化合物,或相应的酚衍生物,得到本发明的下列化合物。
实施例1(1):
2-(N-烯丙基-N-(3-(2-(2-异丙基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.35(己烷∶乙酸乙酯=4∶1)。
实施例1(2):
2-(N-烯丙基-N-(3-(2-(2-(4-甲基哌嗪-1-基)-5-甲基噻唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.43(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.19(dd,J=8.0,8.0Hz,1H),6.93-6.86(m,2H),6.78(m,1H),5.87(ddt,J=16.5,10.0,6.4Hz,1H),5.21(m,1H),5.15(m,1H),4.19(t,J=7.0Hz,2H),4.15(q,J=7.0Hz,2H),3.75(s,2H),3.46-3.37(m,4H),3.30(s,2H),3.27(d,J=6.5(Hz,2H),2.95(t,J=7.0Hz,2H),2.56-2.48(m,4H),2.33(s,3H),2.25(s,3H),1.26(t,J=7.0Hz,3H)。
实施例1(3):
2-(N-烯丙基-N-(3-(2-(2-(4-(1,2,3-噻二唑-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.66(己烷∶乙酸乙酯=1∶1);
NMR(CDCl3):δ8.71(s,1H),8.13(s,4H),7.21(dd,J=7.9,7.9Hz,1H),6.98-6.75(m,3H),5.87(m,1H),5.30-5.08(m,2H),4.26(t,J=6.6Hz,2H),4.14(q,J=7.2Hz,2H),3.75(s,2H),3.38-3.20(m,4H),3.00(t,J=6.6Hz,2H),2.41(s,3H),1.25(t,J=7.2Hz,3H)。
实施例1(4):
2-(N-烯丙基-N-(3-(2-(2-(4-环己基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.65(己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ7.94-7.84(m,2H),7.32-7.23(m,2H),7.19(dd,J=7.8,7.8Hz,1H),6.96-6.86(m,2H),6.79(m,1H),5.87(ddt,J=17.1,10.2,6.6Hz,1H),5.28-5.10(m,2H),4.23(t,J=6.6Hz,2H),4.14(q,J=7.2Hz,2H),3.74(s,2H),3.29(s,2H),3.26(d,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H),2.53(m,1H),2.36(s,3H),1.96-1.28(m,10H),1.25(t,J=7.2Hz,3H)。
实施例1(5):
2-(N-烯丙基-N-(3-(2-(2-(4-(四氢吡喃-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0-20(己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ7.96-7.88(m,2H),7.34-7.24(m,2H),7.20(dd,J=8.1,8.1Hz,1H),6.96-6.86(m,2H),6.79(m,1H),5.87(ddt,J=17.1,10.2,6.6Hz,1H),5.28-5.10(m,2H),4.23(t,J=6.6Hz,2H),4.20-4.04(m,4H),3.74(s,2H),3.60-3.48(m,2H),3.30(s,2H),3.26(d,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H),2.79(m,1H),2.37(s,3H),1.94-1.70(m,4H),1.25(t,J=7.2Hz,3H)。
实施例1(6):
2-(N-烯丙基-N-(3-(2-(5-甲基-2-哌啶子基噻唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
NMR(CDCl3):δ7.19(t,J=8.1Hz,1H),6.92-6.87(m,2H),6.60(m,1H),5.87(m,1H),5.26-5.12(m,2H),4.19(t,J=7.2Hz,2H),4.14(q,J=7.2Hz,2H),3.75(s,2H),3.40-3.32(m,4H),3.30(s,2H),3.27(d,J=6.3Hz,2H),2.94(t,J=7.2Hz,2H),1.71-1.54(m,6H),1.26(t,J=7.2Hz,3H)。
实施例1(7):
2-(N-烯丙基-N-(3-(2-(2-苯基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.46(己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ8.03-7.93(m,2H),7.49-7.36(m,3H),7.20(dd,J=7.8,7.8Hz,1H),6.96-6.87(m,2H),6.80(m,1H),5.87(m,1H),5.28-5.10(m,2H),4.24(t,J=6.8Hz,2H),4.14(q,J=7.0Hz,2H),3.75(s,2H),3.30(s,2H),3.28(m,2H),2.98(t,J=6.8Hz,2H),2.38(s,3H),1.25(t,J=7.0Hz,3H)。
实施例1(8):
2-(N-烯丙基-N-(3-(2-(2-(6-二甲基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.28(己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ8.74(m,1H),7.99(dd,J=9.0,2.4Hz,1H),7.20(dd,J=8.0,8.0Hz,1H),6.94-6.86(m,2H),6.79(m,1H),6.53(m,1H),5.87(ddt,J=16.8,10.0,6.5Hz,1H),5.21(m,1H),5.14(m,1H),4.22(t,J=7.0Hz,2H),4.14(q,J=7.0Hz,2H),3.75(s,2H),3.30(s,2H),3.27(d,J=6.5Hz,2H),3.14(s,6H),2.95(t,J=7.0Hz,2H),2.34(s,3H),1.25(t,J=7.0Hz,3H)。
实施例1(9):
2-(N-烯丙基-N-(3-(2-(2-(4-二甲基氨基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.26(己烷∶乙酸乙酯=4∶1);
实施例1(10):
2-(N-烯丙基-N-(3-(2-(5-甲基-2-苯噁唑-4-基)乙氧基)苄基)氨基)-2-甲基丙酸甲酯
TLC:Rf0.48(己烷∶乙酸乙酯=4∶1);
NMR(CDCl3):δ8.02-7-94(m,2H),7.48-7.37(m,3H),7.17(dd,J=8.0,8.0Hz,1H),6.98-6.88(m,2H),6.73(m,1H),5.78(ddt,J=16.5,10.0,6.5Hz,1H),5.00(m,1H),4.90(m,1H),4.24(t,J=6.5Hz,2H),3.77(s,2H),3.69(s,3H),3.28(d,J=6.5Hz,2H),2.98(t,J=6.5Hz,2H),2.38(s,3H),1.38(s,6H)。
实施例1(11):
2-(N-烯丙基-N-(3-(2-(2-(6-吗啉代吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0-44(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.76(d,J=2.4Hz,1H),8.04(dd,J=9.0,2.4Hz,1H),7.19(t,J=9.2Hz,1H),6.96-6.85(m,2H),6.83-6.74(m,1H),6.64(d,J=9.0Hz,1H),5.98-5.74(m,1H),5.27-5.04(m,2H),4.28-4.06(m,4H),3.87-3.78(m,4H),3.74(s,2H),3.65-3.55(m,4H),3.32-3.22(m,4H),2.95(t,J=7.0Hz,2H),2.35(s,3H),1.25(m,3H)。
实施例1(12):
2-(N-烯丙基-N-(3-(2-(2-(6-哌嗪代吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.33(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.72(d,J=2.4Hz,1H),7.97(dd,J=9.0,2.4Hz,1H),7.19(t,J=8.0Hz,1H),6.96-6.85(m,2H),6.79(m,1H),6.64(d,J=9.0Hz,1H),5.98-5.73(m,1H),5.27-5.04(m,2H),4.28-4.03(m,4H),3.74(s,2H),3.61(brs,4H),3.32-3.22(m,4H),2.94(t,J=6.6Hz,2H),2.34(s,3H),1.65(brs,6H),1.25(m,3H)。
实施例1(13):
2-(N-烯丙基-N-(3-(2-(2-(6-二乙基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.48(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.71(d,J=2.6Hz,1H),7.95(dd,J=9.2,2.6Hz,1H),7.19(t,J=6.8Hz,1H),6.95-6.75(m,3H),6.47(d,J=9.2Hz,1H),5.85(m,1H),5.21(d,J=17.2Hz,1H),5.14(d,J=10.3Hz,1H),4.22(t,J=6.8Hz,2H),4.14(q,J=7.2Hz,2H),3.74(s,2H),3.55(q,J=7.0Hz,4H),3.29(s,2H),3.27(d,J=6.4Hz,2H),2.91(t,J=6.8Hz,2H),2.34(s,3H),1.35-1.15(m,9H)。
实施例1(14):
2-(N-烯丙基-N-(3-(2-(2-(6-吡咯烷基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.80(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.73(d,J=2.4Hz,1H),7.98(dd,J=8.8,2.4Hz,1H),7.19(t,J=7.2Hz,1H),6.93-6.75(m,2H),6.91(s,1H),6.37(d,J=8.8Hz,1H),5.98-5.74(m,1H),5.29-5.09(m,2H),4.22((t,J=6.6Hz,2H),4.16(q,J=7.2Hz,2H),3.74(s,2H),3.50(m,4H),3.29(s,2H),3.26(d,J=6.6Hz,2H),2.94(t,J=6.6Hz,2H),2.34(s,3H),2.02(m,4H),1.24(t,J=7.2Hz,3H)。
实施例1(15):
2-(N-烯丙基-N-(3-(2-(2-(4-吗啉代苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
NMR(CDCl3):δ7.87(d,J=9.0Hz,2H),7.20(t,J=8.1Hz,1H),6.95-6.87(m,4H),6.79(m,1H),5.86(m,1H),5.25-5.11(m,2H),4.23(t,J=6.6Hz,2H),4.14(q,J=6.9Hz,2H),3.87(t,J=4.5Hz,4H),3.74(s,2H),3.32-3.20(m,8H),2.96(t,J=6.6Hz,2H),2.35(s,3H),1.25(t,J=6.9Hz,3H)。
实施例1(16):
2-(N-烯丙基-N-(3-(2-(2-吗啉基-5-甲基噻唑-4-基)乙氧基)苄基)氨基)乙酸叔丁酯
TLC:Rf0.85(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.19(t,J=8.4Hz,1H),6.94-6.87(m,2H),6.77(m,1H),5.86(m,1H),5.26-5.10(m,2H),4.19(t,J=6.9Hz,2H),3.79(t,J=4.5Hz,4H),3.75(s,2H),3.37(t,J=4.5Hz,4H),3.26(d,J=6.6Hz,2H),3.21(s,2H),2.95(t,J=6.9Hz,2H),2.05(s,3H),1.46(s,9H)。
实施例1(17):
2-(N-烯丙基-N-(4-(2-(5-甲基-2-苯噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯
TLC:Rf0.64(己烷∶乙酸乙酯=1∶1);
NMR(CDCl3):δ8.00-7.95(m,2H),7.44-7.39(m,3H),7.23(d,J=8.7Hz,2H),6.85(d,J=8.7Hz,2H),5.94-5.80(m,1H),5.23-5.11(m,2H),4.23(t,J=6.6Hz,2H),4.14(q,J=7.2Hz,2H),3.70(s,2H),3.27(s,2H),3.24(d,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H),2.37(s,3H),1.25(t,J=7.2Hz,3H)。
实施例2:
2-(N-烯丙基-N-(3-(2-(2-(6-(全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
在室温下向实施例1中制备的化合物(777mg)的乙醇和四氢呋喃(20mL,1∶1)溶液中加入2N氢氧化钠水溶液(3.0mL),搅拌混合物15小时。用2N盐酸将反应混合物调整到约pH5,并用乙酸乙酯萃取。依次用水和盐水洗涤萃取物,在无水硫酸镁上干燥并浓缩,得到具有以下物理数据的本发明化合物(546mg)。
TLC:Rf0.18(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.71(d,J=2.4Hz,1H),7.96(dd,J=9.0,2.4Hz,1H),7.24(dd,J=7.8,7.5Hz,1H),6.93-6.82(m,3H),6.51(d,J=9.0Hz,1H),5.96-5.80(m,1H),5.35-5.26(m,2H),4.23(t,J=6.9Hz,2H),3.81(s,2H),3.67(dd,J=6.0,6.0Hz,4H),3.34(d,J=6.9Hz,2H),3.29(s,2H),3.00-2.70(br,1H),2.94(t,J=6.9Hz,2H),2.34(s,3H),1.84-1.72(m,4H),1.59-1.50(m,4H)。
实施例2(1)-实施例2(17):
利用如实施例2所述的相同过程,使用实施例1(1)-实施例1(17)中制备的化合物代替实施例1中制备的化合物,然后根据需要使用常规方法将其转化为相应的盐,得到本发明的下列化合物。
实施例2(1):
2-(N-烯丙基-N-(3-(2-(2-异丙基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.32(氯仿∶甲醇∶乙酸=100∶10∶1);
NMR(CDCl3):δ7.20(dd,J=8.0,8.0Hz,1H),6.94-6.78(m,3H),5.92(m,1H),5.30(d,J=11.4Hz,1H),5.29(d,J=15.0Hz,1H),4.15(t,J=7.0Hz,2H),3.88(s,2H),3.38(d,J=7.0Hz,2H),3.31(s,2H),2.99(sept,J=7.0Hz,2H),2.86(t,J=7.0Hz,2H),2.24(s,3H),1.30(d,J=7.0Hz,6H)。
实施例2(2):
2-(N-烯丙基-N-(3-(2-(2-(4-甲基哌嗪-1-基)-5-甲基噻唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.69(氯仿∶甲醇∶水=50∶20∶1);
NMR(CDCl3):δ7.20(dd,J=8.0,8.0Hz,1H),6.95-6.87(m,2H),6.81(dd,J=8.0,2.0Hz,1H),5.93(m,1H),5.28(d,J=16.8Hz,1H),5.27(d,J=10.5Hz,1H),4.19(t,J=7.0Hz,2H),3.88(s,2H),3.45(dd,J=5.0,5.0Hz,4H),3.38(d,J=6.5Hz,2H),3.31(s,2H),2.92(t,J=7.0Hz,2H),2.59(dd,J=5.0,5.0Hz,4H),2.37(s,3H),2.24(s,3H)。
实施例2(3):
2-(N-烯丙基-N-(3-(2-(2-(4-(1,2,3-噻二唑-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸钠盐
TLC:Rf0.36(氯仿∶甲醇=8∶1);
NMR(CDCl3):δ9.74(s,1H),8.28(d,J=8.6Hz,2H),8.07(d,J=8.6Hz,2H),7.16(dd,J=7.8,7.8Hz,1H),6.95-6.70(m,3H),5.80(m,1H),5.19-4.96(m,2H),4.20(t,J=6.5Hz,2H),3.67(s,2H),3.19(d,J=6.0Hz,2H),2.94(t,J=6.5Hz,2H),2.77(s,2H),2.38(s,3H)。
实施例2(4):
2-(N-烯丙基-N-(3-(2-(2-(4-环己基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.32(氯仿∶甲醇=8∶1);
NMR(CDCl3):δ7.86(d,J=8.4Hz,2H),7.30-7.18(m,3H),7.12-7.00(m,2H),6.88(m,1H),6.03(m,1H),5.56(brs,1H),5.48-5.30(m,2H),4.36-4.04(m,4H),3.68(d,J=6.3Hz,2H),3.52(s,2H),2.93(t,J=6.6Hz,2H),2.51(m,1H),2.34(s,3H),1.96-1.68(m,5H),1.52-1.14(m,5H)。
实施例2(5):
2-(N-烯丙基-N-(3-(2-(2-(4-(四氢吡喃-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.39(氯仿∶甲醇=4∶1);
NMR(CDCl3):δ7.91(d,J=8.1Hz,2H),7.36-7.24(m,3H),7.16(m,1H),7.05(m,1H),6.92(m,1H),6.14(m,1H),5.54-5.38(m,2H),5.08(brs,1H),4.34-4.02(m,6H),3.76(d,J=6.3Hz,2H),3.62-3.54(m,4H),2.94(t,J=6.6Hz,2H),2.80(m,1H),2.38(s,3H),1.92-1.70(m,4H)。
实施例2(6):
2-(N-烯丙基-N-(3-(2-(5-甲基-2-哌啶子基噻唑-4-基)乙氧基)苄基)氨基)乙酸1/2钙盐
TLC:0.55(氯仿∶甲醇=5∶1);
NMR(CDCl3):δ7.13(t,J=8.1Hz,1H),6.89-6.80(m,2H),6.72(m,1H),5.80(m,1H),5.16-4.98(m,2H),4.09(t,J=6.9Hz,2H),3.67(s,2H),3.36-3.12(m,6H),2.92(s,2H),2.80(t,J=6.9Hz,2H),2.16(s,3H),1.58-1.48(m,6H)。
实施例2(7):
2-(N-烯丙基-N-(3-(2-(5-甲基-2-苯噁唑-4-基)乙氧基)苄基)氨基)乙酸
游离态
TLC:Rf0.21(氯仿∶甲醇=8∶1);
NMR(CDCl3):δ8.02-7.90(m,2H),7.48-7.35(m,3H),7.23(m,1H),7.05-6.83(m,3H),5.96(m,1H),5.44-5.28(m,2H),4.22(t,J=6.6Hz,2H),4.12(s,2H),3.6-(m,2H),3.47(s,2H),2.94(t,J=6.6Hz,2H),2.35(s,3H)。
钠盐
TLC:Rf0.61(氯仿∶甲醇=4∶1);
NMR(DMSO-d6):δ7.95-7.90(m,2H),7.55-7.45(m,3H),7.15(dd,J=8.8Hz,1H),6.95-6.70(m,3H),5.80(m,1H),5.20-5.00(m,2H),4.20(t,J=6.5Hz,2H),3.70(s,2H),3.20(d,J=7Hz,2H),2.95(t,J=6.5Hz,2H),2.80(s,2H),2.35(s,3H)。
实施例2(8):
2-(N-烯丙基-N-(3-(2-(2-(6-二甲基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.26(氯仿∶甲醇∶乙酸=100∶10∶1);
NMR(CDCl3):δ8.73(d,J=2.4Hz,1H),7.99(dd,J=2.4,9.0,1.5Hz,1H),7.24(dd,J=8.0,8.0Hz,1H),6.94-6.81(m,3H),6.52(d,J=9.0Hz,1H),5.90(m,1H),5.31(d,J=11.2Hz,1H),5.30(d,J=15.8Hz,1H),4.22(t,J=7.0Hz,2H),3.85(s,2H),3.36(d,J=7.0Hz,2H),3.31(s,2H),3.14(s,6H),2.93(t,J=7.0Hz,2H),2.34(s,3H)。
实施例2(9):
2-(N-烯丙基-N-(3-(2-(2-(4-二甲基氨基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.31(氯仿∶甲醇∶乙酸=100∶10∶1);
NMR(CDCl3):δ7.83(m,2H),7.22(dd,J=8.0,8.0Hz,1H),6.94-6.80(m,3H),6.70(m,2H),5.89(m,1H),5.29(d,J=11.8Hz,1H),5.28(d,J=15.2Hz,1H),4.22(t,J=7.0Hz,2H),3.84(s,2H),3.35(d,J=7.0Hz,2H),3.29(s,2H),3.00(s,6H),2.93(t。J=7.0Hz,2H),2.32(s,3H)。
实施例2(10):
2-(N-烯丙基-N-(3-(2-(2-苯基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)-2-甲基丙酸
游离态
TLC:Rf0.32(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.02-7.95(m,2H),7.47-7.39(m,3H),7.25(m 1H),6.96-6.89(m,2H),6.85(m,1H),5.85(ddt,J=16.8,10.2,6.6Hz,1H),5.21(m,1H),5.18(m,1H),4.25(t,J=7.0Hz,2H),3.74(s,2H),3.32(d,J=6.6Hz,2H),2.98(t,J=7.0Hz,2H),2.38(s,3H),1.45(s,6H)。
钠盐
TLC:Rf0.42(氯仿∶甲醇=10∶1);
NMR(DMSO-d6):δ7.96-7.86(m,2H),7.56-7.43(m,3H),7.12(dd,J=8.0,8.0Hz,1H),6.99(brs,1H),6.89(d,J=8.0Hz,1H),6.69(dd,J=8.0,2.0Hz,1H),5.75(ddt,J=17.0,10.5,6.0Hz,1H),4.92(m,1H),4.76(m,1H),4.18(t,J=7.0Hz,2H),3.76(s,2H),3.29(d,J=6.0Hz,2H),2.92(t,J=7.0Hz,2H),2.36(s,3H),1.17(s,6H)。
实施例2(11):
2-(N-烯丙基-N-(3-(2-(2-(6-吗啉基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.22(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.76(d,J=2.2Hz,1H),8.04(dd,J=9.0,2.2Hz,1H),7.24(t,J=8.0Hz,1H),6.96-6.82(m,3H),6.64(d,J=9.0Hz,1H),6.01-5.78(m,1H),5.32(d,J=10.8Hz,1H),5.31(d,J=15.4Hz,1H),4.22(t,J=6.8Hz,2H),3.84(s,2H),3.82(t,J=5.0Hz,4H),3.59(t,J=5.0Hz,4H),3.37(d,J=6.8Hz,2H),3.31(s,2H),2.94(t,J=6.8Hz,2H),2.35(s,3H)。
实施例2(12):
2-(N-烯丙基-N-(3-(2-(2-(6-哌啶子基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.28(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.72(d,J=2.2Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.23(t,J=8.0Hz,1H),6.97-6.79(m,3H),6.64(d,J=9.0Hz,1H),6.02-5.77(m,1H),5.31(d,J=9.8Hz,1H),5.29(d,J=16.0Hz,1H),4.21(t,J=6.8Hz,2H),3.85(s,2H),3.60(brs,4H),3.36(d,J=7.0Hz,2H),3.30(s,2H),2.92(t,J=6.8Hz,2H),2.33(s,3H),1.65(brs,6H)。
实施例2(13):
2-(N-烯丙基-N-(3-(2-(2-(6-二乙基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.22(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.71(d,J=2.4Hz,1H),7.95(dd,J=9.0,2.4Hz,1H),7.23(t,J=7.8Hz,1H),6.97-6.81(m,3H),6.47(d,J=9.0Hz,1H),6.00-5.78(m,1H),5.31(d,J=10.8Hz,1H),5.30(d,J=15.8Hz,1H),4.22(t,J=7.0Hz,2H),3.84(s,2H),3.55(q,J=7.2Hz,4H),3.36(d,J=7.4Hz,2H),3.30(s,2H),2.93(t,J=7.0Hz,2H),2.33(s,3H),1.99(t,J=7.2Hz,6H)。
实施例2(14):
2-(N-烯丙基-N-(3-(2-(2-(6-吡咯烷基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.49(氯仿∶甲醇=6∶1);
NMR(CDCl3):δ8.73(d,J=2.2Hz,1H),7.98(dd,J=8.8,2.2Hz,1H),7.23(t,J=8.0Hz,1H),6.97-6.81(m,3H),6.38(d,J=8.8Hz,1H),6.04-5.77(m,1H),5.30(d,J=10.4Hz,1H),5.29(d,J=15.6Hz,1H),4.22(t,J=7.0Hz,2H),3.80(s,3H),3.50(m,4H),3.33(d,J=6.6Hz,2H),3.28(s,2H),2.93(t,J=7.0Hz,2H),2.34(s,2H),2.02(m,4H)。
实施例2(15):
2-(N-烯丙基-N-(3-(2-(2-(4-吗啉基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸氢氯化物
TLC:Rf0.25(氯仿∶甲醇=9∶1);
NMR(DMDO-d6):δ7.74(d,J=9.0Hz,2H),7.20(t,J=8.1Hz,1H),7.01(d,J=9.0Hz,2H),6.91-6.77(m,3H),5.81(m,1H),5.22-5.09(m,2H),4.17(t,J=6.3Hz,2H),3.73(t,J=4.2Hz,4H),3.68(s,2H),3.52-3.08(m,9H),2.87(t,J=6.3Hz,2H),2.31(s,3H)。
实施例2(16):
2-(N-烯丙基-N-(3-(2-(5-甲基-2-吗啉基噻唑-4-基)乙氧基)苄基)氨基)乙酸二氢氯化物
TLC:Rf0.28(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ10.96(br,1H),7.34(t,J=8.1Hz,1H),7.24(m,1H),7.09(d,J=8.1Hz,1H),6.99(dd,J=8.1,2.1Hz,1H),6.03(m,1H),5.56-5.47(m,2H),4.35(s,2H),4.24(t,J=6.3Hz,2H),3.89(s,2H),3.82(d,J=6.9Hz,2H),3.76-3.54(m,8H),3.07(t,J=6.3Hz,2H),2.34(s,3H)。
实施例2(17):
2-(N-烯丙基-N-(4-(2-(5-甲基-2-苯基噁唑-4-基)乙氧基)苄基)氨基)乙酸
TLC:Rf0.14(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.00-7.95(m,2H),7.43-7.39(m,3H),7.23(d,J=8.4Hz,2H),6.89(d,J=8.4Hz,2H),5.95-5.80(m,1H),5.37-5.28(m,2H),4.24(t,J=6.6Hz,2H),3.84(s,2H),3.35(d,J=7.2Hz,2H),3.29(s,2H),2.98(t,J=6.6Hz,2H),2.60-2.20(brs,1H),2.38(s,3H)。
制备例1
按照常规方法混合下列组分,并冲压出每片含有50mg活性成分的100片片剂。
·2-(N-烯丙基-N-(3-(2-(2-(6-(全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸 5.0g
·羧甲基纤维素钙(崩解剂) 0.2g
·硬脂酸镁(润滑剂) 0.1g
·微晶纤维素 4.7g
制备例2
在按照常规方法混合下列组分后,用常规方法对得到的溶液灭菌,并分别取其5ml份装到安瓿(amples)中,使用常规方法冻干,得到100安瓿的各含有20mg活性成分的注射剂。
·2-(N-烯丙基-N-(3-(2-(2-(6-(全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸 2.0g
·甘露醇 20g
·蒸馏水 1000ml
序列表
<110>ONO药物有限公司(ONO Pharmaceutical Co.,Ltd.)
<120>羧酸衍生物和包含这种衍生物作为活性成分的药物
<130>ONF-4357PCT
<150>JP2001-346583
<151>2001-11-12
<160>3
<170>PatentIn Ver.2.1
<210>1
<211>85
<212>DNA
<213>人工序列
<220>
<223>包含4段重复Gal4蛋白应答序列的增强子序列
<400>1
tcgacggagt actgtcctcc gcgacggagt actgtcctcc gcgacggagt actgtcctcc 60
gcgacggagt actgtcctcc gagct 85
<210>2
<211>9
<212>PRT
<213>未知
<220>
<223>由SV-40 T-抗原衍生的核定位信号
<400>2
Ala Pro Lys Lys Lys Arg Lys Val Gly
1 5
<210>3
<211>9
<212>PRT
<213>流感病毒
<220>
<223>凝血素抗原决定基
<400>3
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
1 5
Claims (16)
1.式(I)代表的羧酸衍生物化合物或其无毒盐,
其中X和Y各自独立为C1-4亚烷基,
Z为-O-或-S-,
R1、R2、R3和R4各自独立为氢原子或C1-8烷基,
R5为C2-8烯基,
A为-O-或-S-,
D为D1、D2、D3、D4或D5,
D1为C1-8烷基,
环1为饱和的3-7节单杂芳基,其含有一个氮原子和任意的另外一个选自氧、硫和氮原子的杂原子,
环2为
(1)任意部分或完全饱和的C3-10单-或双-碳环芳基,或
(2)任意部分或完全饱和的3-10节单-或双-杂芳基,其含有1-4个选自氧、氮和硫原子的杂原子,
R6为(1)氢原子、(2)C1-8烷基、(3)C1-8烷氧基、(4)CF3、(5)OCF3、(6)卤原子、(7)硝基或(8)NR7R8,
R7或R8为氢原子或C1-8烷基,或
R7和R8和与其连接的氮原子一起形成饱和的3-7节单杂芳基,其含有一个氮原子和任意的另外一个选自氧、硫和氮原子的杂原子,并且饱和杂芳基可任意地用C1-8烷基取代,
E为CH或氮原子,并且
m为1-3的整数。
2.根据权利要求1的化合物或其无毒盐,其中Z为-S-。
3.根据权利要求1的化合物或其无毒盐,其中Z为-O-,D为D1、D2、D3或D4。
4.根据权利要求1的化合物或其无毒盐,其中D为D1。
5.根据权利要求1的化合物或其无毒盐,其中D为D2。
6.根据权利要求1的化合物或其无毒盐,其中D为D3。
7.根据权利要求1的化合物或其无毒盐,其中D为D4。
8.根据权利要求1的化合物或其无毒盐,其中D为D5。
9.根据权利要求4的化合物,其为
(1)2-(N-烯丙基-N-(3-(2-(2-异丙基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,或
(2)2-(N-烯丙基-N-(3-(2-(2-异丙基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
或它们的无毒盐。
10.根据权利要求5的化合物,其为
(1)2-(N-烯丙基-N-(3-(2-(2-(4-甲基哌嗪-1-基)-5-甲基噻唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(2)2-(N-烯丙基-N-(3-(2-(5-甲基-2-哌啶子基噻唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(3)2-(N-烯丙基-N-(3-(2-(2-吗啉代-5-甲基噻唑-4-基)乙氧基)苄基)氨基)乙酸叔丁酯,
(4)2-(N-烯丙基-N-(3-(2-(2-(4-甲基哌嗪-1-基)-5-甲基噻唑-4-基)乙氧基)苄基)氨基)乙酸,
(5)2-(N-烯丙基-N-(3-(2-(5-甲基-2-哌啶子基噻唑-4-基)乙氧基)苄基)氨基)乙酸,或
(6)2-(N-烯丙基-N-(3-(2-(5-甲基-2-吗啉代噻唑-4-基)乙氧基)苄基)氨基)乙酸,
或它们的无毒盐。
11.根据权利要求6的化合物,其为
(1)2-(N-烯丙基-N-(3-(2-(2-(4-(1,2,3-噻二唑-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(2)2-(N-烯丙基-N-(3-(2-(2-(4-环己基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(3)2-(N-烯丙基-N-(3-(2-(2-(4-四氢吡喃-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(4)2-(N-烯丙基-N-(3-(2-(2-(4-(1,2,3-噻二唑-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
(5)2-(N-烯丙基-N-(3-(2-(2-(4-环己苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,或
(6)2-(N-烯丙基-N-(3-(2-(2-(4-四氢吡喃-4-基)苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
或它们的无毒盐。
12.根据权利要求7的化合物,其为
(1)2-(N-烯丙基-N-(3-(2-(2-(6-(全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,或
(2)2-(N-烯丙基-N-(3-(2-(2-(6-(全氢氮杂-1-基)吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
或它们的无毒盐。
13.根据权利要求8的化合物,其为
(1)2-(N-烯丙基-N-(3-(2-(2-苯基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(2)2-(N-烯丙基-N-(3-(2-(2-(6-二甲基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(3)2-(N-烯丙基-N-(3-(2-(2-(4-二甲基氨基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(4)2-(N-烯丙基-N-(3-(2-(5-甲基-2-苯噁唑-4-基)乙氧基)苄基)氨基)-2-甲基丙烯酸甲酯,
(5)2-(N-烯丙基-N-(3-(2-(2-(6-吗啉代吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(6)2-(N-烯丙基-N-(3-(2-(2-(6-哌啶子基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(7)2-(N-烯丙基-N-(3-(2-(2-(6-二乙基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(8)2-(N-烯丙基-N-(3-(2-(2-(6-吡咯烷基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(9)2-(N-烯丙基-N-(3-(2-(2-(4-吗啉代苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(10)2-(N-烯丙基-N-(4-(2-(5-甲基-2-苯噁唑-4-基)乙氧基)苄基)氨基)乙酸乙酯,
(11)2-(N-烯丙基-N-(3-(2-(5-甲基-2-苯噁唑-4-基)乙氧基)苄基)氨基)乙酸,
(12)2-(N-烯丙基-N-(3-(2-(2-(6-二甲基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
(13)2-(N-烯丙基-N-(3-(2-(2-(4-二甲基氨基苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸。
(14)2-(N-烯丙基-N-(3-(2-(2-苯基-5-甲基噁唑-4-基)乙氧基)苄基)氨基)-2-甲基丙酸,
(15)2-(N-烯丙基-N-(3-(2-(2-(6-吗啉代吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
(16)2-(N-烯丙基-N-(3-(2-(2-(6-哌啶子基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
(17)2-(N-烯丙基-N-(3-(2-(2-(6-二乙基氨基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
(18)2-(N-烯丙基-N-(3-(2-(2-(6-吡咯烷基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
(19)2-(N-烯丙基-N-(3-(2-(2-(4-吗啉代苯基)-5-甲基噁唑-4-基)乙氧基)苄基)氨基)乙酸,或
(20)2-(N-烯丙基-N-(4-(2-(5-甲基-2-苯基噁唑-4-基)乙氧基)苄基)氨基)乙酸,
或它们的无毒盐。
14.一种过氧化物酶体增殖子激活的受体调节剂,作为活性成分包含根据权利要求1的式(I)代表的化合物或其无毒盐。
15.一种用于预防和/或治疗与代谢紊乱有关的疾病如糖尿病、肥胖、X综合症、高胆固醇血症或高脂蛋白血症,高脂血症,动脉粥样硬化症,高血压,循环疾病,过度饱食或缺血性心脏病的药剂,作为活性成分包含根据权利要求1的式(I)代表的化合物或其无毒盐。
16.一种升高HDL胆固醇药、降低LDL胆固醇和/或VLDL胆固醇药、减轻糖尿病或X综合症危险因子的药剂,作为活性成分包含根据权利要求1的式(I)代表的化合物或其无毒盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001346583 | 2001-11-12 | ||
JP346583/2001 | 2001-11-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1608056A true CN1608056A (zh) | 2005-04-20 |
Family
ID=19159734
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA028262646A Pending CN1608056A (zh) | 2001-11-12 | 2002-11-11 | 羧酸衍生物化合物和包含这种化合物作为活性成分的药剂 |
Country Status (18)
Country | Link |
---|---|
US (1) | US7323456B2 (zh) |
EP (1) | EP1445256A4 (zh) |
JP (1) | JPWO2003042194A1 (zh) |
KR (1) | KR20050044853A (zh) |
CN (1) | CN1608056A (zh) |
AU (1) | AU2002363776B2 (zh) |
BR (1) | BR0214049A (zh) |
CA (1) | CA2465861A1 (zh) |
HU (1) | HUP0402072A3 (zh) |
IL (1) | IL161768A0 (zh) |
MX (1) | MXPA04004442A (zh) |
NO (1) | NO20041878L (zh) |
NZ (1) | NZ532812A (zh) |
PL (1) | PL370405A1 (zh) |
RU (1) | RU2296760C2 (zh) |
TW (1) | TW200300681A (zh) |
WO (1) | WO2003042194A1 (zh) |
ZA (1) | ZA200403594B (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080125403A1 (en) | 2004-04-02 | 2008-05-29 | Merck & Co., Inc. | Method of Treating Men with Metabolic and Anthropometric Disorders |
EP1951692B1 (en) * | 2005-11-07 | 2010-08-18 | Irm Llc | Oxazole and thiazole ppar modulator |
AR077428A1 (es) * | 2009-07-29 | 2011-08-24 | Sanofi Aventis | (aza) indolizinacarboxamidas ciclicas su preparacion y su uso como agentes farmaceuticos |
WO2012027331A1 (en) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5466687A (en) * | 1992-10-22 | 1995-11-14 | Dr. Karl Thomae Gmbh | Arylidene-1-azacycloalkanes and arylalkyl-1-azacyclo-alkanes, their salts, medicaments containing these compounds and their use, and processes for their preparation |
GB9604242D0 (en) | 1996-02-28 | 1996-05-01 | Glaxo Wellcome Inc | Chemical compounds |
US6180660B1 (en) * | 1997-08-26 | 2001-01-30 | Merck & Co., Inc. | Cholesterol-lowering therapy |
EP1067109B1 (en) * | 1998-03-10 | 2009-12-09 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid derivatives and drugs containing the same as the active ingredient |
GB9817118D0 (en) * | 1998-08-07 | 1998-10-07 | Glaxo Group Ltd | Pharmaceutical compounds |
TW200528436A (en) | 1999-09-22 | 2005-09-01 | Bristol Myers Squibb Co | Substituted acid derivatives useful as antiodiabetic and antiobesity agents and method |
US7105556B2 (en) * | 2001-05-30 | 2006-09-12 | Bristol-Myers Squibb Company | Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method |
-
2002
- 2002-11-06 TW TW091132640A patent/TW200300681A/zh unknown
- 2002-11-11 IL IL16176802A patent/IL161768A0/xx unknown
- 2002-11-11 PL PL02370405A patent/PL370405A1/xx unknown
- 2002-11-11 US US10/495,158 patent/US7323456B2/en not_active Expired - Fee Related
- 2002-11-11 CA CA002465861A patent/CA2465861A1/en not_active Abandoned
- 2002-11-11 WO PCT/JP2002/011729 patent/WO2003042194A1/ja active IP Right Grant
- 2002-11-11 NZ NZ532812A patent/NZ532812A/en unknown
- 2002-11-11 HU HU0402072A patent/HUP0402072A3/hu unknown
- 2002-11-11 JP JP2003544030A patent/JPWO2003042194A1/ja active Pending
- 2002-11-11 EP EP02803104A patent/EP1445256A4/en not_active Withdrawn
- 2002-11-11 MX MXPA04004442A patent/MXPA04004442A/es not_active Application Discontinuation
- 2002-11-11 CN CNA028262646A patent/CN1608056A/zh active Pending
- 2002-11-11 RU RU2004117874/04A patent/RU2296760C2/ru not_active IP Right Cessation
- 2002-11-11 KR KR1020047007089A patent/KR20050044853A/ko not_active Application Discontinuation
- 2002-11-11 AU AU2002363776A patent/AU2002363776B2/en not_active Expired - Fee Related
- 2002-11-11 BR BR0214049-7A patent/BR0214049A/pt not_active IP Right Cessation
-
2004
- 2004-05-07 NO NO20041878A patent/NO20041878L/no not_active Application Discontinuation
- 2004-05-11 ZA ZA200403594A patent/ZA200403594B/en unknown
Also Published As
Publication number | Publication date |
---|---|
RU2004117874A (ru) | 2006-01-10 |
HUP0402072A3 (en) | 2008-08-28 |
US20040254370A1 (en) | 2004-12-16 |
JPWO2003042194A1 (ja) | 2005-03-10 |
MXPA04004442A (es) | 2004-08-12 |
EP1445256A1 (en) | 2004-08-11 |
RU2296760C2 (ru) | 2007-04-10 |
HUP0402072A2 (hu) | 2005-02-28 |
NZ532812A (en) | 2005-02-25 |
BR0214049A (pt) | 2004-10-13 |
EP1445256A4 (en) | 2006-01-04 |
KR20050044853A (ko) | 2005-05-13 |
IL161768A0 (en) | 2005-11-20 |
NO20041878D0 (no) | 2004-05-07 |
US7323456B2 (en) | 2008-01-29 |
AU2002363776B2 (en) | 2008-04-17 |
PL370405A1 (en) | 2005-05-30 |
NO20041878L (no) | 2004-08-12 |
ZA200403594B (en) | 2004-12-02 |
CA2465861A1 (en) | 2003-05-22 |
WO2003042194A1 (fr) | 2003-05-22 |
TW200300681A (en) | 2003-06-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1186324C (zh) | 稠合杂芳基衍生物 | |
CN1305872C (zh) | 喹唑啉类化合物的制备方法 | |
CN1279040C (zh) | 用于治疗的莨菪烷衍生物 | |
CN1255403C (zh) | 用作磷酸二酯酶抑制剂的β-咔啉衍生物 | |
CN1165308C (zh) | 用于减少呼吸抑制和缓减μ阿片样化合物的副作用的组合物和方法 | |
CN1284944A (zh) | 整联蛋白受体拮抗剂 | |
CN1659151A (zh) | 用于治疗糖尿病、肥胖和异常脂血症的11-β-羟甾醇脱氢酶1抑制剂 | |
CN1913778A (zh) | 趋化因子受体活性的氨基环戊基吡啶并吡嗪酮调节剂 | |
CN1419452A (zh) | 协同治疗癌症的方法和组合物 | |
CN1582277A (zh) | 用作糖原合酶激酶3β抑制剂的酰胺衍生物 | |
CN1747926A (zh) | 取代酰胺化合物 | |
CN1276790A (zh) | 酰胺基噻唑衍生物及其制备方法与药物组合物 | |
CN1529692A (zh) | N-芳基苯乙酰胺衍生物及包含所述化合物的药物组合物 | |
CN101048412A (zh) | 哌啶基氨基-噻吩并[2,3-d]嘧啶化合物 | |
CN1703408A (zh) | 作为葡糖激酶激活剂、可用于治疗ⅱ型糖尿病的取代的(噻唑-2-基)酰胺或磺酰胺 | |
CN1290165A (zh) | 苯并噻唑蛋白酪氨酸激酶抑制剂 | |
CN1314899A (zh) | 视黄酸类相关的受体机能调节剂 | |
CN1522246A (zh) | 作为微粒体甘油三酯转移蛋白(mtp)和/或载脂蛋白b(apo b)分泌抑制剂的三酰胺取代的吲哚、苯并呋喃及苯并噻吩 | |
CN1826328A (zh) | 经取代的吡啶-2-基胺类似物 | |
CN1678317A (zh) | 用作治疗呕吐、抑郁症、焦虑症和咳嗽的神经激肽-1(nk-1)拮抗剂的1-酰氨基-4-苯基-4-苄氧基甲基-哌啶衍生物和相关化合物 | |
CN1871244A (zh) | 作为腺苷受体配体的噻唑并吡啶衍生物 | |
CN1454211A (zh) | 作为Xa因子抑制剂的含氮杂双环化合物 | |
CN1918145A (zh) | 作为趋化因子受体活性调节剂的氨基杂环类化合物 | |
CN1423566A (zh) | 体重增加抑制剂 | |
CN1856312A (zh) | 治疗急性和/或慢性神经系统疾病的mGluR2拮抗剂和AChE抑制剂的组合产品 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
AD01 | Patent right deemed abandoned | ||
C20 | Patent right or utility model deemed to be abandoned or is abandoned |