CN107880006B - The compound as SGLT-2 inhibitor containing cyclohexane structure - Google Patents
The compound as SGLT-2 inhibitor containing cyclohexane structure Download PDFInfo
- Publication number
- CN107880006B CN107880006B CN201711195816.4A CN201711195816A CN107880006B CN 107880006 B CN107880006 B CN 107880006B CN 201711195816 A CN201711195816 A CN 201711195816A CN 107880006 B CN107880006 B CN 107880006B
- Authority
- CN
- China
- Prior art keywords
- compound
- application
- sglt
- agent
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 82
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 title claims abstract description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 22
- 206010012601 diabetes mellitus Diseases 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 6
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 5
- 201000001421 hyperglycemia Diseases 0.000 claims description 5
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- 201000008980 hyperinsulinism Diseases 0.000 claims description 4
- 208000004104 gestational diabetes Diseases 0.000 claims description 3
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 235000009754 Vitis X bourquina Nutrition 0.000 claims 1
- 235000012333 Vitis X labruscana Nutrition 0.000 claims 1
- 240000006365 Vitis vinifera Species 0.000 claims 1
- 235000014787 Vitis vinifera Nutrition 0.000 claims 1
- 229930182478 glucoside Natural products 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 description 23
- 238000000034 method Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 235000002639 sodium chloride Nutrition 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000003472 antidiabetic agent Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- -1 methoxyl group Chemical group 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 7
- 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 7
- 230000003178 anti-diabetic effect Effects 0.000 description 7
- 229960003834 dapagliflozin Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 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 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 208000008589 Obesity Diseases 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 3
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 229960001713 canagliflozin Drugs 0.000 description 3
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 201000001119 neuropathy Diseases 0.000 description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010029164 Nephrotic syndrome Diseases 0.000 description 2
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000033626 Renal failure acute Diseases 0.000 description 2
- 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 2
- 108091006269 SLC5A2 Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 2
- ZXOCGDDVNPDRIW-NHFZGCSJSA-N Tofogliflozin Chemical compound O.C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 ZXOCGDDVNPDRIW-NHFZGCSJSA-N 0.000 description 2
- 201000011040 acute kidney failure Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940125708 antidiabetic agent Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001720 carbohydrates Chemical group 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- VUSWCWPCANWBFG-UHFFFAOYSA-N cyclohex-3-ene-1-carboxylic acid Chemical compound OC(=O)C1CCC=CC1 VUSWCWPCANWBFG-UHFFFAOYSA-N 0.000 description 2
- 238000004807 desolvation Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 208000009928 nephrosis Diseases 0.000 description 2
- 231100001027 nephrosis Toxicity 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- VGEREEWJJVICBM-UHFFFAOYSA-N phloretin Chemical compound C1=CC(O)=CC=C1CCC(=O)C1=C(O)C=C(O)C=C1O VGEREEWJJVICBM-UHFFFAOYSA-N 0.000 description 2
- IOUVKUPGCMBWBT-UHFFFAOYSA-N phloridzosid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-UHFFFAOYSA-N 0.000 description 2
- IOUVKUPGCMBWBT-QNDFHXLGSA-N phlorizin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-QNDFHXLGSA-N 0.000 description 2
- 235000019139 phlorizin Nutrition 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 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 2
- 229960003611 pramlintide Drugs 0.000 description 2
- 108010029667 pramlintide Proteins 0.000 description 2
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 229950006667 tofogliflozin Drugs 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- 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
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- ZWTDXYUDJYDHJR-UHFFFAOYSA-N (E)-1-(2,4-dihydroxyphenyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one Natural products OC1=CC(O)=CC=C1C=CC(=O)C1=CC=C(O)C=C1O ZWTDXYUDJYDHJR-UHFFFAOYSA-N 0.000 description 1
- SZLZWPPUNLXJEA-UHFFFAOYSA-N 11,17-dimethoxy-18-[3-(3,4,5-trimethoxy-phenyl)-acryloyloxy]-yohimbane-16-carboxylic acid methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(OC)C1OC(=O)C=CC1=CC(OC)=C(OC)C(OC)=C1 SZLZWPPUNLXJEA-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- PTIFVLOBVCIMKL-UHFFFAOYSA-N 2-[3-[1-(4-chlorophenyl)cyclopropyl]-[1,2,4]triazolo[4,3-a]pyridin-8-yl]propan-2-ol Chemical compound N=1N=C2C(C(C)(O)C)=CC=CN2C=1C1(C=2C=CC(Cl)=CC=2)CC1 PTIFVLOBVCIMKL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- 102100022622 Alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase Human genes 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- BZCALJIHZVNMGJ-HSZRJFAPSA-N Fasiglifam Chemical compound CC1=CC(OCCCS(C)(=O)=O)=CC(C)=C1C1=CC=CC(COC=2C=C3OC[C@@H](CC(O)=O)C3=CC=2)=C1 BZCALJIHZVNMGJ-HSZRJFAPSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- OZLGRUXZXMRXGP-UHFFFAOYSA-N Fluo-3 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(Cl)C(=O)C=C3OC3=CC(O)=C(Cl)C=C32)N(CC(O)=O)CC(O)=O)=C1 OZLGRUXZXMRXGP-UHFFFAOYSA-N 0.000 description 1
- 102100040134 Free fatty acid receptor 4 Human genes 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 101710196151 Gamma-glutamyl phosphate reductase 1 Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- 102100033839 Glucose-dependent insulinotropic receptor Human genes 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 1
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- 101000972916 Homo sapiens Alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase Proteins 0.000 description 1
- 101000890672 Homo sapiens Free fatty acid receptor 4 Proteins 0.000 description 1
- 101000996752 Homo sapiens Glucose-dependent insulinotropic receptor Proteins 0.000 description 1
- 101000581402 Homo sapiens Melanin-concentrating hormone receptor 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000013016 Hypoglycemia 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
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 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 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
- WHSOLWOTCHFFBK-ZQGJOIPISA-N Luseogliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)S2)O)=C(OC)C=C1C WHSOLWOTCHFFBK-ZQGJOIPISA-N 0.000 description 1
- 102100027375 Melanin-concentrating hormone receptor 1 Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- YQHMWTPYORBCMF-UHFFFAOYSA-N Naringenin chalcone Natural products C1=CC(O)=CC=C1C=CC(=O)C1=C(O)C=C(O)C=C1O YQHMWTPYORBCMF-UHFFFAOYSA-N 0.000 description 1
- 102100038991 Neuropeptide Y receptor type 2 Human genes 0.000 description 1
- 102100029549 Neuropeptide Y receptor type 5 Human genes 0.000 description 1
- 102000028435 Neuropeptide Y4 receptor Human genes 0.000 description 1
- 108010002245 Neuropeptide Y4 receptor Proteins 0.000 description 1
- 108010046593 Neuropeptide Y5 receptor Proteins 0.000 description 1
- 102400000319 Oxyntomodulin Human genes 0.000 description 1
- 101800001388 Oxyntomodulin Proteins 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- MFOCDFTXLCYLKU-CMPLNLGQSA-N Phendimetrazine Chemical compound O1CCN(C)[C@@H](C)[C@@H]1C1=CC=CC=C1 MFOCDFTXLCYLKU-CMPLNLGQSA-N 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- IOUVKUPGCMBWBT-DARKYYSBSA-N Phloridzin Natural products O[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-DARKYYSBSA-N 0.000 description 1
- 229940126902 Phlorizin Drugs 0.000 description 1
- SZLZWPPUNLXJEA-FMCDHCOASA-N Rescinnamine Natural products O=C(O[C@H]1[C@@H](OC)[C@@H](C(=O)OC)[C@@H]2[C@H](C1)CN1[C@@H](c3[nH]c4c(c3CC1)ccc(OC)c4)C2)/C=C/c1cc(OC)c(OC)c(OC)c1 SZLZWPPUNLXJEA-FMCDHCOASA-N 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 101000930003 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- DAYKLWSKQJBGCS-NRFANRHFSA-N aleglitazar Chemical compound C1=2C=CSC=2C(C[C@H](OC)C(O)=O)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 DAYKLWSKQJBGCS-NRFANRHFSA-N 0.000 description 1
- 229950010157 aleglitazar Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- XORXDJBDZJBCOC-UHFFFAOYSA-N azanium;acetonitrile;acetate Chemical compound [NH4+].CC#N.CC([O-])=O XORXDJBDZJBCOC-UHFFFAOYSA-N 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960004890 diethylpropion Drugs 0.000 description 1
- XXEPPPIWZFICOJ-UHFFFAOYSA-N diethylpropion Chemical compound CCN(CC)C(C)C(=O)C1=CC=CC=C1 XXEPPPIWZFICOJ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229960004580 glibenclamide 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
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 150000008131 glucosides Chemical class 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
- 239000004519 grease Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000035879 hyperinsulinaemia Effects 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229950000991 ipragliflozin Drugs 0.000 description 1
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 229950004397 luseogliflozin Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000003695 memory enhancer Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 PXZWGQLGAKCNKD-DPNMSELWSA-N 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 108010089579 neuropeptide Y2 receptor Proteins 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000030613 peripheral artery disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960000436 phendimetrazine Drugs 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- WPDCHTSXOPUOII-UHFFFAOYSA-N propan-2-yl 4-[5-methoxy-6-[(2-methyl-6-methylsulfonylpyridin-3-yl)amino]pyrimidin-4-yl]oxypiperidine-1-carboxylate Chemical compound N1=CN=C(OC2CCN(CC2)C(=O)OC(C)C)C(OC)=C1NC1=CC=C(S(C)(=O)=O)N=C1C WPDCHTSXOPUOII-UHFFFAOYSA-N 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- SMSAPZICLFYVJS-QEGASFHISA-N rescinnamine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)\C=C\C1=CC(OC)=C(OC)C(OC)=C1 SMSAPZICLFYVJS-QEGASFHISA-N 0.000 description 1
- 229960001965 rescinnamine Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to the compounds as SGLT-2 inhibitor, have better choice with C- glucoside and cyclohexane structure structure, and to SGLT-2.
Description
Technical field
The application provides novel to be controlled as the compound of SGLT-2 inhibitor, containing their compositions and using them
The method for treating or preventing diabetes and related pathologies.
Background technique diabetes are the gradually debilitating illnesss to grow in intensity, lead to various capilaries and big blood vessel
Complication.The most common type type-2 diabetes mellitus of diabetes is characterized in that and the compensatory hyperinsulinaemia in a period of time
The relevant cumulative insulin resistance of hypoinsulinism afterwards.
Entitled sodium-glucose-cotransporter (the sodium-dependent glucose of SGLT Chinese
Transporters), mainly there are SGLT-1 and SGLT-2.SGLT-1 is mainly distributed on small intestine, related with the absorption of glucose,
It is distributed in that renal proximal tubules are S3 sections farther away, the glucose of reabsorption 10%, it is close bent small that SGLT-2 albumen is then distributed in kidney
Pipe is responsible for most glucose (90%) in glomerular filtrate being transported into blood again, to maintain internal blood
The stabilization and balance of sugar.SGLT protein inhibitor by block the albumen transporting mechanism, make glucose with urine discharge to
Blood glucose is reduced, thus is not relying on insulin mechanism, all there is therapeutic effect for I type and type-2 diabetes mellitus, and be not susceptible to
Hypoglycemia is dangerous, does not increase diabetic's weight.
Studies have shown that can lead to serious diarrhea or even threat to life when SGLT-1 is blocked, and SGLT-2 is suppressed
When, only lead to kidney discharge sugar, there is no apparent adverse reactions.
The SGLT-2 inhibitor found earliest is natural products phloridzin (Phlorizin), but since it is easy to be internal
Glycosidase be hydrolyzed into glucosides and phloretin, and to the poor selectivity of SGLT-1 and SGLT-2, adverse reaction is larger, therefore does not have
There is the therapeutic agent as diabetes.The existing 6 kinds of SGLT-2 inhibitor listing in the whole world at present, is respectively as follows: Canagliflozin
(canagliflozin), Dapagliflozin (Dapagliflozin), Empagliflozin (En Gelie is net), Ipragliflozin are (according to lattice
Column are net), Luseogliflozin (glug column are net) and Tofogliflozin (tofogliflozin).Wherein, Bristol Myers Squibb is public
The Dapagliflozin of department has passed through the approval of FDA, EU Committee and state food pharmaceuticals administration general bureau (CFDA) in beauty
State, Europe and Discussion on Chinese Listed.
It remains desirable, however, that more SGLT-2 inhibitor are developed, especially for the chemical combination of SGLT-2 selective depression
Object.
High Yunlong of Shandong University etc. finds that the compound that C ring is hexamethylene has better than Dapagliflozin in the course of the research
Inhibiting rate, however, not having a report that B ring is replaced with to hexamethylene at present.
This application involves the compound of Formula I of the novel ability for having and adjusting SGLT-2, above compound potentially may be used
For treating or preventing diabetes and related pathologies.The compound has novel structure, i.e., the B ring being connected with saccharide ring is flexibility
Cyclohexane structure.
Summary of the invention
The application provides substituted compound of Formula I and its tautomer, the pharmaceutical salts that can be used as SGLT-2 inhibitor.
The application, which also provides, is used to prepare the application compound or its tautomer, the method for pharmaceutical salts and intermediate.
The application also provides pharmaceutical composition, and it includes pharmaceutical carrier and at least one the application compound or its mutually variations
Structure body, pharmaceutical salts.
The application compound can be used for treating and/or preventing a variety of diseases relevant to SGLT-2 or obstacle, such as glycosuria
Disease and related pathologies, microvascular complication relevant to diabetes, macrovascular complications relevant with diabetes, cardiovascular disease
Disease, metabolic syndrome and its composition symptom, impaired glucose metabolism, obesity and Other diseases.
The application compound can be used in therapy.
The application compound can be used for preparing for treating and/or preventing a variety of diseases relevant to SGLT-2 or obstacle
Drug.
The application compound can be used alone, join with the other compound combinations of the application or with one or more other medicaments
With.
Specific embodiment
I. the application compound
In the first aspect, the application especially provides compound of formula I or its tautomer, pharmaceutical salts:
Wherein:
R1It is selected from: C1-6Alkyl, C3-6Naphthenic base or C3-6Naphthenic base C1-3Alkyl, the C1-6Alkyl can be by the cycloalkanes
Base can be replaced by hydroxyl, amino, halogen, the C3-6Naphthenic base can be by hydroxyl, amino, halogen or C1-3Alkyl replaces.
Preferably, R1Selected from C1-6 alkyl, the C1-6Alkyl can be by hydroxyl, amino, halogen by the naphthenic base
Replace.
In the second aspect, the application provides the compound or its tautomer, pharmaceutical salts for being selected from exemplary embodiment.
In preferred embodiments, the application compound has≤0.02 μM of hSGLT-2EC50Value, and its is right
The selectivity of hSGLT-2/hSGLT-1 is at 1000 times or more.
II. the other embodiments of the application
In another embodiment, the application provide composition, it includes at least one the application compound or its mutually
Tautomeric, pharmaceutical salts.
In another embodiment, the application provides pharmaceutical composition, and it includes pharmaceutical carriers and this at least one Shen
It please compound or its tautomer, pharmaceutical salts.
In another embodiment, the application provides pharmaceutical composition, and it includes pharmaceutical carrier and therapeutically effective amounts
At least one the application compound or its tautomer, pharmaceutical salts or solvate.
In another embodiment, the application offer is used to prepare the application compound or its tautomer, medicinal
The method of salt.
In another embodiment, the application offer is used to prepare the application compound or its tautomer, medicinal
The intermediate of salt.
In another embodiment, the application is provided for treating and/or preventing a variety of diseases relevant to SGLT-2
Or the method for obstacle comprising to need the patient of above-mentioned treatment and/or prevention individually or optionally with another the applicationization
Close at least one the application compound of object and/or at least one other type therapy agent combination medicine-feeding therapeutically effective amount.
Can be prevented according to the application, adjust or treatment include to the example of the SGLT-2 relevant disease of activity or illness but
It is not limited to diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes mellitus, insulin resistance, hyperinsulinemia, view
The renal syndrome of film lesion, neuropathy, nephropathy, nephrosis, acute kidney injury, the heart, acute coronary syndromes
Sign, wound healing delay, atherosclerosis and its sequelae, core function abnormality, congestive heart failure, myocardial ischemia, in
Wind, metabolic syndrome, hypertension, obesity, Fatty Liver Disease.
In another embodiment, the application is provided for treating and/or preventing diabetes, hyperglycemia, gestation sugar
Urinate the method for disease, obesity, dyslipidemia, hypertension and cognitive impairment comprising to the trouble for needing above-mentioned treatment and/or prevention
Person is individually or optionally effective with another the application compound and/or the treatment of at least one other type therapy agent combination medicine-feeding
At least one the application compound of amount.
In another embodiment, the application provides the application compound being used in therapy.
The application can be implemented in other specific forms, without departing from its spirit or essential characteristics.The application covers herein
All combinations of mentioned the application preferred aspect.It should be understood that any and all embodiment of the application is combinable
Any other embodiments or multiple embodiments describe other embodiments.It is to be further understood that embodiment is every
One individual element is its own independent embodiment.In addition, any element of embodiment is intended to and any embodiment
Any and all other factor combination is to describe other embodiments.
III. chemical
Depending on method condition, the application final product is obtained with free (neutrality) or salt form.These final products
Free form and salt are within the scope of the application.If it is required, then another form can be converted to a kind of form of compound.
Free alkali or acid can be converted to salt；Salt can be converted to free compound or another salt；It can be by the application isomers chemical combination
The mixture of object is separated into individual isomers.The application compound, its free form and salt can be with a variety of tautomerism bodily forms
Formula exists, and wherein hydrogen atom is transposed in the other parts of molecule and thus the chemical bond between the atom of molecule is reset.
It should be understood that all tautomeric forms that may be present are included in the application.
The term as used herein " alkyl " is intended to include branch and straight-chain radical of saturated aliphatic alkyl with specified carbon atom number
Group.For example, " C1-6Alkyl " indicates the alkyl with 1 to 6 carbon atom.Similarly, C3-6Naphthenic base then indicates there is 3-6 on ring
The naphthenic base of a carbon atom.
Term " pharmaceutical " is used to refer to herein those following compounds, substance, composition and/or dosage form: reasonable
In the range of medical judgment, suitable for contacting use with the tissue of human and animal without high toxicity, irritation, allergic reaction excessively
And/or other problems or complication and match with reasonable benefit/risk ratio.
In addition, compound of formula I can have prodrug forms.Prodrug in the application scope and spirit be in vivo convert with
Any compound of bioactivator (i.e. compound of formula I) is provided.The various forms of prodrug is as known in the art.
The application compound can be prepared with various ways known to organic synthesis field technical staff.Following sides can be used
In method and synthetic organic chemistry field known synthetic method or by its version that those skilled in the art are understood come
Synthesize the application compound.Preferred method includes but is not limited to those described below method.It is being suitable for agents useful for same and substance
And it is suitable for implementing reaction in the solvent or solvent mixture of the conversion realized.Organic synthesis field technical staff should understand that
It is that functional group present on molecule should be consistent with the conversion proposed.Sometimes this is judged to modify synthesis step
Rapid sequence selects a kind of specific program scheme rather than another kind is to obtain the application desired compound.
Reaction described in this part and technology can be used to prepare the application compounds.Equally, it is described below
In the explanation of synthetic method, it should be appreciated that all proposition reaction conditions (including solvent selection, reaction atmosphere, reaction temperature
Degree, duration of experiment and post processor) standard conditions for being used for the reaction are selected, the condition should be by art technology
Personnel readily recognize.It will be apparent for a person skilled in the art that the limitation of the substituent group compatible with reaction condition, then
Alternative must be used.
The synthesis of compound
It can be used by the illustrative methods described in following scheme and working Examples and those skilled in the art
Related open source literature program carry out preparation of compounds of formula I.
Scheme 1:
3- cyclohexenecarboxylic acid (not splitting) and HBr addition, the isolated bromo- hexahydrobenzoid acid of 3-, after acyl chloride reaction with
Phenyl alkyl ether reaction, carbonyl reduction reaction, later again with 2,3,4,6- tetra--D- trimethyl silicon substrates-D-Glucose acid lactone is anti-
It answers, extra methoxyl group obtains final product on last deprotection base and saccharide ring.
It is mentioned briefly above the synthetic route of compound, specific synthesis step is shown in embodiment part.
The characterization of compound
HPLC/MS method used in the characterization or purifying of compound:
Using following methods in Shimadzu SCL-10A liquid chromatograph and Waters ZQ mass spectrograph (desolvation gas
Body: nitrogen；Desolvation temperature: 250 DEG C；Ion source temperature: 120 DEG C；Positivity electrospray conditions) on implement analytic type HPLC/
MS (unless otherwise indicated): the linear gradient of 0%-100% solvent B lasts 2min, wherein keeping 1min in 100%B；?
220nm UV is visible；Column: Luna C18 (2) 30mm × 4.60mm；5m particle (is heated to 40 DEG C of temperature)；Flow velocity: 5mL/min；
Solvent A: 10%ACN, 90% water, 0.1%TFA；Or 10%MeOH, 90% water, 0.1%TFA；With solvent B:90%ACN,
90% water, 0.1%TFA；Or 90%MeOH, 10% water, 0.1%TFA.
Using following method, analytic type HPLC (unless otherwise indicated) is carried out on Shimadzu SIL-10A with determinization
It closes object purity (retention time that the retention time unless otherwise indicated, being listed in embodiment refers to the 1st column):
Orthogonal method:
The linear gradient of 10%-100% solvent B lasts 15min；It is visual that UV is carried out in 220nm and 254nm；Column 1:
SunFire C183.5μm,4.6x150mm；3.5 μm of column 2:Xbridge Phenyl, 4.6x150mm；Flow velocity: 1mL/min is (right
For two columns)；Solvent A: 5%MeCN-95%H2O-0.05%TFA；Solvent B:95%MeCN-5%H2O-0.05%
TFA。
Or
Zorbax method
The linear gradient of 10%-100% solvent B lasts 8min；UV visualization is carried out in 220nm；Column:
ZorbaxSBC183.5μm,4.6x75mm；Flow velocity: 2.5mL/min；Solvent A: 10%MeOH-90%H2O-0.2%H3PO4；
With solvent B:90%MeOH-90%H2O-0.2%H3PO4.
Or
Analytic type LC/MS method
Gradient: 0-100%B lasts 3min, then keeps 0.75min in 100%B；UV visualization is carried out in 220nm；Column:
Waters XBridge UPLC BEH C18,2.1 × 50mm, 1.7- μm of particle；Mobile phase A: the 5:95 with 10mM ammonium acetate
Acetonitrile: water；Or 5:95 has the acetonitrile of 0.05%TFA: water；Mobile phase B: the 95:5 acetonitrile with 10mM ammonium acetate: water；Or
Person 95:5 has the acetonitrile of 0.05%TFA: water；Temperature: 50 DEG C；Flow velocity: 1.11mL/min.
NMR employed in the characterization of compound
It is obtained using the Bruker conversion light spectrometer operated at 400MHz1H NMR spectra (unless otherwise indicated).
The report spectroscopic data in the form of chemical shift (multiplicity, hydrogen number, coupling constant (being indicated by Hz)), and for1H
It is reported in the form of the ppm (δ unit) relative to internal standard object (tetramethylsilane=0ppm) for NMR spectra, or
Referring to residual solvent peak, (CD3SOCD2H 2.49ppm, CD2HOD 3.30ppm, CHD2CN 1.94, CHCl3 are
7.26ppm, CDHCl2 5.32ppm.
IV. biology
External hSGLT-1/hSGLT-2 measurement
Intracellular Ca2+ measurement based on FDSS
Using pDEST 3 × flag gene expression system generate expression hSGLT-1/hSGLT-2 cell line and by its
Cultivate in culture medium comprising following components: F12 (Gibco number 11765), 10% deprive the fetal calf serum of lipid, 250 μ g/
ML bleomycin (zeocin) and 500 μ g/mL G418.It is surveyed to implement the calcium flux based on fluorescence imaging plate readout instrument (FLIPR)
It is fixed to measure intracellular Ca2+Reaction, is put down the cell for expressing hSGLT-2 with 20,000 cells/20 μ L culture mediums/hole density
It is layered in phenol red and serum-free DMEM (the Gibco number 21063-029) in 384 orifice plates (BD Biocoat number 356697) simultaneously
It is incubated overnight.Using BD kit number 80500-310 or 80500-301, there is the third sulphur of 1.7mM using 20 holes μ L/ at 37 DEG C
Relax (probenecid) and Fluo-3 hanks buffer salt solution (Hank ' s buffered salt solution) by cell
Incubate 30min.Compound is dissolved in DMSO and is diluted to expectation concentration with measurement buffer and with 3 × solution (20 μ L/
Hole) it is added in cell.Fluorescence/luminescence reader FDSS (Hamamatsu) is run to read intracellular Ca2+Response.
Untested compound is configured to 10 μM of solution, 5 times of dilution, obtains a series of samples to be tested every time.By above-mentioned
IC is calculated using origin software after method test50Value, test result are as shown in table 1.
Table 1
As seen from Table 1, this application provides a kind of the SGLT-2 inhibitor with novel structure, the change being currently prepared
It closes object activity and is slightly below Dapagliflozin etc., but there is preferable selectivity, subsequently through the fractionation and substitution of chiral structure
The modification of base is expected to obtain the compound of better effect.By the data of embodiment 1-3, those skilled in the art can be reasonable
Deducing compound with similar structure also has preferable selectivity.
V. it applies
The application compound has the activity as SGLT-2 regulator, and thus can be used for treating and SGLT-2 activity phase
The disease of pass.Via adjusting SGLT-2, the application compound can be preferably used as adjusting insulin and/or intestinal hormones (such as
GLP-1, GIP, PYY, CCK and amylin) generation/secretion.
Therefore, the application compound can be administered to mammal (the preferably mankind) to treat various symptom and illness, including
But be not limited to treat, prevent or slow down the progress of following disease: diabetes and related pathologies, capilary relevant to diabetes are simultaneously
Send out disease, macrovascular complications relevant to diabetes, cardiovascular disease, metabolic syndrome and its various composition symptom, inflammatory disease
Disease and Other diseases.Therefore it is believed that the application compound can be used for preventing, inhibit or treat diabetes, hyperglycemia, glucose
Tolerance is impaired, gestational diabetes mellitus, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetes
Property nephrosis, acute kidney injury, the renal syndrome of the heart, acute coronary syndrome, wound healing delay, atherosclerosis and
Its sequelae (acute coronary syndrome, myocardial infarction, angina pectoris, peripheral artery disease, intermittent claudication, myocardial ischemia,
Apoplexy, heart failure), metabolic syndrome, hypertension, obesity, Fatty Liver Disease, dyslipidemia, hyperlipidemia, high triglyceride
Mass formed by blood stasis, hypercholesterolemia, low HDL, high LDL, reangiostenosis, peripheral arterial disease, lipid disorders disease, such as NASH are (non-
Alcoholic fatty liver is scorching), hepatopathys, neurodegenerative disease, the cognition such as NAFLD (nonalcoholic fatty liver disease) and cirrhosis damage
Wound, dull-witted and treatment side effect relevant to diabetes, lipodystrophy and the sclerotin as caused by corticosteroid treatment are dredged
Loose disease.
Dosage form (pharmaceutical composition) suitable for administration can contain about 1 milligram to about 2000 milligrams active constituent/dosage unit.
In these medical compositions, with the total weight of composition, active constituent usually by with about 0.1 weight % to 95 weight %'s
Amount exists.
Exemplary capsule agent for oral administration contain at least one the application compound (250mg), lactose (75mg) and
Magnesium stearate (15mg).It passes the mixture through 60 mesh sieves and is packaged into No. 1 gelatine capsule.
Typical injectable formulation can be prepared as follows: be set at least one the application compound (250mg) with sterile manner
It is lyophilized and seals in bottle, with sterile manner.For carry out using, vial content is mixed with 2mL physiological saline, with generate
Injectable formulation.
The application range includes at least one the applicationization that (combining individually or with pharmaceutical carrier) includes therapeutically effective amount
Close pharmaceutical composition of the object as active constituent.Optionally, the application compound can be used alone, with the other compounds of the application
Combination is combined with one or more other therapeutic agents (such as antidiabetic or other pharmaceutically active substances).
The application compound can be with other SGLT-2 regulators or its one or more that can be used for treating above-mentioned illness
Its suitable therapeutic agent combination, the therapeutic agent includes: antidiabetic, antihyperglycemic agents, anti-hyperinsulinemia agent, anti-view
The agent of film lesion, anti-neuropathy agent, anti-nephropathy agent, antiatherosclerotic, antiischemic agents, rescinnamine, anti-obesity
Agent, lipidemia agent, anti hypertriglyceridemia agent, anti-hypercholesterolemiccompounds agent, anti-restenosis agent, resists anti-lipid abnormal agent
Pancreatitis agent, lipid lowering agent, anoretic, memory enhancers, anti-dull-witted agent, cognition promotor, appetite inhibitor, heart failure therapy
Agent, peripheral arterial disease therapeutic agent and anti-inflammatory agent.
If desired, the application compound can be with one or more other type antidiabetic agent and/or one kind or more
The other type therapy agent combinations of kind, can be administered orally, with one dosage type low temperature with separated oral dosage form or by being administered to
Medicine.Optionally with the application SGLT-2 receptor modulators associated with other type antidiabetic agent can be a kind of, two kinds, three kinds
Or more antidiabetic or antihyperglycemic agents, the antidiabetic or antihyperglycemic agents can be taken orally with one dosage type low temperature to
Medicine, with separated oral dosage form or by drug administration by injection to generate other pharmacologic benefits.
With the application compound associated with antidiabetic include but is not limited to insulin secretagogue element or insulin sensitizer,
Other SGLT-2 receptor modulators or other antidiabetics.These medicaments include but is not limited to inhibitors of dipeptidyl IV
(DPP4i；For example, sitagliptin, saxagliptin, Egelieting, vildagliptin), (such as melbine, benzene second are double for biguanides
Guanidine), sulfonyl ureas (such as glibenclamide, Glimepiride, Glipizide), glucosidase inhibitor (such as acarbose,
Miglitol), PPAR gamma agonist (such as thiazolidinediones (such as Rosiglitazone, Pioglitazone), PPAR α/γ it is dual swash
Dynamic agent (such as Mo Geliezha, replace Ge Liezha, aleglitazar), activators of glucokinase (such as Fyfe, M.C.T.et al., Drugs
Of the Future, 34 (8): described in 641-653 (2009), and by this, it is incorporated herein by reference), it is other
SGLT-2 receptor modulators (such as TAK-875), GPR119 receptor modulators (such as MBX-2952, PSN821, APD597),
GPR120 receptor modulators (such as institute in such as Shimpukade, B.etal.J.Med.Chem.2012,55 (9), 4511-4515
State), sodium-glucose transporter -2 (SGLT2) inhibitor (such as Dapagliflozin, canagliflozin, Yi Palie are net, Rui Gelie is net),
11b-HSD-1 inhibitor (such as MK-0736, BI35585, BMS-823778 and LY2523199), MGAT inhibitor are (such as such as
Barlind,J.G.et al.Bioorg.Med.Chem.Lett.2013,23(9),2721-2726；Or US
Described in 20130143843A1), amylin analogs (such as pramlintide) and/or insulin.About for treating diabetes
Summary that is current and that therapy newly occur can be found in: Mohler, M.L.etal., MedicinalReseaRch Reviews, 29
(1):125-195(2009),andMizuno,C.S.etal.,Current Medicinal Chemistry,15:61-74
(2008)。
The SGLT-2 receptor modulators of Formulas I are also optionally combined with the medicament for treating diabetic complication.These
Medicament includes pkc inhibitor and/or AGE inhibitor.
The SGLT-2 receptor modulators of Formulas I are also optionally combined with one or more reduction appetite agent, the reduction food
Agent is intended to as (for example) diethylpropion, phendimetrazine, Phentermine, orlistat, sibutramine, lorcaserin, pramlintide, support pyrrole
Ester, MCHR1 receptor antagonist, oxyntomodulin, naltrexone, amylin peptide, NPY Y5 receptor modulators, NPY Y2 receptor tune
Agent, NPY Y4 receptor modulators, west are saved for taking charge of he, 5HT2c receptor modulators etc..The compound of structure I can also be with pancreas hyperglycemia
Agonist (such as Exenatide, Liraglutide, GPR-1 (1-36) amide, GLP-1 (7-36) of plain 1 receptor of sample peptide (GLP-1R)
Amide, GLP-1 (7-37)) combination is (disclosed in U.S. Patent No. 5,614,492 of such as Habener, by reference
The disclosure content of the patent is incorporated herein), the medicament can via injection, through intranasal or given by percutaneous or buccal device
Medicine.About for treat the current of obesity and newly there is therapy summary can be found in: Melnikova, I.et al., Nature
Reviews Drug Discovery,5:369-370(2006)；Jones,D.,Nature Reviews:Drug
Discovery,8:833-834(2009)；Obici,S.,Endocrinology,150(6):2512-2517(2009)；and
Elangbam,C.S.,Vet.Pathol.,46(1):10-24(2009)。
When being combined with the application compound, above-mentioned other therapeutic agents can be in above-mentioned patent or by ordinary skill
The amount that personnel determine in other ways uses.
By the application, it will be apparent for a person skilled in the art that make each component in the application combination product (no matter
With single formulation be administered or be administered in same time by same way with divided mode) between contact minimum these shapes
Formula and other forms.
The application compound can be administered alone or with one or more other therapeutic agent combination medicine-feedings." combination medicine-feeding " or
" combination treatment " means to be administered simultaneously the application compound and one or more other therapeutic agents to treated mammal.Work as group
When closing administration, each component can be administered simultaneously or sequential administration in any order in different time points.Therefore, administration each group can be separated
Divide but the time is close enough to provide desired response to treatment.
The application compound also acts as the test for being related to SGLT-2 receptor or standard or reference compound in measurement, example
Such as it is used as quality standard or control.Above compound may be provided in commercial kit for being related to SGLT-2 or anti-diabetic
Active study of pharmacy.For example, the application compound can be used as reference in measurement with compare its known activity with unknown
Active compound.This will ensure that experimenter is appropriately carried out measurement and provides and compares foundation, especially test compound as ginseng
In the case of the derivative for examining compound.When the new measurement of research and development or scheme, the application compound can be used to test its validity.
The application compound can also be used to be related in the diagnostic assay of SGLT-2.
It is evident that the application other feature, gives described show during being described below exemplary implementation scheme
Example property embodiment is for illustrating the application and being not intended to limit the application.
Embodiment
Embodiment 1
40% hydrobromic acid solution (50ml, 0.36mol) is added in 3- cyclohexenecarboxylic acid II (commercially available 25g, 0.2mol) at room temperature,
It is stirred to react 6h, ethyl acetate extraction is concentrated, and silica gel chromatograph post separation obtains 3- bromo- hexahydrobenzoid acid III (8.2g, yield
40%).
By 3-Br- hexahydrobenzoid acid III (4.1g, 20mmol) anhydrous DMF (0.1ml) and methylene chloride (20ml) in ice water
Lower stirring is bathed, is added dropwise oxalyl chloride (2.6ml, 30mmol), continues to stir 2h after being added dropwise to reaction solution clarification.It removes under reduced pressure molten
Agent is added methylene chloride (5ml) in residue and methyl phenyl ethers anisole, ice salt bath is cooled to -10 DEG C hereinafter, anhydrous aluminum chloride is added portionwise
0.6g*5 times, control reaction temperature is no more than 0 DEG C, the reaction was continued after addition 3h.Mixed liquor is added in trash ice, pH is adjusted
To neutrality, stood after stirring.Organic phase is separated, with methylene chloride aqueous phase extracted 5ml*2 times, merges organic phase.Organic phase is with full
With brine It 10ml*2 times, filter, be concentrated to get white solid IV4.8g.
Under nitrogen atmosphere, THF (50ml) and sodium borohydride (0.77g, 20mmol) is added in above-mentioned white solid.Stir 1h
Afterwards, ice salt bath be cooled to -10 DEG C hereinafter, anhydrous aluminum chloride is added portionwise 0.6g*5 times and control reaction temperature be no more than 0 DEG C, delay
Slowly being warming up to 0 DEG C is stirred to react 3h, then heated overnight at reflux.Decompression steams THF, is cooled to room temperature, and slowly plus water removed
Measure sodium borohydride.Stir 3h in ice bath, be extracted with ethyl acetate, merge organic phase, saturated common salt water washing, drying, filtering,
Concentration, residue obtain white solid V3.9g with re crystallization from toluene.
Under anhydrous and oxygen-free condition, ice salt bath are cooling, 2,3,4,6- tetra--D- trimethyl silicon substrates-D-Glucose acid lactone
(10mmol, the compounds Shi Changyong intermediate such as synthesis Dapagliflozin, can be obtained using N-methylmorpholine/THF condition) is dissolved in 15ml
In tetrahydrofuran, the tetrahydrofuran that the LiCl that 20ml contains methyl Grignard and 1mol/L that concentration is 1mol/L is added dropwise is molten
The KI (0.02-0.03g) of catalytic amount is added in liquid, stirs 2h.The tetrahydrofuran solution 10ml of suspension V (3.1g) is added dropwise, control is anti-
Temperature is answered not higher than -10 DEG C, the reaction was continued 3h.The methanol solution 40ml of methanesulfonic acid (MSA, 4ml) is added dropwise, switchs to ice bath 2h, room
Temperature is stirred overnight.Saturated sodium bicarbonate 5ml quenching reaction is added dropwise, adjusts pH to 8, boils off organic solvent.Ethyl acetate extraction 3
Secondary * 10ml, saturated sodium chloride solution wash 2 * 20ml, filter after anhydrous slufuric acid ammonium is dry, filtrate rotary evaporation obtains yellowish
Color grease 2.55g.
Light yellow oil is dissolved in acetonitrile/dichloromethane solution 30ml of 1:1, is cooled to -10 to -5 DEG C, three second are added
Then base silane 5.5ml is added dropwise 3.3ml boron trifluoride etherate, stirs 6h under ice bath.Saturated sodium bicarbonate 20ml is added
Quenching reaction continuously adds saturated sodium bicarbonate solution and adjusts pH to 8-9, boils off organic solvent.Ethyl acetate extracts * three times
10ml, saturated sodium chloride solution wash twice * 20ml, filter after anhydrous slufuric acid ammonium is dry, filtrate is beaten in 50% ethanol solution
Slurry overnight, filters, with pure water * 10ml three times, is dried to obtain the compound of formula I 1.89g that R1 is methyl.(HPLC normalization
98.9%) it is that method, which measures purity,.
LC-MS:[M+H] 366.45.
1H NMR(400MHz,CDCl3): 1.41-1.63 (9H, m), 1.87 (1H, m), 2.53 (2H, d), 3.38 (1H, d),
3.51 (2H, d), 3.60 (3H, m), 3.72 (1H, t), 3.84 (3H, s), 3.96 (1H, t), 4.37 (1H, t), 4.52 (2H, t),
6.81 (2H, d), 7.15 (2H, d).
Experimental example 2:
Using above-mentioned the same terms, methyl phenyl ethers anisole is changed to phenetole, obtains R1For the compound of formula I 1.97g (HPLC of ethyl
97.8%) purity is.
LC-MS:[M+H] 380.47.
1H NMR(400MHz,CDCl3): 1.28 (3H, t), 1.40-1.64 (9H, m), 1.85 (1H, m), 2.53 (2H, d),
3.36 (1H, d), 3.52 (2H, d), 3.60 (3H, m), 3.72 (1H, t), 4.01 (3H, m), 4.38 (1H, t), 4.52 (2H, t),
6.80 (2H, d), 7.13 (2H, d).
Embodiment 3:
Using above-mentioned the same terms, methyl phenyl ethers anisole is changed to propyloxy phenyl base ether, obtains R1For the compound of formula I of isopropyl
2.03g (HPLC purity is 98.0%).
LC-MS:395.50 [M+H].
1H NMR(400MHz,CDCl3): 1.25 (6H, d), 1.43-1.61 (9H, m), 1.84 (1H, m), 2.51 (2H, d),
3.39 (1H, d), 3.52 (2H, d), 3.62 (3H, m), 3.71 (1H, t), 3.97 (1H, t), 4.34 (1H, t), 4.51 (2H, t),
4.70 (1H, m), 6.83 (2H, d), 7.16 (2H, d).
Claims (5)
1. compound of formula I,
Wherein: R1It is selected from: methyl, ethyl or isopropyl.
2. the preparation method of compound described in claim 1, which is characterized in that its reaction route is as shown in reaction equation
3. including the pharmaceutical composition of claim 1 compound.
4. claim 1 compound is preparing the application in SGLT-2 inhibitor medicaments.
5. application as claimed in claim 4, which is characterized in that the drug is used to prepare treatment diabetes, hyperglycemia, grape
Impaired glucose tolerance, gestational diabetes mellitus, insulin resistance, hyperinsulinemia drug application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711195816.4A CN107880006B (en) | 2017-11-24 | 2017-11-24 | The compound as SGLT-2 inhibitor containing cyclohexane structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711195816.4A CN107880006B (en) | 2017-11-24 | 2017-11-24 | The compound as SGLT-2 inhibitor containing cyclohexane structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107880006A CN107880006A (en) | 2018-04-06 |
| CN107880006B true CN107880006B (en) | 2019-07-02 |
Family
ID=61775161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711195816.4A Active CN107880006B (en) | 2017-11-24 | 2017-11-24 | The compound as SGLT-2 inhibitor containing cyclohexane structure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107880006B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2025003461A1 (en) * | 2023-06-30 | 2025-01-02 | Institut National de la Santé et de la Recherche Médicale | Methods of treatment of metabolic disorders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104861002A (en) * | 2014-02-26 | 2015-08-26 | 天津药物研究院 | 3,6-anhydroglucose structure-containing phenyl C-glucoside derivatives and their preparation method and use |
-
2017
- 2017-11-24 CN CN201711195816.4A patent/CN107880006B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN107880006A (en) | 2018-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2712033C2 (en) | Deuterated derivative of chenodeoxycholic acid and pharmaceutical composition containing said compound | |
| EP3564253B1 (en) | Antidepressant compound and preparation method and application thereof | |
| JP4128615B2 (en) | Piperidine and pyrrolidine | |
| CN104903296A (en) | Dihydropyrazole GPR40 modulators | |
| EP3191453B1 (en) | Phenyl-(aza)cycloalkyl carboxylic acid gpr120 modulators | |
| KR20160092015A (en) | Crystalline form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists | |
| CN106810582A (en) | Compounds, preparation methods and applications of glucopyranosyl derivatives | |
| CN107880006B (en) | The compound as SGLT-2 inhibitor containing cyclohexane structure | |
| CN106458987B (en) | For treating the pyrrolidines GPR40 regulator of disease such as diabetes | |
| CN107602523B (en) | Genipin analogue, preparation method and application thereof | |
| CN106674294A (en) | Crystalline form of glucopyranosyl derivatives | |
| CN107903231B (en) | The compound as SGLT-2 inhibitor containing adamantane structure | |
| CN107903247B (en) | The compound as SGLT-2 inhibitor containing hydroxy piperidine structure | |
| RU2284328C2 (en) | Crystals of taxane derivatives and method for their preparing | |
| EP4163287A1 (en) | A class of aryl glucoside derivatives, preparation method therefor and application thereof | |
| WO2019000224A1 (en) | Bisindolylmaleimide derivative and preparation method and use thereof | |
| JP6197113B2 (en) | Novel SGLT1 inhibitor | |
| CN107778336A (en) | The crystal form of glucopyranosyl derivatives | |
| CN111039880A (en) | Application of miconazole and derivative thereof as TGR5 agonist | |
| CZ20011216A3 (en) | Benzamide derivatives | |
| CN104292210B (en) | Nitric oxide donors class compound containing pyridine, preparation method and the usage | |
| JP7273997B2 (en) | Crystal forms of SGLT inhibitors and uses thereof | |
| EP4166547A1 (en) | Aryl glucoside derivative | |
| RU2203656C1 (en) | Pharmaceutical composition with antidiabetic effect based on oxovanadium derivative and method for it preparing | |
| CN109608415A (en) | Thiazole carboxamides and their synthesis and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |