CN105949220A - 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 - Google Patents
噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 Download PDFInfo
- Publication number
- CN105949220A CN105949220A CN201610303702.6A CN201610303702A CN105949220A CN 105949220 A CN105949220 A CN 105949220A CN 201610303702 A CN201610303702 A CN 201610303702A CN 105949220 A CN105949220 A CN 105949220A
- Authority
- CN
- China
- Prior art keywords
- thiazole
- ketone
- triazine
- phenyl
- methoxyphenyl
- 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.)
- Granted
Links
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title abstract description 9
- YTQQIHUQLOZOJI-UHFFFAOYSA-N 2,3-dihydro-1,2-thiazole Chemical class C1NSC=C1 YTQQIHUQLOZOJI-UHFFFAOYSA-N 0.000 title abstract 4
- -1 4-thiazole derivative compounds Chemical class 0.000 claims abstract description 70
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 26
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 95
- 238000002360 preparation method Methods 0.000 claims description 79
- 239000000460 chlorine Substances 0.000 claims description 27
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 24
- 229910052794 bromium Inorganic materials 0.000 claims description 24
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 239000002207 metabolite Substances 0.000 claims description 11
- DSRNCGHNVDTSBE-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-(4-methylphenyl)hydrazine Chemical compound C1=CC(C)=CC=C1NNC1=CC=C(Cl)C=C1 DSRNCGHNVDTSBE-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000005936 piperidyl group Chemical group 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 10
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 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 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 150000002466 imines Chemical class 0.000 claims description 3
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 6
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims 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 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 150000002118 epoxides Chemical class 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- 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 abstract description 21
- 239000008103 glucose Substances 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 13
- 230000003914 insulin secretion Effects 0.000 abstract description 13
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 7
- 208000013016 Hypoglycemia Diseases 0.000 abstract description 6
- 230000001419 dependent effect Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 106
- 238000000034 method Methods 0.000 description 82
- 230000015572 biosynthetic process Effects 0.000 description 77
- 238000003786 synthesis reaction Methods 0.000 description 77
- 239000007787 solid Substances 0.000 description 75
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 63
- 239000011734 sodium Substances 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 239000002585 base Substances 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 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 24
- 235000002639 sodium chloride Nutrition 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 102000004877 Insulin Human genes 0.000 description 12
- 108090001061 Insulin Proteins 0.000 description 12
- 229940125396 insulin Drugs 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 206010012601 diabetes mellitus Diseases 0.000 description 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 11
- 239000003826 tablet Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000003248 secreting effect Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000002775 capsule Substances 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229940076134 benzene Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 210000000582 semen Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 235000009392 Vitis Nutrition 0.000 description 2
- 241000219095 Vitis Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical class 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
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 229950007655 esilate Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960003329 sulfinpyrazone Drugs 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 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
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- KILNVBDSWZSGLL-KXQOOQHDSA-O 1,2-di-O-palmitoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-O 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical class CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- RSAXVDMWQCQTDT-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-oxoacetic acid Chemical compound OC(=O)C(=O)C1=CC=C(Cl)C=C1 RSAXVDMWQCQTDT-UHFFFAOYSA-N 0.000 description 1
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000007934 ACTH-independent macronodular adrenal hyperplasia Diseases 0.000 description 1
- 238000012815 AlphaLISA Methods 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-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
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-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
- 239000001828 Gelatine Substances 0.000 description 1
- 229920002907 Guar gum Polymers 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
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 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
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 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
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- UUVBYOGFRMMMQL-UHFFFAOYSA-N calcium;phosphoric acid Chemical compound [Ca].OP(O)(O)=O UUVBYOGFRMMMQL-UHFFFAOYSA-N 0.000 description 1
- 229940025250 camphora Drugs 0.000 description 1
- 239000010238 camphora Substances 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229950004783 cipionate Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 125000002704 decyl 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])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate 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
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001421 myristyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant 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
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical class ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 125000004079 stearyl 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])C([H])([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])C([H])([H])[H] 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,涉及噻唑并[3,2‑b]‑1,2,4‑三嗪类衍生物及其应用。噻唑并[3,2‑b]‑1,2,4‑三嗪类衍生物包括噻唑并[3,2‑b]‑1,2,4‑三嗪类衍生物、该类化合物的立体异构体和药学上适用的盐,其结构通式如下所示:噻唑并[3,2‑b]‑1,2,4‑三嗪类衍生物以及该类化合物药学上适用的酸加成的盐,可以与现有药物合并或单独使用作为葡萄糖浓度依赖型胰岛素分泌促进剂,用于II型糖尿病的治疗。与现有技术相比,该类化合物是葡萄糖浓度依赖型胰岛素分泌促进剂,可在高葡萄糖浓度下促进胰岛素分泌,而在低葡萄糖浓度下,不影响胰岛素的分泌,从而避免了低血糖副作用的发生。
Description
技术领域:
本发明属于医药技术领域,涉及噻唑并[3,2-b]-1,2,4-三嗪类衍生物及其在制备治疗糖尿病药物中的应用。具体涉及噻唑并[3,2-b]-1,2,4-三嗪类衍生物以及该类化合物的立体异构体和药学上适用的盐。
背景技术:
糖尿病是一种影响全球的,影响所有年龄段人群的慢性、终身性疾病。近些年来,很多糖尿病治疗药物已经上市,低血糖是其中最普遍发生的一个副作用。磺脲类药物是目前临床上广泛使用的一种糖尿病治疗药,该药低血糖副作用的发生率为5%~20%。
因此,理想的糖尿病治疗药,应该是在高血糖条件下,促进胰岛素分泌,降低血糖浓度,而在血糖降低之后,不再影响胰岛素的分泌,从而避免低血糖的发生。
本发明所述化合物作为全新结构类型的葡萄糖浓度依赖型胰岛素分泌促进剂,结构类型新颖,体外药效评价结果显示,药效作用符合理想糖尿病治疗药的特征,即在高葡萄糖浓度下(10mmol·L–1),可促进胰岛素分泌,而在低葡萄糖浓度(2mmol·L–1)下,不影响胰岛素的分泌,从而避免了低血糖副作用的发生。因此,具有良好的应用价值和开发应用前景。
发明内容:
本发明提供了一种新结构类型的葡萄糖浓度依赖型胰岛素分泌促进剂,该化合物及其衍生物可以与现有药物合并或单独使用,通过在不同血糖浓度下,不同程度地促进胰岛素分泌,从而控制血糖浓度,改善糖尿病症状,避免低血糖副作用的发生。
本发明涉及式I化合物、其立体异构体或其药学上适用的酸加成的盐,其前体药物和药物活性代谢物,以及上述化合物的药物可接受的盐:
其中
n1和n2为0至1的整数;
R1可以任意选择1个、2个或3个H,卤素,-OH,C1-C4烷氧基,C1-C4烷基,-NO2,-O(CH2)n3NR3R4,-O(CH2)n4CONR5R6;
R2可以任意选择1个、2个或3个-O(CH2)n5CH3;
n3为2至4的整数,n4为1至3的整数,n5为1至5的整数;
其中R3R4独立地选自C1-C4烷基,或R3R4与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯基,所述取代基为:卤素、C1-C4烷基、C1-C4烷氧基、羟基、硝基,优选2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴;
R5R6独立的选自C1-C4烷基,或R5R6与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯基,所述取代基为:卤素、C1-C4烷基、C1-C4烷氧基、羟基、硝基,优选2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴。
优选地,n1和n2为0至1的整数;
R1可以任意选择1个、2个或3个H,卤素,-OH,甲氧基,甲基,-NO2,-O(CH2)n3NR3R4,-O(CH2)n4CONR5R6;
R2可以任意选择1个、2个或3个-O(CH2)n5CH3;
n3为2至4的整数,n4为1至3的整数,n5为1至5的整数;
其中R3、R4独立地选自甲基或乙基,或R3R4与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯环基团,所述取代基为:2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴;
R5、R6独立的选自甲基或乙基,或R5R6与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯基,所述取代基为:2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴。
本发明还优选如下化合物,包括但不限于其前体药物、药物活性代谢物以及其药学上可接受的盐。
3-苯基-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-氯苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苯基)-3-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基-3-甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-苯基-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-氯苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-溴苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基-3-甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-苯基-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲氧基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基-3-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苯基)-3-[4-(4-氯苯胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[4-(4-氯苯胺基)甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-溴苯基)-3-[3-甲氧基-4-(4-氯苯胺基)甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-乙氧基苯基)-3-[4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-乙氧基苯 基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-乙氧基苯基)-3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苯基)-3-(4-苄胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苯基)-3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-(4-甲基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(2-甲氧基苄基)-3-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-羟基苄基)-3-(2-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-羟基苄基)-3-(3-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-羟基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(3-甲氧基-4-羟基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(3-甲氧基-4-羟基苄基)-3-(2-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-(4-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{2-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[2-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-(2-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]- 1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[(4-吗啉基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(二乙胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{2-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-[2-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮。
“药物可接受的盐”指保留了式I化合物的生物效力和性质,并与合适的非毒性有机或无机酸或有机或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐的实例包括醋酸盐,己二酸盐,藻酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,柠檬酸盐,樟脑酸盐,樟脑磺酸盐,环戊丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,富马 酸盐,葡庚糖酸盐,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,氢氯酸盐,氢溴酸盐,氢碘酸盐,2-羟基乙磺酸盐,乳酸盐,马来酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,草酸盐,扑酸盐,果胶酯酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,新戊酸盐,丙酸盐,琥珀酸盐,硫酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐和十一酸盐。碱盐包括铵盐,碱金属盐,例如钠和钾盐,碱土金属盐,例如钙和镁盐,有机碱的盐,例如二环己胺盐,N-甲基-D-葡糖胺盐,和氨基酸的盐,例如精氨酸,赖氨酸等,而且,碱性含氮基团可以用这样的试剂季铵化,例如低级烷基卤化物,如甲基,乙基,丙基和丁基的氯,溴和碘化物;硫酸二烷基酯,如硫酸二甲酯,二乙酯,二丁酯和二戊酯;长链卤化物,如癸基,月桂基,肉豆蔻基和硬脂酰基的氯,溴和碘化物;芳烷基卤化物,如苄基和苯乙基的溴化物等。优选用于生成酸加成盐的酸包括盐酸和醋酸。
“药学上可接受的”如药学上可接受地载体、赋性剂、前体药物等,指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。
“药学活性代谢物”指药学上可接受并有效的式I化合物的代谢产物。
本发明还提供了通式(I)所述的化合物在制备治疗糖尿病药物中的应用。
本发明也涉及具有糖尿病治疗作用的药用组合物,该组合物含有本发明所述的化合物或其药学上适用的酸加成盐以及药学上适用的载体。
本发明还涉及治疗哺乳动物糖尿病的方法,该方法包括给哺乳动物服用糖尿病治疗有效剂量的专利保护化合物或衍生物或其药学上适用的酸加成盐以及药学上适用的载体。
本发明中应用的术语“卤素”包括氯、溴或氟。
“取代的”,除非另外说明,指取代基可以在一个或多个位置存在,取代基独立地选自具体地选项。
本发明化合物可以通过不同的方法给患者服用,例如以胶囊剂或片剂口服,以无菌溶液剂或混悬剂给药,并且在某些情况下,可以以溶液剂形式静脉注射。可以将本发明的游离碱化合物以其药学上适用的酸加成盐形式进行配制和服用。
对于一般的成人而言,本发明化合物每天的剂量通常为约1~300mg/kg体重,并可以按单剂量或均分剂量给药。对于给药,如果服用溶液剂或混悬剂,那么本发明化合物的浓度至少为1%(质量分数),以4%~70%(质量分数)(以单位的总质量为基础)较好。非经胃肠道给药的剂量单位一般含有约5mg~100mg有效化合物。
本发明化合物可以与惰性稀释剂或可食用的载体一起口服给药,或者它们可以封装在明胶胶囊中,或者压成片剂。所述制剂应含有至少0.5%活性化合物,但是根据具体的剂型,浓度可以改变,可以为4%~70%(质量分数)(以单位的总质量为基础)。口服剂量单位一般含有1.0mg~300mg有效化合物。
对于药理应用,式I化合物优选以其药用酸加成盐的形式给药。当然化合物的有效剂量将根据所用每个化合物的效力、所要治疗疾病的严重性和性质、要治疗的特定患者而变化。一般,以约0.01mg到约20mg/kg体重/天的剂量,化合物系统给药可得到有效的结果。应以较低剂量开始治疗。随后可以固体剂型如胶囊、片剂、或粉剂,或以液态形式如溶液或悬液口服给药。这些化合物还可以灭菌溶液或悬液的形式经肠外注射。
在本发明的方法的实施例中,优选将活性成分掺入到含有药用载体的组合物中,其中含有约5%~90%(质量分数)的本发明化合物或其药用盐。“药用载体”指用于配制给动物内服的药物活性化合物的已知药用赋形剂,它们在使用条件下是基本无毒和非致畸的。可以用制备片剂、胶囊、酏剂、糖浆、乳剂、分散体和可湿性及起泡沫的粉剂的已知技术制备此组合物,它可含有已知在制备特定类型组合物中有用的适当赋形剂。优选的给药途径是口服给药。为口服给药,可将式I化合物配制成固态或液态制剂如胶囊、丸剂、片剂、锭剂、糖锭、熔化物、粉剂、溶液、悬剂、或乳剂。固体单位剂量形式可以是胶囊,它可以是普通的硬壳或软壳明胶型,其中含有例如表面活性剂、润滑剂、和惰性填充剂如乳糖、蔗糖、磷酸钙和玉米淀粉。在另一实施方案中,本发明化合物可与常规的基质如乳糖、蔗糖、和玉米淀粉一起压片,添加粘合剂如阿拉伯胶、玉米淀粉、或明胶;用于在帮助片剂崩解和溶解的崩解剂如马铃薯淀粉、藻酸、玉米淀粉、和瓜耳胶;用于提高片剂颗粒的流动性防止片剂材料粘附在片剂冲模和冲床上的润滑剂,如滑石粉、硬脂酸、或硬脂酸镁、钙或锌;和用于提高片剂的外观使它们对病人更易接受的包衣材料,着色剂和调味剂。用于口服液态剂型的适当赋形剂包括水和醇如乙醇、苯甲醇、和聚乙烯醇,添加或不添加药用表面活性剂、悬浮剂、或浮化剂。本发明式I化合物还可肠外给药,即皮下、静脉内、肌内、或腹膜内,以生理可接受的稀释剂中的化合物的可注射剂型给药,其中还含有药用载体,可为无菌液体或液合混合物如水、盐水、葡萄糖水溶液和有关的糖溶液,醇如乙醇、异丙醇、或十六烷醇,二醇如丙二醇或聚乙二醇,甘油缩酮如2,2-二甲基-l,3-二氧戊环-4-甲醇,醚如聚乙二醇400,油,脂肪酸,脂肪酸酯或甘油酯,或乙酰化脂肪酸甘油酯,加或不加药学上可接受的表面活性剂如皂或洗涤剂,悬浮剂如果胶、卡波沫、甲基纤维素、异丙基甲基纤维素、或酸甲基纤维素,或乳化剂和其它药学上可接受的添加剂。可用于本发明的肠外制剂的油的实例为那些来自石油、动物、植物、或合成的油,例如花生油、豆油、芝麻油、棉籽油、玉米油、橄榄油和矿物油。适当的脂肪酸包括油酸、硬脂酸、和异硬脂酸。适合的脂肪酸酯例如为油酸乙酯和肉豆蔻酸异丙酯。适宜的皂包括脂肪酸碱金属盐,胺盐和三乙醇胺盐,适宜的表面活性剂,包括阳离子表面活性剂如二甲基二烷基卤化胺、烷基,烷基吡啶鎓卤化物;阴离子表面活性剂如烷基、芳基、磺酸盐,烷基、醚、和单甘油酯硫酸盐、和磺基琥珀酸盐;非离子表面活性剂如脂肪胺氧化物,脂肪酸烷醇酰胺,和聚氧亚乙 基聚亚丙基共聚物;和两性表面活性剂如氨基丙酸烷基酯、和烷基咪唑啉季铵盐,及其混合物。本发明的肠外用组合物一般在溶液中含有约0.5%到约25%(质量分数)的式I化合物。可以使用防腐剂和缓冲剂。为了将注射位点的刺激至最小或将其消除,这种组合物可含有亲水—亲脂平衡值(HLB)为约12到约17的非离子表面活性剂。在这种制剂中此表面活性剂的量为约5%到约15%(质量分数)。这种表面活性剂可以是具有以上HLB值的单一成分或两种或多种成分的具有所需HLB的混合物。用于肠外用制剂的表面活性剂的实例是聚己烯脱水山梨醇脂肪酸酯类,例如脱水山梨醇单油酸酯和环氧乙烷与一疏水基的高分子量加合物,通过环氧丙烷与丙二醇缩合而成。本发明复合物还可以经皮给药。这可通过简单地制备所需化合物的溶液来进行,优选用已知促进透皮吸收的溶剂如乙醇或二甲基亚砜(DMSO)加或不加其他赋形剂来制备溶液。优选的经皮给药使用贮器和多孔膜型的药物或具有固体基质变化的药物来进行。这些装置一般含有限定其一个外表面的背衬、一个可透过活性药物的限定另一个表面的粘性层和于外表面间的含有活性药物的至少一个贮器。或者,活性药物包含在分布于整个可透性粘性层中的许多微胶丸中。无论哪种情形,活性药物从贮器或微胶囊通过一膜连续地运送至可透过活性药物的粘性层,后者与患者的皮肤或粘膜接触。如果活性药物透过皮肤被吸收,则可控制的和预定流速的活性药物施用于患者。当用微胶囊时,包被剂还起到膜的作用。将本发明化合物透皮给药的另一装置中,药物活性化合物包含在基质中,它从基质中以预期的逐步、恒定和可控制的速度释放。基质对化合物通过扩散或微孔流的释放是通透性的。在这些系统中至少有两类释放是可能的。当基质为非多孔性时发生扩散释放。药物活性化合物溶解在基质中并扩散透过基质本身。当药物活性化合物在基质的小孔中通过液相运输时,发生微孔流释放。
本发明的化合物是葡萄糖浓度依赖型胰岛素分泌促进剂,可在高葡萄糖浓度下(10mmol·L–1),促进胰岛素分泌,而在低葡萄糖浓度(2mmol·L–1)下,不影响胰岛素的分泌,从而避免了低血糖副作用的发生。
具体实施方式:
流程1概括了制备本发明化合物的合成步骤。
流程1
其中,
n1和n2为0至1的整数;
R1可以任意选择地由1个、2个或3个独立地选自H,卤素,-OH,C1-C4烷氧基,C1-C4烷基,-NO2,-O(CH2)n3NR3R4,-O(CH2)n4CONR5R6;
R2可以任意选择地由1个、2个或3个独立地选自-O(CH2)n5CH3;
n3为2至4的整数,n4为1至3的整数,n5为1至5的整数;
其中R3R4独立地选自C1-C4烷基,或R3R4与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地 选自氢和取代或未取代的苯环基团,所述取代基为:卤素、C1-C4烷基、C1-C4烷氧基、羟基、硝基,优选2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴;
R5R6独立的选自C1-C4烷基,或R5R6与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯环基团,所述取代基为:卤素、C1-C4烷基、C1-C4烷氧基、羟基、硝基,优选2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴。
以下述实例详细叙述本发明。但是,应当明白,本发明不限于具体叙述的下述实例。
实施例1:3-苯基-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
合成通法1:将芳基苯乙烯0.2mol,氢氧化钠0.4mol,水80mL加入到500mL圆底烧瓶中,加热至70℃,将高锰酸钾0.5mol在0.5h之内分批加入,反应10min后再用乙醇50mL将未反应的高锰酸钾进行破坏,将反应液进行抽滤,保留滤液,减压蒸馏除去大部分水,用浓盐酸将浓缩的滤液进行酸化,再用二氯甲烷萃取,除去溶剂,冷却得到淡黄色固体,乙醇重结晶,得到2-芳基-2-氧代乙酸。
按照合成通法1,得到2-(4-氯苯基)-2-氧代乙酸白色粉末,收率60.0%。熔点为88~90℃(文献值89~91℃)。。
合成通法2:将上步得到的2-芳基2-氧代乙酸0.01mol,硫代氨基脲0.01mol,乙醇40mL,水40mL依次加入到250mL圆底烧瓶中,搅拌,加热回流反应12h,冷却到室温,减压蒸馏,蒸除溶剂,得到大量乳白色固体,抽滤,烘干,乙醇重结晶,得到3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮。
按照合成通法2,得到3,4-二氢-6-(4-氯苯基)-3-硫代-1,2,4-三嗪-5(2H)-酮白色固体粉末,收率72.4%。ESI-MS(m/z):237.6(M-H)-,239.6(M+2-H)-。
合成通法3:在0℃条件下,向0.005mol醋酸钠的15mL冰乙酸溶液中加入0.010mol的3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮和0.011mol的氯代苯乙酮类化合物或溴代苯乙酮类化合物。室温搅拌30min,缓慢升温至回流后继续反应2h,TLC监测反应进程,反应完毕后冷却至室温,将反应液浓缩至干,加入饱和食盐水溶液,室温下搅拌30min,并用乙酸乙酯萃取。有机层经干燥和浓缩得到粗产品,乙醇重结晶,得到目标化合物3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮。
按照合成通法3,得到3-苯基-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4- 三嗪-7-酮,白色固体,收率39.4%。1H-NMR(600MHz,DMSO-d6):δ8.09(2H,d,J=8.4Hz),7.78(2H,d),7.56~7.60(5H,m),7.55(1H,s);ESI-MS(m/z):339.9(M+H)+,341.9(M+2+H)+,361.9(M+Na)+,363.9(M+2+Na)+。
实施例2:3-(4-甲基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-甲基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率42.0%。1H-NMR(300MHz,DMSO-d6):δ8.09(2H,d,J=8.7Hz),7.67(2H,d,J=8.1Hz),7.57(2H,d,J=8.7Hz),7.53(1H,s),7.37(2H,d,J=8.1Hz),2.39(3H,s);ESI-MS(m/z):354.1(M+H)+,356.0(M+2+H)+,376.1(M+Na)+,378.0(M+2+Na)+,392.0(M+K)+,394.0(M+2+K)+。
实施例3:3-(4-氯苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-氯苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率36.1%。1H-NMR(300MHz,DMSO-d6):δ8.08(2H,d,J=8.52Hz),7.80(2H,d,J=8.58Hz),7.64(1H,s),7.62(2H,d),7.55(2H,d,J=8.52Hz);ESI-MS(m/z):373.8(M+H)+,375.8(M+2+H)+,377.8(M+4+H)+,413.1(M+K)+。
实施例4:6-(4-氯苯基)-3-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到6-(4-氯苯基)-3-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率29.6%。1H-NMR(300MHz,DMSO-d6):δ8.25(2H,d),7.98(2H,d),7.55(1H,s),7.56(2H,d),7.36(2H,d);ESI-MS(m/z):418.0(M+H)+,420.0(M+2+H)+,440.0(M+Na)+,442.0(M+2+Na)+,456.0(M+K)+,457.9(M+2+K)+。
实施例5:3-(4-羟基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-羟基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率12.9%。1H-NMR(600MHz,DMSO-d6):δ10.02(1H,s),8.10(2H,d),7.64(1H,s),7.52~7.61(2H,m),7.40(2H,d),6.93(2H,d);ESI-MS(m/z):353.7(M-H)-,355.6(M+2-H)-。
实施例6:3-(4-羟基-3-甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-羟基-3-甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率23.4%。1H-NMR(600MHz,DMSO-d6):δ8.14(2H,d,J=9.0Hz),7.57(2H,d,J=8.4Hz),7.46(1H,s),7.40(1H,s),7.21(1H,d),6.94(1H,d),3.83(3H,s);ESI-MS(m/z):383.8(M-H)-,385.8(M+2-H)-,419.8(M+Cl)-。
实施例7:3-苯基-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-苯基-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4- 三嗪-7-酮,白色固体,收率50.1%。1H-NMR(300MHz,DMSO-d6):δ8.01(2H,d,J=8.4Hz),7.77~7.80(2H,m),7.70(2H,d),7.60(1H,s),7.54~7.58(3H,m);ESI-MS(m/z):384.0(M+H)+,386.0(M+2+H)+,406.0(M+Na)+,408.9(M+2+Na)+,422.0(M+K)+,424.0(M+2+K)+。
实施例8:3-(4-甲基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-甲基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率31.0%。1H-NMR(600MHz,DMSO-d6):δ8.01(2H,d,J=8.4Hz),7.86(2H,d,J=9.0Hz),7.66~7.72(3H,m),7.53(1H,s),2.39(3H,s);ESI-MS(m/z):398.0(M+H)+,400.0(M+2+H)+,420.0(M+Na)+,422.0(M+2+Na)+,436.0(M+K)+,438.0(M+2+K)+。
实施例9:3-(4-氯苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-氯苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率12.4%。1H-NMR(300MHz,DMSO-d6):δ8.01(2H,d,J=8.55Hz),7.80(2H,d,J=8.58Hz),7.76(1H,s),7.69(2H,d,J=8.67Hz),7.64(2H,d);ESI-MS(m/z):417.7(M+H)+,419.8(M+2+H)+,439.7(M+Na)+,441.7(M+2+Na)+,457.7(M+K)+。
实施例10:3-(4-溴苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-溴苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,淡黄色固体,收率19.8%。1H-NMR(600MHz,DMSO-d6):δ8.02(2H,d,J=9.0Hz),7.78(2H,d),7.73~7.74(2H,m),7.71(2H,d,J=9.0Hz),7.65(1H,s);ESI-MS(m/z):461.9(M+H)+,463.9(M+2+H)+,483.9(M+Na)+,485.9(M+2+Na)+,499.8(M+K)+,501.9(M+2+K)+,503.9(M+4+K)+。
实施例11:3-(4-羟基-3-甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-(4-羟基-3-甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率16.8%。1H-NMR(600MHz,DMSO-d6):δ8.06(2H,d,J=8.4Hz),7.72(2H,d),7.46(1H,s),7.39(1H,s),7.21(1H,d),6.94(1H,d),3.82(3H,s);ESI-MS(m/z):427.9(M-H)-,429.8(M+2-H)-。
实施例12:3-苯基-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备。
按照合成通法3,得到3-苯基-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,淡黄色固体,收率31.2%。1H-NMR(300MHz,DMSO-d6):δ8.09(2H,d),7.75~7.79(2H,m),7.55(1H,s),7.52~7.54(3H,m),7.00(2H,d),4.07(2H,q),1.33(3H,t);ESI-MS(m/z):350.1(M+H)+, 372.1(M+Na)+,388.1(M+K)+,721.2(2M+Na)+。
实施例13:3-(4-甲氧基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法3,得到3-(4-甲氧基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率18.3%。1H-NMR(600MHz,DMSO-d6):δ8.11(2H,d,J=8.4Hz),7.73(2H,d,J=9.0Hz),7.44(1H,s),7.11(2H,d,J=9.0Hz),7.02(2H,d,J=9.0Hz),4.09(2H,q),3.84(3H,s),1.35(3H,t);ESI-MS(m/z):380.1(M+H)+,402.1(M+Na)+,418.0(M+K)+。
实施例14:3-(4-羟基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法3,得到3-(4-羟基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率42.8%。1H-NMR(600MHz,DMSO-d6):δ8.12(2H,d,J=9.0Hz),7.60(2H,d,J=9.0Hz),7.38(1H,s),7.02(2H,d,J=9.0Hz),6.92(2H,d,J=9.0Hz),4.09(2H,q),1.35(3H,t);ESI-MS(m/z):366.1(M+H)+,388.1(M+Na)+,404.1(M+K)+。
实施例15:3-(4-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法3,得到3-(4-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,淡黄色固体,收率18.9%。1H-NMR(600MHz,DMSO-d6):δ8.12(2H,d,J=9.0Hz),7.73(2H,d,J=8.4Hz),7.45(1H,s),7.12(2H,d,J=8.4Hz),7.04(2H,d,J=9.0Hz),3.83(3H,s),3.82(3H,s);ESI-MS(m/z):366.3(M+H)+。
实施例16:3-(4-羟基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法3,得到3-(4-羟基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率21.1%。1H-NMR(600MHz,DMSO-d6):δ8.13(2H,d,J=9.0Hz),7.61(2H,d,J=9.0Hz),7.38(1H,s),7.04(2H,d,J=9.0Hz),6.93(2H,d,J=9.0Hz),3.82(3H,s);ESI-MS(m/z):352.1(M+H)+,374.1(M+Na)+,390.1(M+K)+,725.2(2M+Na)+。
实施例17:3-(4-羟基-3-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法3,得到3-(4-羟基-3-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率63.9%。1H-NMR(600MHz,DMSO-d6):δ8.16(2H,d),7.43(1H,s),7.41(1H,d),7.21(1H,s),7.05(2H,d),6.94(1H,d),3.83(3H,s),3.82(3H,s);ESI-MS(m/z):382.3(M+H)+,404.3(M+Na)+,420.2(M+K)+。
实施例18:3-[4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
合成通法4:室温搅拌条件下,向0.002mol的3-(4-羟基苯基)-6-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的丙酮或乙醇溶液中加入相应的 0.002mol氯乙酰胺,并加入0.002mol缚酸剂(无水碳酸钾或三乙胺)和0.0003mol碘化钾催化剂后,回流反应,TLC跟踪反应进程,待反应完毕后冷却至室温,将反应液浓缩至干,加入饱和食盐水30mL,乙醚萃取。有机层经干燥和浓缩得到粗产品,乙醇重结晶,得到所需的目标化合物。
按照合成通法4,得到3-[4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率48.8%。1H-NMR(600MHz,DMSO-d6):δ8.01(2H,d,J=8.4Hz),7.70(4H,d),7.48(1H,s),7.06(2H,d),4.89(2H,s),3.35(2H,q),3.29(2H,q),1.17(3H,t),1.04(3H,t);ESI-MS(m/z):469.1(M+H)+,471.1(M+2+H)+,491.1(M+Na)+,493.1(M+2+Na)+。
实施例19:3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率36.8%。1H-NMR(600MHz,DMSO-d6):δ8.73(1H,s),8.09(2H,d,J=7.8Hz),7.74(2H,d,J=8.4Hz),7.55(2H,d,J=8.4Hz),7.50(1H,s),7.22~7.31(5H,m),7.14(2H,d,J=7.8Hz),4.66(2H,s),4.36(2H,d);ESI-MS(m/z):503.1(M+H)+,505.2(M+2+H)+,525.1(M+Na)+,527.1(M+2+Na)+,541.2(M+K)+,543.1(M+2+K)+。
实施例20:6-(4-氯苯基)-3-[4-(4-氯苯胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到6-(4-氯苯基)-3-[4-(4-氯苯胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率31.3%。1H-NMR(600MHz,DMSO-d6):δ10.59(1H,s),8.10(2H,d,J=8.4Hz),7.74(2H,d,J=8.4Hz),7.70(2H,d,J=9.0Hz),7.65~7.68(2H,m),7.50(1H,s),7.34~7.40(2H,m),7.16(2H,d,J=8.4Hz),4.77(2H,s);ESI-MS(m/z):523.2(M+H)+,545.1(M+Na)+,561.1(M+K)+。
实施例21:3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率61.5%。1H-NMR(600MHz,DMSO-d6):δ8.12(2H,d,J=9.0Hz),7.58(2H,d,J=8.4Hz),7.52(1H,s),7.46(1H,s),7.29(1H,d),7.02(1H,d),4.92(2H,s),3.81(3H,s),3.60(4H,t),3.47(4H,t);ESI-MS(m/z):513.2(M+H)+,535.2(M+Na)+,537.1(M+2+Na)+,551.1(M+K)+。
实施例22:3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率44.8%。 1H-NMR(600MHz,DMSO-d6):δ8.54(1H,s),8.12(2H,d,J=9.0Hz),7.57(2H,d,J=8.4Hz),7.54(1H,s),7.48(1H,s),7.24~7.32(5H,m),7.22(1H,d),7.07(2H,d,J=8.4Hz),4.65(2H,s),4.35(2H,d),3.82(3H,s);ESI-MS(m/z):533.1(M+H)+,535.1(M+2+H)+,555.1(M+Na)+,557.1(M+2+Na)+。
实施例23:3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率43.9%。1H-NMR(600MHz,DMSO-d6):δ8.72(1H,t),8.02(2H,d),7.73(2H,d),7.69(2H,d),7.49(1H,s),7.22~7.31(5H,m),7.14(2H,d),4.66(2H,s),4.36(2H,s);ESI-MS(m/z):547.1(M+H)+,569.1(M+Na)+,571.1(M+2+Na)+,585.1(M+K)+,587.1(M+2+K)+。
实施例24:3-[4-(4-氯苯胺基)甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,3-[4-(4-氯苯胺基)甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率66.3%。1H-NMR(600MHz,DMSO-d6):δ11.08(1H,s),8.02(2H,d,J=7.8Hz),7.68~7.73(6H,m),7.50(1H,s),7.38(2H,d,J=7.8Hz),7.16(2H,d,J=7.8Hz),4.87(2H,s);ESI-MS(m/z):567.1(M+H)+,589.0(M+Na)+,591.0(M+2+Na)+,605.0(M+K)+,607.0(M+2+K)+。
实施例25:3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率66.4%。 1H-NMR(600MHz,DMSO-d6):δ8.53(1H,s),8.04(2H,d,J=7.8Hz),7.70(2H,d,J=7.8Hz),7.54(1H,s),7.48(1H,s),7.32(1H,d),7.21~7.30(5H,m),7.07(2H,d,J=8.4Hz),4.65(2H,s),4.35(2H,d),3.82(3H,s);ESI-MS(m/z):577.1(M+H)+,579.1(M+2+H)+,599.1(M+Na)+,601.0(M+2+Na)+,615.1(M+K)+。
实施例26:6-(4-溴苯基)-3-[3-甲氧基-4-(4-氯苯胺基)甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到6-(4-溴苯基)-3-[3-甲氧基-4-(4-氯苯胺基)甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率77.2%。 1H-NMR(600MHz,DMSO-d6):δ10.48(1H,s),8.05(2H,d,J=8.4Hz),7.70(2H,d,J=8.4Hz),7.68(2H,d,J=9.0Hz),7.52(1H,d),7.49(1H,s),7.38(2H,d,J=8.4Hz),7.31(1H,s),7.09(1H,d),4.82(2H,s),3.88(3H,s);ESI-MS(m/z):594.8(M-H)-,596.8(M+2-H)-,630.8(M+Cl)-,632.8(M+2+Cl)-。
实施例27:6-(4-乙氧基苯基)-3-[4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到6-(4-乙氧基苯基)-3-[4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,淡黄色固体,收率38.6%。 1H-NMR(600MHz,DMSO-d6):δ8.10(2H,d),7.71(2H,d),7.44(1H,s),7.09(2H,d,J=7.2Hz),7.01(2H,d,J=7.2Hz),4.95(2H,s),4.09(2H,q),3.60(4H,t),3.48(4H,t),1.34(3H,t);ESI-MS(m/z):493.4(M+H)+,515.4(M+Na)+。
实施例28:3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率63.9%。1H-NMR(600MHz,DMSO-d6):δ8.14(2H,d,J=8.4Hz),7.47(2H,d),7.29(1H,d),6.97~7.02(3H,m),4.88(2H,s),4.09(2H,q),3.90(3H,s),3.31(4H,q),1.34(3H,t),1.17(3H,t),1.04(3H,t);ESI-MS(m/z):509.3(M+H)+,531.3(M+Na)+。
实施例29:6-(4-乙氧基苯基)-3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到6-(4-乙氧基苯基)-3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率49.9%。1H-NMR(600MHz,DMSO-d6):δ8.15(2H,d),7.48(1H,d),7.43(1H,s),7.39(1H,s),7.30(1H,d),7.03(2H,d,J=7.8Hz),4.93(2H,s),4.09(2H,q),3.84(3H,s),3.56(4H,t),3.40(4H,t),1.34(3H,t);ESI-MS(m/z):523.2(M+H)+,545.2(M+Na)+,561.1(M+K)+。
实施例30:6-(4-甲氧基苯基)-3-(4-苄胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到6-(4-甲氧基苯基)-3-(4-苄胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,黄色固体,收率25.4%。1H-NMR(600MHz,DMSO-d6):δ8.73(1H,s),8.13(2H,d),7.75(2H,d),7.46(1H,s),7.22~7.30(5H,m),7.15(2H,d),7.03(2H,d),4.67(2H,s),4.37(2H,s),3.81(3H,s);ESI-MS(m/z):496.9(M-H)-,532.9(M+Cl)-,542.9(M+COO)-。
实施例31:6-(4-甲氧基苯基)-3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法4,得到6-(4-甲氧基苯基)-3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率60.2%,1H-NMR(600MHz,DMSO-d6):δ8.15(2H,d,J=8.4Hz),7.47(2H,d),7.29(1H,d),6.98~7.05(3H,m),4.88(2H,s),3.84(3H,s),3.82(3H,s),3.32(4H,q),1.17(3H,t),1.04(3H,t);ESI-MS(m/z):495.4(M+H)+,517.4(M+Na)+。
实施例32:6-苄基-3-(4-甲基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
合成通法5:将取代的苯甲醛0.1mol,乙酰甘氨酸0.12mol,无水醋 酸钠0.12mol和乙酸酐50g依次加入到100mL的三颈瓶中,控温90℃,搅拌反应5h,冷至室温后,有固体析出,抽滤,滤饼用冷水洗涤,丙酮重结晶,得到2-甲基-4-亚苄基噁唑酮类化合物。
将2-甲基-4-亚苄基噁唑酮类化合物0.1mol,水100mL,丙酮50mL依次加入到250mL圆底烧瓶中,加热回流搅拌反应3h,TLC监测反应完成后,冷却到室温,析出大量固体,抽滤,滤饼用冷水和少量丙酮冲洗,得到α-乙酰氨基-β-芳基丙烯酸类化合物。
将α-乙酰氨基-β-芳基丙烯酸类化合物0.1mol,1mol·L–1的HCl溶液220mL,依次加入到500mL圆底烧瓶中,加热回流反应5h,TLC监测反应完成后,停止反应,冷却,析出大量黄色固体,抽滤,丙酮重结晶,得到β-芳基丙酮酸类化合物。
将β-芳基丙酮酸类化合物0.1mol,硫代氨基脲0.1mol,乙醇60mL,水60mL加入到250mL圆底烧瓶中,用1mol·L–1的氢氧化钠溶液将反应体系的pH值调至11,加热回流反应5h,冷却到室温,再用浓盐酸将反应体系的pH值调至2,有大量乳白色固体析出,抽滤,烘干,乙醇重结晶,得到相应的目标化合物。
按照合成通法5,得到6-苄基-3-(4-甲基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率64.5%。1H-NMR(300MHz,CDCl3):δ7.42~7.45(2H,d,J=8.2Hz),7.22~7.38(7H,m),6.77(1H,s),4.12(2H,s),2.43(3H,s);EI-MS(m/z):51,65,77,91,104,115,130,147,159,190,202,216,242,262,279,304,329,333(M)+。
实施例33:6-(2-甲氧基苄基)-3-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(2-甲氧基苄基)-3-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率78.1%。1H-NMR(600MHz,DMSO-d6):δ7.80(1H,s),7.60(2H,d,J=8.4Hz),7.41(2H,d,J=8.4Hz),7.27(1H,t),7.17(1H,d),7.02(1H,d),6.88(1H,t),4.00(2H,s),3.73(3H,s);ESI-MS(m/z):384.0(M+H)+,791.9(2M+Na+H)+。
实施例34:6-(4-甲氧基苄基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(4-甲氧基苄基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率68.0%。1H-NMR(600MHz,DMSO-d6):δ7.57(2H,d,J=8.4Hz),7.40(1H,s),7.20(2H,d,J=9.0Hz),6.97(2H,d,J=9.0Hz),6.87(2H,d,J=8.4Hz),3.90(2H,s),3.81(3H,s),3.73(3H,s);ESI-MS(m/z):380.0(M+H)+,780.9(2M+Na)+。
实施例35:6-(4-甲氧基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(4-甲氧基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率62.7%。1H-NMR(600MHz,DMSO-d6):δ10.0(1H,s),7.48(2H,d,J=8.4Hz),7.33(1H,s),7.21(2H,d, J=8.4Hz),6.87(2H,d,J=8.4Hz),6.80(2H,d,J=8.4Hz),3.91(2H,s),3.76(3H,s);ESI-MS(m/z):366.0(M+H)+,752.8(2M+Na)+。
实施例36:6-(4-甲氧基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(4-甲氧基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率61.4%。1H-NMR(600MHz,DMSO-d6):δ9.79(1H,s),7.25(1H,s),7.17(1H,d),7.13(2H,d,J=8.4Hz),6.80(1H,d,J=8.4Hz),6.72(1H,s),6.68(1H,d),3.80(2H,s),3.70(3H,s),2.05(3H,s);ESI-MS(m/z):380.0(M+H)+,780.8(2M+Na)+。
实施例37:6-(4-羟基苄基)-3-(2-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(4-羟基苄基)-3-(2-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率75.4%。1H-NMR(300MHz,DMSO-d6):δ10.06(1H,s),9.30(1H,s),7.45(1H,s),7.43(2H,t),7.13(2H,d,J=8.4Hz),7.07(2H,d),6.98(2H,t),6.72(2H,d,J=8.4Hz),3.83(2H,s);ESI-MS(m/z):351.9(M+H)+,724.8(2M+Na)+。
实施例38:6-(4-羟基苄基)-3-(3-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(4-羟基苄基)-3-(3-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率71.4%。1H-NMR(300MHz,DMSO-d6):δ7.60(1H,s),7.57(2H,d),7.23(2H,d),7.08(2H,d,J=8.4Hz),6.68(1H,d,J=8.4Hz),3.86(2H,s),2.16(3H,s);ESI-MS(m/z):366.3(M+H)+,388.2(M+Na)+;。
实施例39:6-(4-羟基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(4-羟基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率67.6%。1H-NMR(600MHz,DMSO-d6):δ9.80(1H,s),9.25(1H,s),7.25(2H,s),7.18(1H,d),7.00(2H,d,J=8.4Hz),6.73(1H,s),6.68(2H,d),6.66(2H,d,J=8.4Hz),3.74(2H,s),2.06(3H,s);ESI-MS(m/z):365.9(M+H)+,752.8(2M+Na)+。
实施例40:6-(3-甲氧基-4-羟基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(3-甲氧基-4-羟基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率55.0%。1H-NMR(600MHz,DMSO-d6):δ9.95(1H,s),8.82(1H,s),7.50(2H,d,J=7.8Hz),7.33(1H,s),6.88(1H,s),6.80(2H,d,J=7.8Hz),6.65~6.69(2H,m),3.86(2H,s),3.72(3H,s);ESI-MS(m/z):381.9(M+H)+,784.8(2M+Na)+。
实施例41:6-(3-甲氧基-4-羟基苄基)-3-(2-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法5,得到6-(3-甲氧基-4-羟基苄基)-3-(2-羟基苯基)-7H- 噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率69.5%。1H-NMR(600MHz,DMSO-d6):δ9.92(1H,s),8.78(1H,s),7.33~7.37(3H,m),6.98(1H,d),6.88(1H,t),6.81(1H,s),6.62~6.65(2H,m),3.76(2H,s),3.69(3H,s);ESI-MS(m/z):381.9(M+H)+,784.8(2M+Na)+。
实施例42:6-苄基-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
合成通法6:6-芳甲基-3-(羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物0.002mol与相应的β-氯乙基胺盐酸盐0.002mol或氯乙酰胺0.002mol溶于50mL丙酮中,加入碳酸钾0.02mol,搅拌下回流反应12h,TLC监测反应完全后,抽滤,浓缩反应液至干,乙醇重结晶,得到目标化合物。
按照合成通法6,得到6-苄基-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率51.5%。1H-NMR(300MHz,CDCl3):δ7.46(2H,d,J=8.8Hz),7.25~7.36(5H,m),6.92(2H,d,J=8.8Hz),6.72(1H,s),4.18(2H,t),4.12(2H,s),2.83(2H,t),2.56(4H,t),1.65(4H,m),1.48(2H,m);ESI-MS(m/z):447.0(M+H)+,893.0(2M+H)+,915.9(2M+Na)+。
实施例43:6-苄基-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率39.0%。1H-NMR(300MHz,DMSO-d6):δ7.57(2H,d,J=8.8Hz),7.40(1H,s),7.24~7.33(5H,m),6.98(2H,d,J=8.8Hz),4.15(2H,t),3.97(2H,s),3.59(4H,t),2.71(2H,t),2.48(4H,t);ESI-MS(m/z):449.1(M+H)+。
实施例44:6-苄基-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率41.4%。1H-NMR(300MHz,CDCl3):δ7.46(2H,d,J=8.7Hz),7.25~7.36(5H,m),6.92(2H,d,J=8.7Hz),6.71(1H,s),4.12(4H,t),2.93(2H,t),2.69(4H,m),1.11(6H,m);ESI-MS(m/z):435.0(M+H)+。
实施例45:6-苄基-3-(4-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-(4-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率35.7%。1H-NMR(300MHz,CDCl3):δ7.47(2H,d,J=8.7Hz),7.25~7.36(5H,m),6.98(2H,d,J=8.7Hz),6.72(1H,s),4.77(2H,s),4.12(2H,s),3.13(3H,s),3.02(3H,s);ESI-MS(m/z):421.0(M+H)+。
实施例46:6-苄基-3-{2-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-{2-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率39.0%。1H-NMR(300MHz,DMSO-d6):δ7.50(1H,t),7.42(2H,d),7.22(5H,m),7.13(1H,d),7.05(1H,t),4.00(2H,t),3.89(2H,s),3.40(4H,t),2.36(2H,t),2.18(4H,t);EI-MS(m/z):56,70,91,100,111,134,149,163,192,218,330,448(M)+。
实施例47:6-苄基-3-[2-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-[2-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率43.7%。1H-NMR(600MHz,DMSO-d6):δ7.50(1H,t),7.41(2H,d),7.15~7.22(5H,m),7.11(1H,d),7.03(1H,t),3.91(4H,t),3.89(2H,s),2.41(2H,t),2.27(4H,m),0.72(6H,m);ESI-MS(m/z):435.0(M+H)+。
实施例48:6-苄基-3-(2-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-(2-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率58.3%,1H-NMR(600MHz,DMSO-d6):δ7.47(1H,s),7.45(2H,t),7.19~7.25(5H,m),7.04(2H,m),4.76(2H,s),3.88(2H,s),2.89(3H,s),2.78(3H,s);ESI-MS(m/z):421.0(M+H)+。
实施例49:6-苄基-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率43.4%,1H-NMR(600MHz,DMSO-d6):δ7.43(1H,d),7.38(2H,s),7.23~7.30(5H,m),6.98(1H,d),4.13(2H,t),3.88(2H,s),2.70(2H,t),2.46(4H,t),2.13(3H,s),1.50(4H,t),1.39(2H,s);ESI-MS(m/z):461.0(M+H)+。
实施例50:6-苄基-3-{3-甲基-4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-{3-甲基-4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率37.8%,1H-NMR(300MHz,CDCl3):δ7.24~7.39(7H,m),6.83(1H,d),6.70(1H,s),4.20(2H,t),4.13(2H,s),3.77(4H,t),2.90(2H,t),2.65(4H,t),2.24(3H,s);ESI-MS(m/z):463.2(M+H)+,925.3(2M+H)+。
实施例51:6-苄基-3-[3-甲基-4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-[3-甲基-4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率40.1%,1H-NMR(300MHz,DMSO-d6):δ7.21~7.43(8H,m),6.96(1H,d),4.06(2H,t),3.97(2H,s),2.82(2H,t),2.56(4H,m),2.13(3H,s),1.00(6H,m);ESI-MS(m/z):449.0(M+H)+,897.0(2M+H)+,919.0(2M+Na)+。
实施例52:6-苄基-3-[3-甲基-4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-[3-甲基-4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率41.6%,1H-NMR(600MHz,DMSO-d6):δ7.44(1H,d),7.38(2H,t),7.22~7.31(5H,m),6.98(1H,d),4.11(2H,t),3.98(2H,s),2.68(2H,t),2.23(6H,s),2.14(3H,s);ESI-MS(m/z):421.0(M+H)+。
实施例53:6-苄基-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率44.2%,1H-NMR(600MHz,DMSO-d6):δ7.41(1H,d),7.37(2H,d),7.23~7.30(5H,m),6.87(1H,d),4.90(2H,s),3.98(2H,s),3.44(4H,br),2.18(3H,s),1.60(2H,d),1.54(2H,s),1.45(2H,s);ESI-MS(m/z):475.0(M+H)+。
实施例54:6-苄基-3-{3-甲基-4-[(4-吗啉基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-{3-甲基-4-[(4-吗啉基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率38.8%,1H-NMR(600MHz,DMSO-d6):δ7.42(2H,d),7.38(1H,s),7.22~7.31(5H,m),6.89(1H,d),4.94(2H,s),3.98(2H,s),3.63(2H,m),3.58(2H,m),3.50(2H,m),3.47(2H,m),2.19(3H,s);ESI-MS(m/z):477.0(M+H)+。
实施例55:6-苄基-3-[3-甲基-4-(二乙胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-[3-甲基-4-(二乙胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率42.2%,1H-NMR(600MHz,DMSO-d6):δ7.40(2H,d),7.37(1H,s),7.22~7.31(5H,m),6.82(1H,d),4.89(2H,s),3.98(2H,s),3.37(4H,m),2.19(3H,s),1.17(3H,t),1.05(3H,t);ESI-MS(m/z):463.0(M+H)+。
实施例56:6-苄基-3-[3-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-苄基-3-[3-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率40.3%,1H-NMR(300MHz,CDCl3):δ7.24~7.37(7H,m),6.86(1H,d),6.67(1H,s),4.79(2H,s),4.12(2H,s),3.14(3H,s),3.02(3H,s),2.29(3H,s);ESI-MS(m/z):435.0(M+H)+,890.9(M+Na)+。
实施例57:6-(4-甲氧基苄基)-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-甲氧基苄基)-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率36.7%, 1H-NMR(300MHz,CDCl3):δ7.47(2H,d,J=8.7Hz),7.27(2H,d,J=8.4 Hz),6.94(2H,d,J=8.7Hz),6.83(2H,d,J=8.4Hz),6.72(1H,s),4.20(2H,t),4.05(2H,s),3.79(3H,s),2.86(2H,t),2.59(4H,s),1.64(4H,s),1.49(2H,s);ESI-MS(m/z):477.7(M+H)+。
实施例58:6-(4-甲氧基苄基)-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-甲氧基苄基)-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率49.5%,1H-NMR(300MHz,CDCl3):δ7.47(2H,d,J=8.7Hz),7.26(2H,d,J=8.5Hz),6.93(2H,d,J=8.7Hz),6.82(2H,d,J=8.5Hz),6.70(1H,s),4.13(2H,t),4.05(2H,s),3.79(2H,s),2.95(2H,t),2.61~2.73(4H,m),1.04~1.13(6H,m);ESI-MS(m/z):465.0(M+H)+。
实施例59:6-(4-甲氧基苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-甲氧基苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率41.2%,1H-NMR(300MHz,CDCl3):δ7.47(2H,d,J=8.7Hz),7.27(2H,d,J=9.0Hz),6.97(2H,d,J=9.0Hz),6.83(2H,d,J=8.7Hz),6.71(1H,s),4.14(2H,t),4.05(2H,s),3.79(3H,s),2.80(2H,t),2.39(6H,s);ESI-MS(m/z):437.0(M+H)+。
实施例60:6-(4-甲氧基苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-甲氧基苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率68.3%, 1H-NMR(300MHz,CDCl3):δ7.54(2H,d,J=9.0Hz),7.27(2H,d,J=8.4Hz),7.00(2H,d,J=9.0Hz),6.84(2H,d,J=8.7Hz),6.71(1H,s),4.77(2H,s),3.80(3H,s),3.60(2H,d),3.52(2H,d),1.64(6H,d);ESI-MS(m/z):491.1(M+H)+。
实施例61:6-(4-氯苄基)-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-氯苄基)-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率37.3%,1H-NMR(600MHz,DMSO-d6):δ7.51(2H,d,J=9.0Hz),7.41(1H,s),7.38(2H,d,J=8.4Hz),7.31(2H,d,J=8.4Hz),6.95(2H,d,J=9.0Hz),4.15(2H,t),3.98(2H,s),3.59(4H,m),2.73(2H,t),2.49(4H,m);ESI-MS(m/z):483.0(M+H)+。
实施例62:6-(4-氯苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-氯苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率40.8%,1H-NMR(600MHz,DMSO-d6):δ7.51(2H,d,J=8.4Hz),7.41(1H,s),7.38(2H,d,J =8.4Hz),7.32(2H,d,J=8.4Hz),6.95(2H,d,J=8.4Hz),4.11(2H,t),3.99(2H,s),2.67(2H,t),2.25(6H,s);ESI-MS(m/z):440.9(M+H)+,882.8(2M+H)+。
实施例63:6-(4-氯苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-氯苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率41.4%,1H-NMR(600MHz,DMSO-d6):δ7.52(2H,d,J=8.4Hz),7.42(1H,s),7.37(2H,d,J=8.4Hz),7.32(2H,d,J=8.4Hz),6.92(2H,d,J=8.4Hz),4.88(2H,s),3.90(2H,s),3.44(2H,s),3.41(2H,s),1.60(2H,s),1.55(2H,s),1.45(2H,s);ESI-MS(m/z):495.0(M+H)+。
实施例64:6-(4-氯苄基)-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-氯苄基)-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率42.4%, 1H-NMR(600MHz,DMSO-d6):δ7.31~7.38(7H,m),6.93(1H,d),4.12(2H,t),3.98(2H,s),2.71(2H,t),2.47(4H,m),2.13(3H,s),1.50(4H,m),1.38(2H,m);ESI-MS(m/z):495.0(M+H)+,990.9(2M+H+)。
实施例65:6-(4-氯苄基)-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-氯苄基)-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率28.4%, 1H-NMR(600MHz,DMSO-d6):δ7.25~7.37(7H,m),6.84(1H,t),4.89(2H,s),3.97(2H,s),3.45(4H,d),2.16(3H,s),1.59(2H,s),1.55(2H,s),1.45(2H,s);ESI-MS(m/z):509.0(M+H)+。
实施例66:6-(4-氯苄基)-3-{2-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-氯苄基)-3-{2-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,白色固体,收率25.3%,1H-NMR(600MHz,DMSO-d6):δ7.21~7.30(6H,m),6.89(1H,s),6.83(1H,dd),4.12(2H,t),3.88(2H,s),2.68(2H,s),2.45(4H,s),2.09(3H,s),1.51(4H,d),1.39(2H,s);ESI-MS(m/z):495.0(M+H)+。
实施例67:6-(4-氯苄基)-3-[2-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备
按照合成通法6,得到6-(4-氯苄基)-3-[2-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮,浅黄色固体,收率38.4%, 1H-NMR(600MHz,DMSO-d6):δ7.22~7.31(6H,m),6.88(1H,s),6.81(1H,dd),4.87(2H,s),3.88(2H,s),3.02(3H,s),2.86(3H,s),2.10(3H,s);ESI-MS(m/z):469.0(M+H)+。
实施例67:
本发明化合物作为选择性胰岛素分泌促进剂的活性,可以按许多标准的生物学实验或药理学实验测定。
选择性胰岛素分泌促进剂的活性测定实验。
材料与方法:
使用胰腺INS-1E细胞,测试目标化合物对葡萄糖依赖型胰岛素分泌能力的影响。在384孔板上培养INS-1E细胞,将该细胞用指定浓度(2μM或10μM)的目标化合物在高浓度(5mM葡萄糖和1.5μM的3-异丁基-1-甲基黄嘌呤)的葡萄糖条件下,处理1h。使用胰岛素AlphaLISATM试剂盒测定胰岛素分泌能力(ng·mL-1),纯化人胰岛素作为内标,计算受试化合物对胰岛素分泌能力的影响(%增加分泌量)。
从上述初筛结果中,选取具有对胰岛素分泌能力有较强影响的化合物,进行进一步的生物活性筛选:将384孔板上培养的INS-1E细胞,用指定浓度的目标化合物,分别在高浓度(5mM葡萄糖和1.5μM的3-异丁基-1-甲基黄嘌呤)的葡萄糖条件下和低浓度(0.1mM葡萄糖和1.5μM的3-异丁基-1-甲基黄嘌呤)的葡萄糖条件下,处理1h。使用胰岛素AlphaLISATM试剂盒测定胰岛素分泌能力(ng·mL-1),纯化人胰岛素作为内标,计算半数有效浓度EC50值。比较目标化合物分别在高浓度和低浓度葡萄糖条件下,对胰岛素分泌能力的影响,选择理想的选择性胰岛素分泌促进剂。
部分样品在高浓度葡萄糖条件下,对胰岛素分泌能力的影响,列表如下(n=3):
部分样品分别在高浓度和低浓度葡萄糖条件下,对胰岛素分泌能力的影响,列表如下(n=3):
在下述制剂中,“活性成分”是指式Ⅰ化合物,或其盐或其溶剂化物。
实施例68:片剂配方
生产工艺:(1).将项目1,2和3在合适的混合器中混合15min。(2).将步骤1的粉末混合物用20%Povidone K30溶液制粒。(3).在50℃干燥步骤2的颗粒。(4).将步骤3的颗粒通过合适的整粒装置。(5).将项目 5加入磨碎后的步骤4的颗粒中,并混合3min。(6).将步骤5的颗粒在合适的压片机上压片。
实施例69:胶囊配方
生产工艺:(1).将项目1,2和3在合适的混合器中混合15min。(2).加入项目4和5并混合3min。(3).填充到胶囊内。
实施例70:注射液/乳剂
生产工艺:(1).将项目1溶于项目2中。(2).将项目3、4和5加入项目6并混合至分散,然后均化。(3).将步骤1的溶液加入步骤2的混合物中,并均化至分散液透明。(4).无菌滤过0.2μm滤纸并填充到小瓶内。
实施例71:注射液/乳剂
生产工艺:(1).将项目1溶于项目2中。(2).将项目3、4和5加入项目6并混合至分散,然后均化。(3).将步骤1的溶液加入步骤2的混合物中,并均化至分散液透明。(4).无菌滤过0.2μm滤纸并填充到小瓶内。
实施例72:含有脂质体的配方配方
A.滴注配方的制备
在一玻璃管中混合合成的二棕榈酰基卵磷脂(45mg),二肉豆蔻酰 基卵磷脂(7mg),二棕榈酰基磷脂酰甘油(1mg)和活性化合物(5mg),将所有组份溶解在氯仿中,用N2蒸发掉大部分溶剂,然后减压,由此,在玻璃管表面形成脂质薄膜.在该脂质中加入水溶液(0.9%NaCl),在高于脂质的转相温度下形成脂质体,所得悬液含有大小范围为极小囊泡至2μm的脂质体。
B.吸入用配方的制备
按实施例A制备脂质体,其中的水溶液含有10%乳糖,乳糖与脂质之比为7:3。将该脂质体悬液用干冰冷冻,并且进行冷冻干燥,将干燥产物微粉化,所得颗粒的质均空气动力学直径(MMAD)约为2μm。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其他形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (10)
1.一种式(Ⅰ)所示的化合物,其前体药物和药物活性代谢物,及药学上可接受的盐:
其中
n1和n2为0至1的整数;
R1可以任意选择地由1个、2个或3个独立地选自H,卤素,-OH,C1-C4烷氧基,C1-C4烷基,-NO2,-O(CH2)n3NR3R4,-O(CH2)n4CONR5R6;
R2可以任意选择地由1个、2个或3个独立地选自-O(CH2)n5CH3;
n3为2至4的整数,n4为1至3的整数,n5为1至5的整数;
其中R3、R4独立地选自C1-C4烷基,或R3R4与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯基,所述取代基为卤素、C1-C4烷基、C1-C4烷氧基、羟基、硝基,优选2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴;
R5、R6独立的选自C1-C4烷基,或R5R6与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯基,所述取代基为:卤素、C1-C4烷基、C1-C4烷氧基、羟基、硝基,优选2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴。
2.权利要求1所述的化合物,其前体药物和药物活性代谢物,及药学上可接受的盐:其中,
R1可以任意选择1个、2个或3个H,卤素,-OH,甲氧基,甲基,-NO2,-O(CH2)n3NR3R4,-O(CH2)n4CONR5R6。
3.权利要求1或2所述的化合物,其前体药物和药物活性代谢物,及药学上可接受的盐:其中,
R3、R4独立地选自甲基或乙基,或R3R4与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯基,所述取代基为2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴。
4.权利要求1-3任何一项所述的化合物,其前体药物和药物活性代谢物,及药学上可接受的盐:其中,
R5、R6独立的选甲基或乙基,或R5R6与它们相连的氮原子一起组成吡咯烷基,甲基吡咯烷基,二甲基吡咯烷基,哌啶基,吗啉基,苄胺基,4-氯苯胺基,4-甲基苯胺基或六亚甲基亚胺基环;或分别独立地选自氢和取代或未取代的苯基,所述取代基为:2-甲基,2-乙基,2-甲氧基,2-乙氧基,2-氯,2-溴,2-羟基,2-硝基,3-硝基,4-甲基,4-乙基,4-甲氧基,4-乙氧基,4-氯,4-溴,4-羟基,4-硝基,2,4-二氯,2,4,6-三氯,2,4-二溴,2,4,6-三溴。
5.权利要求1-4任何一项述的化合物,其前体药物和药物活性代谢物,及药学上可接受的盐:选自,
3-苯基-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-氯苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苯基)-3-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基-3-甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-苯基-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-氯苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-溴苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基-3-甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-苯基-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲氧基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基苯基)-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-羟基-3-甲氧基苯基)-6-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苯基)-3-[4-(4-氯苯胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[4-(4-氯苯胺基)甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-(3-甲氧基-4-苄胺基甲酰基甲氧基苯基)-6-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-溴苯基)-3-[3-甲氧基-4-(4-氯苯胺基)甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-乙氧基苯基)-3-[4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-6-(4-乙氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-乙氧基苯基)-3-[3-甲氧基-4-(4-吗啉基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苯基)-3-(4-苄胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苯基)-3-[3-甲氧基-4-(2-二乙胺基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-(4-甲基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(2-甲氧基苄基)-3-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-羟基苄基)-3-(2-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-羟基苄基)-3-(3-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-羟基苄基)-3-(2-甲基-4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(3-甲氧基-4-羟基苄基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(3-甲氧基-4-羟基苄基)-3-(2-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-(4-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{2-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[2-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-(2-二甲胺基甲酰基甲氧基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-{3-甲基-4-[(4-吗啉基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(二乙胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-苄基-3-[3-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-甲氧基苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{4-[2-(4-吗啉基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-[4-(2-二甲胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-[4-(1-哌啶基)甲酰基甲氧基苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{3-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{3-甲基-4-[(1-哌啶基)甲酰基甲氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-{2-甲基-4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮;
6-(4-氯苄基)-3-[2-甲基-4-(二甲胺基甲酰基甲氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮。
6.一种药物组合物,包括作为活性成分的权利要求1-5中任何一项的化合物、其前体药物和药物活性代谢物,及药学上可接受的盐和药学上可接受的载体或赋形剂。
7.一种药物制剂,包含权利要求1-5任何一项所述的化合物、其前体药物和药物活性代谢物,及药学上可接受的盐或权利要求6所述的药物组合物。
8.权利要求1-5任何一项所述的化合物、其前体药物和药物活性代谢物,及药学上可接受的盐在制备治疗II型糖尿病药物中的应用。
9.权利要求6所述的药物组合物在制备治疗II型糖尿病药物中的应用。
10.权利要求7所述的药物制剂在制备治疗II型糖尿病药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610303702.6A CN105949220B (zh) | 2016-05-10 | 2016-05-10 | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610303702.6A CN105949220B (zh) | 2016-05-10 | 2016-05-10 | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105949220A true CN105949220A (zh) | 2016-09-21 |
CN105949220B CN105949220B (zh) | 2018-05-25 |
Family
ID=56913973
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610303702.6A Expired - Fee Related CN105949220B (zh) | 2016-05-10 | 2016-05-10 | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105949220B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101503414A (zh) * | 2009-03-04 | 2009-08-12 | 沈阳药科大学 | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
US20110237527A1 (en) * | 2010-03-23 | 2011-09-29 | Albany Molecular Research, Inc. | Sglt-2 inhibitors, methods of making them, and uses thereof |
CN103012438A (zh) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | 烷氧基取代的噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
-
2016
- 2016-05-10 CN CN201610303702.6A patent/CN105949220B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101503414A (zh) * | 2009-03-04 | 2009-08-12 | 沈阳药科大学 | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
US20110237527A1 (en) * | 2010-03-23 | 2011-09-29 | Albany Molecular Research, Inc. | Sglt-2 inhibitors, methods of making them, and uses thereof |
CN103012438A (zh) * | 2012-11-15 | 2013-04-03 | 沈阳药科大学 | 烷氧基取代的噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
Non-Patent Citations (11)
Also Published As
Publication number | Publication date |
---|---|
CN105949220B (zh) | 2018-05-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5775464B2 (ja) | 非晶質cddo−meを含有する遅延放出性経口投薬組成物 | |
ES2636087T3 (es) | Un antagonista de receptores de endotelina y angiotensina II de bifenilsulfonamida para tratar la glomeruloesclerosis | |
ES2307219T3 (es) | Nebivolol y sus sales farmaceuticamente aceptables, procedimiento de preparacion y composiciones farmaceuticas de nebivolol. | |
US8455662B2 (en) | Formulations for benzimidazolyl pyridyl ethers | |
TWI384984B (zh) | 抗癌口服藥學組成物 | |
CN102885813A (zh) | 用于治疗过度增生性疾病的药物组合物 | |
AU2011376953A1 (en) | Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof | |
JP2007512350A (ja) | カルベジロール組成物の治療および送達方法 | |
US20100087481A1 (en) | Oral pharmaceutical formulations for antidiabetic compounds | |
SG182175A1 (en) | Stabilized amorphous forms of imatinib mesylate | |
CN101503414B (zh) | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 | |
AU2022381220A1 (en) | Formulations of psilocybin analogs and methods of use | |
US9169238B2 (en) | Solid pharmaceutical composition | |
EP2050436A1 (en) | Pharmaceutical composition containing dutasteride | |
CN103012438B (zh) | 烷氧基取代的噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 | |
CN105949220A (zh) | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 | |
CN105777712B (zh) | 四氢异喹啉类衍生物及其应用 | |
TW200800198A (en) | Pharmaceutical dosage forms and compositions | |
JP2007504190A (ja) | 3−[(2−{[4−(ヘキシルオキシカルボニルアミノ−イミノ−メチル)−フェニルアミノ]−メチル}−1−メチル−1h−ベンズイミダゾール−5−カルボニル)−ピリジン−2−イル−アミノ]−エチルプロピオネート及びそれらの塩の新規経口投与形態 | |
CN102133188B (zh) | 一种西洛他唑脂质体固体制剂 | |
US11266649B2 (en) | Pharmaceutical formulations | |
TW202233179A (zh) | 藥物配製物 | |
KR20230024389A (ko) | 우티델론의 고체 경구용 제제 | |
EP4164618A1 (en) | 3d laser sintering processes for improved drug delivery | |
JP2011063567A (ja) | 保存安定性の向上した錠剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180525 |