CN104610190B - One class contains halogenophenyl thiazole carboxylic acid amides's compounds and the purposes of cyclopropyl amidine structure - Google Patents
One class contains halogenophenyl thiazole carboxylic acid amides's compounds and the purposes of cyclopropyl amidine structure Download PDFInfo
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- CN104610190B CN104610190B CN201510072480.7A CN201510072480A CN104610190B CN 104610190 B CN104610190 B CN 104610190B CN 201510072480 A CN201510072480 A CN 201510072480A CN 104610190 B CN104610190 B CN 104610190B
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- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical class NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 4
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001409 amidines Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 108091006269 SLC5A2 Proteins 0.000 abstract description 20
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 abstract description 20
- 108091006277 SLC5A1 Proteins 0.000 abstract description 19
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 abstract description 19
- 239000003112 inhibitor Substances 0.000 abstract description 9
- -1 saccharide glycoside Chemical class 0.000 abstract description 6
- 229930182470 glycoside Natural products 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 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 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- RYVMUASDIZQXAA-UHFFFAOYSA-N pyranoside Natural products O1C2(OCC(C)C(OC3C(C(O)C(O)C(CO)O3)O)C2)C(C)C(C2(CCC3C4(C)CC5O)C)C1CC2C3CC=C4CC5OC(C(C1O)O)OC(CO)C1OC(C1OC2C(C(OC3C(C(O)C(O)C(CO)O3)O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OCC(O)C(O)C1O RYVMUASDIZQXAA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 239000012097 Lipofectamine 2000 Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 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 2
- 239000007788 liquid Substances 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 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 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 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
- 229940122069 Glycosidase inhibitor Drugs 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 102100040918 Pro-glucagon Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 description 1
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960001713 canagliflozin Drugs 0.000 description 1
- 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 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction 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
- 230000003203 everyday effect Effects 0.000 description 1
- 238000009207 exercise therapy Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
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- 239000003316 glycosidase inhibitor Chemical class 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- FYFFGSSZFBZTAH-UHFFFAOYSA-N methylaminomethanetriol Chemical compound CNC(O)(O)O FYFFGSSZFBZTAH-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
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- 238000004321 preservation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
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- 239000011541 reaction mixture Substances 0.000 description 1
- 230000030558 renal glucose absorption Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 108091008146 restriction endonucleases Proteins 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The present invention relates to the drug world relevant to type 2 diabetes mellitus.Specifically, the present invention relates to the double target spot inhibitor of the class halogenophenyl thiazole carboxylic acid amides class non-saccharide glycoside SGLT2/SGLT1 containing cyclopropyl amidine structure, its preparation method and their application in preparing type 2 diabetes mellitus medicine.Wherein, wherein, R1Selected from halogenic substituent.
Description
Technical field
The present invention relates to the drug world of the treatment of type 2 diabetes mellitus.Specifically, the present invention relates to 2 type sugar
Urine sick medicative class halogenophenyl thiazole carboxylic acid amides's class non-saccharide glycoside containing cyclopropyl amidine structure
The double target spot inhibitor of SGLT2/SGLT1, its preparation method and in purposes pharmaceutically.
Background technology
Diabetes are a kind of metabolic diseases being characterized with hyperglycemia.Hyperglycemia is then owing to insulin secretion lacks
Fall into or its biological agent is impaired, or both have concurrently and cause.Long-standing hyperglycemia during diabetes, causes various
Tissue, particularly eye, kidney, heart, blood vessel, neural chronic lesion, dysfunction.There is no radical cure at present
The method of diabetes, but diabetes progression suitably can be controlled by multiple treatment means.Mainly include
Several aspects: the education of diabetics, self-monitoring of blood glucose, Diet Therapy, exercise therapy and Drug therapy.
Oral hypoglycaemic medicine is by a variety of, such as sulfonylurea, biguanides, thiazolidinediones, glycosidase inhibitor
Class, etc., but these medicines generally have various different side effect, such as hepatotoxicity, hypoglycemia, abdomen
Swollen, heart disease risk, etc..Therefore the medicine of brand-new action target spot is urgent needs clinically.
Sodium-glucose co-transporters body (sodium-glucose linked transporter, SGLT) is that a kind of glucose turns
Fortune albumen, has two kinds of i.e. SGLT1 and SGLT2 of hypotype, and both all have distribution in renal proximal tubules, right
In kidney, the contribution of glucose reabsorption is respectively 10% and 90%, and in addition SGLT1 is also distributed about intestinal
In, it is responsible for the absorption of glucose in intestinal together with GLUT.Suppression SGLT2 can make the Fructus Vitis viniferae in renal tubules
Sugar can not the most heavily be absorbed into blood and discharge with urine, thus reduces blood sugar concentration, listing at present
SGLT2 inhibitor has multiple, such as dapagliflozin, canagliflozin and empagliflozin etc..
The inhibitor of these listings is all selective SGLT2 inhibitor, the most weak to SGLT1 inhibitory action.
At the initial stage of SGLT2 inhibitor research and development, the selectivity of SGLT2/SGLT1 was considered as once critically important finger
Mark, because suppression SGLT1 may cause intestines and stomach side reaction in theory.But research in recent years shows,
This theoretic worry it is not necessary that, and confirmed by the clinical trial of LX4211
(Zambrowicz B,et al.Effects of LX4211,a dual sodium-dependent glucose
cotransporters 1and 2inhibitor,on postprandial glucose,insulin,glucagon-like
peptide 1,and peptide tyrosine in a dose-timing study in healthy subjects,Clin Ther.,
2013,35(8),1162-1173.e8).Owing to SGLT2/SGLT1 inhibitor can be on the basis of suppression SGLT2
On suppress SGLT1 further, and this suppression can increase the discharge of glucose in urine in kidney and reduce Portugal in intestinal
The absorption of grape sugar, the most this kind of inhibitor is considered as a kind of brand-new selection controlling blood glucose.
The invention discloses halogenophenyl thiazole carboxylic acid amides's class non-saccharide glycoside of a class cyclopropyl amidine structure
The double target spot inhibitor of SGLT2/SGLT1, these compounds can be used for the medicine of preparation treatment type 2 diabetes mellitus.
Summary of the invention
It is an object of the present invention to provide and a kind of there is the double target spot inhibitory activity of good SGLT2/SGLT1,
There is the non-glucoside compound of class of formula I.
It is a further object to provide the method that preparation has compounds of formula I.
It is also another object of the present invention to provide containing compounds of formula I answering in terms for the treatment of type 2 diabetes mellitus
With.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has compounds of formula I and has a following structural formula:
Wherein, R1Selected from halogenic substituent.
The compound of preferred formula I has following structure,
Logical formula (I) compound of the present invention is synthesized by following route:
Compound II uses HCl gas treatment in presence of methyl alcohol, obtains compound III；Compound III deposits at alkali
React with amine IV lower, obtain the compound V containing amidine structure；Compound V reacts with compound VI,
To compound VII；Compound VII is condensed with compound VIII in the presence of DCC, obtains compound I, its
Middle R1Defined as described above.
Compound of Formula I of the present invention has the double inhibition effect of SGLT2/SGLT1, can be as effectively
Composition is for preparing the medicine of type 2 diabetes mellitus.The activity of compound of Formula I of the present invention is by being subject to
Body binding tests is verified.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The agent that such as every day takes
Amount, about in the range of 1mg-1000mg/ people, is divided into once or is administered for several times.Actual take formula I of the present invention
The dosage of compound can be determined according to relevant situation by doctor.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only
For illustrating, and it is not intended to limit the present invention.Those skilled in the art are made according to the teachings of the present invention
Various changes all should be within the protection domain required by the application claim.
The synthesis of embodiment 1 compound I-1
A. the synthesis of compound III
7.55g (100mmol) compound II is dissolved in 100mL absolute methanol, slowly leads under ice-water bath cooling
Enter dry HCl gas, be substantially saturated to solution, then overnight at room temperature stirring.Collected by suction solid,
Ambient temperature in vacuum is dried, and obtains white solid, is compound III.
B. the synthesis of compound V-1
12.96g (90mmol) compound III and 5.13g (90mmol) IV-1 is dissolved in the DMF that 100mL is dried
In, stir under room temperature, add 12.14g (120mmol) triethylamine, be then warming up to 80 DEG C of reactions, until
TLC checks that reaction completes (usual 3 hours).After having reacted, after reactant mixture is the coldest, it is poured into 300mL
In frozen water, stirring, use the CH of 100mL × 32Cl2Extraction, merges extraction phase, and anhydrous sodium sulfate is dried.
Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification,
To compound V-1, white solid, ESI-MS, m/z=133 ([M+H]+)。
C. the synthesis of compound VII-1
7.92g (60mmol) compound V-1 and 6.13g (60mmol) compound VI is dissolved in what 50mL was dried
In THF, stir under room temperature, until TLC detection reaction completes (usual one week).After having reacted, reaction
Mixture is poured in 200mL frozen water, stirring, uses the CH of 50mL × 32Cl2Extraction, merges extraction
Phase, anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, the remnants obtained
Thing uses column chromatography purification, obtains compound VII-1, white solid, ESI-MS, m/z=199 ([M+H]+)。
D. the synthesis of compound I-1
5.94g (30mmol) compound VII-1 and 7.17g (30mmol) VIII-1 is dissolved in what 100mL was dried
In THF, stir under room temperature, then add 6.81g (33mmol) N, N'-dicyclohexyl carbodiimide (DCC)
With 1.00g DMAP (DMAP), then it is stirred overnight under room temperature.After having reacted, toward reaction
Adding 100mL methyl tertiary butyl ether(MTBE) in mixture, be stirred for 1 hour, sucking filtration, filtrate pours into 500mL
In frozen water, stirring, use the CH of 100mL × 32Cl2Extraction, merges extraction phase, and anhydrous sodium sulfate is dried.
Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and the residue obtained uses column chromatography purification,
To compound I-1, white solid, ESI-MS, m/z=420 ([M+H]+)。
Embodiment 2-10
With reference to embodiment 1 method, synthesize compound listed in Table.
Embodiment 11 Compound ira vitro is to people SGLT2 and the suppression of people SGLT1
Prepared by people's SGLT2 expression vector
The full length cDNA clone (purchased from GenScript company) expressing people SGLT2 (is put at cDNA two ends
Hind III and Not I site) sub-clone is to the Hind of pEAK15 expression vector (Theracos company of the U.S.)
Between III and Not I site.The method of the clone's digestion with restriction enzyme containing target gene determines.
Prepared by people's SGLT2 stably transfected cell line
Utilize the restricted enzyme Nsi I digestion plasmid containing people SGLT2, be allowed to linearisation, use agarose
Linear DNA is purified by gel electrophoresis.With transfection reagent Lipofectamine2000 (Invitrogen company)
DNA after purification is proceeded to HEK293 cell (Theracos company of the U.S.).Cell after transfection is being contained
In 37 DEG C in the DMEM culture medium of 10% hyclone, 5%CO2Under the conditions of cultivate after 24 hours, identical
Growth medium in add purine mycin (Invitrogen company) continue cultivate 2 weeks, will through screening after have fast
The cell of purine chloramphenicol resistance is inoculated in 96 new orifice plates (one, every hole cell), in the cultivation containing purinase element
Base is cultivated, until cell length is to converging state.There is the cell clone of puromycin-resistant by reflection
Methyl-α-D-[the U-of SGLT2 activity14C] (experimental technique is below in pyranoside picked-up test screening further
In be described in detail).Select there is the cell clone of highest signal to noise ratio for follow-up methyl-α-D-[U-14C] pyranose
Glycosides picked-up test.
Prepared by people's SGLT1 express cell
PDream2.1 expression vector containing total length people SGLT1cDNA is purchased from GenScript company.Plasmid
Expanding in bacillus coli DH 5 alpha, this strain culturing is in the Luria-Bertani (LB) containing ampicillin
In culture medium.Plasmid is extracted with QIAGEN Plasmid Midi test kit (QIAGEN company).With
Lipofectamine 2000 transfection reagent, turns people's SGLT1 expression vector plasmid according to the method for workbook
Enter COS-7 cell (purchased from American type culture collection).Transfectional cell is containing 10%DMSO's
In-80 DEG C of preservations in DMEM.
Methyl-α-D-[U-14C] pyranoside picked-up test
Before test, the cell expressing SGLT1 and SGLT2 respectively is connect with the DMEM containing 10%FBS
Kind dodges plate (PerkinElmer company) in 96 holes ScintiPlate liquid, and (every hole adds 100 μ L culture fluid, containing 1 × 105
Individual cell), and in 37 DEG C, cultivate 48 hours under the conditions of 5%CO2.Cell is with 150 μ L buffer in sodium
(137mM NaCl, 5.4mM KCl, 2.8mM CaCl2, 1.2mM MgCl2, 10mM trihydroxy methyl amino
Methane/N-2-hydroxyethyl piperazine-N '-ethane sulfonic acid [Tris/Hepes], pH7.2) or without sodium buffer (137mM
N-methyl-glucamine, 5.4mM KCl, 2.8mM CaCl2,1.2mM MgCl2,10mM Tris/Hepes,
PH7.2) twice is washed.Testing compound is dissolved in containing 25% human plasma and 40 μ Ci/mL methyl-α-D-[U-14C] pyrans
Glucosides (Amersham Biosciences/GE Healthcare) containing sodium or without in sodium buffer, being prepared as one is
The testing compound solution of row suitable concn.The 96 every holes of orifice plate add 50 μ L testing compound solutions, vibration
Cultivate 2 hours (SGLT1 analysis) or 1.5 hours (SGLT2 analysis).Cell is with 150 μ L cleaning buffer solutions
(137mM N-METHYL-ALPHA-L-GLUCOSAMINE, 10mM Tris/Hepes, pH7.2) washes twice, dodges meter with TopCount liquid
Number instrument (Perkin Elmer company) carries out quantitative analysis to the picked-up of methyl-α-D-[U-14C] pyranoside.Sodium depends on
Rely property pyranoside intake to be the intake obtained with the process containing sodium buffer to deduct without the process of sodium buffer
The difference (meansigma methods of three wells) of the intake obtained.
Shown in the following list of result.
The IC that people SGLT2 and people SGLT1 is suppressed by the part of compounds of the present invention50Value
Above-mentioned IC50Measurement result show, comparing single target spot inhibitor, the compound of the present invention is strong simultaneously
SGLT2 target spot inhibitor and SGLT1 target spot inhibitor, can be used to preparation treatment type 2 diabetes mellitus medicine
Thing.
Claims (4)
1. there is the compound of general formula I,
Wherein, R1Selected from halogenic substituent.
2. compound of Formula I defined in claim 1, selected from following compounds,
3. synthesis claim 1-2 arbitrary defined in belong to the method for compounds of formula I:
Compound II uses HCl gas treatment in presence of methyl alcohol, obtains compound III；Compound III deposits at alkali
React with amine IV lower, obtain the compound V containing amidine structure；Compound V reacts with compound VI,
To compound VII；Compound VII is condensed with compound VIII in the presence of DCC, obtains compound I, its
Middle R1Definition such as claim 1-2 arbitrary described.
4. the defined compound of Formula I of one of claim 1-2 answering in terms of preparation treatment type 2 diabetes mellitus medicine
With.
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