CN115304604A - 一种双靶点西格列汀衍生物 - Google Patents
一种双靶点西格列汀衍生物 Download PDFInfo
- Publication number
- CN115304604A CN115304604A CN202210032332.2A CN202210032332A CN115304604A CN 115304604 A CN115304604 A CN 115304604A CN 202210032332 A CN202210032332 A CN 202210032332A CN 115304604 A CN115304604 A CN 115304604A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- substituted
- unsubstituted
- compound
- diabetes
- 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
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical class C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 22
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 20
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 238000011321 prophylaxis Methods 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims description 28
- -1 2, 4, 5-trifluorophenyl Chemical group 0.000 claims description 24
- 125000002837 carbocyclic group Chemical group 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 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 claims description 18
- 229940079593 drug Drugs 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 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 claims description 13
- 239000008103 glucose Substances 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 229960004034 sitagliptin Drugs 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 102000004877 Insulin Human genes 0.000 claims description 7
- 108090001061 Insulin Proteins 0.000 claims description 7
- 230000009102 absorption Effects 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 7
- 229940125396 insulin Drugs 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- JSBJQQZPQJIGFJ-UHFFFAOYSA-N 1-fluoro-4-(4-methylphenyl)benzene Chemical compound C1=CC(C)=CC=C1C1=CC=C(F)C=C1 JSBJQQZPQJIGFJ-UHFFFAOYSA-N 0.000 claims description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 4
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 4
- 229960003105 metformin Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 4
- 229940080818 propionamide Drugs 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 3
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 claims description 3
- 229960002632 acarbose Drugs 0.000 claims description 3
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229960004580 glibenclamide Drugs 0.000 claims description 3
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 3
- 230000003914 insulin secretion Effects 0.000 claims description 3
- 229960002397 linagliptin Drugs 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229960005095 pioglitazone Drugs 0.000 claims description 3
- 210000001519 tissue Anatomy 0.000 claims description 3
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 2
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 claims description 2
- 108010011459 Exenatide Proteins 0.000 claims description 2
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 claims description 2
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 claims description 2
- 229940122355 Insulin sensitizer Drugs 0.000 claims description 2
- 108010019598 Liraglutide Proteins 0.000 claims description 2
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 2
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 claims description 2
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 claims description 2
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 claims description 2
- 229960001667 alogliptin Drugs 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 229960001713 canagliflozin Drugs 0.000 claims description 2
- 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 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229950009226 ciglitazone Drugs 0.000 claims description 2
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- 229960001519 exenatide Drugs 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 229960000346 gliclazide Drugs 0.000 claims description 2
- 229960004346 glimepiride Drugs 0.000 claims description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 claims description 2
- 229960001381 glipizide Drugs 0.000 claims description 2
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 2
- 229960003468 gliquidone Drugs 0.000 claims description 2
- 230000004153 glucose metabolism Effects 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 229950000991 ipragliflozin Drugs 0.000 claims description 2
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229960002701 liraglutide Drugs 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 229960001110 miglitol Drugs 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 229960000698 nateglinide Drugs 0.000 claims description 2
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 230000035515 penetration Effects 0.000 claims description 2
- 230000002093 peripheral effect Effects 0.000 claims description 2
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 claims description 2
- 229960003243 phenformin Drugs 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000030558 renal glucose absorption Effects 0.000 claims description 2
- 229960002354 repaglinide Drugs 0.000 claims description 2
- 229960004586 rosiglitazone Drugs 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 210000003462 vein Anatomy 0.000 claims description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 2
- 229960001254 vildagliptin Drugs 0.000 claims description 2
- 229960001729 voglibose Drugs 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 230000003449 preventive effect Effects 0.000 claims 2
- 210000004400 mucous membrane Anatomy 0.000 claims 1
- 239000007923 nasal drop Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000007920 subcutaneous administration Methods 0.000 claims 1
- 102100040134 Free fatty acid receptor 4 Human genes 0.000 abstract description 11
- 101000890672 Homo sapiens Free fatty acid receptor 4 Proteins 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 10
- 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 abstract description 9
- 238000001727 in vivo Methods 0.000 abstract description 5
- 230000033228 biological regulation Effects 0.000 abstract description 2
- 208000030159 metabolic disease Diseases 0.000 abstract description 2
- 230000028327 secretion Effects 0.000 abstract description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract 2
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 abstract 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 abstract 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract 1
- 229940122199 Insulin secretagogue Drugs 0.000 abstract 1
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 11
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 8
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 6
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 6
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 6
- 102100040918 Pro-glucagon Human genes 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000005626 carbonium group Chemical group 0.000 description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 6
- 108070000009 Free fatty acid receptors Proteins 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 230000002218 hypoglycaemic effect Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LPGBXHWIQNZEJB-UHFFFAOYSA-N 3-[4-[[5-fluoro-2-(4-methylphenyl)phenyl]methoxy]phenyl]propanoic acid Chemical compound C1=CC(C)=CC=C1C1=CC=C(F)C=C1COC1=CC=C(CCC(O)=O)C=C1 LPGBXHWIQNZEJB-UHFFFAOYSA-N 0.000 description 3
- 101800001982 Cholecystokinin Proteins 0.000 description 3
- 102100025841 Cholecystokinin Human genes 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 102100040133 Free fatty acid receptor 2 Human genes 0.000 description 3
- 102000004157 Hydrolases Human genes 0.000 description 3
- 108090000604 Hydrolases Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229940107137 cholecystokinin Drugs 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 125000006618 5- to 10-membered aromatic heterocyclic group Chemical group 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 description 2
- 102100040136 Free fatty acid receptor 3 Human genes 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical group C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical group C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 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
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- KOHMUAMPZUHGNV-UHFFFAOYSA-N 3-[4-[(5-chloro-2,2-dimethyl-3h-1-benzofuran-7-yl)methoxy]-2,3-dimethylphenyl]propanoic acid Chemical compound C1=C(CCC(O)=O)C(C)=C(C)C(OCC=2C=3OC(C)(C)CC=3C=C(Cl)C=2)=C1 KOHMUAMPZUHGNV-UHFFFAOYSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- FWDBZJBJTDRIIY-UHFFFAOYSA-N CC(C)(C)[K] Chemical compound CC(C)(C)[K] FWDBZJBJTDRIIY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010065941 Central obesity Diseases 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
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 101150050349 FFAR2 gene Proteins 0.000 description 1
- 101150108864 Ffar1 gene Proteins 0.000 description 1
- 101150008543 Ffar3 gene Proteins 0.000 description 1
- 101710142060 Free fatty acid receptor 1 Proteins 0.000 description 1
- 101710142059 Free fatty acid receptor 2 Proteins 0.000 description 1
- 101710142057 Free fatty acid receptor 3 Proteins 0.000 description 1
- 101710142055 Free fatty acid receptor 4 Proteins 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
- 102100033864 G-protein coupled receptor 84 Human genes 0.000 description 1
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
- 102000058061 Glucose Transporter Type 4 Human genes 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 description 1
- 101000890668 Homo sapiens Free fatty acid receptor 2 Proteins 0.000 description 1
- 101000890662 Homo sapiens Free fatty acid receptor 3 Proteins 0.000 description 1
- 101001069589 Homo sapiens G-protein coupled receptor 84 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010065716 Pharyngeal inflammation Diseases 0.000 description 1
- 102000007074 Phospholipase C beta Human genes 0.000 description 1
- 108010047834 Phospholipase C beta Proteins 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 101100264077 Xenopus laevis wrn gene Proteins 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000006377 glucose transport Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 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
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 208000030212 nutrition disease Diseases 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Abstract
本发明提供式(I)表示的化合物及其生理学可接受盐，其中各个符号如说明书中所定义。所述化合物或其盐在体内代谢后具有GPR120受体和DPP‑IV酶双重功能调节作用，一方面引起GLP‑1分泌增加，另一方面抑制GLP‑1被DPP‑IV降解。并且作为胰岛素促分泌素或预防或治疗糖尿病、代谢综合征、及其相关疾病等的药物是有用的
Description
技术领域
本发明涉及一类双靶点化合物、其制备方法及含有该化合物的药物或药物组合物以及其作为治疗剂特别是作为GPR120受体激动剂和DPP-IV酶抑制剂在预防或治疗糖尿病、代谢综合征、及其相关疾病等的药物的用途。
背景技术
糖尿病是一种能量代谢疾病，主要分为1型糖尿病(胰岛素依赖型糖尿病)和2型糖尿病(非-胰岛素依赖型糖尿病)。目前全球约有4.25亿糖尿病患者，平均每11个人中就有1位患病。其中2型糖尿病患者约占糖尿病患者总数的90～95％。
糖尿病可以通过饮食调节和锻炼治疗。当这些不能缓解症状时，需要进行药物治疗。目前糖尿病的药物治疗方法包括：双胍类如二甲双胍，能够减少肝脏中葡萄糖的形成；磺酰脲类如格列本脲，能够刺激胰腺β细胞分泌更多的胰岛素；噻唑烷二酮类如匹格列酮，通过激活氧化物酶体增殖物激活受体γ(PPAR-γ)增强胰岛素的生物效用；α-葡萄糖苷酶抑制剂如阿卡波糖，能够抑制肠道内葡萄糖的生成；胰高血糖素样肽-1(GLP-1)类似物如利拉鲁肽，能够促进胰腺的β细胞分泌胰岛素；二肽基肽酶IV(DPP-IV)抑制剂如西格列汀，能够抑制体内GLP-1的降解。但是，现有的治疗糖尿病的方法都有一定的缺陷。例如胰岛素注射剂和磺酰脲类，可能引起低血糖和体重增加副作用；二甲双胍类、α-葡萄糖苷酶抑制剂和GLP-1类似物可能引起胃肠道副作用；PPAR-γ激动剂可能引起体重增加和水肿副作用；DPP-IV抑制剂可能引起咽上部炎、头疼和感染副作用。针对多个领域的研究正在进行，以期为市场带来更有效的新型降血糖药物。
游离脂肪酸受体(FFAR)是近几年去孤儿化的G蛋白偶联受体(GPCRs)。目前已确定的游离脂肪酸受体有G蛋白偶联受体40(GPR40)家族，包括GPR40(也称游离脂肪酸受体1，FFA1)、GPR41(也称也称游离脂肪酸受体3，FFA3)、GPR43(也称游离脂肪酸受体2，FFA2)以及其它家族的GPR84、GPR120。近年来，以G蛋白偶联受体120(GPR120)为代表的游离脂肪酸受体在糖尿病治疗领域受到广泛关注。GPR120又称游离脂肪酸受体4(free fat acidreceptors，FFA4)是G蛋白偶联受体家族(GPCRs)的成员之一，与GPCRs具有相似的跨膜结构。
GPR120在体内参与调节多种生理功能，①促进胰高血糖素样肽(GLP-1)、葡萄糖依赖性促胰岛素分泌肽(GIP)和胆囊收缩素(CCK)的分泌。激活GPR120能够通过PLC-β/IP3通路增加响应细胞内Ca2+浓度，促使L细胞分泌GLP-1，K细胞分泌GIP，I细胞分泌CCK；②促进葡萄糖转运，增加胰岛素敏感性。激活GPR120能够通过Gαq/11/PI3K/AKT/GLUT4通路促进脂肪细胞对葡萄糖的摄取；因此，激活GPR120可以通过多条通路调节血糖。然而GLP-1在体内很容易被DPP-IV代谢失活，半衰期只有1～2min，因此严重影响了GPR120激动剂的降血糖作用。
DPP-IV属于二肽基肽酶家族，由766个氨基酸组成，是一个相对分子质量为110KDa的跨膜糖蛋白，广泛存在于哺乳动物体液和多种组织。基本结构主要包括：细胞内N-末端区域(1-6位残基)，跨膜区域(2-28位残基)以及胞外区域(29-766位残基)。胞外区域根据结构及功能特点又分为α/β水解酶区域和八片层β螺旋区域。α/β水解酶区域表现为α/β水解酶折叠，含有催化三联体Ser630-Asp708-His740，是DPP-IV水解GLP-1和GIP的场所，DPP-IV抑制剂能够通过抑制DPP-IV的活性增加GLP-1的浓度降低血糖。
西格列汀，英文名称sitagliptin，分子式C16H15F6N5O，分子量407.31，CAS号486460-32-6，属于DPP-4的选择性抑制剂。具有抗糖尿病作用。
本发明涉及结构新颖的双靶点化合物，该类化合物即具有GPR120激动活性又具有DPP-IV抑制活性。因此所述通式(I)化合物及其药用盐潜在的用于治疗或者预防糖尿病及相关疾病是有效的。
发明内容
本发明所要解决的技术问题是提供一种双靶点西格列汀衍生物以及上述衍生物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
本发明目的的技术方案是：一种双靶点西格列汀衍生物，具有下述通式(I)：
其中：
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环；
R1和R2相同或不同，并各自为H、D、F、Cl、Br、取代或未取代的C1-C6烷基、C3-C10碳环、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R3为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R4和R5相同或不同，并各自为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
作为优选，其是通式(II)所示的化合物或其可药用的盐：
其中：
R1和R2相同或不同，并各自为H、D、F、Cl、Br、取代或未取代的C1-C6烷基、C3-C10碳环、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R3为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R4和R5相同或不同，并各自为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
作为优选，其是通式(III)所示的化合物或其可药用的盐：
其中：
R1和R2相同或不同，并各自为H、D、F、Cl、Br、取代或未取代的C1-C6烷基、C3-C10碳环、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
优选化合物选自但不限于下列化合物：
(R)-3-(4-((4-氟-4'-甲基-[1,1'-联苯]-2-)甲氧基)苯基)-N-(4-氧-4-(3-(三氟甲基)-5,6-二氢-[1,2,4]三氮唑[4,3-a]吡嗪-7(8H)-)-1-(2,4,5-三氟苯基)丁酰-2-)丙酰胺。
所述的盐为盐酸盐、磷酸盐、硫酸盐、碳酸盐、硝酸盐、柠檬酸盐、酒石酸盐、马来酸盐、琥珀酸盐、磺酸盐、对甲苯磺酸盐、甲磺酸盐、苯甲酸盐、富马酸盐。
所述的药物组合物表示含有一种或多种本发明通式(I)所述化合物或其可药用的盐联合一种或多种治疗糖尿病药物与其他化学组分的混合物，其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收，利于活性成分在生物体内发挥生物活性，降低副作用。
所述的药物组合物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
所述的治疗糖尿病药物，包括胰岛素、胰岛素类似物、促进胰岛β细胞分泌胰岛素的药物、促进外周组织增加葡萄糖利用的药物、抑制肠道葡萄糖吸收的药物、胰岛素增敏剂、促进葡萄糖代谢的药物或者抑制肾脏葡萄糖重吸收的药物等，其优选实例包括胰岛素、胰岛素类似物、格列苯脲、格列喹酮、格列齐特、格列吡嗪、格列美脲、瑞格列奈、那格列奈、二甲双胍、苯乙双胍、环格列酮、罗格列酮、吡格列酮、利拉鲁肽、艾塞那肽、利司那肽、阿必鲁肽、阿卡波糖、伏格波糖、米格列醇、沙格列汀、西格列汀、维格列汀、利格列汀、阿格列汀、曲格列汀、达格列净、卡格列净、艾格列净、Ipragliflozin、Luseogliflozin以及Tofogliflozin等。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，所述的药物还包括药学上可以接受的载体如稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体或润滑剂。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，该药物可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮肉、皮下、静脉、粘膜组织，或是被其他物质混合或包裹后导入机体等。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，该药物可制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。
所述代谢综合征及其相关疾病为蛋白质、脂肪、碳水化合物等物质代谢发生紊乱的病理状态，包括肥胖(Després J P,Lemieux I,Alméras N.Abdominal obesity and themetabolic syndrome[M]Overweight and the Metabolic Syndrome.Springer US,2006:137-152)、高血糖(Grundy S M,Cleeman J I,Daniels S R,et al.Diagnosis andmanagement of the metabolic syndrome[J].Circulation,2005,112(17):2735-2752)、血脂异常(Charlton M.Obesity,hyperlipidemia,and metabolic syndrome[J].LiverTransplantation,2009,15(S2))、高血黏(Irace C,Scavelli F,Carallo C,et al.Plasmaand blood viscosity in metabolic syndrome[J].Nutrition,Metabolism andCardiovascular Diseases,2009,19(7):476-480)、高尿酸(Yoo T W,Sung K C,Shin H S,et al.Relationship between serum uric acid concentration and insulinresistance and metabolic syndrome[J].Circulation Journal,2005,69(8):928-933)、高脂肪肝(Marchesini G,Bugianesi E,Forlani G,et al.Nonalcoholic fatty liver,steatohepatitis,and the metabolic syndrome[J].Hepatology,2003,37(4):917-923)和高胰岛素血症(Han T S,Williams K,Sattar N,et al.Analysis of obesity andhyperinsulinemia in the development of metabolic syndrome:San Antonio HeartStudy[J].Obesity,2002,10(9):923-931；Grundy S M,Brewer H B,Cleeman J I,etal.Definition of metabolic syndrome[J].Circulation,2004,109(3):433-438)等，但不限于举例范围。
发明的详细说明
除非另有说明，否则说明书和权利要求书中的的术语具有下述含义。
“C1-C4烷基”可以提及例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。
“C1-C6烷基”可以提及如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等。
“C3-C10碳环”可以提及例如环丙烷、环丁烷、环戊烷、环己烷等饱和碳环；环丁烯、环戊烯、环己烯等不饱和碳环及苯环等芳香碳环。
“杂环”可以提及例如5-10元杂环，构成杂环的原子除了含有碳原子外，还含有一种或两种选自N、S、O的1至4个杂原子，优选5-10元非芳香杂环或5-10元芳香杂环等。具体地，非芳香杂环例如四氢呋喃、四氢吡喃、吡咯烷基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基等；芳香杂环例如噻吩基、呋喃基、吡啶基、噻唑基、嘧啶基、吡唑基、咪唑基等。
“杂环基”可以提及例如5-10元(单环、双环或三环)杂环基，构成杂环的原子除了含有碳原子外，还含有一种或两种选自N、S、O的1至4个杂原子，优选5-10元非芳香杂环或5-10元芳香杂环等。具体地，非芳香杂环例如四氢呋喃、四氢吡喃、吡咯烷基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基等；芳香杂环例如噻吩基、呋喃基、吡啶基、噻唑基、嘧啶基、吡唑基、咪唑基等。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本发明化合物的合成方法。
可如方案一所示制备式(I)的化合物。
化合物(I)可以通过将通式(IV)表示的化合物和通式(V)表示的化合物在碱和缩合剂的存在下反应制备得到。
方案一：
其中
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环；
R1和R2相同或不同，并各自为H、D、F、Cl、Br、取代或未取代的C1-C6烷基、C3-C10碳环、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R3为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R4和R5相同或不同，并各自为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
W表示离去基团，可以提及例如OH、Cl、Br、I等。
作为所述的碱包括无机碱和有机碱，所述的无机碱可以提及例如，碱金属碳酸盐类例如碳酸钠、碳酸钾、碳酸铯等；碱金属碳酸氢盐类例如碳酸氢钾等；碱金属氢氧化物例如氢氧化锂、氢氧化钠、氢氧化钾等；所述的无机碱可以提及例如三乙胺、吡啶、二甲基吡啶、正丁基锂、叔丁基钾等。
作为所述的缩合剂包括二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、O-(7-氮杂苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐(HATU)、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐(HBTU)、O-(5-氯苯并三氮唑-1-基)-二(二甲胺基)碳鎓六氟磷酸盐(HCTU)、O-(苯并三氮唑-1-基)-二(二甲胺基)碳鎓四氟硼酸盐(TBTU)、O-(N-丁二酰亚胺基)-二(二甲胺基)碳鎓四氟硼酸盐(TSTU)、O-(N-endo-5-降莰烯-2,3-二碳二酰亚胺)-二(二甲胺基)碳鎓四氟硼酸盐(TNTU)、苯并三氮唑-1-基氧-三(四氢吡咯基)鏻鎓六氟磷酸盐(PyBOP)、7-氮杂苯并三氮唑-1-基氧-三(四氢吡咯基)鏻鎓六氟磷酸盐(PyAOP)等。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
(R)-3-(4-((4-氟-4'-甲基-[1,1'-联苯]-2-)甲氧基)苯基)-N-(4-氧-4-(3-(三氟甲基)-5,6-二氢-[1,2,4]三氮唑[4,3-a]吡嗪-7(8H)-)-1-(2,4,5-三氟苯基)丁酰-2-)丙酰胺(编号I-1)经1步反应合成，反应式如下：
化合物IV(2.00g，4.91mmol)溶于100mL二氯甲烷中，依次加入化合物V(1.79g，4.91mmol)和二环己基碳二亚胺(2.03g，9.82mmol)，常温反应24h。反应结束后加入200mL水淬灭反应，用200mL二氯加完萃取，有机层水洗2次后，加入50g无水硫酸镁干燥，干燥2h后过滤，减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系：石油醚和乙酸乙酯)，得到目标产物I-1(2.81g，白色固体)，产率：77.55％。
I-1的核磁共振表征：
1H NMR(500MHz,DMSO-d6)δ7.78(t,J＝9.6Hz,1H),7.45–7.36(m,2H),7.33(dd,J＝8.5,5.9Hz,1H),7.30–7.26(m,3H),7.26–7.20(m,3H),6.98(d,J＝8.0Hz,2H),6.74(d,J＝8.5Hz,2H),4.97(s,1H),4.89(s,2H),4.85(d,J＝5.4Hz,1H),4.40–4.27(m,1H),4.27–4.16(m,1H),4.06(s,1H),4.00–3.87(m,2H),2.89–2.81(m,1H),2.74–2.54(m,5H),2.33(s,3H),2.20(t,J＝7.6Hz,1H),2.13(t,J＝7.4Hz,1H).
13C NMR(125MHz,DMSO-d6)δ171.40,169.76,161.87,156.65,156.32,151.37,149.19,147.52,145.11,142.83,137.95,137.24,137.12,136.48,134.05,132.29,129.49,129.42,129.33,123.04,119.53,118.93,115.86 115.32,105.88,67.49,46.40,44.01,41.61,38.82,37.87,37.64,32.87,30.58,21.11.
实施例2
(R)-3-(4-((4-氟-4'-甲基-[1,1'-联苯]-2-)甲氧基)苯基)-N-(4-氧-4-(3-(三氟甲基)-5,6-二氢-[1,2,4]三氮唑[4,3-a]吡嗪-7(8H)-)-1-(2,4,5-三氟苯基)丁酰-2-)丙酰胺(编号I-1)经1步反应合成，反应式如下：
化合物IV(2.00g，4.91mmol)溶于100mL二氯甲烷中，冷却至-5℃，加入三乙胺(0.99g，9.81mmol)后，缓慢滴加50mL二氯甲烷溶解的V(1.88g，4.91mmol)滴完后常温反应24h。反应结束后加入200mL水淬灭反应，用100mL二氯加完萃取，有机层水洗2次后，加入50g无水硫酸镁干燥，干燥2h后过滤，减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系：石油醚和乙酸乙酯)，得到目标产物I-1(3.12g，白色固体)，产率：84.30％。
实施例3
本发明中化合物的体内降糖活性可以通过使用如下所述的测定系统测定：
正常小鼠口服糖耐量试验(OGTT)：10周龄昆明种清洁级小鼠，体重18～22g，雄性，随机分为4组，每周8只。空白对照组(空白溶媒：0.5％的羧甲基纤维素)，阳性药对照组1(西格列汀：10mg/kg)，阳性药对照组2(TUG-891：10mg/kg)，受试化合物组(5mg/kg)，每组8只，实验前小鼠禁食不禁水12小时，各组均口服灌胃给药，断尾取血，测定血糖值(记为-30min)。然后4组小鼠分别灌胃给予空白溶媒、西格列汀、TUG-891和受试化合物I-1，30min后测定血糖值记为0min，之后立即按10ml/kg灌胃给予浓度为2g/10ml的葡萄糖溶液，并于15，30，60，120min测定血糖值。结果见表1。
表1：化合物对正常小鼠口服糖耐量的影响(
n＝8)
正常小鼠口服糖耐量试验表明：I-1在低剂量条件下(5mg/kg)能够明显改善正常小鼠的口服糖耐量，活性明显优于GPR120激动剂TUG-891(10mg/kg)，活性与DPP-IV抑制剂西格列汀(10mg/kg)相当。说明化合物I-1具有较好的降血糖作用。
实施例5
含活性剂I-1的片剂：
按常规方法将原辅料混合，制粒，干燥，压片。
Claims (10)
1.权利要求通式(I)所示的化合物或其可药用的盐：
其中：
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环；
R1和R2相同或不同，并各自为H、D、F、Cl、Br、取代或未取代的C1-C6烷基、C3-C10碳环、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R3为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R4和R5相同或不同，并各自为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
2.根据权利要求1所述的通式(I)的化合物或其可药用的盐，其是通式(II)所示的化合物或其可药用的盐：
其中：
R1和R2相同或不同，并各自为H、D、F、Cl、Br、取代或未取代的C1-C6烷基、C3-C10碳环、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R3为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R4和R5相同或不同，并各自为H、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
3.根据权利要求2所述的通式(II)的化合物或其可药用的盐，其是通式(III)所示的化合物或其可药用的盐：
其中：
R1和R2相同或不同，并各自为H、D、F、Cl、Br、取代或未取代的C1-C6烷基、C3-C10碳环、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-。
4.根据权利要求1-3任一所述的通式(I)化合物及其可药用盐，该化合物选自，但不限于举例范围：
(R)-3-(4-((4-氟-4'-甲基-[1,1'-联苯]-2-)甲氧基)苯基)-N-(4-氧-4-(3-(三氟甲基)-5,6-二氢-[1,2,4]三氮唑[4,3-a]吡嗪-7(8H)-)-1-(2,4,5-三氟苯基)丁酰-2-)丙酰胺。
5.一种药物组合物，所述药物组合物含有治疗有效剂量的根据权利要求1-3中任意一项所述通式(I)所示的化合物、其可药用的盐及一种或多种治疗糖尿病药物。
6.权利要求1-3任一所述的通式(I)化合物、其可药用盐或权利要求5所述的药物组合物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
7.权利要求5所述的治疗糖尿病药物，包括胰岛素、胰岛素类似物、促进胰岛β细胞分泌胰岛素的药物、促进外周组织增加葡萄糖利用的药物、抑制肠道葡萄糖吸收的药物、胰岛素增敏剂、促进葡萄糖代谢的药物或者抑制肾脏葡萄糖重吸收的药物等，其优选实例包括胰岛素、胰岛素类似物、格列苯脲、格列喹酮、格列齐特、格列吡嗪、格列美脲、瑞格列奈、那格列奈、二甲双胍、苯乙双胍、环格列酮、罗格列酮、吡格列酮、利拉鲁肽、艾塞那肽、利司那肽、阿必鲁肽、阿卡波糖、伏格波糖、米格列醇、沙格列汀、西格列汀、维格列汀、利格列汀、阿格列汀、曲格列汀、达格列净、卡格列净、艾格列净、Ipragliflozin、Luseogliflozin以及Tofogliflozin等。
8.权利要求6中所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，所述的药物还包括药学上可以接受的载体如稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体或润滑剂。
9.权利要求6中所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，该药物可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮肉、皮下、静脉、粘膜组织，或是被其他物质混合或包裹后导入机体等。
10.权利要求6中所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，该药物可制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210032332.2A CN115304604B (zh) | 2022-01-12 | 2022-01-12 | 一种双靶点西格列汀衍生物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210032332.2A CN115304604B (zh) | 2022-01-12 | 2022-01-12 | 一种双靶点西格列汀衍生物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115304604A true CN115304604A (zh) | 2022-11-08 |
| CN115304604B CN115304604B (zh) | 2024-03-26 |
Family
ID=83855254
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210032332.2A Active CN115304604B (zh) | 2022-01-12 | 2022-01-12 | 一种双靶点西格列汀衍生物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115304604B (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102946726A (zh) * | 2010-04-05 | 2013-02-27 | 卡帝拉药物有限公司 | 新型降血糖化合物 |
-
2022
- 2022-01-12 CN CN202210032332.2A patent/CN115304604B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102946726A (zh) * | 2010-04-05 | 2013-02-27 | 卡帝拉药物有限公司 | 新型降血糖化合物 |
Non-Patent Citations (1)
| Title |
|---|
| GABRIELE CARULLO ET AL.: "GPR120/FFAR4 Pharmacology: Focus on Agonists in Type 2 Diabetes Mellitus Drug Discovery", 《J. MED. CHEM.》, vol. 64, pages 6 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115304604B (zh) | 2024-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2624021C2 (ru) | СОЕДИНЕНИЯ ТИЕНИЛ[3, 2-d]ПИРИМИДИН-4-ОН, СПОСОБ ПОЛУЧЕНИЯ, ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ И ИХ ПРИМЕНЕНИЕ | |
| CN105518008B (zh) | 氨基吡喃环衍生物及其组合物和应用 | |
| CN103664873B (zh) | 作为二肽基肽酶iv(dpp-iv)抑制剂的3-(3-氨基哌啶-1-基)-5-氧代-1,2,4-三嗪衍生物 | |
| TW200530202A (en) | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes | |
| MXPA03011448A (es) | Derivados de n-arilfenilacetamida y composicion farmaceutica que los contienen. | |
| US11203597B2 (en) | Crystalline spirocyclic compound, a dosage form containing, a method for using in treatment of disease, and a method for recrystallizing | |
| US20230201185A1 (en) | Treatment of type 2 diabetes or obesity or overweight with 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2s)-oxetan-2-ylmethyl]-1h-benzimidazole-6-carboxylic acid or a pharmaceutically salt thereof | |
| WO2012090225A2 (en) | Novel cocrystals / molecular salts of metformin with oleoylethanolamide as an effective anti-diabetic + anti- obesity agent | |
| JP2012512186A (ja) | アミドチアゾール誘導体、その製造方法および使用 | |
| CN102898400B (zh) | Gpr119激动剂及其应用 | |
| US20220152004A1 (en) | Heterocyclyl(phenyl)methanol compounds useful in the treatment of hyperglycaemia | |
| US20200268687A1 (en) | Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia | |
| JP2008530198A (ja) | ４−ヒドロキシイソロイシンのジアステレオ異性体及びこれらの使用 | |
| TW201904967A (zh) | 以稠合雙環吡唑治療代謝疾病之方法 | |
| WO2009128360A1 (ja) | 糖尿病治療剤 | |
| CN115304604B (zh) | 一种双靶点西格列汀衍生物 | |
| CN115246816B (zh) | 一种双靶点阿格列汀衍生物 | |
| CN111393372B (zh) | 一种苯并咪唑衍生物及其制备方法和用途 | |
| CN113929698A (zh) | 二芳基庚烷二聚体及其药物组合物与其制备方法和应用 | |
| WO2010050422A1 (ja) | 糖尿病治療剤 | |
| CN102153538B (zh) | 苯并环衍生物 | |
| CN115572223A (zh) | 一种苯丙酸衍生物及其用途 | |
| CN101768133A (zh) | 二苯基乙烯类衍生物及其用途 | |
| CN109305957B (zh) | 苯基吡啶类化合物及其在dpp-4酶抑制剂的应用 | |
| CN101648891B (zh) | 芳基环丁基化合物及其在制备减肥药物中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |