CN102807568B - Thiadiazoles derivative class DPP-IV inhibitor - Google Patents
Thiadiazoles derivative class DPP-IV inhibitor Download PDFInfo
- Publication number
- CN102807568B CN102807568B CN201110154294.XA CN201110154294A CN102807568B CN 102807568 B CN102807568 B CN 102807568B CN 201110154294 A CN201110154294 A CN 201110154294A CN 102807568 B CN102807568 B CN 102807568B
- Authority
- CN
- China
- Prior art keywords
- methyl
- alkyl
- amino
- thiadiazoles
- xanthine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 title claims abstract description 34
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 title claims abstract description 30
- 150000004867 thiadiazoles Chemical class 0.000 title claims abstract description 25
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 118
- 238000006243 chemical reaction Methods 0.000 claims description 77
- -1 cyano methyl Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 36
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 125000004429 atom Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 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 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000008103 glucose Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 208000008589 Obesity Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000001629 suppression Effects 0.000 claims description 3
- 208000010444 Acidosis Diseases 0.000 claims description 2
- 206010070901 Diabetic dyslipidaemia Diseases 0.000 claims description 2
- 208000007976 Ketosis Diseases 0.000 claims description 2
- 206010027417 Metabolic acidosis Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 235000019789 appetite Nutrition 0.000 claims description 2
- 230000036528 appetite Effects 0.000 claims description 2
- 230000008901 benefit Effects 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims description 2
- 230000004140 ketosis Effects 0.000 claims description 2
- 230000000926 neurological effect Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 16
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 8
- 238000001727 in vivo Methods 0.000 abstract description 5
- 230000004060 metabolic process Effects 0.000 abstract description 4
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 104
- 239000000243 solution Substances 0.000 description 90
- 238000000034 method Methods 0.000 description 72
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 54
- 238000013019 agitation Methods 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 30
- 238000010992 reflux Methods 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 27
- 238000001035 drying Methods 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 239000012141 concentrate Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 125000003118 aryl group Chemical group 0.000 description 19
- 239000003480 eluent Substances 0.000 description 17
- 150000002431 hydrogen Chemical class 0.000 description 17
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 16
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- 238000000746 purification Methods 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- LNNXOEHOXSYWLD-UHFFFAOYSA-N 1-bromobut-2-yne Chemical compound CC#CCBr LNNXOEHOXSYWLD-UHFFFAOYSA-N 0.000 description 12
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical class C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 12
- 229910052794 bromium Inorganic materials 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- UDGKZGLPXCRRAM-UHFFFAOYSA-N 1,2,5-thiadiazole Chemical class C=1C=NSN=1 UDGKZGLPXCRRAM-UHFFFAOYSA-N 0.000 description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 238000005352 clarification Methods 0.000 description 9
- GMSNIKWWOQHZGF-UHFFFAOYSA-N 3-methyl-9H-xanthine Chemical compound O=C1NC(=O)N(C)C2=C1N=CN2 GMSNIKWWOQHZGF-UHFFFAOYSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000012047 saturated solution Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 230000009466 transformation Effects 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 7
- 238000006911 enzymatic reaction Methods 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 6
- 125000002769 thiazolinyl group Chemical group 0.000 description 6
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical group 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 5
- 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 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 229960002397 linagliptin Drugs 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 238000013016 damping Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000011535 reaction buffer Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- ZJKGRSJMFDIRPX-UHFFFAOYSA-N 5-methyl-3-nitropyridin-2-amine Chemical compound CC1=CN=C(N)C([N+]([O-])=O)=C1 ZJKGRSJMFDIRPX-UHFFFAOYSA-N 0.000 description 3
- LCJXSRQGDONHRK-UHFFFAOYSA-N 6-methyl-3-nitropyridin-2-amine Chemical compound CC1=CC=C([N+]([O-])=O)C(N)=N1 LCJXSRQGDONHRK-UHFFFAOYSA-N 0.000 description 3
- QTEQVEJOXGBDGI-UHFFFAOYSA-N 8-bromo-3-methyl-7h-purine-2,6-dione Chemical compound O=C1NC(=O)N(C)C2=C1NC(Br)=N2 QTEQVEJOXGBDGI-UHFFFAOYSA-N 0.000 description 3
- 239000004342 Benzoyl peroxide Substances 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 3
- 102000051325 Glucagon Human genes 0.000 description 3
- 108060003199 Glucagon Proteins 0.000 description 3
- 102100040918 Pro-glucagon Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 3
- 229960004666 glucagon Drugs 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 3
- DZYHXPQXBBQBRZ-UHFFFAOYSA-N (4,5-difluoro-2,1,3-benzothiadiazol-6-yl)methanol Chemical class OCC1=CC=2C(=NSN=2)C(=C1F)F DZYHXPQXBBQBRZ-UHFFFAOYSA-N 0.000 description 2
- JEPSDNHHYDVNQQ-UHFFFAOYSA-N (4-methyl-2,1,3-benzothiadiazol-6-yl)methanol Chemical class CC1=CC(=CC2=NSN=C12)CO JEPSDNHHYDVNQQ-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- AITFREYTVOPXOT-UHFFFAOYSA-N 5-methylpyridine-2,3-diamine Chemical compound CC1=CN=C(N)C(N)=C1 AITFREYTVOPXOT-UHFFFAOYSA-N 0.000 description 2
- XATOCNYGIWXIQM-UHFFFAOYSA-N 6-methylpyridine-2,3-diamine Chemical compound CC1=CC=C(N)C(N)=N1 XATOCNYGIWXIQM-UHFFFAOYSA-N 0.000 description 2
- MPZNPXUESSGCMK-UHFFFAOYSA-N CC1=CC(=C(C(=C1C(=O)O)N)N)C Chemical compound CC1=CC(=C(C(=C1C(=O)O)N)N)C MPZNPXUESSGCMK-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- VNHKVRZSTVBOOW-UHFFFAOYSA-N [4-(trifluoromethyl)-2,1,3-benzothiadiazol-6-yl]methanol Chemical class OCC1=CC=2C(=NSN=2)C(=C1)C(F)(F)F VNHKVRZSTVBOOW-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000004900 laundering Methods 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- JZTRZQAGDIKTHA-UHFFFAOYSA-N methyl 3,4-diamino-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(=C(C(=C1)N)N)C(F)(F)F JZTRZQAGDIKTHA-UHFFFAOYSA-N 0.000 description 2
- FBIAHHQDEJEJOL-UHFFFAOYSA-N methyl 4-amino-3-nitro-5-(trifluoromethyl)benzoate Chemical compound COC(C1=CC(=C(C(=C1)C(F)(F)F)N)[N+](=O)[O-])=O FBIAHHQDEJEJOL-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229960004937 saxagliptin Drugs 0.000 description 2
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 2
- 108010033693 saxagliptin Proteins 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960004034 sitagliptin Drugs 0.000 description 2
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- FIOJWGRGPONADF-UHFFFAOYSA-N (sulfinylamino)benzene Chemical compound O=S=NC1=CC=CC=C1 FIOJWGRGPONADF-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- FFWQLZFIMNTUCZ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CBr FFWQLZFIMNTUCZ-UHFFFAOYSA-N 0.000 description 1
- JMNOONULDANZRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene Chemical compound FC1=CC=C(CBr)C(C(F)(F)F)=C1 JMNOONULDANZRZ-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- WEPXLRANFJEOFZ-UHFFFAOYSA-N 2,3,4-trifluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(F)=C1F WEPXLRANFJEOFZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BWOIVIORGIENRE-UHFFFAOYSA-N 2-amino-3-methyl-5-nitrobenzoic acid Chemical compound CC1=CC([N+]([O-])=O)=CC(C(O)=O)=C1N BWOIVIORGIENRE-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- XAPRFOJQNGFJSZ-UHFFFAOYSA-N 3-methyl-5-nitrobenzoic acid Chemical compound CC1=CC(C(O)=O)=CC([N+]([O-])=O)=C1 XAPRFOJQNGFJSZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTGYCJNEAUXQNV-UHFFFAOYSA-N 4-amino-3-methyl-5-nitrobenzoic acid Chemical compound CC1=CC(C(O)=O)=CC([N+]([O-])=O)=C1N QTGYCJNEAUXQNV-UHFFFAOYSA-N 0.000 description 1
- KBXIMAGOJCNRBG-UHFFFAOYSA-N 4-chloro-6-methyl-2,1,3-benzothiadiazole Chemical class C1=C(C)C=C(Cl)C2=NSN=C21 KBXIMAGOJCNRBG-UHFFFAOYSA-N 0.000 description 1
- HIMXEWXCCDNTTG-UHFFFAOYSA-N 4-fluoro-6-methyl-2,1,3-benzothiadiazole Chemical class FC1=CC(=CC=2C1=NSN=2)C HIMXEWXCCDNTTG-UHFFFAOYSA-N 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- XDQJAYFCPRWDOL-UHFFFAOYSA-N 5-methyl-2,1,3-benzothiadiazole Chemical class C1=C(C)C=CC2=NSN=C21 XDQJAYFCPRWDOL-UHFFFAOYSA-N 0.000 description 1
- DJKKFJXLPYADNJ-UHFFFAOYSA-N 5-methyl-2H-1,2,5-thiadiazole Chemical class CN1C=CNS1 DJKKFJXLPYADNJ-UHFFFAOYSA-N 0.000 description 1
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 1
- CNARNEHQLBMJON-UHFFFAOYSA-N 6-(chloromethyl)-4,5-difluoro-2,1,3-benzothiadiazole Chemical class ClCC1=CC=2C(=NSN=2)C(=C1F)F CNARNEHQLBMJON-UHFFFAOYSA-N 0.000 description 1
- QUXLCYFNVNNRBE-UHFFFAOYSA-N 6-methylpyridin-2-amine Chemical compound CC1=CC=CC(N)=N1 QUXLCYFNVNNRBE-UHFFFAOYSA-N 0.000 description 1
- SFIWIEFIJQKWQZ-UHFFFAOYSA-N 7-benzyl-8-bromo-3-methylpurine-2,6-dione Chemical compound C1=2C(=O)NC(=O)N(C)C=2N=C(Br)N1CC1=CC=CC=C1 SFIWIEFIJQKWQZ-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 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 1
- 102100024881 C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8 Human genes 0.000 description 1
- CXOUWQQOTJNJKP-AWEZNQCLSA-N CC#CC[n]1c(N(CC2)C[C@H]2N)nc(N(C)C(N2Cc3cc4n[s]nc4cc3)=O)c1C2=O Chemical compound CC#CC[n]1c(N(CC2)C[C@H]2N)nc(N(C)C(N2Cc3cc4n[s]nc4cc3)=O)c1C2=O CXOUWQQOTJNJKP-AWEZNQCLSA-N 0.000 description 1
- YBAKKVGMQWQHHD-UHFFFAOYSA-N CC#CC[n]1c(N2CCNCC2)nc(N(C)C(N2Cc3cc4n[s]nc4c(F)c3)=O)c1C2=O Chemical compound CC#CC[n]1c(N2CCNCC2)nc(N(C)C(N2Cc3cc4n[s]nc4c(F)c3)=O)c1C2=O YBAKKVGMQWQHHD-UHFFFAOYSA-N 0.000 description 1
- XZXZFPJEAXEESB-UHFFFAOYSA-N CC(C)=CC[n]1c(Br)nc(N(C)C(N2)=O)c1C2=O Chemical compound CC(C)=CC[n]1c(Br)nc(N(C)C(N2)=O)c1C2=O XZXZFPJEAXEESB-UHFFFAOYSA-N 0.000 description 1
- QSNWERKISUMIGS-UHFFFAOYSA-N CN(c1c(C(N2)=O)[n](Cc(ccc(F)c3)c3OC)c(Br)n1)C2=O Chemical compound CN(c1c(C(N2)=O)[n](Cc(ccc(F)c3)c3OC)c(Br)n1)C2=O QSNWERKISUMIGS-UHFFFAOYSA-N 0.000 description 1
- KOMUNSZETBWSCB-LJQANCHMSA-N CN(c1c(C(N2Cc3cc4n[s]nc4cc3)=O)[n](Cc(cccc3)c3C#N)c(N(CCC3)C[C@@H]3N)n1)C2=O Chemical compound CN(c1c(C(N2Cc3cc4n[s]nc4cc3)=O)[n](Cc(cccc3)c3C#N)c(N(CCC3)C[C@@H]3N)n1)C2=O KOMUNSZETBWSCB-LJQANCHMSA-N 0.000 description 1
- PMKDURANRORPNY-QGZVFWFLSA-N CN(c1c(C(N2Cc3cc4n[s]nc4cc3)=O)[n](Cc(cccc3)c3F)c(N(CCC3)C[C@@H]3N)n1)C2=O Chemical compound CN(c1c(C(N2Cc3cc4n[s]nc4cc3)=O)[n](Cc(cccc3)c3F)c(N(CCC3)C[C@@H]3N)n1)C2=O PMKDURANRORPNY-QGZVFWFLSA-N 0.000 description 1
- DRVWHACVPDSECW-QGZVFWFLSA-N CN(c1c(C(N2Cc3cc4n[s]nc4cc3)=O)[n](Cc(cccc3)c3[N+]([O-])=O)c(N(CCC3)C[C@@H]3N)n1)C2=O Chemical compound CN(c1c(C(N2Cc3cc4n[s]nc4cc3)=O)[n](Cc(cccc3)c3[N+]([O-])=O)c(N(CCC3)C[C@@H]3N)n1)C2=O DRVWHACVPDSECW-QGZVFWFLSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VUXGEAUSMONADG-LJQANCHMSA-N Cc1c(C[n]2c(N(CCC3)C[C@@H]3N)nc(N(C)C(N3Cc4cc5n[s]nc5cc4)=O)c2C3=O)cccc1 Chemical compound Cc1c(C[n]2c(N(CCC3)C[C@@H]3N)nc(N(C)C(N3Cc4cc5n[s]nc5cc4)=O)c2C3=O)cccc1 VUXGEAUSMONADG-LJQANCHMSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 1
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101710151321 Melanostatin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- 102100028427 Pro-neuropeptide Y Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 241000144290 Sigmodon hispidus Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100022831 Somatoliberin Human genes 0.000 description 1
- 101710142969 Somatoliberin Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- 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 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 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
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002946 cyanobenzyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- LPEZIAPDJJLVHP-UHFFFAOYSA-N n-chloro-4-methylaniline Chemical compound CC1=CC=C(NCl)C=C1 LPEZIAPDJJLVHP-UHFFFAOYSA-N 0.000 description 1
- KLOQOWQKKZSVJD-UHFFFAOYSA-N n-fluoro-4-methylaniline Chemical compound CC1=CC=C(NF)C=C1 KLOQOWQKKZSVJD-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of such as formula shown in I, there is thiadiazoles derivative of DPP-IV inhibit activities and preparation method thereof, its pharmaceutical composition, and the purposes of the disease that DPP-IV suppresses is benefited from treatment, especially treats the purposes of type ii diabetes.Thiadiazoles derivative provided by the invention has extraordinary DPP-IV inhibit activities.And there is extraordinary internal metabolism level and most suitable Half-life in vivo, be expected to become suitable DPP-IV inhibitor class medicine.
Description
Technical field
The present invention relates to a kind of newly there is thiadiazoles derivative of DPP-IV inhibit activities and preparation method thereof, its pharmaceutical composition, and the purposes of disease that DPP-IV suppresses is benefited from treatment, especially treats the purposes of type ii diabetes.
Background technology
Diabetes are a kind of multi-pathogenesis diseases, show in fasted conditions or oral glucose resistance test that the glucose level after taking glucose raises or hyperglycemia.The uncontrollable hyperglycemia continued adds early stage M & M, therefore becomes a very important public health issue.
Diabetes mainly divide two types, and type i diabetes also claims insulin-dependent diabetes mellitus, almost can not produce Regular Insulin in patient oneself body.Type ii diabetes also claims non insulin dependent diabetes, insulin level in this kind of patient body and normal people are on close level even higher, but in insulin sensitive tissues main in these patient bodies all there is insulin resistant in carbohydrate metabolism and lipid metabolism.
DPP IV (DPP-IV) is a kind of serine protease, and it has expression in a lot of tissue in vivo, as intestines, liver, lung, kidney etc., and in T lymphocyte in circulation.It is responsible for the metabolic cleavage of some endogenous peptide (GLP-1 (7-36), hyperglycemic-glycogenolytic factor) in body, and the verified protein decomposing activity having multiple other peptide (GHRH, NPY, GLP-2, VIP) of external antagonism.
GLP-1 (7-36) is a kind of peptide be made up of 30 amino acid, is derived by the post translational processing process of front glucagon in small intestine.GLP-1 (7-36) has effect in multiple body, comprises stimulating insulin secretion, suppressing glucagon to secrete, promote satiety and delay stomach emptying etc.Based on its physiology behavior, believe that the effects beneficial of GLP-1 (7-36) is in prevention and therapy type ii diabetes and obesity.Such as, have been found that GLP-1 (7-36) exogenous administration in diabetic subject (inputting continuously) is effective to this kind of patient group.Unfortunately, GLP-1 (7-36) degrades rapidly in vivo, has very short transformation period (t
1/2< 1.5 minutes).The DPP-IV cultivated based on heredity to reject in the research of mouse and the body of selective DPP-IV inhibitors/in vitro study, has shown the primary degrading enzyme that DPP-IV is GLP-1 in body (7-36).GLP-1 (7-36) is GLP-1 (9-36) by DPP-IV efficient degradation, and the latter is served as the physiological antagonist of GLP-1 (7-36) by supposition.Therefore believe in body and suppress DPP-IV to can be used for the generation strengthened endogenous GLP-1 (7-36) level and weaken its antagonist GLP-1 (9-36).Thus, believe that DPP-IV inhibitor is the medicine that can be used for preventing, delay its progress and/or treating the illness mediated by DPP-IV, as diabetes, especially type ii diabetes.
The compound that what existing market was on sale have DPP-IV inhibit activities to be used for the treatment of diabetes has Egelieting (alogliptin), sitagliptin (sitagliptin), BMS-477118 (saxagliptin), Vildagliptin (vidagliptin) and BI 1356 (linagliptin) etc.Wherein effect is preferably the BI 1356 just gone on the market in the recent period, but has bibliographical information BI 1356 internal metabolism level lower, and in rat, mouse and human body, the BI 1356 in blood plasma about 80% exists with prototype.In human body, when taking dose is less than 50mg, the transformation period is 70-80 hour, and when taking dose is greater than 50mg, the transformation period is 128-184 hour.And observe slight drug accumulation (rate of accumulation 1.18-2.03) (ExpertOpin.Investig.Drugs (2010) 19 (1): 133-140).
Summary of the invention
The invention provides a kind of thiadiazoles derivative compounds such as formula I and enantiomer, diastereomer, the pharmacy acceptable salt of above-claimed cpd, solvate, polymorphic form be provided,
Wherein X, Y and Z are selected from C or N independently of one another;
R
1, R
2and R
3be selected from hydrogen, halogen, cyano group, trifluoromethyl, substituted or unsubstituted C independently of one another
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl ,-OR
7,-NR
8r
9,-C (O) R
10,-SR
7;
R
7be selected from hydrogen, substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl;
R
8and R
9be selected from hydrogen, substituted or unsubstituted C independently of one another
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl ,-C (O) R
10, or R
8and R
9the 3-6 unit heterocyclic radical containing one or more atom N is jointly formed altogether be connected atom N;
R
10be selected from substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic radical;
R
6be selected from hydrogen, substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
2-6thiazolinyl, substituted or unsubstituted C
2-6alkynyl, substituted or unsubstituted C
3-6cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, cyano methyl or methoxycarbonyl-methyl.
R
15and R
16be selected from hydrogen, halogen, cyano group, hydroxyl, substituted or unsubstituted C independently of one another
1-6alkyl, amino, alkoxyl group, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C
3-6cycloalkyl, substituted or unsubstituted heterocyclic radical;
Or R
15with R
16altogether, five yuan of fragrant heterocycle Q are formed together with connected C atom;
Q is
A, B are identical or different, are selected from C, N independently of one another;
R
4and R
17be selected from hydrogen, alkyl, alkoxyl group, halogen, cyano group, hydroxyl ,-CH independently of one another
2r
11, wherein R
11be selected from alkynyl, thiazolinyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radical;
R
5be selected from hydrogen, alkyl, alkoxyl group, halogen, cyano group, hydroxyl ,-NR
12r
13;
R
12and R
13be selected from hydrogen, substituted or unsubstituted C independently of one another
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic radical ,-C (O) R
14,-C (S) R
14,-S (O) R
14,-S (O
2) R
14;
R
12and R
13also substituted or unsubstituted 3-7 unit heterocyclic radical, such as piperidines, piperazine, pyrrolidyl etc. containing one or more atom N can be formed altogether with the atom N be connected; Substituting group is selected from amino, alkylamino, can be exemplified as 3-amino-piperadine-1-base, 3-alkylamino-piperidine-1-base, 3-amino-piperazine-1-base, 3-alkylamino-piperazine-1-base, 3-amino-pyrroles-1-base, 3-alkylamino-pyrroles-1-base;
R
14be selected from C
1-6alkyl, C
3-6cycloalkyl, aryl, heteroaryl, heterocyclic radical.
In the above-mentioned definition of compound of Formula I, R
1, R
2, R
3preferred hydrogen, halogen, trifluoromethyl, substituted or unsubstituted C independently of one another
1-6alkyl; Preferred hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl further.
R
6preferred hydrogen, substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl, more preferably substituted or unsubstituted C
1-6alkyl.
Preferred R
15with R
16altogether, five yuan of fragrant heterocycle Q are formed together with connected C atom;
Q is
R
4and R
17preferably independently be selected from hydrogen, substituted or unsubstituted C separately
1-6alkyl ,-CH
2r
11, wherein R
11be selected from alkynyl, thiazolinyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radical;
R
5preferably from-NR
12r
13; Preferred R
12and R
13the substituted or unsubstituted 5-6 unit heterocyclic radical containing one or more atom N is formed altogether with the atom N be connected, such as piperidines, piperazine, pyrrolidyl etc., preferred 3-amino-piperadine-1-base, 3-alkylamino-piperidine-1-base, 3-amino-piperazine-1-base, 3-alkylamino-piperazine-1-base, 3-amino-pyrroles-1-base, 3-alkylamino-pyrroles-1-base; More preferably 3-amino-piperadine-1-base.
The present invention provides the compound and enantiomer, diastereomer that are typically formula II on the other hand, provides the pharmacy acceptable salt of above-claimed cpd, solvate, polymorphic form,
wherein, X and Z is selected from C or N independently of one another;
A, B are identical or different, are selected from C, N independently of one another;
R
1, R
2, R
3be selected from hydrogen, halogen, cyano group, trifluoromethyl, substituted or unsubstituted C independently of one another
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl ,-OR
7,-NR
8r
9,-C (O) R
10,-SR
7;
R
7be selected from hydrogen, substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl;
R
8and R
9be selected from hydrogen, substituted or unsubstituted C independently of one another
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl ,-C (O) R
10, or R
8and R
9the 3-6 unit heterocyclic radical containing one or more atom N is jointly formed altogether be connected atom N;
R
10be selected from substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic radical;
R
4independently be selected from hydrogen, substituted or unsubstituted C
1-6alkyl ,-CH
2r
11, wherein R
11be selected from alkynyl, thiazolinyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic radical;
R
5be selected from-NR
12r
13; R
12and R
13be selected from hydrogen, substituted or unsubstituted C independently of one another
1-6alkyl, substituted or unsubstituted C
3-6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic radical ,-C (O) R
14,-C (S) R
14,-S (O) R
14,-S (O
2) R
14; Or R
12and R
13also the substituted or unsubstituted 5-6 unit heterocyclic radical containing one or more atom N can be formed altogether with the atom N be connected, such as piperidines, piperazine, pyrrolidyl etc., substituting group is selected from amino, alkylamino, can be exemplified as 3-amino-piperadine-1-base, 3-alkylamino-piperidine-1-base, 3-amino-piperazine-1-base, 3-alkylamino-piperazine-1-base, 3-amino-pyrroles-1-base, 3-alkylamino-pyrroles-1-base.
Term used herein has following implication:
Term " halogen " refers to fluorine, chlorine, bromine or iodine, preferred fluorine or chlorine.
Term " hydroxyl " refers to-OH group.
Term " cyano group " refers to-CN group.
Term " amino " refers to-NH
2group ,-NH (C
1-6alkyl) group and-N (C
1-6alkyl)
2.Amino object lesson includes but not limited to-NH
2,-NHCH
3,-N (CH
3)
2,-NHC
2h
5or-N (C
2h
5)
2deng.
Term " C
1-6alkyl " refer to the saturated aliphatic hydrocarbon group of the straight or branched be made up of carbon atom and hydrogen atom, it is connected with the rest part of molecule by singly-bound, and it has 1-6 carbon atom.Described alkyl can be non-substituted or by one or more be selected from the substituting group of alkyl, alkoxyl group, amino, halogen or hydroxyl replace.The limiting examples of non-substituted alkyl includes but not limited to such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, tert-butyl, n-amyl group, 2-methyl butyl, neo-pentyl, n-hexyl or 2-methylhexyl etc.
Term " aryl " refers to the full carbon monocycle of the π-electron system with total conjugated or the aromatic group of fused polycycle, and it has 6-14 carbon atom, preferably has 6-12 carbon atom, most preferably has 6 carbon atoms.Aryl can be non-substituted or be selected from one or two following substituting group and replaced: alkyl, alkoxyl group, aryl, aralkyl, amino, halogen, cyano group or hydroxyl etc.The limiting examples of non-substituted aryl includes but not limited to phenyl, naphthyl or anthryl.
Term " aralkyl " refers to the non-substituted C as hereinbefore defined replaced by an aryl as hereinbefore defined
1-6alkyl.The limiting examples of aralkyl includes but not limited to-CH
2-phenyl ,-(CH
2)
2-phenyl, cyanobenzyls ,-(CH
2)
3-phenyl ,-CH
2-CH (CH
3)-phenyl ,-(CH
2)
4-phenyl ,-CH
2-CH (CH
3)-CH
2-phenyl or-CH
2-CH
2-CH (CH
3)-phenyl etc.
Term " heteroaryl " refer to comprise hydrogen atom, the aromatic group of a 3-5 carbon atom, 1-2 to be selected from nitrogen, oxygen and sulphur heteroatomic 5 yuan or 6 rings.Heteroaryl can be non-substituted or replace by substituents: alkyl, alkoxyl group, aryl, aralkyl, amino, halogen and hydroxyl.The limiting examples of non-substituted heteroaryl includes but not limited to pyrroles, furans, thiophene, imidazoles, oxazole, pyrazoles, pyridine or pyrimidine.
Term " heterocyclic radical " refers to the monocycle non-aromatic cyclic group with heteroatomic five yuan or hexa-atomic of one or two nitrogen, oxygen, sulphur etc.Heterocyclic radical can be non-substituted or replace by substituents: alkyl, alkoxyl group, aryl, aralkyl, amino, halogen or hydroxyl.The limiting examples of non-substituted heterocyclic radical has pyrrolidyl, piperidyl, piperazinyl or morpholinyl etc.
Term " C
3-6cycloalkyl " refer to the saturated rings alkane be made up of 3-6 carbon atom; include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl etc.; cycloalkyl can be replacement or non-substituted, and substituting group can be selected from amino, alkyl, alkoxyl group, aryl, aralkyl, amino, halogen or hydroxyl etc.
Term " thiazolinyl " refers to the alkyl containing 2-6 carbon atom and the straight or branched at least containing 1 double bond, thiazolinyl can be non-substituted or be selected from following substituting group and replaced: alkyl, alkoxyl group, hydroxyl, amino or halogen etc., the object lesson of non-substituted thiazolinyl includes but not limited to vinyl, propenyl, 2-propenyl, 1-butylene base, crotyl, 1-pentenyl or 1-hexenyl etc.
Term " alkynyl " refers to the straight or branched unsaturated alkyl containing 2-6 carbon atom and at least 1 triple bond, alkynyl can be non-substituted or be selected from following substituting group and replaced: alkyl, alkoxyl group, hydroxyl, amino or halogen etc., the object lesson of non-substituted alkynyl such as includes but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base or 2-butyne base etc.
Formula I provided by the invention or formula II compound concrete example as follows, but be not limited to following compounds:
Further aspect of the present invention provides the preparation method of compound of Formula I, comprises the step making formula VIII compound and formula IX compound that condensation reaction occur in the basic conditions,
Wherein, X, Y, Z, R
1-R
16identical with defining in general formula I, L is leavings group, is selected from halogen, sulfonates compounds, preferred chlorine, bromine, methanesulfonates, more preferably bromine; Alkaline condition points in reaction solution to add alkaline matter, as salt of wormwood, sodium carbonate etc.
Should be appreciated that when having free-NH in formula IX structure
2during group, first should protect amino with blocking group conventional in this area, as used conventional amino protecting group Boc etc., use conventional method deprotection base after condensation reaction completes again, obtaining compound of Formula I.
Further aspect of the present invention provides following formula VIII compound or its salt, and it is the important intermediate of synthesizing compound of Formula I of the present invention:
Wherein, X, Y, Z, R
1-R
3identical with defining in general formula I, L is leavings group, is selected from halogen, sulfonates compounds, preferred chlorine, bromine, methanesulfonates, more preferably bromine;
Formula VIII compound can be prepared by following step:
Wherein, X, Y, Z, R
1-R
3identical with defining in general formula I, R
0be selected from methyl or ester group, L is leavings group, is selected from halogen or sulfonates compounds, preferred chlorine, bromine, methanesulfonates, more preferably bromine.
Concrete reaction can see intermediate 3, the preparation method of intermediate 4,5,6,7,8,9 etc.
The compound of formula IX can test method commercially or conveniently prepare.
Further aspect of the present invention provides a kind of preparation method of formula II compound, comprises the steps:
Wherein, R
1, R
2, R
3, R
4, R
5, X, Z, A, B be identical with defining in general formula I I; L, L
0for leavings group, be selected from halogen, sulfonates compounds, preferred chlorine, bromine, alkaline condition points in reaction solution to add alkaline matter, as salt of wormwood, sodium carbonate etc.
Should be appreciated that and work as HR
5free-NH is had in group
2during group, first should protect amino with blocking group conventional in this area, as used conventional amino protecting group Boc etc., use conventional method deprotection base after condensation reaction completes again, obtaining Compounds of formula II.
Typical reaction is exemplified as:
Wherein, R
1-R
5, X, Z be identical with defining in general formula I I; L, L
0for leavings group, be selected from halogen, sulfonates compounds, preferred chlorine, bromine, alkaline condition points in reaction solution to add alkaline matter, as diisopropyl ethyl amine, salt of wormwood, sodium carbonate etc.
Further aspect of the present invention provides the compound or its salt of following formula, and it is the important intermediate preparing Compounds of formula II of the present invention:
Wherein, R
1, R
2, R
3, R
4, X, Z, A, B be identical with defining in general formula I I; L
0for leavings group, be selected from halogen, sulfonates compounds, preferred chlorine, bromine.
The present invention is provided for the pharmaceutical composition to organism administration on the other hand, it contains compound and corresponding isomer, the diastereomer of general formula I or general formula I I, or its pharmacy acceptable salt, solvate, polymorphic form etc. are as active ingredient, and one or more medicine acceptable carrier, vehicle and/or media.
" pharmaceutical composition " refer to one or more compound or its salts of the present invention with usually accept in the art for bioactive compounds is delivered to organism, such as people, the preparation of carrier, vehicle and/or medium.The object of pharmaceutical composition is conducive to giving compound of the present invention to organism.
Term " medicine acceptable carrier " refers to organism without obvious stimulation effect, and can not damage the biological activity of this active compound and those carriers of performance and thinner." the acceptable vehicle of medicine and/or medium " refer to active ingredient together administration, the inert substance that is conducive to active ingredient administration." medicine acceptable carrier, vehicle and/or medium " includes but not limited to that by FDA's license be acceptable any carrier for people or livestock animals, vehicle, medium, glidant, sweetener, thinner, sanitas, dyestuff/tinting material, flavoring toughener, tensio-active agent, wetting agent, dispersion agent, disintegrating agent, suspending agent, stablizer, isotonic agent, solvent or emulsifying agent.The limiting examples of described vehicle comprises calcium carbonate, calcium phosphate, various sugar and each kind of starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol etc.
In a pure form or with the suitable the compounds of this invention of pharmaceutical compositions or the administration of the acceptable salt of its medicine by providing any acceptable mode of administration of the medicament of similar applications to carry out.Pharmaceutical composition of the present invention is by preparing compound of the present invention and the suitable acceptable supporting agent of medicine, thinner or excipient composition, and solid-state, semi-solid state, liquid state or gaseous state preparation can be mixed with, as tablet, pill, capsule, pulvis, granule, paste, emulsion, suspension agent, solution, suppository, injection, inhalation, gelifying agent, microballoon and aerosol etc.
The classical pathway giving the compounds of this invention or the acceptable salt of its medicine or its pharmaceutical composition includes but not limited to oral, rectum, thoroughly mucous membrane, through enteral administration, or local, in skin, suction, parenteral, sublingual, intravaginal, nose, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferred route of administration is oral administration.
Pharmaceutical composition of the present invention can adopt method manufacture well-known in the art, as the hybrid system, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc. of routine.
In preferred embodiments, pharmaceutical composition is oral form.For oral administration, by being mixed with medicine acceptable carrier well known in the art, vehicle and/or medium by active compound, this pharmaceutical composition can be prepared.These carrier vectors, vehicle and medium can make compound of the present invention be formulated into tablet, pill, lozenge, sugar-coat agent, capsule, liquid, gelifying agent, slurry agent, suspension agent etc., for the oral administration to patient.
Solid oral composition can be prepared by the mixing of routine, filling or tabletting method.Such as, obtain by following method: described active compound is mixed with solid excipient, the mixture of gained of optionally milling, if needed, add the assistant agent that other is suitable, then this mixture is processed into particle, obtains the core of tablet or sugar-coat agent.The auxiliary material be applicable to includes but not limited to: tackiness agent, thinner, disintegrating agent, lubricant, glidant, sweeting agent or correctives etc.As Microcrystalline Cellulose, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and starch paste; Talcum, starch, Magnesium Stearate, calcium stearate or stearic acid; Lactose, sucrose, starch, mannitol, Sorbitol Powder or Si Liaodengji dicalcium phosphate feed grade; Silicon-dioxide; Croscarmellose sodium, pre-paying starch, primojel, alginic acid, W-Gum, yam starch, methylcellulose gum, agar, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone etc.Optionally can carry out dressing to the core of sugar-coat agent according to method known in usual medicinal practice, especially use enteric coating.
Pharmaceutical composition is also applicable to administered parenterally, as the sterile solution agent of suitable unit dosage, suspensoid or freeze-drying prods.Suitable vehicle can be used, such as weighting agent, buffer reagent or tensio-active agent.
The compounds of this invention is 1-50mg, preferred 1-10mg by the intravenous route dosage reached needed for result for the treatment of, and is 1-100mg by oral route, and be preferably 1-30mg, be more preferably 1-10mg, each individuality is use 1-3 time every day.
Further aspect of the present invention relates to the compound of general formula I or general formula I I or its pharmacy acceptable salt and corresponding isomer, diastereomer, and solvate, polymorphic form benefit from the purposes in the medicine of the disease that DPP-IV suppresses in treatment or prevention.The described disease benefiting from DPP-IV suppression is selected from type ii diabetes, diabetic dyslipidaemia, glucose tolerance (IGT) disease, fasted plasma glucose attenuating (IFG) disease, metabolic acidosis, ketosis, appetite stimulator, obesity, various cancer, neurological conditions or disorder of immune system etc., preferably includes type ii diabetes.
The compound that thiadiazoles derivative provided by the invention replaces has extraordinary DPP-IV inhibit activities.And there is extraordinary internal metabolism level and most suitable Half-life in vivo, be expected to become suitable DPP-IV inhibitor class medicine.
Embodiment
Specific embodiment below, its objective is and make those skilled in the art more clearly understand and to implement the present invention.They should not be considered to limitation of the scope of the invention, and are exemplary illustration of the present invention and Typical Representative.Those skilled in the art should understand that: also have other route of synthesis forming the compounds of this invention, provide nonrestrictive embodiment below.
All all operations relating to the raw material of oxidizable or facile hydrolysis carry out all under nitrogen protection.Except as otherwise noted, the raw material that the present invention uses is all market has directly been bought directly use without being further purified.
The silica gel (200-300 order) that column chromatography chromatogram adopts Qingdao Chemical Co., Ltd. to produce.Precoated plate (the silica gel 60PF that thin-layer chromatography adopts E.Merck company to produce
254, 0.25 millimeter).Nucleus magnetic resonance chromatogram (NMR) uses VarianVNMRS-400 nmr determination.Liquid matter is used in conjunction (LC/MS) and uses FINNIGANThermoLCQAdvantageMAX, AgilentLC1200series (pillar:: WatersSymmetryC18,
4.6x50 millimeter, 5 microns, 35 DEG C), adopt ESI (+) ion mode.
Experimental section
the bromo-3-methyl-xanthine of intermediate 1:8-
Step 1:6-amino-1-methylpyrimidine-2,4 (1H, 3H)-diketone
MU (74.08g, 1.0mol) and ethyl cyanoacetate (124.0g, 1.10mol) are added in ethanol (1L) solution of sodium ethylate (142.0g, 2.1mol), stirring heating refluxes 12 hours.Be cooled to room temperature, concentrating under reduced pressure.Residue is soluble in water, continues reflux 2 hours.After being cooled to room temperature, regulate PH to be that 4-6 separates out white solid with concentrated hydrochloric acid, filter, washing, vacuum-drying, obtains 6-amino-1-methylpyrimidine-2,4 (1H, 3H)-diketone (77.0g), yield: 54.3%.
1HNMR(400MHz，DMSO-d6)：δ＝10.28(s，1H)，6.74(s，2H)，4.53(s，1H)，3.15(s，3H)。
Step 2:6-amino-1-methyl-5-nitroso-group pyrimidine-2,4 (1H, 3H)-diketone
Under agitation condition, to 6-amino-1-methylpyrimidine-2,4 (1H, 3H)-diketone (28.2g, in water (500mL) 0.2mol) and acetic acid (3.0mL) mixed solution, repeatedly add Sodium Nitrite (15.2g, 0.22moL) on a small quantity, finish, react 12 hours at 60 DEG C.Filter after being cooled to room temperature, after solid massive laundering, then use methanol wash, last vacuum-drying, obtain 6-amino-1-methyl-5-nitroso-group pyrimidine-2,4 (1H, 3H)-diketone (28.9g, Pink solid), yield: 85.0%.
1HNMR(400MHz，DMSO-d6)：δ＝13.05(s，1H)，11.51(s，1H)，9.14(s，1H)，3.15(s，3H)。
Step 3:5,6-diaminostilbene-methylpyrimidine-2,4 (1H, 3H)-diketone
Under agitation condition, to 6-amino-1-methyl-5-nitroso-group pyrimidine-2,4 (1H, 3H)-diketone (28.0g, in ammoniacal liquor (250mL) suspension liquid 0.16mol), repeatedly add Sodium Hydrosulphite (114.6g, 0.66mol) on a small quantity, react 12 hours at 60 DEG C.Filter after being cooled to room temperature, after solid massive laundering, then use methanol wash, last vacuum-drying, obtain 5,6-diaminostilbene-methylpyrimidine-2,4 (1H, 3H)-diketone (19.2g, white solid), yield: 75.0%.
1HNMR(400MHz，DMSO-d6)：δ＝10.53(brs，1H)，6.10(s，2H)，3.19(s，3H)，2.79(s，2H)。
Step 4:3-methyl-xanthine
By 5,6-diaminostilbene-methylpyrimidine-2,4 (1H, 3H)-diketone (9.3g, 60mmol), the mixed solution of formic acid (3.2mL) and water (70mL) stirs, reflux 12 hours.After being cooled to room temperature, add sodium hydroxide (5.0g, 125.0mmol), then continue reflux 2 hours.After being cooled to room temperature, regulate PH to 4.0 with acetic acid, separate out solid, filter, washing, vacuum-drying, obtains 3-methyl-xanthine (8.6g, yellow solid), yield: 86.9%.
1HNMR(400MHz，DMSO-d6)：δ＝13.50(s，1H)，11.07(s，1H)，7.99(s，1H)，3.35(s，3H)。
The bromo-3-methyl-xanthine of step 5:8-
Under agitation condition, in acetic acid (150mL) suspension liquid of 3-methyl-xanthine (8.6g, 52.7mol) and sodium-acetate (8.2g, 100mmol), drip bromine (10.0g, 62.5mmol).Dropwise, react 12 hours at 70 DEG C.Filter after being cooled to room temperature, solid acetic acid and the drying of washing final vacuum, obtain the bromo-3-methyl-xanthine of 8-(7.7g. white solid), yield: 60.4%.
1HNMR(400MHz，DMSO-d6)：δ＝14.30(brs，1H)，11.17(s，1H)，3.31(s，3H)。
intermediate 2:5-brooethyl benzo [1,2,5] thiadiazoles
Step 1: thionyl aniline
Aniline (the 46.5g of new distillation is added in the three-necked bottle of 500mL, 0.5mol) with 250mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (40mL) and toluene (40mL), after dropwising, reflux 2 hours, reaction solution becomes the clear solution of clarification, is directly used in next step reaction after being cooled to room temperature.
Step 2:5-methyl benzo [1,2,5] thiadiazoles
Upwards walk in reaction solution and add 4-methyl isophthalic acid, 2-phenylenediamine (30.5g, 0.25mol), under agitation condition, reflux 12 hours, is cooled to room temperature, uses dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filters, with pillar layer separation (with petroleum ether-ethyl acetate=16: 1 is eluent) after solvent concentration, obtain 5-methyl benzo [1,2,5] thiadiazoles (31.9g, white solid), yield: 85.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.76(d，J＝8.9Hz，1H)，7.60(m，1H)，7.25(m，1H)，2.43(s，3H)。
Step 3:5-brooethyl benzo [1,2,5] thiadiazoles
5-methyl benzo [1 is added in the three-necked bottle of 500mL, 2,5] thiadiazoles (15.0g, 0.1mol), N-bromo-succinimide (17.8g, 0.1mol), benzoyl peroxide (2.0g) and tetracol phenixin (250mL), reflux 24 hours under agitation condition.After cool to room temperature, filter, concentrated filtrate, with column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent), obtain 5-brooethyl benzo [1,2,5] thiadiazoles (17.2g, white solid), yield: 75.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.01(s，1H)，7.99(s，1H)，7.656-7.629(dd，J＝8.8Hz，1.6Hz，1H)，4.64(s，2H)。
intermediate 3:6-brooethyl-4-fluorobenzene also [1,2,5] thiadiazoles
Step 1:N-(the fluoro-4-aminomethyl phenyl of 2-) ethanamide
0 DEG C, under agitation condition, in the dichloromethane solution (200mL) of the fluoro-4-monomethylaniline (12.5g, 0.1mol) of 2-, slowly drip the dichloromethane solution (50mL) of acetic anhydride (12mL, 0.13mol).Dropwise rear 0 DEG C of reaction 1 hour.Reaction solution is poured into water (500mL), PH is regulated to be 7 with saturated sodium bicarbonate aqueous solution, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and obtains N-(the fluoro-4-aminomethyl phenyl of 2-) ethanamide (15.0g), yield: 90.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.13-8.09(m，1H)，7.26(brs，1H)，6.93-6.88(m，2H)，2.31(s，3H)，2.21(s，3H)。
The fluoro-4-methyl of step 2:2--6-N-methyl-p-nitroaniline
At 0 DEG C, under agitation condition, N-(the fluoro-4-aminomethyl phenyl of 2-) ethanamide (16.7g, 0.1mol) is repeatedly joined (95%, 200mL) in salpeter solution on a small quantity, add rear maintenance 0 DEG C and continue reaction 1 hour.Reaction solution is poured in frozen water, separates out solid, filter, obtain N-(the fluoro-4-methyl of 2--6-nitrophenyl) ethanamide (20.0g).
N-(the fluoro-4-methyl of 2--6-nitrophenyl) ethanamide (20.0g) is dissolved in the mixing solutions of methyl alcohol (200mL) and concentrated hydrochloric acid (200mL).Under agitation condition, 70 DEG C are reacted 4 hours.After being cooled to room temperature, reaction solution is poured into water (500mL), PH is regulated to be 7 with saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filters, and filtrate concentrates, column chromatography separating purification (with petroleum ether-ethyl acetate=8: 1 is eluent), obtains the fluoro-4-methyl of 2--6-N-methyl-p-nitroaniline (10.8g) yield: 63.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.74(s，1H)，7.09-7.06(dd，J＝2.0Hz，11.6Hz，1H)，5.96(brs，2H)，2.28(s，3H)。
The fluoro-5-methyl-o-phenylenediamine of step 3:3-
Pd/C (1g, 10%) is added in the methanol solution (100mL) of 2-fluoro-4-methyl-6-N-methyl-p-nitroaniline (1.7g, 10mmol).Under the atmosphere of hydrogen of a pressure, room temperature reaction 48 hours.By reacting liquid filtering, obtain the fluoro-5-methyl-o-phenylenediamine (1.3g) of 3-after concentrated, yield: 93.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝6.31-6.38(m，2H)，3.45(brs，4H)，2.19(s，3H)。
Step 4:4-fluoro-6-methyl benzo [1,2,5] thiadiazoles
Aniline (the 3.72g of new distillation is added in the three-necked bottle of 250mL, 40mmol) with 50mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (4mL) and toluene (50mL), after dropwising, reflux 2 hours, reaction solution becomes the clear solution of clarification, is directly used in next step reaction after being cooled to room temperature.
Upwards walk in reaction solution and add the fluoro-5-methyl-o-phenylenediamine (2.8g, 20mmol) of 3-, reflux 12 hours under agitation condition, be cooled to room temperature, use dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filter, with column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent) after solvent concentration, obtain 4-fluoro-6-methyl benzo [1,2,5] thiadiazoles (2.5g, white solid), yield: 73.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.57-7.56(q，J＝1.2Hz，2.4Hz，1H)，7.09-7.06(dd，J＝1.2Hz，10.8Hz，1H)，2.54-2.53(d，J＝1.2Hz，3H)。
Step 5:6-brooethyl-4-fluorobenzene is [1,2,5] thiadiazoles also
4-fluoro-6-methyl benzo [1 is added in the three-necked bottle of 250mL, 2,5] thiadiazoles (1.0g, 5.9mmol), N-bromo-succinimide (1.16g, 6.5mmol), benzoyl peroxide (catalytic amount) and tetracol phenixin (100mL), reflux 24 hours under agitation condition.After cool to room temperature, filter, concentrated filtrate, with column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent), obtain 6-brooethyl-4-fluorobenzene also [1,2,5] thiadiazoles (1.03g, white solid), yield: 70.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.807(s，1H)，7.32-7.29(dd，J＝1.6Hz，10.4Hz，1H)，4.61(s，2H)。
intermediate 4:6-brooethyl-4-chlorobenzene also [1,2,5] thiadiazoles
Step 1:N-(the chloro-4-aminomethyl phenyl of 2-) ethanamide
0 DEG C, under agitation condition, in the dichloromethane solution (200mL) of the chloro-4-monomethylaniline (14.2g, 0.1mol) of 2-, slowly drip the dichloromethane solution (50mL) of acetic anhydride (12mL, 0.13mol).Dropwise rear 0 DEG C of reaction 1 hour.Reaction solution is poured into water (500mL), PH is regulated to be 7 with saturated sodium bicarbonate aqueous solution, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and obtains N-(the chloro-4-aminomethyl phenyl of 2-) ethanamide (15.8g), yield: 85.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.15(m，1H)，7.26(brs，1H)，6.80(m，2H)，2.30(s，3H)，2.21(s，3H)。
The chloro-4-methyl of step 2:2--6-N-methyl-p-nitroaniline
At 0 DEG C, under agitation condition, N-(the chloro-4-aminomethyl phenyl of 2-) ethanamide (15.8g, 8.6mmol) is repeatedly joined (95%, 200mL) in salpeter solution on a small quantity, under finishing rear 0 DEG C of condition, continues reaction 1 hour.Reaction solution is poured in frozen water, separates out solid, filter, obtain N-(the chloro-4-methyl of 2--6-nitrophenyl) ethanamide.
N-(the chloro-4-methyl of 2--6-nitrophenyl) ethanamide is dissolved in the mixing solutions of methyl alcohol (200mL) and concentrated hydrochloric acid (200mL).Under agitation condition, 70 DEG C are reacted 4 hours.After being cooled to room temperature, reaction solution is poured into water (500mL), PH is regulated to be 7 with saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filters, and filtrate concentrates, column chromatography separating purification (with petroleum ether-ethyl acetate=10: 1 is eluent), obtains the chloro-4-methyl of 2--6-N-methyl-p-nitroaniline (12.1g) yield: 75.3%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.819(s，1H)，7.569-7.565(d，J＝1.6Hz，1H)，7.101(brs，2H)，2.195(s，3H)。
The chloro-5-methyl-o-phenylenediamine of step 3:3-
Raney's nickel (2g) is added in the methanol solution (250mL) of 2-chloro-4-methyl-6-N-methyl-p-nitroaniline (7.48g, 42.3mmol).Under the atmosphere of hydrogen of a pressure, room temperature reaction 12 hours.Reaction solution after filtration, obtains the chloro-5-methyl-o-phenylenediamine (4.7g) of 3-after concentrated, yield: 74.6%.
1HNMR(400MHz，CDCl3-d3)：δ＝6.305(s，1H)，6.275(s，1H)，4.759(brs，2H)，4.385(brs，2H)，2.108(s，3H)。
Step 4:4-chloro-6-methyl benzo [1,2,5] thiadiazoles
Aniline (the 3.5g of new distillation is added in the three-necked bottle of 250mL, 44.8mmol) with 50mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (5.87g, 49.0mmol) and toluene (50mL), after dropwising, reflux 2 hours, reaction solution becomes the clear solution of clarification.Next step reaction is directly used in after being cooled to room temperature.
Upwards walk in reaction solution and add the chloro-5-methyl-o-phenylenediamine of 3-(3.5g, 22.4mmol), reflux 12 hours under agitation condition, be cooled to room temperature, use dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filter, 4-chloro-6-methyl benzo [1,2,5] thiadiazoles (2.0g is obtained with column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent) after solvent concentration, white solid), yield: 71.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.857-7.855(d，J＝0.8Hz，1H)，7.78(s，1H)，2.512(s，3H)。
Step 5:6-brooethyl-4-chlorobenzene is [1,2,5] thiadiazoles also
4-chloro-6-methyl benzo [1 is added in the three-necked bottle of 250mL, 2,5] thiadiazoles (1.2g, 6.5mmol), N-bromo-succinimide (1.39g, 7.8mmol), benzoyl peroxide (catalytic amount) and tetracol phenixin (100mL), reflux 12 hours under agitation condition.After cool to room temperature, filter, concentrated filtrate, with column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent), obtain 6-brooethyl-4-chlorobenzene also [1,2,5] thiadiazoles (0.71g, white solid), yield: 41.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.197(s，1H)，7.934(s，1H)，4.965(s，2H)。
intermediate 5:6-chloromethyl-4-methyl benzo [1,2,5] thiadiazoles
Step 1:4-acetylaminohydroxyphenylarsonic acid 3-tolyl acid
0 DEG C, under agitation condition, to amino-3 tolyl acid (60.0g of 4-, triethylamine (121g is slowly dripped in dichloromethane solution (800mL) 0.4mol), 1.19mol), after dropwising, continue wherein to drip acetic anhydride (81.0g, 0.79mol).Dropwise rear room temperature reaction 60 hours.Reaction solution is poured into water, and with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filters, and filtrate concentrates, and obtains 4-acetylaminohydroxyphenylarsonic acid 3-tolyl acid (43.0g), yield: 56.0%.
1HNMR(400MHz，DMSO-d6)：δ＝9.45(s，1H)，7.94(s，1H)，7.91(s，2H)，2.32(s，3H)，2.13(s，3H)。
Step 2:4-acetylaminohydroxyphenylarsonic acid 3-methyl-5 nitrobenzoic acid
At 0 DEG C, under agitation condition, 4-acetylaminohydroxyphenylarsonic acid 3-tolyl acid (43.0g, 0.22mol) is repeatedly joined in nitric acid (60%) and vitriol oil mixed solution (410mL) on a small quantity, under finishing rear 0 DEG C of condition, continues reaction 1 hour.Reaction solution is poured in frozen water, separates out solid, filter, vacuum-drying obtains 4-acetylaminohydroxyphenylarsonic acid 3-methyl-5-nitro phenylformic acid (38.0g), yield: 72.0%.
1HNMR(400MHz，CD3OD-d4)：δ＝8.29(s，1H)，8.18(s，1H)，2.39(s，3H)，2.16(s，3H)。
Step 3:4-amino-3-methyl-5-nitro phenylformic acid
The mixing solutions of 4-acetylaminohydroxyphenylarsonic acid 3 methyl-5-nitro phenylformic acid (38.0g, 0.16mol) and 3N hydrochloric acid (800mL), under agitation, heating reflux reaction 4 hours.After being cooled to room temperature, filter, vacuum-drying obtains 4-amino-3-methyl-5-nitro phenylformic acid (23.0g) yield: 74.0%.
1HNMR(400MHz，DMSO-d6)：δ＝12.79(brs，1H)，8.45(s，1H)，7.79(s，1H)，7.60(brs，2H)，2.22(s，3H)。
Step 4:4-amino-3-methyl-5-nitro methyl benzoate
In the methanol solution of amino-3 methyl-5 nitrobenzoic acid (23.0g, 0.12mol) of 4-, (500mL) adds the 5mL vitriol oil.Under agitation condition, heating reflux reaction 12 hours.After being cooled to room temperature, in concentrated for reaction solution falling back, regulate PH to weakly alkaline with saturated sodium bicarbonate aqueous solution. be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and obtains 4-amino-3 methyl-5-nitro methyl benzoate (23.4g) yield: 95.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.77(s，1H)，7.94(s，1H)，6.56(brs，2H)，3.90(s，3H)，2.29(s，3H)。
Step 5:3,4-diamino-5-methyl-toluate
Raney's nickel (15g) is added in the methanol solution (500mL) of amino-3 methyl-5-nitro methyl benzoate (23.4g, 0.11mol) of 4-.Under the atmosphere of hydrogen of a pressure, room temperature reaction 12 hours.Reaction solution after filtration, obtains 3,4-diamino-5-methyl-toluate (20.1g) after concentrated, yield: 100%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.41(s，1H)，7.32(s，1H)，3.84(s，3H)，3.82(brs，2H)，3.30(brs，2H)，2.21(s，3H)。
Step 6:7-methyl benzo [1,2,5] thiadiazoles-5-carboxylate methyl ester
Aniline (the 20.8g of new distillation is added in the three-necked bottle of 500mL, 0.22mmol) with 250mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (31.4g, 0.26mol) and toluene (100mL), after dropwising, reflux 2 hours, reaction solution becomes the clear solution of clarification.Next step reaction is directly used in after being cooled to room temperature.
Upwards walk in reaction solution and add 3,4-diamino-5-methyl-toluate (20.1g, 0.11mol), reflux 12 hours under agitation condition, be cooled to room temperature, use dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filters, with column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent) after solvent concentration, obtain 7-methyl benzo [1,2,5] thiadiazoles-5-carboxylate methyl ester (14.6g), yield: 63.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.58(s，1H)，7.98(s，1H)，4.00(s，3H)，2.78(s，3H)。
Step 7:6-methylol-4-methyl benzo [1,2,5] thiadiazoles
At 0 DEG C, under agitation condition, to 7-methyl benzo [1,2, in the ethanolic soln of 5] thiadiazoles-5-carboxylate methyl ester (14.6g, 70.1mmol), (250ml) adds sodium borohydride (5.3g, 140.2mmol), then a small amount of repeatedly add calcium chloride (7.9g, 70.1mmol) wherein.Finish, room temperature reaction 8 hours.Reaction solution is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying in concentrating and falling back, and filters, and filtrate concentrates, and obtains 6-methylol-4-methyl benzo [1,2,5] thiadiazoles (11.6g) yield: 92.1%.
1HNMR(400MHz，DMSO-d6)：δ＝7.82(s，1H)，7.49(s，1H)，5.57-5.54(t，J＝6.0Hz，1H)，4.72-4.71(q，J＝1.2Hz，J＝6.0Hz，2H)，2.72(s，3H)。
Step 8:6-chloromethyl-4-methyl benzo [1,2,5] thiadiazoles
At 0 DEG C, under agitation condition, 6-methylol-4-methyl benzo [1,2,5] thiadiazoles (11.6g, 64.4mmol) is added to (20mL) in thionyl chloride, finishes, room temperature reaction 4 hours.In concentrated for reaction solution falling back, PH weakly alkaline is regulated with saturated sodium bicarbonate aqueous solution solution. be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, obtain 6-chloromethyl-4-methyl benzo [1,2,5] thiadiazoles (10.9g) yield: 85.0%.
1HNMR(400MHz，DMSO-d6)：δ＝8.06(s，1H)，7.62(s，1H)，5.00(s，2H)，2.75(s，3H)。
intermediate 6:6-chloromethyl-4-trifluoromethyl benzo [1,2,5] thiadiazoles
Step 1:2-nitro-4-cyano group-6-5-trifluoromethylaniline
At 0 DEG C, under agitation condition, a small amount of for saltpetre (9.0g, 88.6mmol) repeatedly be added to 4-cyano group-2-5-trifluoromethylaniline (15.0g, in concentrated sulfuric acid solution 80.6mmol) (250mL), at finishing latter 0 DEG C, continue reaction 1 hour.Reaction solution is poured in frozen water, separates out solid, and filter, vacuum-drying obtains 2-nitro-4-cyano group-6-5-trifluoromethylaniline (15.8g), yield: 85.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.68(s，1H)，7.72(s，1H)。
Step 2:3-nitro-4-amino-5-trifluoromethyl benzoic acid methyl ester
At 0 DEG C, under agitation condition, continue to pass into hydrogen chloride gas 2 hours in the methanol solution (500mL) of 2-nitro-4-cyano group-6-5-trifluoromethylaniline (15.8g, 68.4mmol).Logical complete, reflux 12 hours.Be cooled to room temperature, in concentrated for reaction solution falling back, regulate PH to weakly alkaline with saturated sodium bicarbonate aqueous solution. be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and pillar layer separation (with petroleum ether-ethyl acetate=4: 1 is eluent), obtains 3-nitro-4-amino-5-trifluoromethyl benzoic acid methyl ester (15.0g) yield: 83.0%.
1HNMR(400MHz，DMSO-d6)：δ＝8.73(s，1H)，8.17(s，1H)，7.91(brs，2H)，3.84(s，3H)。
Step 3:3,4-diamino-5-trifluoromethyl benzoic acid methyl ester
Raney's nickel (10g) is added in the methanol solution (500mL) of 3-nitro-4-amino-5-trifluoromethyl benzoic acid methyl ester (15.0g, 56.8mmol).Under the atmosphere of hydrogen of a pressure, room temperature reaction 6 hours.Reaction solution after filtration, obtains 3,4-diamino-5-trifluoromethyl benzoic acid methyl ester (13.3g) after concentrated, yield: 100%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.79(s，1H)，7.55(s，1H)，4.42(brs，2H)，3.87(s，3H)，3.39(brs，2H)。
Step 4:7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-carboxylate methyl ester
Aniline (the 10.6g of new distillation is added in the three-necked bottle of 500mL, 113.6mmol) with 200mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (16.2g, 136.2mmol) and toluene (50mL), after dropwising, reflux 1 hour, reaction solution becomes the clear solution of clarification.Next step reaction is directly used in after being cooled to room temperature.
Upwards walk in reaction solution and add 3,4-diamino-5-trifluoromethyl benzoic acid methyl ester (13.3g, 56.8mmol), heated overnight at reflux under agitation condition.Be cooled to room temperature, use dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filter, filtrate concentrates rear pillar layer separation (with petroleum ether-ethyl acetate=10: 1 is eluent), obtain 7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-carboxylate methyl ester (11.3g), yield: 76.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.94(s，1H)，8.57(s，1H)，4.05(s，3H)。
Step 5:6-methylol-4-trifluoromethyl benzo [1,2,5] thiadiazoles
At 0 DEG C, under agitation condition, to 7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-carboxylate methyl ester (11.3g, in ethanolic soln 43.2mmol), (250ml) adds sodium borohydride (3.3g, 86.3mmol), then a small amount of repeatedly add calcium chloride (4.8g, 43.2mmol) wherein, finish, react 6 hours under room temperature.Reaction solution is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying in concentrating and falling back, and filters, and filtrate concentrates, and obtains 6-methylol-4-trifluoromethyl benzo [1,2,5] thiadiazoles (8.5g) yield: 84.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.19(s，1H)，7.96(s，1H)，4.95(s，2H)。
Step 6:6-chloromethyl-4-trifluoromethyl benzo [1,2,5] thiadiazoles
At 0 DEG C, under agitation condition, 6-methylol-4-trifluoromethyl benzo [1,2,5] thiadiazoles (8.5g, 36.2mmol) is added to (20mL) in thionyl chloride, finishes, react 6 hours under room temperature.In concentrated for reaction solution falling back, regulate PH to weakly alkaline with saturated sodium bicarbonate aqueous solution. be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, obtain 6-chloromethyl-4-trifluoromethyl benzo [1,2,5] thiadiazoles (8.3g) yield: 91.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.21(s，1H)，8.00(s，1H)，4.79(s，2H)。
intermediate 7:6-chloromethyl-4,5-difluoro benzo [1,2,5] thiadiazoles
Step 1:2,3,4-tri-fluorine-5-nitro benzoic acid
At 0 DEG C, under agitation condition, 2,3,4-trifluoro-benzoic acid (50.0g, 0.28mol) repeatedly joins in the mixed solution of nitrosonitric acid (16.8mL) and the vitriol oil (250mL) on a small quantity, after finishing, continue reaction at 0 DEG C 3 hours.Reaction solution is poured in frozen water, separates out solid, filter, vacuum-drying obtains 2,3,4-tri-fluorine-5-nitro benzoic acid (55.0g), yield: 87.6%.
1HNMR(400MHz，DMSO-d6)：δ＝8.44-8.39(m，1H)。
The fluoro-4-amino of step 2:2,3-bis--5-nitrobenzoic acid
At 0 DEG C, under agitation condition, to 2,3, ammoniacal liquor (30%, 130mL) is dripped in the suspension liquid of 4-tri-fluorine-5-nitro benzoic acid (55.0g, 0.25mol) in water, in dropping process, solution becomes clarification, after dropwising, react 6 hours under room temperature, reaction solution is cooled to 0 DEG C, slowly drip concentrated hydrochloric acid wherein under agitation condition, make the PH of reaction solution reach about 2.Separate out solid, after filtration, washing, obtains the fluoro-4-amino of 2,3-bis--5-nitrobenzoic acid (41.7g) after drying, yield: 76.9%.
1HNMR(400MHz，DMSO-d6)：δ＝13.49(brs，1H)，8.40-8.38(dd，J＝2.0Hz，7.6Hz，1H)，7.99(brs，2H)。
The fluoro-4-amino of step 3:2,3-bis--5-nitrobenzene methyl
To 2, the fluoro-4-amino of 3-bis--5-nitrobenzoic acid (41.7g, in methanol solution 0.19mol), (500mL) adds the 10mL vitriol oil, heating reflux reaction 12 hours under agitation condition, be cooled to room temperature, in concentrated for reaction solution falling back, regulate PH to weakly alkaline with saturated sodium bicarbonate aqueous solution. be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and obtains the fluoro-4-amino of 2,3-bis--5-nitrobenzene methyl (43.2g) yield: 97.3%.
1HNMR(400MHz，DMSO-d6)：δ＝8.41-8.38(dd，J＝2.0Hz，7.2Hz，1H)，8.08(brs，2H)。
Fluoro-4, the 5-diamino-methyl benzoates of step 4:2,3-bis-
To 2, the fluoro-4-amino of 3-bis--5-nitrobenzene methyl (43.2g, Raney's nickel (30g) is added in methanol solution (1000mL) 186.1mmol), under the atmosphere of hydrogen of a pressure, react 12 hours under room temperature, reaction solution after filtration, 2 are obtained after concentrated, fluoro-4, the 5-diamino-methyl benzoates (35.7g) of 3-bis-, yield: 95.0%.
1HNMR(400MHz，DMSO-d6)：δ＝6.85-6.83(dd，J＝2.0Hz，7.6Hz，1H)，5.60(brs，2H)，4.84(brs，2H)，3.73(s，3H)。
Step 5:6,7-difluoro benzo [1,2,5] thiadiazoles-5-carboxylate methyl ester
Aniline (the 32.9g of new distillation is added in the three-necked bottle of 1000mL, 353.2mmol) with 500mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (50.4g, 423.8mmol) and toluene (100mL), after dropwising, reflux 2 hours, reaction solution becomes the clear solution of clarification.Next step reaction is directly used in after being cooled to room temperature.
Upwards walk in reaction solution and add 2,3-bis-fluoro-4,5-diamino-methyl benzoate (35.7g, 176.6mmol), heated overnight at reflux under agitation condition, be cooled to room temperature, use dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filter, filtrate concentrates rear column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent), obtains 6,7-difluoro benzo [1,2,5] thiadiazoles-5-carboxylate methyl ester (25.4g), yield: 62.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.48-8.46(dd，J＝2.0Hz，6.0Hz，1H)，4.04(s，3H)。
Step 6:6-methylol-4,5-difluoro benzo [1,2,5] thiadiazoles
At 0 DEG C, under agitation condition, to 6, 7-difluoro benzo [1, 2, 5] thiadiazoles-5-carboxylate methyl ester (25.4g, in ethanolic soln 110.3mmol), (250ml) adds sodium borohydride (8.3g, 220.7mmol), then a small amount of repeatedly add calcium chloride (12.2g wherein, 110.3mmol), finish, react 6 hours under room temperature, during reaction solution concentrates and falls back, be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, obtain 6-methylol-4, 5-difluoro benzo [1, 2, 5] thiadiazoles (17.8g) yield: 79.8%.
1HNMR(400MHz，DMSO-d6)：δ＝7.92-7.90(dd，J＝1.6Hz，6.0Hz，1H)，5.73-5.70(t，J＝5.6Hz，1H)，4.75-4.73(d，J＝5.6Hz，2H)。
Step 7:6-chloromethyl-4,5-difluoro benzo [1,2,5] thiadiazoles
At 0 DEG C, under agitation condition, 6-methylol-4,5-difluoro benzo [1,2,5] thiadiazoles (17.8g, 88.0mmol) be added to (100mL) in thionyl chloride, finish, react 8 hours under room temperature, in concentrated for reaction solution falling back, regulate PH to weakly alkaline with saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and obtains 6-chloromethyl-4,5-difluoro benzo [1,2,5] thiadiazoles (16.5g) yield: 84.7%.
1HNMR(400MHz，DMSO-d6)：8.240-8.220(dd，J＝2.0Hz，6.4Hz，1H)，5.04(s，2H)。
intermediate 8:5-brooethyl-[1,2,5] thiadiazoles also [3,4-b] pyridine
Step 1:2-amino-3-nitro-6-picoline
At 0 DEG C, under agitation condition, to 2-amino-6-picoline (21.6g, nitric acid (70% is slowly dripped in concentrated sulfuric acid solution (100mL) 0.2mol), 20mL, 0.32mol), dropwise rear room temperature reaction 12 hours, reaction solution is poured in frozen water, separate out yellow solid, filter, dry, obtain 2-amino-3-nitro-6-picoline (8.0g), yield: 26.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.31-8.29(d，J＝8.4Hz，1H)，6.60-6.58(d，J＝8.8Hz，1H)，5.10(brs，2H)，2.76(s，3H)。
Step 2:2,3-diamino-6-picoline
To 2-amino-3-nitro-6-picoline (15.3g, Pd/C (2g is added in methanol solution (500mL) 0.1mol), 10%), under the atmosphere of hydrogen of a pressure, react 48 hours under room temperature, reacting liquid filtering, after concentrated, obtain 2,3-diamino-6-picoline (10.0g), yield: 80.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝6.82-6.80(d，J＝7.2Hz，1H)，6.47-6.45(d，J＝7.6Hz，1H)，4.27(brs，2H)，3.18(brs，2H)，2.33(s，3H)。
Step 3:5-methyl-[1,2,5] thiadiazoles also [3,4-b] pyridine
Aniline (the 7.45g of new distillation is added in the three-necked bottle of 250mL, 80mmol) with 50mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (12mL) and toluene (20mL), after dropwising, reflux 2 hours, reaction solution becomes the clear solution of clarification.Next step reaction is directly used in after being cooled to room temperature.
Upwards walk in reaction solution and add 2,3-diamino-6-picoline (4.9g, 40.0mmol), reflux 12 hours under agitation condition, be cooled to room temperature, use dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filters, filtrate concentrates rear column chromatography separating purification (with petroleum ether-ethyl acetate=8: 1 is eluent), obtain 5-methyl-[1,2,5] thiadiazoles also [3,4-b] pyridine (2.6g), yield: 43.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.22-8.20(d，J＝9.2Hz，1H)，7.45-7.43(d，J＝9.2Hz，1H)，2.82(s，3H)。
Step 4:5-brooethyl-[1,2,5] thiadiazoles also [3,4-b] pyridine
5-methyl-[1 is added in the three-necked bottle of 250mL, 2, 5] thiadiazoles also [3, 4-b] pyridine (1.51g, 10.0mmol), N-bromo-succinimide (1.96g, 11.0mmol), azo isobutyronitrile (catalytic amount) and tetracol phenixin (50mL), reflux 12 hours under agitation condition, cool to room temperature, filter, concentrated filtrate, with column chromatography separating purification (with petroleum ether-ethyl acetate=8: 1 is eluent), obtain 5-brooethyl-[1, 2, 5] thiadiazoles also [3, 4-b] pyridine (0.98g), yield: 42.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.37-8.35(d，J＝8.8Hz，1H)，7.76-7.74(d，J＝8.8Hz，1H)，4.74(s，2H)。
intermediate 9:6-brooethyl-[1,2,5] thiadiazoles also [3,4-b] pyridine
Step 1:2-amino-3-nitro-5-picoline
Room temperature, under agitation condition, to 2-amino-5-picoline (21.6g, nitric acid (70% is slowly dripped in concentrated sulfuric acid solution (100mL) 0.2mol), 20mL, 0.32mol), react 2 hours at 55 DEG C after dropwising, be cooled to room temperature, reaction solution is poured in frozen water, sodium hydroxide solution with 40% regulates PH to 9, with chloroform extraction, and organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, and obtains 2-amino-3-nitro-5-picoline (6.48g), yield: 25.5%.
1HNMR(400MHz，DMSO-d6)：δ＝8.28(s，1H)，8.21(s，1H)，7.72(brs，2H)，2.21(s，3H)。
Step 2:2,3-diamino-5-picoline
To 2-amino-3-nitro-5-picoline (6.48g, Pd/C (1g is added in methanol solution (200mL) 42.3mmol), 10%), under the atmosphere of hydrogen of a pressure, react 12 hours under room temperature, reacting liquid filtering, after concentrated, obtain 2,3-diamino-5-picoline (4.7g), yield: 90.4%.
1HNMR(400MHz，DMSO-d6)：δ＝7.06(s，1H)，6.67(s，1H)，6.15(brs，2H)，4.95(brs，2H)，2.02(s，3H)。
Step 3:6-methyl-[1,2,5] thiadiazoles also [3,4-b] pyridine
Aniline (the 7.0g of new distillation is added in the three-necked bottle of 250mL, 75.2mmol) with 50mL toluene, frozen water cools, under agitation condition, the mixture of slow dropping sulfur oxychloride (12mL) and toluene (20mL), after dropwising, reflux 2 hours, reaction solution becomes the clear solution of clarification.Next step reaction is directly used in after being cooled to room temperature.
Upwards walk in reaction solution and add 2,3-diamino-5-picoline (4.0g, 32.5mmol), reflux 12 hours under agitation condition, be cooled to room temperature, use dilute hydrochloric acid successively, saturated solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying, filters, filtrate concentrates rear column chromatography separating purification (with petroleum ether-ethyl acetate=20: 1 is eluent), obtain 6-methyl-[1,2,5] thiadiazoles also [3,4-b] pyridine (3.5g), yield: 71.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.95(s，1H)，8.08(s，1H)，2.60(s，3H)。
Step 4:6-brooethyl-[1,2,5] thiadiazoles also [3,4-b] pyridine
6-methyl-[1 is added in the three-necked bottle of 250mL, 2, 5] thiadiazoles also [3, 4-b] pyridine (2.0g, 13.2mmol), N-bromo-succinimide (2.58g, 14.5mmol), azo isobutyronitrile (0.003.0.02mmol) and tetracol phenixin (50mL), reflux 12 hours under agitation condition, after cool to room temperature, filter, concentrated filtrate, with column chromatography separating purification (with petroleum ether-ethyl acetate=16: 1 is eluent), obtain 6-brooethyl-[1, 2, 5] thiadiazoles also [3, 4-b] pyridine (1.8g), yield: 60.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝9.12(s，1H)，8.32(s，1H)，4.68(s，2H)。
Embodiment 1:
8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2- butine-1-base)-3-methyl-xanthine
Universal synthesis method:
The bromo-7-of step 1:8-(2-butyne-1-base)-3-methyl-xanthine
Under agitation condition, to 8-bromine 3-methyl-xanthine (3.0g, N 12.2mmol), bromo-2-butyne (the 2.0g of 1-is added in the suspension liquid of dinethylformamide (50mL), 15mmol) with diisopropyl ethyl amine (1.9g, 14.7mmol), react 4 hours at 40 DEG C, be cooled to during room temperature falls back, separate out solid, filter, solids washed with water, vacuum-drying, obtains the bromo-7-of 8-(2-butyne-1-base)-3-methyl-xanthine (3.1g, white solid), yield: 84.3%.
1HNMR(400MHz，DMSO-d6)：δ＝11.31(s，1H)，5.036-5.030(d，J＝2.4Hz，2H)，3.31(s，3H)，1.785-1.773(t，J＝2.4Hz，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
Under agitation condition, to the bromo-7-of 8-(2-butyne-1-base)-3-methyl-xanthine (1.1g, N 3.7mmol), 5-brooethyl benzo [1 is added in the suspension liquid of dinethylformamide (50mL), 2, 5] thiadiazoles (1.0g, 4.4mmol) with salt of wormwood (1.1g, 7.4mmol), react 4 hours at 80 DEG C, be cooled to during room temperature falls back, separate out solid, filter, solid water and washed with diethylether, vacuum-drying, obtain 1-(benzo [1, 2, 5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine (1.5g, white solid), yield: 90.9%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.01(s，1H)，7.957-7.934(d，J＝9.2Hz，1H)，7.742-7.720(d，J＝8.8Hz，1H)，5.37(s，2H)，5.12(s，2H)，3.57(s，3H)，1.816-1.813(d，J＝1.2Hz，3H)。
Step 3:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
Under agitation condition, to 1-(benzo [1, 2, 5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine (0.4g, N 0.9mmol), (R)-3-Boc-amino piperidine (0.22g is added in the suspension liquid of dinethylformamide (50mL), 1.1mmol) with salt of wormwood (0.25g, 1.8mmol), react 4 hours at 80 DEG C, be cooled to during room temperature falls back, separate out solid, filter, solid water and washed with diethylether, vacuum-drying, obtain 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1, 2, 5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine (0.38g, white solid), yield: 75.5%.MSm/z[ESI]：565.0[M+1]。
Step 4:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
Under agitation condition, to 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1, 2, 5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine (0.38g, in dichloromethane solution 0.67mmol) (50mL), drip trifluoroacetic acid (10mL), react 4 hours under room temperature, pour in frozen water, regulate PH to alkalescence with saturated sodium bicarbonate solution, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate concentrates, column chromatography separating purification (with methylene chloride-methanol=20: 1 is eluent), obtain 8-((R)-3-amino-piperadine-1-base)-1-(benzo [1, 2, 5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine (0.27g, faint yellow solid), yield: 85.0%, HPLC:97.41%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.98(s，1H)，7.923-7.907(d，J＝6.4Hz，1H)，7.737-7.710(dd，J＝9.2Hz，1.6Hz，1H)，5.36(s，2H)，4.922-4.897(m，2H)，3.657-3.619(m，1H)，3.52(s，3H)，3.488-3.463(m，1H)，3.229-3.181(m，2H)，3.089-3.038(m，1H)，2.017-1.978(m，2H)，1.920-1.895(t，J＝3.6Hz，3H)，1.744-1.711(m，1H)，1.564-1.543(m，1H)。MSm/z[ESI]：465.0[M+1]
Embodiment 2:
8-((R)-3-amino-piperadine-1-base)-1-(7-fluorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7- (2-butyne-1-base)-3-methyl-xanthine
Step 1:1-(7-fluorobenzene is [1,2,5] thiadiazoles-5-methyl also) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, with 6-brooethyl-4-fluorobenzene also [1,2,5] thiadiazoles replacement 5-brooethyl benzo [1,2,5] thiadiazoles, obtained target compound, yield: 80.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.865(s，1H)，7.421-7.394(dd，J＝1.2Hz，10.8Hz，1H)，5.340(s，2H)，5.128-5.117(q，J＝2.4，2H)，3.570(s，3H)，1.822-1.811(t，J＝2.4Hz，3H)。
Step 2:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-fluorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 1, with 1-(7-fluorobenzene also [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 80.0%.MSm/z[ESI]：583.0[M+1]。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(7-fluorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 4 in embodiment 1, with 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-fluorobenzene also [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine replacement 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 70.0%, HPLC:94.12%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.835(s，1H)，7.411-7.382(dd，J＝1.2Hz，10.4Hz，1H)，5.326(s，2H)，4.928-4.895(q，J＝2.0Hz，2H)，3.644-3.605(m，1H)，3.514-3.435(m，4H)，3.323-3.250(m，2H)，3.179-3.147(m，1H)，2.005-1.904(m，2H)，1.833-1.822(t，J＝2.0Hz，3H)，1.751-1.262(m，2H)。MSm/z[ESI]：483.0[M+1]。
embodiment 3:8-((R)-3-amino-piperadine-1-base)-1-(7-chlorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-
(2-butyne-1-base)-3-methyl-xanthine
Step 1:1-(7-chlorobenzene is [1,2,5] thiadiazoles-5-methyl also) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, with 6-brooethyl-4-chlorobenzene also [1,2,5] thiadiazoles replacement 5-brooethyl benzo [1,2,5] thiadiazoles, obtained target compound, yield: 60.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.977-7.974(d，J＝1.2Hz，1H)，7.797-7.794(d，J＝1.2Hz，1H)，5.334(s，2H)，5.131-5.113(q，J＝2.4，2H)，3.572(s，3H)，1.824-1.812(t，J＝2.4Hz，3H)。
Step 2:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-chlorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 1, with 1-(7-chlorobenzene also [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 81.2%.MSm/z[ESI]：599.0[M]，601.0[M+2]，600.0[M+1]。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(7-chlorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 4 in embodiment 1, with 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-chlorobenzene also [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine replacement 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 60.0%, HPLC:97.38%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.947-7.944(d，J＝1.2Hz，1H)，7.795-7.791(d，J＝1.6Hz，1H)，5.322(s，2H)，4.906-4.884(q，J＝2.0Hz，2H)，3.664-3.624(m，1H)，3.522-3.471(m，4H)，3.191-3.026(m，3H)，2.003-1.979(m，2H)，1.924-1.898(t，J＝2.0Hz，3H)，1.740-1.692(m，2H)。MSm/z[ESI]：483.0[M+1]。
embodiment 4:8-((R)-3-amino-piperadine-1-base)-1-(7-methyl benzo [1,2,5] thiadiazoles-5-first
base)-7-(2-butyne-1-base)-3-methyl-xanthine
Step 1:1-(7-methyl benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 5-brooethyl benzo [1,2,5] thiadiazoles with 6-brooethyl-4-methyl benzo [1,2,5] thiadiazoles, obtained target compound, yield: 72.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.805(s，1H)，7.453(s，1H)，5.323(s，2H)，5.134-5.116(q，J＝2.4，2H)，3.570(s，3H)，2.715(s，3H)，1.818-1.806(t，J＝2.4Hz，3H)。
Step 2:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-methyl benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 1, with 1-(7-methyl benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 75.7%.MSm/z[ESI]：579.0[M+1]。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(7-methyl benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 4 in embodiment 1, with 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-methyl benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine replacement 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 85.2%, HPLC:95.49%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.774(s，1H)，7.457(s，1H)，5.317(s，2H)，4.887-4.872(q，J＝2.0Hz，2H)，3.635(m，1H)，3.524(m，4H)，3.118-3.095(m，3H)，2.704(m，3H)，1.990(m，1H)，1.871(s，3H)，1.405(m，1H)。MSm/z[ESI]：479.0[M+1]。
embodiment 5:8-((R)-3-amino-piperadine-1-base)-1-(7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-
methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
Step 1:1-(7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 5-brooethyl benzo [1,2,5] thiadiazoles with 6-brooethyl-4-trifluoromethyl benzo [1,2,5] thiadiazoles, obtained target compound, yield: 81.4%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.264(s，1H)，8.108(s，1H)，5.396(s，2H)，5.129-5.114(q，J＝2.0，2H)，3.571(s，3H)，2.715(s，3H)，1.814(s，3H)。
Step 2:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 1, with 1-(7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 77.5%.MSm/z[ESI]：633.0[M+1]。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 4 in embodiment 1, with 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(7-trifluoromethyl benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine replacement 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 73.8%, HPLC:93.99%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.230(s，1H)，8.109(s，1H)，5.387(s，2H)，4.387(s，2H)，3.676(m，1H)，3.57(m，3H)，3.136(m，2H)，2.957(m，1H)，2.007(m，2H)，1.896(m，2H)，1.829(s，3H)，1.742(m，2H)，1.263(m，1H)。MSm/z[ESI]：533.0[M+1]。
embodiment 6:8-((R)-3-amino-piperadine-1-base)-1-(6,7-difluoro benzo [1,2,5] thiadiazoles-5-
methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
Step 1:1-(6,7-difluoro benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 5-brooethyl benzo [1,2,5] thiadiazoles with 6-brooethyl-4,5-difluoro benzo [1,2,5] thiadiazoles, obtained target compound, yield: 67.3%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.541-7.521(dd，J＝2.0Hz，6.4Hz，1H)，5.300(s，2H)，5.122-5.104(q，J＝2.4，2H)，3.591(s，3H)，1.814-1.803(t，J＝2.0Hz，3H)。
Step 2:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(6,7-difluoro benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 1, with 1-(6,7-difluoro benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 84.7%.MSm/z[ESI]：601.0[M+1]。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(6,7-difluoro benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 4 in embodiment 1, with 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(6,7-difluoro benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine replacement 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 83.7%, HPLC:96.63%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.498-7.476(dd，J＝2.0Hz，6.8Hz，1H)，5.441(s，2H)，4.865-4.851(q，J＝2.0，2H)，3.725-3.704(m，1H)，3.636-3.603(m，1H)，3.549(s，3H)，3.130-3.085(m，2H)，2.944-2.892(m，1H)，2.036-1.999(m，1H)，1.880-1.822(m，1H)，1.772(s，3H)，1.461-1.359(m，4H)。MSm/z[ESI]：501.0[M+1]。
([1,2,5] thiadiazoles is [3,4-b] pyridine-5-first also for-1-for embodiment 7:8-((R)-3-amino-piperadine-1-base)
base)-7-(2-butyne-1-base)-3-methyl-xanthine
Step 1:1-([1,2,5] thiadiazoles is [3,4-b] pyridine-5-methyl also) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, with 5-brooethyl-[1,2,5] thiadiazoles also [3,4-b] pyridine replacement 5-brooethyl benzo [1,2,5] thiadiazoles, obtained target compound, yield: 65.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.30(d，J＝8.8Hz，1H)，7.70(d，J＝8.8Hz，1H)，5.45(s，2H)，5.00(s，2H)，1.90(d，J＝1.2Hz，3H)。
Step 2:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-([1,2,5] thiadiazoles is [3,4-b] pyridine-5-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 1, with 1-([1,2,5] thiadiazoles also [3,4-b] pyridine-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 45.6%.MSm/z[ESI]：566.0[M+1]。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-([1,2,5] thiadiazoles is [3,4-b] pyridine-5-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 4 in embodiment 1, with 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-([1,2,5] thiadiazoles also [3,4-b] pyridine-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine replacement 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 81.5%, HPLC:98.07%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.25(d，J＝8.8Hz，1H)，7.51(d，J＝9.2Hz，1H)，5.29(s，2H)，4.88(q，J＝2.4Hz，2H)，3.65(m，1H)，3.52(s，3H)，3.48(m，1H)，3.25(m，2H)，3.11(m，1H)，2.00(m，3H)，1.82(t，J＝2.4Hz，3H)，1.72(m，2H)。MSm/z[ESI]：466.0[M+1]
([1,2,5] thiadiazoles is [3,4-b] pyridine-6-first also for-1-for embodiment 8:8-((R)-3-amino-piperadine-1-base)
base)-7-(2-butyne-1-base)-3-methyl-xanthine
Step 1:1-([1,2,5] thiadiazoles is [3,4-b] pyridine-6-methyl also) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, with 6-brooethyl-[1,2,5] thiadiazoles also [3,4-b] pyridine replacement 5-brooethyl benzo [1,2,5] thiadiazoles, obtained target compound, yield: 75.0%.
1HNMR(400MHz，CDCl3-d3)：δ＝9.20(s，1H)，8.41(s，1H)，5.32(s，2H)，5.12(s，2H)，1.81(d，J＝1.2Hz，3H)。
Step 2:8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-([1,2,5] thiadiazoles is [3,4-b]-6-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 1, with 1-([1,2,5] thiadiazoles also [3,4-b] pyridine-6-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 63.5%.MSm/z[ESI]：566.0[M+1]。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-([1,2,5] thiadiazoles is [3,4-b] pyridine-6-methyl also)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to the method for step 4 in embodiment 1, with 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-([1,2,5] thiadiazoles also [3,4-b] pyridine-6-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine replacement 8-((R)-3-t-butoxycarbonyl amino-piperidin-1-yl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound, yield: 65.0%, HPLC:97.89%.
1HNMR(400MHz，CDCl3-d3)：δ＝9.25(s，1H)，8.41(s，1H)，5.30(s，2H)，4.91(q，J＝2.4Hz，2H)，3.63(m，1H)，3.51(s，3H)，3.46(m，1H)，3.27(m，2H)，3.15(m，1H)，2.00(m，3H)，1.82(t，J＝2.4Hz，3H)，1.72(m，3H)。MSm/z[ESI]：466.0[M+1]
embodiment 9:8-(1-piperazinyl)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-butyne-1-base)
-3-methyl-xanthine
With reference to step 3 in embodiment 1 and 4 method, replace (R)-3-Boc-amino piperidine with 4-Boc-piperazine, obtained target compound, total recovery: 52.3%, HPLC:96.92%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.983(s，1H)，7.938-7.915(d，J＝9.2Hz，1H)，7.744-7.721(d，J＝9.2Hz，1H)，5.369(s，2H)，4.871(s，2H)，3.532(s，3H)，3.439(s，4H)，3.086(s，4H)，1.829(s，3H)。MSm/z[ESI]：451.0[M+1]。
embodiment 10:8-(1-piperazinyl)-1-(7-fluorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-(2-butyne-1-
base)-3-methyl-xanthine
With reference to step 2 in embodiment 2 and 3 method, replace (R)-3-Boc-amino piperidine with 4-Boc-piperazine, obtained target compound.HPLC：96.05％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.840(s，1H)，7.420-7.390(dd，J＝1.2Hz，J＝10.8Hz，1H)，5.338(s，2H)，4.86(q，J＝2.0Hz，2H)，3.531(s，3H)，3.441-3.417(t，J＝4.4Hz，4H)，3.088-3.063(t，J＝5.0Hz，4H)，1.838-1.827(t，J＝2.0Hz，3H)。MSm/z[ESI]：469.0[M+1]。
embodiment 11:8-(1-piperazinyl)-1-(7-chlorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-(2-butyne-1-
base)-3-methyl-xanthine
With reference to step 2 total in embodiment 3 and 3 method, obtained target compound.HPLC：93.35％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.950(s，1H)，7.796(s，1H)，5.332(s，2H)，4.885-4.870(q，J＝2.0Hz，2H)，3.532-3.516(m，7H)，3.185-3.162(t，J＝4.8Hz，4H)，1.839-1.829(t，J＝2.0Hz，3H)。MSm/z[ESI]：485.0[M]，487[M+2]，486[M+1]。
embodiment 12:8-((R)-3-amino-pyrroles-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-
butine-1-base)-3-methyl-xanthine
With reference to step 3 in embodiment 1 and 4 method, replace (R)-3-Boc-amino piperidine with (R)-3-Boc-amino-pyrroles, obtained target compound.HPLC：99.13％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.972(s，1H)，7.934-7.912(d，J＝8.8Hz，1H)，7.736-7.709(dd，J＝2.0Hz，9.2Hz，1H)，5.352(s，2H)，5.053(s，2H)，3.940-3.881(m，2H)，3.804-3.748(m，2H)，3.509(s，3H)，3.494-3.455(m，1H)，2.222-2.203(m，1H)，1.857-1.804(m，4H)。MSm/z[ESI]：451.0[M+1]。
embodiment 13:8-((S)-3-amino-pyrroles-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-
butine-1-base)-3-methyl-xanthine
With reference to step 3 in embodiment 1 and 4 method, replace (R)-3-Boc-amino piperidine with (S)-3-Boc-amino-pyrroles, obtained target compound.HPLC：98.85％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.972(s，1H)，7.934-7.912(d，J＝8.8Hz，1H)，7.736-7.709(dd，J＝2.0Hz，9.2Hz，1H)，5.352(s，2H)，5.053(s，2H)，3.937-3.880(m，2H)，3.797-3.739(m，2H)，3.509(s，3H)，3.489-3.448(m，1H)，2.222-2.203(m，1H)，1.829-1.804(m，4H)。MSm/z[ESI]：451.0[M+1]。
embodiment 14:8-((2-amino-ethyl) (methyl) is amino)-1-(benzo [1,2,5] thiadiazoles-5-first
base)-7-(2-butyne-1-base)-3-methyl-xanthine
With reference to step 3 in embodiment 1 and 4 method, use 1-N-methyl isophthalic acid ' the amino quadrol of Boc-replaces (R)-3-Boc-amino piperidine, obtained target compound.HPLC：91.66％。
1HNMR(400MHz，CDCl3-d3)：δ＝8.075-8.052(d，J＝9.2Hz，1H)，7.843(s，1H)，7.705-7.685(d，J＝8.0Hz，1H)，5.242(s，2H)，5.020(s，2H)，3.635-3.602(t，J＝6.4Hz，2H)，3.407(s，3H)，3.163(s，3H)，3.080-3.049(t，J＝6.0Hz，2H)，1.799(s，3H)。MSm/z[ESI]：439.0[M+1]。
embodiment 15:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-cyanobenzyls)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-fourth cyanobenzyls)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, with 2-cyano group benzyl bromo for the bromo-2-butyne of 1-, obtained target compound, yield: 63.7%.
1HNMR(400MHz，DMSO-d6)：δ＝11.337(s，1H)，7.921-7.900(q，J＝0.8Hz，7.6Hz，1H)，7.668-7.626(m，1H)，7.527-7.488(t，J＝7.6Hz，8.0Hz，1H)，6.991-6.972(d，J＝7.6Hz，1H)，5.664(s，2H)，3.338(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-cyanobenzyls)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-cyanobenzyls)-3-methyl-xanthine, obtained target compound, yield: 82.6%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.975-7.921(m，2H)，7.755-7.733(dd，J＝1.2Hz，8.0Hz，1H)，7.697-7.671(dd，J＝1.6Hz，8.8Hz，1H)，7.575-7.533(m，1H)，7.462-7.425(t，J＝7.6Hz，7.2Hz，1H)，6.974-6.954(d，J＝8.0Hz，1H)，5.841(s，2H)，5.341(s，2H)，3.601(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-cyanobenzyls)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-cyanobenzyls)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：92.78％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.913-7.896(m，2H)，7.705-7.636(m，2H)，7.580-7.541(t，J＝8.0Hz，7.6Hz，1H)，7.424-7.387(t，J＝7.6Hz，7.2Hz，1H)，7.187-7.167(d，J＝8.0Hz，1H)，5.593(s，2H)，5.317(s，2H)，3.564(s，3H)，3.342-3.393(m，1H)，3.234-3.204(m，1H)，3.043-2.930(m，2H)，2.858-2.834(m，1H)，1.928(m，1H)，1.762(m，1H)，1.642-1.620(m，1H)，1.380-1.354(m，1H)。MSm/z[ESI]：528.0[M+1]
(7-fluorobenzene is [1,2,5] thiadiazoles-5-first also for-1-for embodiment 16:8-((R)-3-amino-piperadine-1-base)
base)-7-(2-cyanobenzyls)-3-methyl-xanthine
Step 1:1-(7-fluorobenzene is [1,2,5] thiadiazoles-5-methyl also) the bromo-7-of-8-(2-cyanobenzyls)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 15, with 6-brooethyl-4-fluorobenzene also [1,2,5] thiadiazoles replacement 5-brooethyl-4 benzo [1,2,5] thiadiazoles, obtained target compound, yield: 74.6%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.825(s，1H)，7.758-7.739(m，1H)，7.580-7.539(m，1H)，7.649-7.358(m，1H)，7.356-7.263(m，1H)，6.977-6.957(d，J＝8.0Hz，1H)，5.840(s，2H)，5.302(s，2H)，3.603(s，3H)。
Step 2:8-((R)-3-amino-piperadine-1-base)-1-(7-fluorobenzene is [1,2,5] thiadiazoles-5-methyl also)-7-(2-cyanobenzyls)-3-methyl-xanthine
With reference to the method for step 3 in embodiment 15, with 1-(7-fluorobenzene also [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-cyanobenzyls)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-cyanobenzyls)-3-methyl-xanthine, obtained target compound.HPLC：93.60％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.765(m，1H)，7.702-7.680(m，1H)，7.563(m，1H)，7.408(m，1H)，7.30(m，1H)，7.203-7.183(d，J＝8.0Hz，1H)，5.597(s，2H)，5.276(s，2H)，3.491(s，3H)，3.34(m，1H)，3.175(m，2H)，2.977(m，2H)，1.93(m，1H)，1.76(m，1H)，1.64(m，1H)，1.38(m，1H)。MSm/z[ESI]：546.0[M+1]
embodiment 17:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-trifluoromethyl benzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-trifluoromethyl benzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, with 2-trifluoromethyl benzyl bromo for the bromo-2-butyne of 1-, obtained target compound, yield: 73.2%.
1HNMR(400MHz，DMSO-d6)：δ＝11.348(s，1H)，7.827-7.808(m，1H)，7.608-7.570(m，1H)，7.539-7.520(m，1H)，6.699-6.680(m，1H)，5.653(s，2H)，3.360(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-trifluoromethyl benzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-trifluoromethyl benzyl)-3-methyl-xanthine, obtained target compound, yield: 76.3%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.961-7.906(m，2H)，7.760-7.742(m，1H)，7.681-7.654(m，1H)，7.467-7.444(m，2H)，6.586-6.568(d，J＝7.2Hz，1H)，5.846(s，2H)，5.320(s，2H)，3.626(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-trifluoromethyl benzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-trifluoromethyl benzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：94.34％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.916-7.888(m，2H)，7.728-7.709(m，1H)，7.667-7.664(m，1H)，7.523-7.485(m，1H)，6.985-6.966(d，J＝7.6Hz，1H)，5.589(s，2H)，5.313(s，2H)，3.581(s，3H)，3.421-3.395(m，1H)，3.256-3.225(m，1H)，2.901-2.869(m，2H)，2.737-2.708(m，1H)，1.913-1.880(m，1H)，1.691-1.654(m，1H)，1.550-1.527(m，1H)，1.260-1.209(m，1H)。MSm/z[ESI]：571.0[M+1]
embodiment 18:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-methyl-benzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-methyl-benzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, with 2-methyl benzyl bromo for the bromo-2-butyne of 1-, obtained target compound, yield: 63.7%.
1HNMR(400MHz，DMSO-d6)：δ＝11.000(s，1H)，7.214-7.168(m，2H)，7.090(m，1H)，6.433-6.414(d，J＝7.6Hz，1H)，5.450(s，2H)，3.343(s，3H)，2.359(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-methyl-benzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-methyl-benzyl)-3-methyl-xanthine, obtained target compound, yield: 80.5%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.961-7.905(m，2H)，7.674-7.648(dd，J＝1.6Hz，8.8Hz，1H)，7.263-7.204(m，2H)，7.135-7.114(m，1H)，6.500-6.481(d，J＝7.6Hz，1H)，5.584(s，2H)，5.310(s，2H)，3.613(s，3H)，2.438(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-methyl-benzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-methyl-benzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target chemical combination without.HPLC：99.26％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.911-7.877(m，2H)，7.644-7.622(d，J＝8.8Hz，1H)，7.264-7.126(m，3H)，6.775-6.756(d，J＝7.6Hz，1H)，5.411(s，2H)，5.302(s，2H)，3.575(s，3H)，3.419-3.390(m，1H)，3.308-3.277(m，1H)，2.963-2.871(m，2H)，2.754-2.703(m，1H)，1.910-1.879(m，1H)，1.692-1.681(m，1H)，1.590-1.475(m，1H)，1.241-1.228(m，1H)。MSm/z[ESI]：517.0[M+1]
embodiment 19:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-nitrobenzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-nitrobenzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, with 2-nitrobenzyl bromo for the bromo-2-butyne of 1-, obtained target compound, yield: 75.8%.
1HNMR(400MHz，DMSO-d6)：δ＝11.321(s，1H)，8.214-8.194(d，J＝8.0Hz，1H)，7.726-7.688(m，1H)，7.639-7.600(m，1H)，6.830-6.811(d，J＝7.6Hz，1H)，5.819(s，2H)，3.389(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-nitrobenzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-nitrobenzyl)-3-methyl-xanthine, obtained target compound, yield: 89.4%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.253-8.233(m，1H)，7.936-7.923(m，2H)，7.581-7.515(m，3H)，6.690-6.671(d，J＝7.6Hz，1H)，6.035(s，2H)，5.290(s，2H)，3.621(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-nitrobenzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-nitrobenzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained targeted compound.HPLC：95.93％。
1HNMR(400MHz，CDCl3-d3)：δ＝8.146-8.127(m，1H)，7.895-7.873(m，2H)，7.628-7.565(m，2H)，7.481-7.442(m，1H)，7.072-7.053(d，J＝7.6Hz，1H)，5.779(s，2H)，5.268(s，2H)，3.489(s，3H)，3.489-3.456(m，1H)，3.258-2.985(m，4H)，1.949(m，1H)，1.793(m，1H)，1.587(m，2H)。MSm/z[ESI]：548.0[M+1]
embodiment 20:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-luorobenzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, replace the bromo-2-butyne of 1-with 2-fluorobenzyl bromide, obtained target compound, yield: 81.8%.
1HNMR(400MHz，DMSO-d6)：δ＝11.304(s，1H)，7.370-7.351(m，1H)，7.262-7.214(m，1H)，7.163-7.125(m，1H)，6.981-6.943(m，1H)，5.522(s，2H)，3.301(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-luorobenzyl)-3-methyl-xanthine, obtained target compound, yield: 87.9%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.981-7.916(m，2H)，7.700-7.673(m，1H)，7.320-7.300(m，1H)，7.12-7.047(m，3H)，5.660(s，2H)，5.347(s，2H)，3.581(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-luorobenzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-luorobenzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：99.55％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.925-7.891(m，2H)，7.670-7.644(m，1H)，7.285-7.251(m，1H)，7.093-7.062(m，3H)，5.442(s，2H)，5.331(s，2H)，3.549(s，3H)，3.431-3.393(m，1H)，3.304-3.274(m，1H)，2.977-2.920(m，2H)，2.768-2.716(m，1H)，1.740(m，1H)，1.639(m，1H)，1.612(m，2H)。MSm/z[ESI]：521.0[M+1]。
embodiment 21:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-bromobenzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-bromobenzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, with 2-bromobenzyl bromo for the bromo-2-butyne of 1-, obtained target compound, yield: 64.5%.
1HNMR(400MHz，DMSO-d6)：δ＝11.323(s，1H)，7.705-7.682(m，1H)，7.330-7.236(m，2H)，6.570-6.547(m，1H)，5.478(s，2H)，3.351(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-bromobenzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-bromobenzyl)-3-methyl-xanthine, obtained target compound, yield: 81.6%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.965-7.910(m，2H)，7.683-7.620(m，2H)，7.239-7.187(m，2H)，6.534-6.514(d，J＝8.0Hz，1H)，5.681(s，2H)，5.304(s，2H)，3.617(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-bromobenzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-bromobenzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：94.05％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.923-7.887(m，2H)，7.662-7.640(m，1H)，7.599-7.581(m，1H)，7.285-7.249(m，1H)，7.180-7.164(m，1H)，6.881-6.862(d，J＝7.6Hz，1H)，5.434(s，2H)，5.314(s，2H)，3.564(s，3H)，3.427-3.403(m，1H)，3.235(m，1H)，2.962(m，2H)，2.951(m，1H)，1.902-1.890(m，1H)，1.752-1.645(m，1H)，1.612-1.591(m，1H)，1.261-1.210(m，1H)。MSm/z[ESI]：581.0[M]，582.0[M+1]，583.0[M+2]。
embodiment 22:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-benzyl
base-3-methyl-xanthine
The bromo-7-benzyl of step 1:8--3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, with benzyl bromo for the bromo-2-butyne of 1-, obtained target compound, yield: 45.2%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.448(brs，1H)，7.403-7.316(m，5H)，5.514(s，2H)，3.521(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-benzyl of-8--3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with 8-bromo-7-benzyl-3-methyl-xanthine, obtained target compound, yield: 71.4%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.990-7.925(m，2H)，7.714-7.688(dd，J＝1.6Hz，9.2Hz，1H)，7.363-7.317(m，5H)，5.567(s，2H)，5.359(s，2H)，3.546(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-benzyl-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-benzyl of-8--3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine obtains target compound.HPLC：98.50％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.935-7.893(m，2H)，7.678-7.651(dd，J＝1.6Hz，9.2Hz，1H)，7.342-7.198(m，5H)，5.405(s，2H)，5.335(s，2H)，3.535(s，3H)，3.439-3.400(m，1H)，3.241(m，1H)，2.996-2.972(m，2H)，2.882-2.850(m，1H)，1.951-1.927(m，1H)，1.758-7-1.749(m，1H)，1.641-1.607(m，1H)，1.260-1.193(m，1H)。MSm/z[ESI]：503.0[M+1]。
embodiment 23:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-trifluoromethyl-4-luorobenzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-trifluoromethyl-4-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, replace the bromo-2-butyne of 1-with 2-trifluoromethyl-4-fluorobenzyl bromide, obtained target compound, yield: 75.4%.
1HNMR(400MHz，DMSO-d6)：δ＝11.338(s，1H)，7.933-7.898(q，J＝5.2Hz，8.8Hz，1H)，7.387(m，1H)，6.661-6.636(d，J＝10.0Hz，1H)，5.638(s，2H)，3.328(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-trifluoromethyl-4-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-trifluoromethyl-4-luorobenzyl)-3-methyl-xanthine, obtained target compound.Yield: 79.6%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.982-7.917(m，2H)，7.778-7.744(m，1H)，7.687-7.663(m，1H)，7.105(m，1H)，6.302-6.280(d，J＝8.8Hz，1H)，5.821(s，2H)，5.324(s，2H)，3.634(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-trifluoromethyl-4-luorobenzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-trifluoromethyl-4-luorobenzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：92.45％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.938-7.895(m，2H)，7.743-7.709(m，1H)，7.668-7.646(m，1H)，7.087(m，1H)，6.711-6.687(d，J＝9.6Hz，1H)，5.553(s，2H)，5.312(s，2H)，3.582(s，3H)，3.446-3.416(m，1H)，3.219-3.189(m，1H)，2.882-2.786(m，3H)，1.948-1.918(m，1H)，1.687(m，1H)，1.567(m，1H)，1.330-1.305(m，1H)。MSm/z[ESI]：589.0[M+1]。
embodiment 24:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(2-methoxyl group-4-luorobenzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(2-methoxyl group-4-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, replace the bromo-2-butyne of 1-with 2-methoxyl group-4-fluorobenzyl bromide, obtained target compound, yield: 54.8%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.111(s，1H)，6.965-6.937(m，1H)，6.833-6.801(q，J＝4.0Hz，8.8Hz，1H)，6.534-6.505(dd，J＝2.8Hz，8.8Hz，1H)，5.509(s，2H)，3.847(s，3H)，3.550(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-methoxyl group-4-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(2-methoxyl group-4-luorobenzyl)-3-methyl-xanthine, obtained target compound, yield: 67.3%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.989-7.914(m，2H)，7.699-7.672(dd，J＝1.6Hz，9.2Hz，1H)，6.965(m，1H)，6.838-6.805(m，1H)，6.491-6.465(dd，J＝2.0Hz，8.4Hz，1H)，5.564(s，2H)，5.329(s，2H)，3.836(s，3H)，3.604(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(2-methoxyl group-4-luorobenzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-methoxyl group-4-luorobenzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：99.68％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.937-7.883(m，2H)，7.665-7.638(m，1H)，6.927-6.920(m，1H)，6.823-6.789(m，1H)，6.594-6.573(m，1H)，5.334(s，2H)，5.309(s，2H)，3.775(s，3H)，3.561(s，3H)，3.486-3.449(m，1H)，3.219-2.882(m，4H)，1.990(m，1H)，1.855(m，1H)，1.691(m，1H)，1.589(m，1H)。MSm/z[ESI]：551.0[M+1]。
embodiment 25:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(4-luorobenzyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(4-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, replace the bromo-2-butyne of 1-with 4-fluorobenzyl bromide, obtained target compound, yield: 51.3%.
1HNMR(400MHz，DMSO-d6)：δ＝11.316(s，1H)，7.331-7.297(m，2H)，7.201-7.178(m，2H)，5.443(s，2H)，3.300(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(4-luorobenzyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(4-luorobenzyl)-3-methyl-xanthine, obtained target compound, yield: 75.8%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.988-7.931(m，2H)，7.715-7.688(dd，J＝1.6Hz，8.8Hz，1H)，7.428-7.393(m，2H)，7.053-7.010(m，2H)，5.524(s，2H)，5.362(s，2H)，3.560(s，3H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(4-luorobenzyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(4-luorobenzyl)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：98.38％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.925-7.902(m，2H)，7.678-7.656(m，1H)，7.245-7.212(m，2H)，7.024-6.983(m，2H)，5.335(s，4H)，3.535(s，3H)，3.428-3.398(m，1H)，3.281(m，1H)，2.980-2.957(m，2H)，2.778-2.749(m，1H)，1.907(m，1H)，1.759(m，1H)，1.615(m，1H)，1.338(m，1H)。MSm/z[ESI]：521.0[M+1]。
embodiment 26:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-
(3-methyl crotyl)-3-methyl-xanthine
The bromo-7-of step 1:8-(3-methyl-2-butene base)-3-methyl-xanthine
With reference to the method for step 1 in embodiment 1, replace the bromo-2-butyne of 1-with 1-bromo-3-methyl-2-butene, obtained target compound, yield: 65.3%.
1HNMR(400MHz，CDCl3-d3)：δ＝8.098(s，1H)，5.308-5.273(m，1H)，4.937-4.919(m，2H)，3.514(s，3H)，1.857(s，3H)，1.744(s，3H)。
Step 2:1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(3-methyl crotyl)-3-methyl-xanthine
With reference to the method for step 2 in embodiment 1, replace 8-bromo-7-(2-butyne-1-base)-3-methyl-xanthine with the bromo-7-of 8-(3-methyl-2-butene base)-3-methyl-xanthine, obtained target compound, yield: 68.9%.
1HNMR(400MHz，CDCl3-d3)：δ＝7.993-7.931(m，2H)，7.730-7.704(dd，J＝1.6Hz，8.8Hz，1H)，5.364(s，2H)，5.302-5.291(m，1H)，4.987-4.971(m，2H)，3.595(s，3H)，1.863(s，3H)，1.745-1.742(s，1.2Hz，1H)。
Step 3:8-((R)-3-amino-piperadine-1-base)-1-(benzo [1,2,5] thiadiazoles-5-methyl)-7-(3-methyl crotyl)-3-methyl-xanthine
With reference to step 3 in embodiment 1, the method of 4, with 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(3-methyl-2-butene base)-3-methyl-xanthine replacement 1-(benzo [1,2,5] thiadiazoles-5-methyl) the bromo-7-of-8-(2-butyne-1-base)-3-methyl-xanthine, obtained target compound.HPLC：91.26％。
1HNMR(400MHz，CDCl3-d3)：δ＝7.955-7.906(m，2H)，7.717-7.692(m，1H)，5.373(m，2H)，5.351(s，2H)，3.49(m，4H)，3.428(m，2H)，3.281(m，2H)，1.987(m，1H)，1.748(m，1H)，1.668(m，8H)。MSm/z[ESI]：481.0[M+1]。
the mensuration of DPP-IV enzyme inhibition activity
The present invention adopts following methods to measure the inhibit activities of the compounds of this invention to DPP-IV enzyme in blood plasma, and this inhibit activities adopts IC
50this index represents, IC
50the concentration of compound during the activity inhibited 50% of i.e. enzyme.
Materials and methods:
Material:
A. white 384 orifice plates (PerkinElmer, CatalogNo.607290/99)
B.HEPES damping fluid: prepare 50ml0.5MHEPES damping fluid with 1MHEPES damping fluid (Invitrogen, CatalogNo.15630-080), get 1MHEPES damping fluid 25ml, add appropriate dH
2o, regulates pH to 7.8 with NaOH, finally adds dH
2o to 50ml.
C. rat plasma: rat eye socket gets blood, adds anticoagulant heparin, centrifugal 10 minutes of 4000rpm, gets the enzyme source of supernatant blood plasma as DPP-IV.
D.DPP-IV enzyme reaction substrate H-Gly-Pro-AMC (Gly-Pro-7-amino-4-methylcoumarin), is synthesized by our company oneself, is dissolved in DMSO to 100mM mother liquor.
e.1MMgCl
2
f.1.5MNaCl
g.10％BAS
h.DMSO
i.dH
2O
J. testing compound: embodiment of the present invention compound
Undertaken by following working order:
1. prepare DPP-IV enzyme reaction buffer solution: 50mMHEPES (pH7.8), 80mMMgCl
2, 150mMNaCl, 1%BSA, be positioned over for subsequent use on ice;
2. dissolve compound to be detected to 100 times of working concentration with DMSO, 96 orifice plates carry out 3 times of gradient dilutions totally 11 concentration, and the 12nd hole adds DMSO as blank, then with enzyme reaction buffer solution dilute 25 times stand-by to 4 times of working concentration;
3. thaw DPP-IV enzyme reaction substrate H-Gly-Pro-AMC, is diluted to 2 times of working concentrations is placed in for subsequent use on ice by enzyme reaction buffer solution;
4. thaw rat plasma, dilutes 25 times to 4 times working concentrations be placed in for subsequent use on ice by enzyme reaction buffer solution;
5. in 384 orifice plates, add the compound of 5 μ l, 4 times of concentration to be measured, then add the rat plasma of 5 μ l, (4 times of working concentrations), centrifugal mixing;
6. add 10 μ l enzyme reaction substrate H-Gly-Pro-AMC (2 times of working concentrations), centrifugal mixing, seals 384 orifice plates by sealer;
7. in incubator (22-23 DEG C), hatch 1 hour;
8. use microplate reader to read the fluorescent signal of reaction: 380nm excites, and reads the emmission spectrum of 460nm wavelength;
9. compound is to DPP-IV enzyme level IC
50generation: the IC using GraFit6 computerized compound
50value.
The DPP-IV inhibit activities of table 1 embodiment of the present invention compound
Testing data in upper table shows, thiadiazole derivative provided by the invention has good DPP-IV inhibit activities, and has excellent DPP-IV enzyme selectivity.
Thiadiazoles derivative provided by the invention also has extraordinary internal metabolism level and most suitable Half-life in vivo.The transformation period of the compounds of this invention 1 in Mice Body is 2.7 hours (quiet note), 3.1 hours (oral); The transformation period of compound 2 in Mice Body is 1.5 hours (quiet note), 2.7 hours (oral).Pharmacokinetic data in the body that table 2 lists the compounds of this invention 2.
The compounds of this invention 2 to CD-1 mouse by intravenous injection or gastric infusion, in SD rat and beasle dog body, is taken a blood sample at specified time (0-24 hour) after administration and uses liquid-mass chromatography (LC/MS/MS) to measure Plasma Concentration.Use Winnonlin computed in software pharmacokinetic parameter again.Result shows that the transformation period of compound 2 in mouse, rat and beasle dog body is 1.5-5.2 hour, is equivalent to the transformation period 8-16 hour in human body.Such transformation period meets drug dosage schedule and do not have drug accumulation once a day.
The pharmacokinetic parameter of table 2 compound 2
Claims (14)
1. the thiadiazoles derivative of a formula I and enantiomer, diastereomer, pharmacy acceptable salt:
Wherein X, Y and Z are selected from C or N independently of one another;
R
1, R
2and R
3be selected from hydrogen, halogen, cyano group, trifluoromethyl, C independently of one another
1-6alkyl, C
3-6cycloalkyl ,-OR
7,-NR
8r
9,-C (O) R
10,-SR
7;
R
7be selected from hydrogen, C
1-6alkyl, C
3-6cycloalkyl;
R
8and R
9be selected from hydrogen, C independently of one another
1-6alkyl, C
3-6cycloalkyl ,-C (O) R
10, or R
8and R
9the 3-6 unit heterocyclic radical containing one or more atom N is jointly formed altogether be connected atom N;
R
10be selected from C
1-6alkyl, C
3-6cycloalkyl;
R
6be selected from hydrogen, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-6cycloalkyl, substituted or unsubstituted phenyl, the substituting group of described phenyl is selected from C
1-6alkyl, amino, halogen, cyano group or hydroxyl, substituted or unsubstituted benzyl, the substituting group of described benzyl is selected from C
1-6alkyl, amino, halogen, cyano group or hydroxyl, cyano methyl or methoxycarbonyl-methyl;
R
15and R
16be selected from hydrogen, halogen, cyano group, hydroxyl, C independently of one another
1-6alkyl, amino, C
3-6cycloalkyl, substituted or unsubstituted piperidyl, the substituting group of described piperidyl is selected from C
1-6alkyl, amino, halogen or hydroxyl;
Or R
15with R
16altogether, five yuan of fragrant heterocycle Q are formed together with connected C atom;
A, B are identical or different, are selected from C, N independently of one another;
R
4and R
17be selected from hydrogen, C independently of one another
1-6alkyl, C
1-6alkoxyl group, halogen, cyano group, hydroxyl, – CH
2r
11, wherein R
11be selected from C
2-6alkynyl, C
2-6thiazolinyl, substituted or unsubstituted phenyl, the substituting group of described phenyl is selected from C
1-6alkyl, C
1-6alkoxyl group, amino, halogen, cyano group or hydroxyl;
R
5be selected from hydrogen, C
1-6alkyl, halogen, cyano group, hydroxyl, – NR
12r
13;
R
12and R
13be selected from hydrogen, substituted or unsubstituted C independently of one another
1-6alkyl, substituting group is selected from amino, C
3-6cycloalkyl ,-C (O) R
14,-C (S) R
14,-S (O) R
14,-S (O
2) R
14;
R
12and R
13also can form the substituted or unsubstituted 3-7 unit heterocyclic radical containing one or more atom N altogether with the atom N be connected, substituting group is selected from amino;
R
14be selected from C
1-6alkyl, C
3-6cycloalkyl.
2. the compound of a formula II and enantiomer, diastereomer, pharmacy acceptable salt:
Wherein X and Z is selected from C or N independently of one another;
A, B are identical or different, are selected from C, N independently of one another;
R
1, R
2, R
3be selected from hydrogen, halogen, cyano group, trifluoromethyl, C independently of one another
1-6alkyl, C
3-6cycloalkyl ,-OR
7,-NR
8r
9,-C (O) R
10,-SR
7;
R
7be selected from hydrogen, C
1-6alkyl, C
3-6cycloalkyl;
R
8and R
9be selected from hydrogen, C independently of one another
1-6alkyl, C
3-6cycloalkyl ,-C (O) R
10, or R
8and R
9the 3-6 unit heterocyclic radical containing one or more atom N is jointly formed altogether be connected atom N;
R
10be selected from C
1-6alkyl, C
3-6cycloalkyl;
R
4independently be selected from hydrogen, C
1-6alkyl, – CH
2r
11, wherein R
11be selected from C
2-6alkynyl, C
2-6thiazolinyl, substituted or unsubstituted phenyl, the substituting group of described phenyl is selected from C
1-6alkyl, C
1-6alkoxyl group, amino, halogen, cyano group or hydroxyl;
R
5xuan Zi – NR
12r
13; R
12and R
13be selected from hydrogen, substituted or unsubstituted C independently of one another
1-6alkyl, substituting group is selected from amino, C
3-6cycloalkyl or R
12and R
13form the substituted or non-substituted unit of the 5-6 containing one or more atom N heterocyclic radical altogether with the atom N be connected, substituting group is selected from amino.
3. the compound described in claim 1 or 2 and enantiomer, diastereomer, pharmacy acceptable salt, wherein R
1, R
2, R
3be selected from hydrogen, halogen, trifluoromethyl, C independently of one another
1-6alkyl.
4. compound according to claim 3 and enantiomer, diastereomer, pharmacy acceptable salt, R
5xuan Zi – NR
12r
13, wherein, R
12and R
13form the substituted or unsubstituted 5-6 unit heterocyclic radical containing one or more atom N altogether with the atom N be connected, substituting group is selected from amino.
5. compound according to claim 4 and enantiomer, diastereomer, pharmacy acceptable salt, wherein R
12and R
133-amino-piperadine-1-base, piperazine-1-base, 3-amino-piperazine-1-base, 3-Amino-pvrrolidine-1-base is formed altogether with the atom N be connected.
6. the compound of following structure and enantiomer, diastereomer, pharmacy acceptable salt:
7. a preparation method for compound of Formula I according to claim 1, comprises the step making formula VIII compound and formula Ⅸ compound that condensation reaction occur in the basic conditions,
Wherein, X, Y, Z, R
1, R
2, R
3, R
6, R
15, R
16identical with defining in general formula I, L is leavings group, is selected from halogen, sulfonate ester group; Alkaline condition points in reaction solution to add alkaline matter.
8. a preparation method for formula II compound according to claim 2, comprises the steps:
Wherein, R
1, R
2, R
3, R
4, R
5, X, Z, A, B be identical with defining in general formula II; L, L
0for leavings group, be selected from halogen, sulfonate ester group, alkaline condition points in reaction solution to add alkaline matter.
9. the preparation method of formula II compound according to claim 8, wherein said alkaline matter is salt of wormwood or sodium carbonate.
10. the compound or its salt of following formula:
Wherein,
Wherein X and Z is selected from C or N independently of one another;
A, B are identical or different, are selected from C, N independently of one another;
R
1, R
2, R
3be selected from hydrogen, halogen, cyano group, trifluoromethyl, C independently of one another
1-6alkyl, C
3-6cycloalkyl ,-OR
7,-NR
8r
9,-C (O) R
10,-SR
7;
R
7be selected from hydrogen, C
1-6alkyl, C
3-6cycloalkyl;
R
8and R
9be selected from hydrogen, C independently of one another
1-6alkyl, C
3-6cycloalkyl ,-C (O) R
10, or R
8and R
9the 3-6 unit heterocyclic radical containing one or more atom N is jointly formed altogether be connected atom N;
R
10be selected from C
1-6alkyl, C
3-6cycloalkyl;
R
4independently be selected from hydrogen, C
1-6alkyl, – CH
2r
11, wherein R
11be selected from C
2-6alkynyl, C
2-6thiazolinyl, substituted or unsubstituted phenyl, the substituting group of described phenyl is selected from C
1-6alkyl, C
1-6alkoxyl group, amino, halogen, cyano group or hydroxyl;
L
0for leavings group, be selected from halogen, sulfonate ester group.
11. 1 kinds of pharmaceutical compositions, comprise generalformulaⅰcompound according to claim 1 or general formula according to claim 2 II compound and enantiomer thereof, diastereomer, pharmacy acceptable salt as active ingredient, and one or more medicine acceptable carrier, vehicle and/or media.
12. generalformulaⅰcompounds according to claim 1 or general formula according to claim 2 II compound and enantiomer thereof, diastereomer, pharmacy acceptable salt benefit from the purposes in the medicine of the disease that DPP-IV suppresses in preparation treatment or prevention.
13. purposes according to claim 12, the disease wherein benefiting from DPP-IV suppression is selected from diabetes, diabetic dyslipidaemia, glucose tolerance (IGT) disease, fasted plasma glucose attenuating (IFG) disease, metabolic acidosis, ketosis, appetite stimulator, obesity, various cancer, neurological conditions or disorder of immune system.
14. purposes according to claim 13, the disease wherein benefiting from DPP-IV suppression is selected from diabetes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110154294.XA CN102807568B (en) | 2011-05-31 | 2011-05-31 | Thiadiazoles derivative class DPP-IV inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110154294.XA CN102807568B (en) | 2011-05-31 | 2011-05-31 | Thiadiazoles derivative class DPP-IV inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102807568A CN102807568A (en) | 2012-12-05 |
| CN102807568B true CN102807568B (en) | 2015-11-25 |
Family
ID=47231454
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110154294.XA Active CN102807568B (en) | 2011-05-31 | 2011-05-31 | Thiadiazoles derivative class DPP-IV inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102807568B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104884457B (en) * | 2013-10-30 | 2016-12-07 | 上海恒瑞医药有限公司 | Pyrazolopyrimidinonefor or pyrrolo-triazine ketones derivant, its preparation method and in application pharmaceutically |
| CN105315301B (en) * | 2014-08-05 | 2018-04-03 | 连云港润众制药有限公司 | The citrate of the inhibitor of thiadiazole DPP IV |
| CN104326937B (en) | 2014-09-03 | 2016-08-24 | 天津市肿瘤研究所 | Antitumoral compounds and medical usage thereof |
| CN108350000A (en) * | 2015-11-27 | 2018-07-31 | 正大天晴药业集团股份有限公司 | The crystallization and application thereof of thiadiazole derivs species DPP-IV inhibitor |
| CN113262227A (en) * | 2016-01-29 | 2021-08-17 | 正大天晴药业集团股份有限公司 | Pharmaceutical compositions of DPP-IV inhibitors |
| CN107936023B (en) * | 2017-12-28 | 2020-09-04 | 安庆奇创药业有限公司 | Synthetic method of linagliptin intermediate |
| CN115073431B (en) * | 2021-04-14 | 2023-09-05 | 盐野义制药株式会社 | Triazine derivative with virus proliferation inhibition effect and pharmaceutical composition containing triazine derivative |
| CN114634422A (en) * | 2022-03-14 | 2022-06-17 | 河北中科金辉药业有限公司 | Preparation method of dinitolmide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19727707A1 (en) * | 1997-06-30 | 1999-01-07 | Bayer Ag | Preparation of 4- and 5-chloro- or bromo-methyl-2,1,3-benzo-thiadiazoles |
| CN101010276A (en) * | 2004-07-26 | 2007-08-01 | 中外制药株式会社 | Novel cyclohexane derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes |
| CN101690815A (en) * | 2000-03-31 | 2010-04-07 | 普罗西迪恩有限公司 | Novel use of dipeptidyl peptidase-iv inhibitor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004173695A (en) * | 2002-11-25 | 2004-06-24 | F Hoffmann La Roche Ag | Crystal structure of dpp-iv and its use |
-
2011
- 2011-05-31 CN CN201110154294.XA patent/CN102807568B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19727707A1 (en) * | 1997-06-30 | 1999-01-07 | Bayer Ag | Preparation of 4- and 5-chloro- or bromo-methyl-2,1,3-benzo-thiadiazoles |
| CN101690815A (en) * | 2000-03-31 | 2010-04-07 | 普罗西迪恩有限公司 | Novel use of dipeptidyl peptidase-iv inhibitor |
| CN101010276A (en) * | 2004-07-26 | 2007-08-01 | 中外制药株式会社 | Novel cyclohexane derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes |
Non-Patent Citations (2)
| Title |
|---|
| Alkyl Side Chain Driven Tunable Red–Yellow–Green Emission: Investigation on the New π-Conjugated Polymers Comprising of 2,7-Carbazole Unit and 2,1,3-Benzo-thiadiazole Units with Different Side Chains;JUNPING DU, et al.;《Journal of Polymer Science: Part A: Polymer Chemistry》;20081231;第46卷;1376–1387 * |
| New Glucocerebrosidase Inhibitors by Exploration of Chemical Diversity of N-Substituted Aminocyclitols Using Click Chemistry and in Situ Screening;Lucía Díaz, et al.;《Journal of Medicinal Chemistry》;20110303;第54卷;2069-2079 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102807568A (en) | 2012-12-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102807568B (en) | Thiadiazoles derivative class DPP-IV inhibitor | |
| CA2583259C (en) | Aromatic ring fused pyrimidine derivative | |
| CN101817833B (en) | DPP-IV inhibitor | |
| JP6966423B2 (en) | Condensed ring pyrimidine amino derivative, its production method, intermediate, pharmaceutical composition and application | |
| JP6731917B2 (en) | Benzene-fused 6-membered ring derivative as DPP-4 inhibitor and use thereof | |
| CN107250137B (en) | The hexa-atomic saturation heterolipid ring class of substituted amino as long-acting DPP-IV inhibitor | |
| CN103130819B (en) | Thiophene [3,2-d] pyrimidin-4-one compounds, its preparation method, pharmaceutical composition and purposes | |
| CN102311448B (en) | Thieno-pyrimidone DPP-IV (dipeptidyl peptidase) inhibitor | |
| CN102264707A (en) | Novel bicyclic heterocyclic compound | |
| CN102643268A (en) | Quinoline and cinnoline compound and application thereof | |
| CA2924353C (en) | Compositions for the treatment of hypertension and/or fibrosis | |
| CN114478520A (en) | Bcl-2 protein apoptosis inducer and application thereof | |
| MX2015002310A (en) | Novel phenyl-pyridine/pyrazine amides for the treatment of cancer. | |
| TW202302587A (en) | Isoquinolinone compound and use thereof | |
| CN101503402A (en) | 2-aniline pyrimidine derivative, as well as preparation and uses thereof | |
| CN102108078A (en) | 1,4-substituted phthalazine compound and preparation method and applications thereof | |
| WO2020156319A1 (en) | N-formamide derivative, preparation method therefor and medical use thereof | |
| CN108341835A (en) | Boron-containing compound as tyrosine kinase inhibitor | |
| CN111718325A (en) | 2,4, 5-substituted pyrimidine compound and preparation method and application thereof | |
| CN111732597B (en) | Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy | |
| JP2018087173A (en) | Anti-malignant brain tumor therapeutic agent | |
| WO2022197755A1 (en) | Imidazopyridinyl inhibitors of plasma kallikrein | |
| CN103601674B (en) | A kind of suppress dipeptides kininase compound and preparation method and purposes | |
| CN103958466B (en) | As the nitrogenous of CRTH2 antagonist and cyclic cpds | |
| CN102311447B (en) | Heterocyclo pyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Applicant after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Applicant after: Beijing Centaurus Biopharma Technology Co., Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Applicant before: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd. Applicant before: Beijing Centaurus Biopharma Technology Co., Ltd. |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: JIANGSU ZHENGDA TIANQING PHARMACEUTICAL CO., LTD. TO: CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: 222062 Lianyungang, Jiangsu Province, Yu Road, Haizhou District No. 369 Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee after: Beijing Centaurus Biopharma Technology Co., Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee before: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Patentee before: Beijing Centaurus Biopharma Technology Co., Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20190516 Address after: No. 369, Yuzhou South Road, Lianyungang, Jiangsu Province Co-patentee after: Capital Pharmaceutical Holdings (Beijing) Co., Ltd. Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 222062 Yuzhou South Road, Haizhou District, Lianyungang, Jiangsu 369 Co-patentee before: Beijing Centaurus Biopharma Technology Co., Ltd. Patentee before: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| CP01 | Change in the name or title of a patent holder |
Address after: No. 369, Yuzhou South Road, Lianyungang, Jiangsu Province Patentee after: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Patentee after: Capital Pharmaceutical Holdings (Beijing) Co.,Ltd. Address before: No. 369, Yuzhou South Road, Lianyungang, Jiangsu Province Patentee before: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Patentee before: Shouyao holding (Beijing) Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |