CN101230059B - 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 - Google Patents
双环氮杂烷类衍生物、其制备方法及其在医药上的用途 Download PDFInfo
- Publication number
- CN101230059B CN101230059B CN 200810004727 CN200810004727A CN101230059B CN 101230059 B CN101230059 B CN 101230059B CN 200810004727 CN200810004727 CN 200810004727 CN 200810004727 A CN200810004727 A CN 200810004727A CN 101230059 B CN101230059 B CN 101230059B
- Authority
- CN
- China
- Prior art keywords
- compound
- pyrroles
- alkyl
- azabicyclo
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 111
- 239000003814 drug Substances 0.000 title claims abstract description 11
- -1 dicyclic aza alkane Chemical class 0.000 claims abstract description 128
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims description 213
- 229910052739 hydrogen Inorganic materials 0.000 claims description 213
- 150000002431 hydrogen Chemical class 0.000 claims description 208
- 238000006243 chemical reaction Methods 0.000 claims description 152
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 141
- 150000001875 compounds Chemical class 0.000 claims description 134
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 128
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 110
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 106
- 238000003756 stirring Methods 0.000 claims description 91
- 239000000243 solution Substances 0.000 claims description 80
- 239000002904 solvent Substances 0.000 claims description 68
- 125000003545 alkoxy group Chemical group 0.000 claims description 66
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 65
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 25
- 230000000694 effects Effects 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 230000002829 reductive effect Effects 0.000 claims description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 125000001544 thienyl group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 125000002541 furyl group Chemical group 0.000 claims description 17
- 125000002883 imidazolyl group Chemical group 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 17
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 14
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 229940095064 tartrate Drugs 0.000 claims description 11
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 9
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000005864 Sulphur Chemical group 0.000 claims description 8
- 239000000377 silicon dioxide Substances 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- RBWNDBNSJFCLBZ-UHFFFAOYSA-N 7-methyl-5,6,7,8-tetrahydro-3h-[1]benzothiolo[2,3-d]pyrimidine-4-thione Chemical compound N1=CNC(=S)C2=C1SC1=C2CCC(C)C1 RBWNDBNSJFCLBZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910001148 Al-Li alloy Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- ICYWWYOKXTYUTJ-UHFFFAOYSA-N [I].C[P](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound [I].C[P](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 ICYWWYOKXTYUTJ-UHFFFAOYSA-N 0.000 claims description 4
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical compound [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- ZRKSVHFXTRFQFL-UHFFFAOYSA-N isocyanomethane Chemical compound C[N+]#[C-] ZRKSVHFXTRFQFL-UHFFFAOYSA-N 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003929 acidic solution Substances 0.000 claims description 3
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- 150000001299 aldehydes Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 6
- 125000002757 morpholinyl group Chemical group 0.000 claims 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 abstract description 2
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 abstract 1
- 229940122344 Peptidase inhibitor Drugs 0.000 abstract 1
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 332
- GUVXZFRDPCKWEM-UHFFFAOYSA-N pentalene Chemical compound C1=CC2=CC=CC2=C1 GUVXZFRDPCKWEM-UHFFFAOYSA-N 0.000 description 205
- 239000000047 product Substances 0.000 description 91
- 125000000217 alkyl group Chemical group 0.000 description 89
- 125000003118 aryl group Chemical group 0.000 description 70
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 69
- 238000001819 mass spectrum Methods 0.000 description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 239000012141 concentrate Substances 0.000 description 60
- 125000001072 heteroaryl group Chemical group 0.000 description 58
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 58
- 230000006837 decompression Effects 0.000 description 55
- 239000000706 filtrate Substances 0.000 description 55
- 239000012074 organic phase Substances 0.000 description 51
- 125000000753 cycloalkyl group Chemical group 0.000 description 50
- 238000000967 suction filtration Methods 0.000 description 49
- 238000001035 drying Methods 0.000 description 48
- 238000010898 silica gel chromatography Methods 0.000 description 48
- 229910052757 nitrogen Inorganic materials 0.000 description 42
- 238000004809 thin layer chromatography Methods 0.000 description 40
- 239000002994 raw material Substances 0.000 description 38
- 239000002585 base Substances 0.000 description 35
- 239000007787 solid Substances 0.000 description 34
- 239000007864 aqueous solution Substances 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 238000012360 testing method Methods 0.000 description 30
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 29
- 239000008103 glucose Substances 0.000 description 29
- 125000004104 aryloxy group Chemical group 0.000 description 28
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000005406 washing Methods 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 150000001733 carboxylic acid esters Chemical class 0.000 description 21
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 21
- 239000003921 oil Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 19
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 239000012153 distilled water Substances 0.000 description 19
- 239000012530 fluid Substances 0.000 description 19
- 239000007788 liquid Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000013016 damping Methods 0.000 description 18
- 238000000605 extraction Methods 0.000 description 18
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 17
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 16
- 238000003810 ethyl acetate extraction Methods 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- 239000000758 substrate Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000007983 Tris buffer Substances 0.000 description 14
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 14
- 238000001514 detection method Methods 0.000 description 13
- 125000001188 haloalkyl group Chemical group 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Natural products O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
- 235000015320 potassium carbonate Nutrition 0.000 description 11
- 229950004288 tosilate Drugs 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- 238000002156 mixing Methods 0.000 description 10
- 229960005181 morphine Drugs 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 0 **(C[C@]1(CC(*)(*)C2)I=C)C[C@@]12I(*)=C Chemical compound **(C[C@]1(CC(*)(*)C2)I=C)C[C@@]12I(*)=C 0.000 description 9
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 9
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 9
- 230000008034 disappearance Effects 0.000 description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000013642 negative control Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 238000007410 oral glucose tolerance test Methods 0.000 description 7
- JMXRZTXLGLBUTE-UHFFFAOYSA-N C(C)C1CC2CC(C(C2C1)C=O)N(C)C Chemical compound C(C)C1CC2CC(C(C2C1)C=O)N(C)C JMXRZTXLGLBUTE-UHFFFAOYSA-N 0.000 description 6
- IPZPGMBJGMZYNO-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CC2CC(C(C2C1)C=O)N(C)C Chemical compound C(C1=CC=CC=C1)C1CC2CC(C(C2C1)C=O)N(C)C IPZPGMBJGMZYNO-UHFFFAOYSA-N 0.000 description 6
- VFBOUQIQWJPPCL-UHFFFAOYSA-N C1(CCCC1)C1CC2CC(C(C2C1)C=O)N(C)C Chemical compound C1(CCCC1)C1CC2CC(C(C2C1)C=O)N(C)C VFBOUQIQWJPPCL-UHFFFAOYSA-N 0.000 description 6
- SOLFXDZIMHNKAF-UHFFFAOYSA-N C1(CCCCC1)C1CC2CC(C(C2C1)(C=O)C)N(C)C Chemical compound C1(CCCCC1)C1CC2CC(C(C2C1)(C=O)C)N(C)C SOLFXDZIMHNKAF-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- 101000804947 Homo sapiens Dipeptidyl peptidase 8 Proteins 0.000 description 5
- 101000804945 Homo sapiens Dipeptidyl peptidase 9 Proteins 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 102100036968 Dipeptidyl peptidase 8 Human genes 0.000 description 4
- 102100036969 Dipeptidyl peptidase 9 Human genes 0.000 description 4
- PLZNPHDJGFDNRM-UHFFFAOYSA-M O.[Na+].[O-][PH2]=O Chemical compound O.[Na+].[O-][PH2]=O PLZNPHDJGFDNRM-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 125000004103 aminoalkyl group Chemical group 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 230000002218 hypoglycaemic effect Effects 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 125000002521 alkyl halide group Chemical group 0.000 description 3
- 230000003139 buffering effect Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- BENKAPCDIOILGV-UHFFFAOYSA-N 4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(O)CC1C(O)=O BENKAPCDIOILGV-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 2
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- BENKAPCDIOILGV-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-RQJHMYQMSA-N 0.000 description 1
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([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
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WIHVICJZDUIIFP-YRQNITAISA-N CC(C)(C)OC(N(C[C@H]1CC(C2)=O)C[C@@]12NN[C@]1(CC(C2)=O)[C@@H]2CNC1)=O Chemical compound CC(C)(C)OC(N(C[C@H]1CC(C2)=O)C[C@@]12NN[C@]1(CC(C2)=O)[C@@H]2CNC1)=O WIHVICJZDUIIFP-YRQNITAISA-N 0.000 description 1
- UMIBBWJNBBRLEZ-PBINXNQUSA-N CN(C)C(N1C[C@H](CC(C2)C#N)[C@H]2C1)=O Chemical compound CN(C)C(N1C[C@H](CC(C2)C#N)[C@H]2C1)=O UMIBBWJNBBRLEZ-PBINXNQUSA-N 0.000 description 1
- UMIBBWJNBBRLEZ-OWUUHHOZSA-N CN(C)C(N1C[C@H](C[C@@H](C2)C#N)[C@H]2C1)=O Chemical compound CN(C)C(N1C[C@H](C[C@@H](C2)C#N)[C@H]2C1)=O UMIBBWJNBBRLEZ-OWUUHHOZSA-N 0.000 description 1
- KIUNBMTZLZYOJD-SCAQPMJSSA-N CN(C)C(N1C[C@H](C[C@@](Cc2ccccc2)(C2)N)[C@H]2C1)=O Chemical compound CN(C)C(N1C[C@H](C[C@@](Cc2ccccc2)(C2)N)[C@H]2C1)=O KIUNBMTZLZYOJD-SCAQPMJSSA-N 0.000 description 1
- SZHXRNWOHZWHNI-SCAQPMJSSA-N CN(C)C(N1C[C@H](C[C@@](Cc2ccccc2)(C2)N=O)[C@H]2C1)=O Chemical compound CN(C)C(N1C[C@H](C[C@@](Cc2ccccc2)(C2)N=O)[C@H]2C1)=O SZHXRNWOHZWHNI-SCAQPMJSSA-N 0.000 description 1
- FKNFBYRLLZQWFK-KEVRVKNQSA-N CN(C)C(N1C[C@H](C[C@@](Cc2ccccc2)(C2)NCC(N(C[C@H](C3)F)[C@@H]3C#N)=O)[C@H]2C1)=O Chemical compound CN(C)C(N1C[C@H](C[C@@](Cc2ccccc2)(C2)NCC(N(C[C@H](C3)F)[C@@H]3C#N)=O)[C@H]2C1)=O FKNFBYRLLZQWFK-KEVRVKNQSA-N 0.000 description 1
- NOQDJUDZGNQHJH-KBVBSXBZSA-N CN[C@](C[C@@H](C1)C(O)=O)(C2)[C@H]1CN2C(N(C)C)=O Chemical compound CN[C@](C[C@@H](C1)C(O)=O)(C2)[C@H]1CN2C(N(C)C)=O NOQDJUDZGNQHJH-KBVBSXBZSA-N 0.000 description 1
- UFKKICSHKBJSKY-VQFNDLOPSA-N C[C@](Cc1ccccc1)(C1)C[C@@H](C2)[C@H]1CN2C(N(C)C)=O Chemical compound C[C@](Cc1ccccc1)(C1)C[C@@H](C2)[C@H]1CN2C(N(C)C)=O UFKKICSHKBJSKY-VQFNDLOPSA-N 0.000 description 1
- 101100037762 Caenorhabditis elegans rnh-2 gene Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- MAOKMKIGLSXYOL-WDSKDSINSA-N NCC(N(C[C@H](C1)F)[C@@H]1C#N)=O Chemical compound NCC(N(C[C@H](C1)F)[C@@H]1C#N)=O MAOKMKIGLSXYOL-WDSKDSINSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 208000022329 Protein metabolism disease Diseases 0.000 description 1
- 125000005631 S-sulfonamido group Chemical group 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- UHJXEQCVCQFFLS-UHFFFAOYSA-N [O].N1=C(N=CC=C1)OC1=NC=CN=C1 Chemical compound [O].N1=C(N=CC=C1)OC1=NC=CN=C1 UHJXEQCVCQFFLS-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical class C1(=CCCC1)* 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
- 230000009849 deactivation Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 235000021185 dessert Nutrition 0.000 description 1
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000003981 vehicle Substances 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
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Description
实施例 | IC50(nM)DPPIV | IC50(nM)DPP8 | IC50(nM)DPP9 |
1 | 16 | 17380 | 5700 |
2 | 24 | 18240 | 5040 |
3 | 14 |
4 | 69 | ||
7 | 50 | ||
8 | 39 | ||
10 | 83 | ||
11 | 13 | 38480 | 2434 |
12 | 13 | 4890 | 16900 |
13 | 10 | 371 | 516 |
18 | 39 | 3320 | 380 |
Claims (20)
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 200810004727 CN101230059B (zh) | 2007-01-23 | 2008-01-23 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
TW97117786A TWI395582B (zh) | 2007-01-23 | 2008-05-15 | 氮雜雙環烷類衍生物、其製備方法及其在醫藥上的用途 |
JP2010543359A JP5438028B2 (ja) | 2008-01-23 | 2008-05-20 | アザビシクロオクタンの誘導体、その製造方法及びそのジペプチジルペプチダーゼivの阻害剤としての用途 |
US12/863,964 US8304411B2 (en) | 2008-01-23 | 2008-05-20 | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
RU2010128972/04A RU2487866C2 (ru) | 2008-01-23 | 2008-05-20 | Производные дициклоазаалкана, способы их получения и их применение в медицине |
EP08748620.5A EP2246347B1 (en) | 2008-01-23 | 2008-05-20 | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
CA2712352A CA2712352C (en) | 2008-01-23 | 2008-05-20 | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
BRPI0822143A BRPI0822143A2 (pt) | 2008-01-23 | 2008-05-20 | derivados de dicicloaza-alcano, processos de preparação e usos médicos dos mesmos |
PCT/CN2008/071014 WO2009094866A1 (fr) | 2008-01-23 | 2008-05-20 | Dérivés de dicycloazaalcane, leurs procédés de préparation et utilisations médicales |
KR1020107018542A KR101469306B1 (ko) | 2008-01-23 | 2008-05-20 | 다이사이클로아자알칸 유도체, 이의 제조 방법 및 의학적 용도 |
AU2008349110A AU2008349110B2 (en) | 2008-01-23 | 2008-05-20 | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
MX2010008049A MX2010008049A (es) | 2008-01-23 | 2008-05-20 | Derivados de dicicloazaalcano, sus procesos de preparacion y usos medicos. |
US13/619,138 US8415349B2 (en) | 2008-01-23 | 2012-09-14 | Dicycloazaalkane derivatives, preparation processes and medical uses thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200710004330.8 | 2007-01-23 | ||
CNA2007100043308A CN101230058A (zh) | 2007-01-23 | 2007-01-23 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
CN 200810004727 CN101230059B (zh) | 2007-01-23 | 2008-01-23 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010102292364A Division CN101914092B (zh) | 2007-01-23 | 2008-01-23 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101230059A CN101230059A (zh) | 2008-07-30 |
CN101230059B true CN101230059B (zh) | 2011-08-17 |
Family
ID=40921929
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 200810004727 Expired - Fee Related CN101230059B (zh) | 2007-01-23 | 2008-01-23 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN101230059B (zh) |
TW (1) | TWI395582B (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2712352C (en) | 2008-01-23 | 2016-05-10 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
CN101904840B (zh) * | 2009-06-08 | 2012-02-08 | 江苏恒瑞医药股份有限公司 | 治疗哺乳动物包括人2型糖尿病的药物组合物 |
CN101919851B (zh) * | 2009-06-09 | 2012-02-08 | 江苏恒瑞医药股份有限公司 | 治疗哺乳动物包括人2型糖尿病的药物组合物 |
AU2011261349A1 (en) * | 2010-06-03 | 2012-12-06 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
TWI484955B (zh) * | 2010-11-05 | 2015-05-21 | Jiangsu Hengrui Medicine Co | 治療包括人類之哺乳動物中第2型糖尿病的醫藥組成物 |
CN103709150B (zh) * | 2012-10-09 | 2017-06-30 | 江苏豪森药业集团有限公司 | 托西酸贝格列汀晶型及其制备方法和用途 |
CN104030967B (zh) * | 2013-03-05 | 2018-01-02 | 连云港恒运药业有限公司 | 一种dpp‑iv抑制剂的中间体、其制备方法和通过其制备dpp‑iv抑制剂的方法 |
CN104109111B (zh) * | 2013-04-22 | 2019-02-12 | 江苏豪森药业集团有限公司 | 托西酸贝格列汀及其中间体的制备方法 |
SG10201913986YA (en) * | 2015-10-16 | 2020-03-30 | Abbvie Inc | PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF |
CN112047869B (zh) * | 2020-08-20 | 2021-12-21 | 华南理工大学 | 一种氮杂5,6-并环化合物的合成方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5736550A (en) * | 1994-05-18 | 1998-04-07 | Nisshin Flour Milling Co., Ltd. | Pyrimidine derivatives |
WO2003074500A2 (en) * | 2002-03-06 | 2003-09-12 | Sanofi-Aventis | N-aminoacetyl-pyrrolidine-2-carbonitriles and their use as ddp-iv inhibitors |
CN1798559A (zh) * | 2003-04-04 | 2006-07-05 | 诺瓦提斯公司 | 用于治疗气管疾病的喹啉-2-酮衍生物 |
-
2008
- 2008-01-23 CN CN 200810004727 patent/CN101230059B/zh not_active Expired - Fee Related
- 2008-05-15 TW TW97117786A patent/TWI395582B/zh not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5736550A (en) * | 1994-05-18 | 1998-04-07 | Nisshin Flour Milling Co., Ltd. | Pyrimidine derivatives |
WO2003074500A2 (en) * | 2002-03-06 | 2003-09-12 | Sanofi-Aventis | N-aminoacetyl-pyrrolidine-2-carbonitriles and their use as ddp-iv inhibitors |
CN1798559A (zh) * | 2003-04-04 | 2006-07-05 | 诺瓦提斯公司 | 用于治疗气管疾病的喹啉-2-酮衍生物 |
Non-Patent Citations (6)
Title |
---|
Daniel P. Becker and Daniel L. Flynn.Studies of the Solid-Phase Pauson-Khand Reaction:Selectivein-situ Enone Reduction to 3-Azabicyclo[3.3.0]octauones.Tetrahedron Letters34 13.1993,34(13),pp.2087-2090. |
Daniel P. Becker and Daniel L. Flynn.Studies of the Solid-Phase Pauson-Khand Reaction:Selectivein-situ Enone Reduction to 3-Azabicyclo[3.3.0]octauones.Tetrahedron Letters34 13.1993,34(13),pp.2087-2090. * |
José Barluenga et al..Zirconium-Mediated Intramolecular Coupling of TerminalAlkynes and Their Subsequent Carbonylation : NovelSynthesis of Seven- and Eight-Membered Heterocycles.Chem. Eur. J.3 8.1997,3(8),pp. 1324-1336. |
José Barluenga et al..Zirconium-Mediated Intramolecular Coupling of TerminalAlkynes and Their Subsequent Carbonylation : NovelSynthesis of Seven- and Eight-Membered Heterocycles.Chem. Eur. J.3 8.1997,3(8),pp. 1324-1336. * |
Marko D. Mihovilovic et al..Application of dry-state adsorption condition (DSAC) Pauson-Khand cyclization for the synthesis of perhydrocyclopenta[c]pyrroles.ARKIVOC 2.2001,(2),28-33. |
Marko D. Mihovilovic et al..Application of dry-state adsorption condition (DSAC) Pauson-Khand cyclization for the synthesis of perhydrocyclopenta[c]pyrroles.ARKIVOC 2.2001,(2),28-33. * |
Also Published As
Publication number | Publication date |
---|---|
TW200946110A (en) | 2009-11-16 |
TWI395582B (zh) | 2013-05-11 |
CN101230059A (zh) | 2008-07-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101914092B (zh) | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 | |
CN101230059B (zh) | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 | |
US8962623B2 (en) | Aminopyrazine compounds | |
TWI475019B (zh) | C型肝炎病毒抑制劑 | |
JP5611959B2 (ja) | C型肝炎ウイルス阻害剤 | |
EP2953457A2 (en) | Erk inhibitors and uses thereof | |
CA2961607C (en) | Mk2 inhibitors and uses thereof | |
JP5815746B2 (ja) | C型肝炎ウイルス阻害剤 | |
WO2020084305A1 (en) | Bicyclic peptide ligands and uses thereof | |
MX2010008269A (es) | Inhibidores de hsp90. | |
EP2424368A1 (en) | Pyrrolotriazine compounds | |
CN105228997A (zh) | Carm1抑制剂及其用途 | |
WO2011123493A1 (en) | Substituted pyrrolotriazines as protein kinase inhibitors | |
AU2016366546B2 (en) | Inhibitors of Bruton's tyrosine kinase and methods of their use | |
JP4257383B2 (ja) | 高選択的Rhoキナーゼ阻害剤 | |
CN105712998A (zh) | 氮杂吲哚类衍生物、其制备方法及其在医药上的应用 | |
CN102216279A (zh) | 一类含有嘧啶酮苯基的化合物、其药物组合物及其制备方法和用途 | |
AU2015291477A1 (en) | Novel 2,5-substituted pyrimidines as PDE inhibitors | |
CN104640847A (zh) | 新型肾素抑制剂 | |
CN104755475A (zh) | Hiv蛋白酶抑制剂 | |
WO2009094866A1 (fr) | Dérivés de dicycloazaalcane, leurs procédés de préparation et utilisations médicales | |
CN101312977A (zh) | 用作激酶调节剂的稠合杂环化合物 | |
CN105308042A (zh) | 作为RORc 调节剂的芳基磺内酰胺衍生物 | |
EP2970228B1 (en) | Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides inhibitors of cathepsin c | |
EP4169575A1 (en) | Condensed ring compounds that inhibit h-pgds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1117164 Country of ref document: HK |
|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
ASS | Succession or assignment of patent right |
Owner name: JIANGSU HAOSOH PHARMACEUTICAL STOCK CO., LTD. |
|
C41 | Transfer of patent application or patent right or utility model | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20100613 Address after: 200245 No. 279, Wen Jing Road, Shanghai, Minhang District Applicant after: Hengrui Pharmaceutical Co., Ltd., Shanghai Co-applicant after: Jiangsu Haosen Pharmaceutical Ltd. Address before: 200245 No. 279, Wen Jing Road, Shanghai, Minhang District Applicant before: Hengrui Pharmaceutical Co., Ltd., Shanghai |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1117164 Country of ref document: HK |
|
C56 | Change in the name or address of the patentee | ||
CP01 | Change in the name or title of a patent holder |
Address after: 200245 No. 279, Wen Jing Road, Shanghai, Minhang District Patentee after: Hengrui Pharmaceutical Co., Ltd., Shanghai Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 200245 No. 279, Wen Jing Road, Shanghai, Minhang District Patentee before: Hengrui Pharmaceutical Co., Ltd., Shanghai Patentee before: Jiangsu Haosen Pharmaceutical Ltd. |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110817 Termination date: 20200123 |
|
CF01 | Termination of patent right due to non-payment of annual fee |