MX2010008049A - Derivados de dicicloazaalcano, sus procesos de preparacion y usos medicos. - Google Patents
Derivados de dicicloazaalcano, sus procesos de preparacion y usos medicos.Info
- Publication number
- MX2010008049A MX2010008049A MX2010008049A MX2010008049A MX2010008049A MX 2010008049 A MX2010008049 A MX 2010008049A MX 2010008049 A MX2010008049 A MX 2010008049A MX 2010008049 A MX2010008049 A MX 2010008049A MX 2010008049 A MX2010008049 A MX 2010008049A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- compound
- aryl
- group
- heteroaryl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 103
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 claims abstract description 6
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 claims abstract description 6
- 229940122344 Peptidase inhibitor Drugs 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 257
- -1 alkyl amide Chemical group 0.000 claims description 236
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 174
- 239000000203 mixture Substances 0.000 claims description 160
- 125000000217 alkyl group Chemical group 0.000 claims description 156
- 125000003118 aryl group Chemical group 0.000 claims description 127
- 125000001072 heteroaryl group Chemical group 0.000 claims description 108
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 102
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 93
- 125000003545 alkoxy group Chemical group 0.000 claims description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 62
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N Minaline Natural products OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims description 53
- 125000004104 aryloxy group Chemical group 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 43
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 41
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 40
- 239000002253 acid Chemical group 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 125000001188 haloalkyl group Chemical group 0.000 claims description 27
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 18
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- ZILVXVYEINTQJF-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-5-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1NCC2CC(=O)CC21 ZILVXVYEINTQJF-UHFFFAOYSA-N 0.000 claims description 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 19
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 2
- 238000003776 cleavage reaction Methods 0.000 claims 2
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims 2
- 230000007017 scission Effects 0.000 claims 2
- 150000003892 tartrate salts Chemical class 0.000 claims 2
- XSEMARCLUCFBCO-UHFFFAOYSA-N 3-tert-butyl-5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid Chemical compound C1C(=O)CC2CN(C(O)=O)C(C(C)(C)C)C21 XSEMARCLUCFBCO-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 159000000021 acetate salts Chemical class 0.000 claims 1
- 150000001860 citric acid derivatives Chemical class 0.000 claims 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims 1
- 150000002429 hydrazines Chemical class 0.000 claims 1
- 150000002440 hydroxy compounds Chemical class 0.000 claims 1
- 150000003893 lactate salts Chemical class 0.000 claims 1
- 150000004701 malic acid derivatives Chemical class 0.000 claims 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 7
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 abstract 1
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- 230000002829 reductive effect Effects 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 66
- 239000000243 solution Substances 0.000 description 65
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 60
- 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 58
- 239000008103 glucose Substances 0.000 description 58
- 238000004949 mass spectrometry Methods 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 229910001868 water Inorganic materials 0.000 description 53
- 239000000284 extract Substances 0.000 description 49
- 238000010898 silica gel chromatography Methods 0.000 description 48
- 238000003756 stirring Methods 0.000 description 47
- 238000012360 testing method Methods 0.000 description 47
- 239000005457 ice water Substances 0.000 description 46
- 238000001816 cooling Methods 0.000 description 44
- 239000007858 starting material Substances 0.000 description 39
- 230000008034 disappearance Effects 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 210000004369 blood Anatomy 0.000 description 31
- 239000008280 blood Substances 0.000 description 31
- 239000003921 oil Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 24
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 23
- 229910052757 nitrogen Inorganic materials 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
- 241000699670 Mus sp. Species 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 20
- 239000012230 colorless oil Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 17
- 239000012154 double-distilled water Substances 0.000 description 17
- 239000007983 Tris buffer Substances 0.000 description 16
- 125000005843 halogen group Chemical group 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 239000000758 substrate Substances 0.000 description 16
- 229940095064 tartrate Drugs 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- 239000011877 solvent mixture Substances 0.000 description 13
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 12
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 12
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 12
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 12
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 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 11
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000013642 negative control Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- RLOQBKJCOAXOLR-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide Chemical compound NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 102100036969 Dipeptidyl peptidase 9 Human genes 0.000 description 8
- 101710087005 Dipeptidyl peptidase 9 Proteins 0.000 description 8
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 8
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 8
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 8
- 238000007410 oral glucose tolerance test Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 8
- 239000011975 tartaric acid Substances 0.000 description 8
- 235000002906 tartaric acid Nutrition 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- 102100036968 Dipeptidyl peptidase 8 Human genes 0.000 description 6
- 101710087011 Dipeptidyl peptidase 8 Proteins 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000002218 hypoglycaemic effect Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 5
- 229960002218 sodium chlorite Drugs 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000004385 trihaloalkyl group Chemical group 0.000 description 5
- LTEVBEYLVWEGPJ-UHFFFAOYSA-N 1-[2-[[2-(piperidine-1-carbonyl)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-5-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound C1CCC(C#N)N1C(=O)CNC(CC1C2)CC1CN2C(=O)N1CCCCC1 LTEVBEYLVWEGPJ-UHFFFAOYSA-N 0.000 description 4
- QEGSKHFEXAXYGO-UHFFFAOYSA-N 5-amino-5-methyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid Chemical compound CC1(N)CC2CN(CC2C1)C(O)=O QEGSKHFEXAXYGO-UHFFFAOYSA-N 0.000 description 4
- CGLSHYJVFOURHP-KSISSFPLSA-N CC1(CC2CN(CC2C1)C(=O)O)NCC(=O)N3CCC[C@H]3C#N Chemical compound CC1(CC2CN(CC2C1)C(=O)O)NCC(=O)N3CCC[C@H]3C#N CGLSHYJVFOURHP-KSISSFPLSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000006096 absorbing agent Substances 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 238000009395 breeding Methods 0.000 description 4
- 230000001488 breeding effect Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 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 4
- GTDBSXAQZGPRFO-UHFFFAOYSA-N n,n-dimethyl-5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C(=O)CC2CN(C(=O)N(C)C)CC21 GTDBSXAQZGPRFO-UHFFFAOYSA-N 0.000 description 4
- XUWVIABDWDTJRZ-UHFFFAOYSA-N propan-2-ylazanide Chemical compound CC(C)[NH-] XUWVIABDWDTJRZ-UHFFFAOYSA-N 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 230000035939 shock Effects 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- BKHDYBMGEZPELT-RGMNGODLSA-N (2s)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.NCC(=O)N1CCC[C@H]1C#N BKHDYBMGEZPELT-RGMNGODLSA-N 0.000 description 3
- HHFUFGKACHWIAV-WHFBIAKZSA-N (2s,4s)-4-fluoropyrrolidine-2-carbonitrile Chemical compound F[C@@H]1CN[C@H](C#N)C1 HHFUFGKACHWIAV-WHFBIAKZSA-N 0.000 description 3
- XPBOQFYNLSDNLB-UHFFFAOYSA-N 1-[2-[[2-(morpholine-4-carbonyl)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-5-yl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound C1CCC(C#N)N1C(=O)CNC(CC1C2)CC1CN2C(=O)N1CCOCC1 XPBOQFYNLSDNLB-UHFFFAOYSA-N 0.000 description 3
- PLCVGHQBKQDYMC-UHFFFAOYSA-N 2-(2-hydroxyacetyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one Chemical compound C1C(=O)CC2CN(C(=O)CO)CC21 PLCVGHQBKQDYMC-UHFFFAOYSA-N 0.000 description 3
- BVFHLZFKRXHQMK-UHFFFAOYSA-N 2-(piperidine-1-carbonyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one Chemical compound C1C2CC(=O)CC2CN1C(=O)N1CCCCC1 BVFHLZFKRXHQMK-UHFFFAOYSA-N 0.000 description 3
- WFPLXVOHETVYQM-UHFFFAOYSA-N 2-(pyrrolidine-1-carbonyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one Chemical compound C1C2CC(=O)CC2CN1C(=O)N1CCCC1 WFPLXVOHETVYQM-UHFFFAOYSA-N 0.000 description 3
- PYYIZEKRAHOYCN-UHFFFAOYSA-N 2-acetyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one Chemical compound C1C(=O)CC2CN(C(=O)C)CC21 PYYIZEKRAHOYCN-UHFFFAOYSA-N 0.000 description 3
- RUKJNXWAKVVIJM-UHFFFAOYSA-N 5-(cyclohexylmethyl)-2-(dimethylcarbamoyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carboxylic acid Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(C(O)=O)CC1CCCCC1 RUKJNXWAKVVIJM-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- JNMIXMFEVJHFNY-UHFFFAOYSA-M methyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 JNMIXMFEVJHFNY-UHFFFAOYSA-M 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- DKLUQCYRAWMYMM-UHFFFAOYSA-N n-methyl-5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C(=O)CC2CN(C(=O)NC)CC21 DKLUQCYRAWMYMM-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000011287 therapeutic dose Methods 0.000 description 3
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 3
- 125000004953 trihalomethyl group Chemical group 0.000 description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- XDOMURQNGATABE-LURJTMIESA-N (2s)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile Chemical compound NCC(=O)N1CCC[C@H]1C#N XDOMURQNGATABE-LURJTMIESA-N 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 2
- BFBAPDUWAWQLDB-UHFFFAOYSA-N 2-(dimethylcarbamoyl)-5-methyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carbonyl azide Chemical compound C1C(C)(C(=O)N=[N+]=[N-])CC2CN(C(=O)N(C)C)CC21 BFBAPDUWAWQLDB-UHFFFAOYSA-N 0.000 description 2
- CHYQHPORSWNFCQ-UHFFFAOYSA-N 2-(dimethylcarbamoyl)-5-methyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carboxylic acid Chemical compound C1C(C)(C(O)=O)CC2CN(C(=O)N(C)C)CC21 CHYQHPORSWNFCQ-UHFFFAOYSA-N 0.000 description 2
- QADCZSIXWFKGPG-UHFFFAOYSA-N 2-(morpholine-4-carbonyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one Chemical compound C1C2CC(=O)CC2CN1C(=O)N1CCOCC1 QADCZSIXWFKGPG-UHFFFAOYSA-N 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
- ODYDEDBPRBMSKE-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrole-2-carboxamide Chemical compound C1CCC2CN(C(=O)N)CC21 ODYDEDBPRBMSKE-UHFFFAOYSA-N 0.000 description 2
- USNABPCGRMEGEC-UHFFFAOYSA-N 5-amino-5-(cyclohexylmethyl)-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(N)CC1CCCCC1 USNABPCGRMEGEC-UHFFFAOYSA-N 0.000 description 2
- KIUNBMTZLZYOJD-UHFFFAOYSA-N 5-amino-5-benzyl-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(N)CC1=CC=CC=C1 KIUNBMTZLZYOJD-UHFFFAOYSA-N 0.000 description 2
- UEFUMHDYFXBMDC-UHFFFAOYSA-N 5-cyclopentyl-2-(dimethylcarbamoyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carboxylic acid Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(C(O)=O)C1CCCC1 UEFUMHDYFXBMDC-UHFFFAOYSA-N 0.000 description 2
- KUJPBYPSHNQMCA-UHFFFAOYSA-N 5-isocyano-n,n,5-trimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C(C)([N+]#[C-])CC2CN(C(=O)N(C)C)CC21 KUJPBYPSHNQMCA-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- BYXYCUABYHCYLY-UHFFFAOYSA-N isoindole-1,3-dione;potassium Chemical compound [K].C1=CC=C2C(=O)NC(=O)C2=C1 BYXYCUABYHCYLY-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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [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
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 2
- 239000001476 sodium potassium tartrate Substances 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- VBJGJHBYWREJQD-UHFFFAOYSA-M sodium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Na+].OP(O)([O-])=O VBJGJHBYWREJQD-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QAKRZINKSNCLEV-YUMQZZPRSA-N tert-butyl (2s,4s)-2-cyano-4-fluoropyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C#N QAKRZINKSNCLEV-YUMQZZPRSA-N 0.000 description 2
- 125000003441 thioacyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 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
- DMQSZIMWOFNPNR-WDSKDSINSA-N (2s,4s)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile Chemical compound F[C@H]1C[C@@H](C#N)N(C(=O)CCl)C1 DMQSZIMWOFNPNR-WDSKDSINSA-N 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 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
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HAPUFQQJJOPOMR-UHFFFAOYSA-N 1H-pyrrol-1-ium 2,2,2-trifluoroacetate Chemical compound c1cc[nH]c1.OC(=O)C(F)(F)F HAPUFQQJJOPOMR-UHFFFAOYSA-N 0.000 description 1
- WUGKWRYESFKELO-UHFFFAOYSA-N 1h-cyclopenta[c]pyrrole-2-carboxylic acid Chemical compound C1=CC2=CN(C(=O)O)CC2=C1 WUGKWRYESFKELO-UHFFFAOYSA-N 0.000 description 1
- XRSFPEFHACEZSM-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-5-one Chemical compound C1NCC2CC(=O)CC21 XRSFPEFHACEZSM-UHFFFAOYSA-N 0.000 description 1
- UTOOCNIYUNLCFI-UHFFFAOYSA-N 2-(dimethylcarbamoyl)-5-ethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carbonyl azide Chemical compound C1N(C(=O)N(C)C)CC2CC(CC)(C(=O)N=[N+]=[N-])CC21 UTOOCNIYUNLCFI-UHFFFAOYSA-N 0.000 description 1
- VQEINUUKDFZNFV-UHFFFAOYSA-N 2-(dimethylcarbamoyl)-5-ethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carboxylic acid Chemical compound C1N(C(=O)N(C)C)CC2CC(CC)(C(O)=O)CC21 VQEINUUKDFZNFV-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- KJMWZOQIHURJAG-GEMLJDPKSA-N 2-chloroacetyl chloride (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile Chemical compound ClCC(=O)Cl.ClCC(=O)N1[C@@H](C[C@@H](C1)F)C#N KJMWZOQIHURJAG-GEMLJDPKSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)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
- GTVUGPOLOIQVEI-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrole-2-carboxylic acid Chemical compound C1CCC2CN(C(=O)O)CC21 GTVUGPOLOIQVEI-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
- PTNHUPJANGKQAM-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;n-methylmethanamine Chemical compound CNC.CC1=CC=C(S(O)(=O)=O)C=C1 PTNHUPJANGKQAM-UHFFFAOYSA-N 0.000 description 1
- NQGLHRJUHFDYOZ-UHFFFAOYSA-N 5-(cyclohexylmethyl)-2-(dimethylcarbamoyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carbonyl azide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(C(=O)N=[N+]=[N-])CC1CCCCC1 NQGLHRJUHFDYOZ-UHFFFAOYSA-N 0.000 description 1
- RFNNMNWNDKWMAE-UHFFFAOYSA-N 5-(cyclohexylmethyl)-5-formyl-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(C=O)CC1CCCCC1 RFNNMNWNDKWMAE-UHFFFAOYSA-N 0.000 description 1
- WWRKIQZKFGMESZ-QYWBRQQASA-N 5-[[2-[(2s,4s)-2-cyano-4-fluoropyrrolidin-1-yl]-2-oxoethyl]amino]-n,n,5-trimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(C)NCC(=O)N1C[C@@H](F)C[C@H]1C#N WWRKIQZKFGMESZ-QYWBRQQASA-N 0.000 description 1
- CZZBSEHBBGRSQO-UHFFFAOYSA-N 5-amino-5-benzyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid Chemical compound NC1(CC2C(CN(C2)C(=O)O)C1)CC1=CC=CC=C1 CZZBSEHBBGRSQO-UHFFFAOYSA-N 0.000 description 1
- RJPVZSDNSNZBEC-UHFFFAOYSA-N 5-amino-5-cyclopentyl-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(N)C1CCCC1 RJPVZSDNSNZBEC-UHFFFAOYSA-N 0.000 description 1
- HJYKOFZGXYYBMZ-UHFFFAOYSA-N 5-amino-5-ethyl-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1N(C(=O)N(C)C)CC2CC(CC)(N)CC21 HJYKOFZGXYYBMZ-UHFFFAOYSA-N 0.000 description 1
- KNVDCIPZIYQYAO-UHFFFAOYSA-N 5-amino-n,n,5-trimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C(C)(N)CC2CN(C(=O)N(C)C)CC21 KNVDCIPZIYQYAO-UHFFFAOYSA-N 0.000 description 1
- OJRRQGUFHNUYPP-UHFFFAOYSA-N 5-benzyl-5-cyano-N,N-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide 5-benzyl-5-formyl-N,N-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound CN(C(=O)N1CC2C(C1)CC(C2)(C#N)CC2=CC=CC=C2)C.CN(C(=O)N2CC1C(C2)CC(C1)(C=O)CC1=CC=CC=C1)C OJRRQGUFHNUYPP-UHFFFAOYSA-N 0.000 description 1
- REXORPMTAFYHLD-UHFFFAOYSA-N 5-cyano-5-(cyclohexylmethyl)-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(C#N)CC1CCCCC1 REXORPMTAFYHLD-UHFFFAOYSA-N 0.000 description 1
- IONCJXLWAIOGTC-UHFFFAOYSA-N 5-cyano-5-cyclopentyl-N,N-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide 5-cyano-N,N-dimethyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide Chemical compound CN(C(=O)N1CC2C(C1)CC(C2)C#N)C.CN(C(=O)N2CC1C(C2)CC(C1)(C1CCCC1)C#N)C IONCJXLWAIOGTC-UHFFFAOYSA-N 0.000 description 1
- MVFZHRIQPVOFCI-UHFFFAOYSA-N 5-cyano-5-ethyl-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1N(C(=O)N(C)C)CC2CC(CC)(C#N)CC21 MVFZHRIQPVOFCI-UHFFFAOYSA-N 0.000 description 1
- MGJIMSRVDNLSAX-UHFFFAOYSA-N 5-cyano-N,N,5-trimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide 2-(dimethylcarbamoyl)-5-methyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carboxylic acid Chemical compound C1C(C)(C#N)CC2CN(C(=O)N(C)C)CC21.C1C(C)(C(O)=O)CC2CN(C(=O)N(C)C)CC21 MGJIMSRVDNLSAX-UHFFFAOYSA-N 0.000 description 1
- KESNPDYOBSBXDJ-UHFFFAOYSA-N 5-cyano-N,N-dimethyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide 5-cyano-N,N,5-trimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound CN(C(=O)N1CC2C(C1)CC(C2)C#N)C.CN(C(=O)N2CC1C(C2)CC(C1)(C)C#N)C KESNPDYOBSBXDJ-UHFFFAOYSA-N 0.000 description 1
- RFIGLHCTFGYDRP-UHFFFAOYSA-N 5-cyclopentyl-2-(dimethylcarbamoyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carbonyl azide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(C(=O)N=[N+]=[N-])C1CCCC1 RFIGLHCTFGYDRP-UHFFFAOYSA-N 0.000 description 1
- UZVXLBWSMRYMCM-UHFFFAOYSA-N 5-cyclopentyl-2-(dimethylcarbamoyl)-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5-carbonyl azide 5-cyclopentyl-5-isocyanato-N,N-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1(CCCC1)C1(CC2C(CN(C2)C(N(C)C)=O)C1)C(=O)N=[N+]=[N-].CN(C(=O)N1CC2C(C1)CC(C2)(N=C=O)C2CCCC2)C UZVXLBWSMRYMCM-UHFFFAOYSA-N 0.000 description 1
- CIVFTXSTTJKEKK-UHFFFAOYSA-N 5-cyclopentyl-5-isocyanato-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C2CN(C(=O)N(C)C)CC2CC1(N=C=O)C1CCCC1 CIVFTXSTTJKEKK-UHFFFAOYSA-N 0.000 description 1
- PIMBQPLFYTVAMP-UHFFFAOYSA-N 5-ethyl-5-formyl-n,n-dimethyl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1N(C(=O)N(C)C)CC2CC(CC)(C=O)CC21 PIMBQPLFYTVAMP-UHFFFAOYSA-N 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- QHRRHKSCTHOYJI-UHFFFAOYSA-N 5-oxo-n-propan-2-yl-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C(=O)CC2CN(C(=O)NC(C)C)CC21 QHRRHKSCTHOYJI-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BNZWLRWRHZWJMW-UHFFFAOYSA-N C(C)C1(CC2C(CN(C2)C(N(C)C)=O)C1)C(=O)N=[N+]=[N-].CN(C(=O)N1CC2C(C1)CC(C2)(N=C=O)CC)C Chemical compound C(C)C1(CC2C(CN(C2)C(N(C)C)=O)C1)C(=O)N=[N+]=[N-].CN(C(=O)N1CC2C(C1)CC(C2)(N=C=O)CC)C BNZWLRWRHZWJMW-UHFFFAOYSA-N 0.000 description 1
- SHKDFWJUTRANNI-UHFFFAOYSA-N C(C1=CC=CC=C1)C1(CC2C(CN(C2)C(N(C)C)=O)C1)C(=O)N=[N+]=[N-].CN(C(=O)N1CC2C(C1)CC(C2)(N=C=O)CC2=CC=CC=C2)C Chemical compound C(C1=CC=CC=C1)C1(CC2C(CN(C2)C(N(C)C)=O)C1)C(=O)N=[N+]=[N-].CN(C(=O)N1CC2C(C1)CC(C2)(N=C=O)CC2=CC=CC=C2)C SHKDFWJUTRANNI-UHFFFAOYSA-N 0.000 description 1
- JBVQLQODEISDIA-UHFFFAOYSA-N C1(CCCCC1)CC1(CC2C(CN(C2)C(N(C)C)=O)C1)C(=O)N=[N+]=[N-].CN(C(=O)N1CC2C(C1)CC(C2)(N=C=O)CC2CCCCC2)C Chemical compound C1(CCCCC1)CC1(CC2C(CN(C2)C(N(C)C)=O)C1)C(=O)N=[N+]=[N-].CN(C(=O)N1CC2C(C1)CC(C2)(N=C=O)CC2CCCCC2)C JBVQLQODEISDIA-UHFFFAOYSA-N 0.000 description 1
- NDYWSWDCOWRLOQ-UHFFFAOYSA-N CCN(CC)SN(CC)CC.F.F.F Chemical compound CCN(CC)SN(CC)CC.F.F.F NDYWSWDCOWRLOQ-UHFFFAOYSA-N 0.000 description 1
- PWELDFDWQQNZLV-UHFFFAOYSA-N CN(C(=O)N1CC2C(C1)CC(C2)C#N)C.CN(C(=O)N2CC1C(C2)CC(C1)(C#N)CC1=CC=CC=C1)C Chemical compound CN(C(=O)N1CC2C(C1)CC(C2)C#N)C.CN(C(=O)N2CC1C(C2)CC(C1)(C#N)CC1=CC=CC=C1)C PWELDFDWQQNZLV-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- XNCOCTMVJVBMKU-UHFFFAOYSA-N FC(C(=O)O)(F)F.N=1C(C=CC1)=O Chemical compound FC(C(=O)O)(F)F.N=1C(C=CC1)=O XNCOCTMVJVBMKU-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- CKJKAXBWBUBBKI-UHFFFAOYSA-N N,N-dimethyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide Chemical compound CN(C(=O)N1CC2C(C1)CCC2)C CKJKAXBWBUBBKI-UHFFFAOYSA-N 0.000 description 1
- AKTQSHIRSZYKJS-UHFFFAOYSA-N N-methylmethanamine Chemical compound CNC.CNC AKTQSHIRSZYKJS-UHFFFAOYSA-N 0.000 description 1
- QGSFEFOIVJYCOS-SDMWGOBESA-N N1[C@H](C(=O)O)C[C@@H](O)C1.C(C)(C)(C)OC(=O)N1[C@@H](C[C@H](C1)O)C(=O)O Chemical compound N1[C@H](C(=O)O)C[C@@H](O)C1.C(C)(C)(C)OC(=O)N1[C@@H](C[C@H](C1)O)C(=O)O QGSFEFOIVJYCOS-SDMWGOBESA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- MFMVDMJNCGUHAT-UHFFFAOYSA-N OC(=O)N1CC2CC(CC2C1)(C=O)C1CCCC1 Chemical compound OC(=O)N1CC2CC(CC2C1)(C=O)C1CCCC1 MFMVDMJNCGUHAT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 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
- 238000000692 Student's t-test Methods 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010043458 Thirst Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- DVZQIVLCXQRVQD-YFKPBYRVSA-N [2-[(2S)-2-carbamoylpyrrolidin-1-yl]-2-oxoethyl]carbamic acid Chemical compound NC(=O)[C@@H]1CCCN1C(=O)CNC(O)=O DVZQIVLCXQRVQD-YFKPBYRVSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000006286 aqueous extract Substances 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
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000013078 crystal Substances 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
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 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
- 125000002433 cyclopentenyl group Chemical group 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
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 108010040030 histidinoalanine Proteins 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
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 206010021654 increased appetite Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- PCEBAZIVZVIQEO-UHFFFAOYSA-N iodocyclopentane Chemical compound IC1CCCC1 PCEBAZIVZVIQEO-UHFFFAOYSA-N 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
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- VZRWJMZZHDOBIO-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrole-2-carboxamide Chemical compound CN(C)C(=O)C1=CC=CN1 VZRWJMZZHDOBIO-UHFFFAOYSA-N 0.000 description 1
- XNTUKPBCFKXFIX-UHFFFAOYSA-N n,n-dimethyl-5-methylidene-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamide Chemical compound C1C(=C)CC2CN(C(=O)N(C)C)CC21 XNTUKPBCFKXFIX-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 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
- 230000022558 protein metabolic process Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- XACWJIQLDLUFSR-UHFFFAOYSA-N pyrrolidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCC1 XACWJIQLDLUFSR-UHFFFAOYSA-N 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- GGNDIMLSSMWKDR-UHFFFAOYSA-N tert-butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate Chemical compound C1C(=O)CC2CN(C(=O)OC(C)(C)C)CC21 GGNDIMLSSMWKDR-UHFFFAOYSA-N 0.000 description 1
- QTNNCICZGXJIAJ-QMMMGPOBSA-N tert-butyl n-[2-[(2s)-2-carbamoylpyrrolidin-1-yl]-2-oxoethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(N)=O QTNNCICZGXJIAJ-QMMMGPOBSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
| 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 |
| PCT/CN2008/071014 WO2009094866A1 (en) | 2008-01-23 | 2008-05-20 | Dicycloazaalkane derivates, preparation processes and medical uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2010008049A true MX2010008049A (es) | 2010-11-12 |
Family
ID=40921930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2010008049A MX2010008049A (es) | 2008-01-23 | 2008-05-20 | Derivados de dicicloazaalcano, sus procesos de preparacion y usos medicos. |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US8304411B2 (enExample) |
| EP (1) | EP2246347B1 (enExample) |
| JP (1) | JP5438028B2 (enExample) |
| KR (1) | KR101469306B1 (enExample) |
| BR (1) | BRPI0822143A2 (enExample) |
| CA (1) | CA2712352C (enExample) |
| MX (1) | MX2010008049A (enExample) |
| RU (1) | RU2487866C2 (enExample) |
| WO (1) | WO2009094866A1 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102174007B (zh) * | 2011-03-11 | 2013-06-12 | 成都博天化工有限责任公司 | [2-(2-氰基-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁基酯的工业化制备方法 |
| RU2618673C2 (ru) | 2011-12-21 | 2017-05-10 | Цзянсу Хэнжуй Медсин Ко., Лтд. | Производные пирролопиримидина, полезные в качестве ингибиторов jak-киназы |
| CN103508931B (zh) | 2012-06-25 | 2016-03-02 | 广东东阳光药业有限公司 | 六氢并环戊二烯衍生物、其制备方法及其在医药上的应用 |
| 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 |
| WO2015048507A1 (en) | 2013-09-26 | 2015-04-02 | Mnemosyne Pharmaceuticals, Inc. | Selective octahydro-cyclopenta[c] pyrrole negative modulators of nr2b |
| JO3579B1 (ar) | 2014-09-26 | 2020-07-05 | Luc Therapeutics Inc | مُعدِلات تفاغرية سالبة لمستقبل nr2b من المركب n-ألكيل أريل-5-أوكسي أريل-ثامن هيدرو-خماسي الحلقة [c] بيرول |
| US20170301620A1 (en) * | 2016-04-15 | 2017-10-19 | International Business Machines Corporation | Structure and process for metal cap integration |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5280028A (en) * | 1992-06-24 | 1994-01-18 | G. D. Searle & Co. | Benzimidazole compounds |
| EP0760368B1 (en) * | 1994-05-18 | 1999-07-28 | Nisshin Flour Milling Co., Ltd. | Pyrimidine derivatives |
| TW492957B (en) | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
| US6110949A (en) * | 1999-06-24 | 2000-08-29 | Novartis Ag | N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| JP4357293B2 (ja) | 2001-06-27 | 2009-11-04 | スミスクライン ビーチャム コーポレーション | ジペプチジルペプチダーゼ阻害剤としてのフルオロピロリジン類 |
| US6861440B2 (en) * | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
| HUP0200849A2 (hu) | 2002-03-06 | 2004-08-30 | Sanofi-Synthelabo | N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra |
| TW200401635A (en) * | 2002-07-23 | 2004-02-01 | Yamanouchi Pharma Co Ltd | 2-Cyano-4-fluoropyrrolidine derivative or salt thereof |
| AU2004226824B2 (en) * | 2003-04-04 | 2008-05-01 | Novartis Ag | Quinoline-2-one-derivatives for the treatment of airways diseases |
| GB0307856D0 (en) * | 2003-04-04 | 2003-05-14 | Novartis Ag | Organic compounds |
| JP4689599B2 (ja) * | 2004-02-27 | 2011-05-25 | 杏林製薬株式会社 | ビシクロ誘導体 |
| FR2870538B1 (fr) * | 2004-05-19 | 2006-07-14 | Servier Lab | Nouveaux derives de pyrrolidines et de thiazolidines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| EP1778688A1 (en) * | 2004-07-22 | 2007-05-02 | Glaxo Group Limited | Antibacterial agents |
| US7423056B2 (en) | 2004-09-03 | 2008-09-09 | Athersys, Inc. | Tricyclic heteroaryl piperazines, pyrrolidines and azetidines as serotonin receptor modulators |
| EP1931633A2 (en) * | 2005-09-05 | 2008-06-18 | Ranbaxy Laboratories Limited | Derivatives of 3-azabicyclo[3.1.0]hexane as dipeptidyl peptidase-iv inhibitors |
| CN101050194B (zh) | 2006-04-05 | 2013-08-21 | 上海恒瑞医药有限公司 | 双环辛烷类衍生物、其制备方法及其在医药上的用途 |
| CN101230059B (zh) | 2007-01-23 | 2011-08-17 | 上海恒瑞医药有限公司 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
| CN101230058A (zh) * | 2007-01-23 | 2008-07-30 | 上海恒瑞医药有限公司 | 双环氮杂烷类衍生物、其制备方法及其在医药上的用途 |
-
2008
- 2008-05-20 MX MX2010008049A patent/MX2010008049A/es active IP Right Grant
- 2008-05-20 BR BRPI0822143A patent/BRPI0822143A2/pt not_active IP Right Cessation
- 2008-05-20 KR KR1020107018542A patent/KR101469306B1/ko not_active Expired - Fee Related
- 2008-05-20 RU RU2010128972/04A patent/RU2487866C2/ru not_active IP Right Cessation
- 2008-05-20 CA CA2712352A patent/CA2712352C/en not_active Expired - Fee Related
- 2008-05-20 JP JP2010543359A patent/JP5438028B2/ja not_active Expired - Fee Related
- 2008-05-20 EP EP08748620.5A patent/EP2246347B1/en not_active Not-in-force
- 2008-05-20 WO PCT/CN2008/071014 patent/WO2009094866A1/zh not_active Ceased
- 2008-05-20 US US12/863,964 patent/US8304411B2/en not_active Expired - Fee Related
-
2012
- 2012-09-14 US US13/619,138 patent/US8415349B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0822143A2 (pt) | 2019-09-24 |
| EP2246347A4 (en) | 2012-01-11 |
| RU2010128972A (ru) | 2012-02-27 |
| KR20100103881A (ko) | 2010-09-28 |
| EP2246347A1 (en) | 2010-11-03 |
| CA2712352A1 (en) | 2009-08-06 |
| AU2008349110A1 (en) | 2009-08-06 |
| WO2009094866A1 (en) | 2009-08-06 |
| JP5438028B2 (ja) | 2014-03-12 |
| JP2011510026A (ja) | 2011-03-31 |
| CA2712352C (en) | 2016-05-10 |
| US8415349B2 (en) | 2013-04-09 |
| RU2487866C2 (ru) | 2013-07-20 |
| US20130012705A1 (en) | 2013-01-10 |
| EP2246347B1 (en) | 2016-09-28 |
| US20100311747A1 (en) | 2010-12-09 |
| US8304411B2 (en) | 2012-11-06 |
| KR101469306B1 (ko) | 2014-12-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2673164C (en) | Derivatives of azabicyclo octane, the method of making them and the uses thereof as inhibitors of dipeptidyl peptidase iv | |
| CN109071497B (zh) | Pad4杂芳基抑制剂 | |
| US8076330B2 (en) | Dipeptidyl peptidase-IV inhibitors | |
| US8415349B2 (en) | Dicycloazaalkane derivatives, preparation processes and medical uses thereof | |
| TWI395582B (zh) | 氮雜雙環烷類衍生物、其製備方法及其在醫藥上的用途 | |
| JP2022506850A (ja) | 化学化合物 | |
| EP4100005A1 (en) | Adamts inhibitors, preparation methods and medicinal uses thereof | |
| CN105658625A (zh) | 作为细胞坏死阻碍剂的吲哚酰胺化合物 | |
| RU2840256C1 (ru) | Соединение, обладающее ингибирующей активностью в отношении kdm5, и его фармацевтическое применение | |
| CA3169225A1 (en) | Adamts inhibitors, preparation methods and medicinal uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG | Grant or registration |