UA73781C2 - Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase - Google Patents

Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase Download PDF

Info

Publication number: UA73781C2
Authority: UA; Ukraine
Prior art keywords: pyrrole; dichloro; carbamoyl; alkyl; thieno
Prior art date: 2000-09-06

Application number

UA2003021026A

Other languages

English (en)

Ukrainian (uk)

Original Assignee

Astrazeneca Ab

Priority date (The priority date 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 date listed.)

2000-09-06

Filing date

2001-08-31

Publication date

2005-09-15

2001-08-31 Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab

2005-09-15 Publication of UA73781C2 publication Critical patent/UA73781C2/uk

Links

239000003112 inhibitor Substances 0.000 title description 7
125000002619 bicyclic group Chemical group 0.000 title description 3
-1 Heterocyclic amide Chemical class 0.000 claims abstract description 271
150000003839 salts Chemical class 0.000 claims abstract description 39
150000002148 esters Chemical class 0.000 claims abstract description 31
230000002401 inhibitory effect Effects 0.000 claims abstract description 11
238000004519 manufacturing process Methods 0.000 claims abstract description 11
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 849
125000000217 alkyl group Chemical group 0.000 claims description 238
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 183
150000001875 compounds Chemical class 0.000 claims description 164
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 77
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 70
125000000623 heterocyclic group Chemical group 0.000 claims description 58
125000005843 halogen group Chemical group 0.000 claims description 51
229910052799 carbon Inorganic materials 0.000 claims description 48
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
125000003118 aryl group Chemical group 0.000 claims description 45
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 37
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 36
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 33
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 30
229910052739 hydrogen Inorganic materials 0.000 claims description 30
239000001257 hydrogen Substances 0.000 claims description 29
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
229910052757 nitrogen Inorganic materials 0.000 claims description 27
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 24
125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 21
241001465754 Metazoa Species 0.000 claims description 17
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 16
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
125000001072 heteroaryl group Chemical group 0.000 claims description 15
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 15
125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
125000005002 aryl methyl group Chemical group 0.000 claims description 14
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 13
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 12
125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 12
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 12
125000004130 indan-2-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])(*)C2([H])[H] 0.000 claims description 12
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
125000006125 ethylsulfonyl group Chemical group 0.000 claims description 11
150000002431 hydrogen Chemical class 0.000 claims description 11
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 11
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
239000003814 drug Substances 0.000 claims description 9
229910052760 oxygen Inorganic materials 0.000 claims description 9
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
125000000753 cycloalkyl group Chemical group 0.000 claims description 8
125000003107 substituted aryl group Chemical group 0.000 claims description 8
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 7
125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 6
230000003301 hydrolyzing effect Effects 0.000 claims description 6
239000002245 particle Substances 0.000 claims description 6
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
229910052717 sulfur Inorganic materials 0.000 claims description 6
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
150000002829 nitrogen Chemical class 0.000 claims description 5
229910052698 phosphorus Inorganic materials 0.000 claims description 5
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
239000011593 sulfur Substances 0.000 claims description 5
125000001589 carboacyl group Chemical group 0.000 claims description 4
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
125000004432 carbon atom Chemical group C* 0.000 claims description 3
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
150000003950 cyclic amides Chemical class 0.000 claims description 2
239000003085 diluting agent Substances 0.000 claims description 2
239000001301 oxygen Substances 0.000 claims description 2
125000006413 ring segment Chemical group 0.000 claims description 2
102000009097 Phosphorylases Human genes 0.000 claims 1
108010073135 Phosphorylases Proteins 0.000 claims 1
238000012876 topography Methods 0.000 claims 1
238000000034 method Methods 0.000 abstract description 160
238000011282 treatment Methods 0.000 abstract description 18
108010046163 Glycogen Phosphorylase Proteins 0.000 abstract description 17
102000007390 Glycogen Phosphorylase Human genes 0.000 abstract description 17
230000000694 effects Effects 0.000 abstract description 14
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
201000010099 disease Diseases 0.000 abstract description 6
230000008569 process Effects 0.000 abstract description 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 197
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 175
239000000203 mixture Substances 0.000 description 131
239000000243 solution Substances 0.000 description 122
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 116
238000005481 NMR spectroscopy Methods 0.000 description 83
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 76
125000003277 amino group Chemical group 0.000 description 75
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
239000007787 solid Substances 0.000 description 54
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
125000002887 hydroxy group Chemical group [H]O* 0.000 description 47
239000011541 reaction mixture Substances 0.000 description 47
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
230000002829 reductive effect Effects 0.000 description 39
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
229910052943 magnesium sulfate Inorganic materials 0.000 description 37
235000019341 magnesium sulphate Nutrition 0.000 description 37
150000001721 carbon Chemical group 0.000 description 31
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 31
239000012265 solid product Substances 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
125000001424 substituent group Chemical group 0.000 description 27
238000006243 chemical reaction Methods 0.000 description 26
125000004093 cyano group Chemical group *C#N 0.000 description 26
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
125000003396 thiol group Chemical group [H]S* 0.000 description 24
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
239000003480 eluent Substances 0.000 description 22
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
241000282414 Homo sapiens Species 0.000 description 21
AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 19
238000004587 chromatography analysis Methods 0.000 description 19
239000000706 filtrate Substances 0.000 description 19
230000005764 inhibitory process Effects 0.000 description 18
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
150000001412 amines Chemical class 0.000 description 17
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 16
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 16
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
239000012074 organic phase Substances 0.000 description 15
238000010992 reflux Methods 0.000 description 14
125000002252 acyl group Chemical group 0.000 description 13
239000008103 glucose Substances 0.000 description 13
239000003921 oil Substances 0.000 description 13
235000019198 oils Nutrition 0.000 description 13
239000000047 product Substances 0.000 description 13
229920006395 saturated elastomer Polymers 0.000 description 13
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
208000001072 type 2 diabetes mellitus Diseases 0.000 description 13
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
239000000284 extract Substances 0.000 description 12
238000001914 filtration Methods 0.000 description 12
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
229910052814 silicon oxide Inorganic materials 0.000 description 12
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
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 11
238000001035 drying Methods 0.000 description 11
239000010410 layer Substances 0.000 description 11
239000000377 silicon dioxide Substances 0.000 description 11
239000000725 suspension Substances 0.000 description 11
241001643597 Evas Species 0.000 description 10
238000004458 analytical method Methods 0.000 description 10
239000012298 atmosphere Substances 0.000 description 10
238000001704 evaporation Methods 0.000 description 10
230000008020 evaporation Effects 0.000 description 10
239000002904 solvent Substances 0.000 description 10
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 9
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 9
239000002253 acid Substances 0.000 description 9
238000001816 cooling Methods 0.000 description 9
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
239000012044 organic layer Substances 0.000 description 9
229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
235000017557 sodium bicarbonate Nutrition 0.000 description 9
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 8
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 8
229910052763 palladium Inorganic materials 0.000 description 8
125000006239 protecting group Chemical group 0.000 description 8
238000012360 testing method Methods 0.000 description 8
238000005406 washing Methods 0.000 description 8
125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 7
229920002527 Glycogen Polymers 0.000 description 7
125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 7
239000008346 aqueous phase Substances 0.000 description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
239000013058 crude material Substances 0.000 description 7
125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 7
229940096919 glycogen Drugs 0.000 description 7
WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
210000004185 liver Anatomy 0.000 description 7
239000000843 powder Substances 0.000 description 7
239000002244 precipitate Substances 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
241000282412 Homo Species 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
238000009835 boiling Methods 0.000 description 6
239000012267 brine Substances 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 6
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 6
PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
125000005505 thiomorpholino group Chemical group 0.000 description 6
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
102000051325 Glucagon Human genes 0.000 description 5
108060003199 Glucagon Proteins 0.000 description 5
125000003545 alkoxy group Chemical group 0.000 description 5
HXXFSFRBOHSIMQ-VFUOTHLCSA-N alpha-D-glucose 1-phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O HXXFSFRBOHSIMQ-VFUOTHLCSA-N 0.000 description 5
125000004429 atom Chemical group 0.000 description 5
239000002585 base Substances 0.000 description 5
239000007853 buffer solution Substances 0.000 description 5
101150059448 cdk7 gene Proteins 0.000 description 5
239000000460 chlorine Substances 0.000 description 5
229910052801 chlorine Inorganic materials 0.000 description 5
DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 5
MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 5
229960004666 glucagon Drugs 0.000 description 5
229950010772 glucose-1-phosphate Drugs 0.000 description 5
230000007062 hydrolysis Effects 0.000 description 5
238000006460 hydrolysis reaction Methods 0.000 description 5
239000012299 nitrogen atmosphere Substances 0.000 description 5
239000012071 phase Substances 0.000 description 5
125000004076 pyridyl group Chemical group 0.000 description 5
239000007858 starting material Substances 0.000 description 5
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 4
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
102000004190 Enzymes Human genes 0.000 description 4
108090000790 Enzymes Proteins 0.000 description 4
206010060378 Hyperinsulinaemia Diseases 0.000 description 4
206010022489 Insulin Resistance Diseases 0.000 description 4
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
241000700159 Rattus Species 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
235000019270 ammonium chloride Nutrition 0.000 description 4
235000011114 ammonium hydroxide Nutrition 0.000 description 4
125000003705 anilinocarbonyl group Chemical group O=C([*])N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
125000003435 aroyl group Chemical group 0.000 description 4
238000003556 assay Methods 0.000 description 4
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
210000004027 cell Anatomy 0.000 description 4
230000008859 change Effects 0.000 description 4
238000004440 column chromatography Methods 0.000 description 4
238000005859 coupling reaction Methods 0.000 description 4
229940088598 enzyme Drugs 0.000 description 4
238000003818 flash chromatography Methods 0.000 description 4
239000006260 foam Substances 0.000 description 4
210000003494 hepatocyte Anatomy 0.000 description 4
230000003451 hyperinsulinaemic effect Effects 0.000 description 4
201000008980 hyperinsulinism Diseases 0.000 description 4
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 4
125000001624 naphthyl group Chemical group 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
239000000741 silica gel Substances 0.000 description 4
229910002027 silica gel Inorganic materials 0.000 description 4
239000011734 sodium Substances 0.000 description 4
238000000638 solvent extraction Methods 0.000 description 4
239000000126 substance Substances 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
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 3
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
HRWCWYGWEVVDLT-UHFFFAOYSA-N 2-amino-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC=C2C(O)C(N)CC2=C1 HRWCWYGWEVVDLT-UHFFFAOYSA-N 0.000 description 3
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 3
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
101000939500 Homo sapiens UBX domain-containing protein 11 Proteins 0.000 description 3
206010051161 Hyperglucagonaemia Diseases 0.000 description 3
239000002841 Lewis acid Substances 0.000 description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
239000012359 Methanesulfonyl chloride Substances 0.000 description 3
241000699670 Mus sp. Species 0.000 description 3
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
208000008589 Obesity Diseases 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
102100029645 UBX domain-containing protein 11 Human genes 0.000 description 3
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
229910021529 ammonia Inorganic materials 0.000 description 3
125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
238000007080 aromatic substitution reaction Methods 0.000 description 3
239000012131 assay buffer Substances 0.000 description 3
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 3
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
239000000872 buffer Substances 0.000 description 3
230000008878 coupling Effects 0.000 description 3
238000010168 coupling process Methods 0.000 description 3
239000012043 crude product Substances 0.000 description 3
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
206010012601 diabetes mellitus Diseases 0.000 description 3
125000004705 ethylthio group Chemical group C(C)S* 0.000 description 3
229910052731 fluorine Inorganic materials 0.000 description 3
238000007429 general method Methods 0.000 description 3
230000004116 glycogenolysis Effects 0.000 description 3
229910052736 halogen Inorganic materials 0.000 description 3
238000005984 hydrogenation reaction Methods 0.000 description 3
230000035880 hyperglucagonemia Effects 0.000 description 3
125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 3
125000002883 imidazolyl group Chemical group 0.000 description 3
229910052740 iodine Inorganic materials 0.000 description 3
238000004255 ion exchange chromatography Methods 0.000 description 3
OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 3
229960004592 isopropanol Drugs 0.000 description 3
150000007517 lewis acids Chemical class 0.000 description 3
239000000463 material Substances 0.000 description 3
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
238000012986 modification Methods 0.000 description 3
230000004048 modification Effects 0.000 description 3
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 3
208000031225 myocardial ischemia Diseases 0.000 description 3
235000020824 obesity Nutrition 0.000 description 3
230000003287 optical effect Effects 0.000 description 3
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
239000003208 petroleum Substances 0.000 description 3
125000003373 pyrazinyl group Chemical group 0.000 description 3
125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 3
125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 3
125000005493 quinolyl group Chemical group 0.000 description 3
230000009467 reduction Effects 0.000 description 3
239000011347 resin Substances 0.000 description 3
229920005989 resin Polymers 0.000 description 3
235000002020 sage Nutrition 0.000 description 3
239000012312 sodium hydride Substances 0.000 description 3
229910000104 sodium hydride Inorganic materials 0.000 description 3
238000003756 stirring Methods 0.000 description 3
208000011580 syndromic disease Diseases 0.000 description 3
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
238000002560 therapeutic procedure Methods 0.000 description 3
125000000335 thiazolyl group Chemical group 0.000 description 3
125000001544 thienyl group Chemical group 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
210000001519 tissue Anatomy 0.000 description 3
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
239000008096 xylene Substances 0.000 description 3
DMICMWRZNBCKBU-NXEZZACHSA-N (1r,2r)-1-methoxy-2,3-dihydro-1h-inden-2-amine Chemical compound C1=CC=C2[C@@H](OC)[C@H](N)CC2=C1 DMICMWRZNBCKBU-NXEZZACHSA-N 0.000 description 2
NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 description 2
FPWBTKXHZVMJPS-UHFFFAOYSA-N (4-phenyl-1,2-oxazol-3-yl)methanamine Chemical compound NCC1=NOC=C1C1=CC=CC=C1 FPWBTKXHZVMJPS-UHFFFAOYSA-N 0.000 description 2
UIEUPSXECSRXQL-UHFFFAOYSA-N (4-phenyl-1,2-oxazol-3-yl)methanol Chemical compound OCC1=NOC=C1C1=CC=CC=C1 UIEUPSXECSRXQL-UHFFFAOYSA-N 0.000 description 2
125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 2
POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 2
VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 2
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
MWDRDSUOQMYFRC-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)-3-(4-fluorophenyl)propanoic acid Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C(=O)O)CC1=CC=C(F)C=C1 MWDRDSUOQMYFRC-UHFFFAOYSA-N 0.000 description 2
WHOUFHZODDPMPG-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)-4-phenylbutanoic acid Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C(=O)O)CCC1=CC=CC=C1 WHOUFHZODDPMPG-UHFFFAOYSA-N 0.000 description 2
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
GNAFSHPNBBLZGU-HZPDHXFCSA-N 2-[(1r,2r)-1-methoxy-2,3-dihydro-1h-inden-2-yl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1[C@H]1[C@H](OC)C2=CC=CC=C2C1 GNAFSHPNBBLZGU-HZPDHXFCSA-N 0.000 description 2
IIMSEFZOOYSTDO-UHFFFAOYSA-N 2-amino-1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2C(O)C(N)CCC2=C1 IIMSEFZOOYSTDO-UHFFFAOYSA-N 0.000 description 2
YEYGYDHGDIVDQK-UHFFFAOYSA-N 2-amino-6-fluoro-2,3-dihydro-1h-inden-1-ol Chemical compound C1=C(F)C=C2C(O)C(N)CC2=C1 YEYGYDHGDIVDQK-UHFFFAOYSA-N 0.000 description 2
FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 2
CWEXMSPEUDRDPH-UHFFFAOYSA-N 2-hydroxyimino-3h-inden-1-one Chemical compound C1=CC=C2C(=O)C(=NO)CC2=C1 CWEXMSPEUDRDPH-UHFFFAOYSA-N 0.000 description 2
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
108091003079 Bovine Serum Albumin Proteins 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
241000282472 Canis lupus familiaris Species 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
101100184531 Drosophila melanogaster Mo25 gene Proteins 0.000 description 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
238000005727 Friedel-Crafts reaction Methods 0.000 description 2
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
241000948268 Meda Species 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
101100494453 Mus musculus Cab39 gene Proteins 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 2
241000283973 Oryctolagus cuniculus Species 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
239000012346 acetyl chloride Substances 0.000 description 2
230000002378 acidificating effect Effects 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
150000001299 aldehydes Chemical class 0.000 description 2
150000008044 alkali metal hydroxides Chemical class 0.000 description 2
125000005236 alkanoylamino group Chemical group 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
238000010171 animal model Methods 0.000 description 2
229910052786 argon Inorganic materials 0.000 description 2
125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 2
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
229910052797 bismuth Inorganic materials 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
229910052794 bromium Inorganic materials 0.000 description 2
239000002775 capsule Substances 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
238000007796 conventional method Methods 0.000 description 2
239000010949 copper Substances 0.000 description 2
YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
239000000839 emulsion Substances 0.000 description 2
238000006911 enzymatic reaction Methods 0.000 description 2
DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
CZKRUVMCGUTRHO-UHFFFAOYSA-N ethyl 2,3-dicarbamoylbenzoate Chemical compound CCOC(=O)C1=CC=CC(C(N)=O)=C1C(N)=O CZKRUVMCGUTRHO-UHFFFAOYSA-N 0.000 description 2
230000005284 excitation Effects 0.000 description 2
230000001747 exhibiting effect Effects 0.000 description 2
238000000605 extraction Methods 0.000 description 2
239000012894 fetal calf serum Substances 0.000 description 2
239000011737 fluorine Substances 0.000 description 2
150000002367 halogens Chemical class 0.000 description 2
WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 2
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
239000011261 inert gas Substances 0.000 description 2
229910052816 inorganic phosphate Inorganic materials 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
238000001990 intravenous administration Methods 0.000 description 2
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-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
125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 2
125000000842 isoxazolyl group Chemical group 0.000 description 2
238000004811 liquid chromatography Methods 0.000 description 2
238000001819 mass spectrum Methods 0.000 description 2
229910052751 metal Inorganic materials 0.000 description 2
239000002184 metal Substances 0.000 description 2
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
125000002950 monocyclic group Chemical group 0.000 description 2
125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 description 2
210000003205 muscle Anatomy 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
230000003647 oxidation Effects 0.000 description 2
238000007254 oxidation reaction Methods 0.000 description 2
DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
125000004193 piperazinyl group Chemical group 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
235000011181 potassium carbonates Nutrition 0.000 description 2
239000000651 prodrug Substances 0.000 description 2
229940002612 prodrug Drugs 0.000 description 2
238000000746 purification Methods 0.000 description 2
125000002098 pyridazinyl group Chemical group 0.000 description 2
125000000714 pyrimidinyl group Chemical group 0.000 description 2
230000035939 shock Effects 0.000 description 2
239000012279 sodium borohydride Substances 0.000 description 2
229910000033 sodium borohydride Inorganic materials 0.000 description 2
229910000029 sodium carbonate Inorganic materials 0.000 description 2
239000011343 solid material Substances 0.000 description 2
230000000638 stimulation Effects 0.000 description 2
UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
150000003457 sulfones Chemical class 0.000 description 2
150000003462 sulfoxides Chemical class 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
239000006188 syrup Substances 0.000 description 2
235000020357 syrup Nutrition 0.000 description 2
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
125000003831 tetrazolyl group Chemical group 0.000 description 2
230000001225 therapeutic effect Effects 0.000 description 2
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
229910052727 yttrium Inorganic materials 0.000 description 2
TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
CGHSFFKOUVMMBR-UHFFFAOYSA-N (2-phenyl-1,3-dioxolan-2-yl)methanamine Chemical compound C=1C=CC=CC=1C1(CN)OCCO1 CGHSFFKOUVMMBR-UHFFFAOYSA-N 0.000 description 1
ZRTGHKVPFXNDHE-UHFFFAOYSA-N (3-methyl-1,2-thiazol-5-yl)azanium;chloride Chemical compound [Cl-].CC=1C=C([NH3+])SN=1 ZRTGHKVPFXNDHE-UHFFFAOYSA-N 0.000 description 1
HLXRHUKOYXGHGU-GMSGAONNSA-N (4r,5r)-4-amino-5-hydroxy-1,3,4,5-tetrahydro-1-benzazepin-2-one Chemical compound O[C@H]1[C@H](N)CC(=O)NC2=CC=CC=C21 HLXRHUKOYXGHGU-GMSGAONNSA-N 0.000 description 1
DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
FBSQFLMMNVFTRT-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinolin-3-amine Chemical compound C1=CC=C2CC(N)CNC2=C1 FBSQFLMMNVFTRT-UHFFFAOYSA-N 0.000 description 1
125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
NJPJEUXBRLCEDZ-UHFFFAOYSA-N 1,2-benzoxazol-3-ylmethanamine Chemical compound C1=CC=C2C(CN)=NOC2=C1 NJPJEUXBRLCEDZ-UHFFFAOYSA-N 0.000 description 1
PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
NOLHRFLIXVQPSZ-UHFFFAOYSA-N 1,3-thiazolidin-4-one Chemical compound O=C1CSCN1 NOLHRFLIXVQPSZ-UHFFFAOYSA-N 0.000 description 1
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
125000005877 1,4-benzodioxanyl group Chemical group 0.000 description 1
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
JZEHWMUIAKALDN-UHFFFAOYSA-N 1-amino-3-phenoxypropan-2-ol Chemical compound NCC(O)COC1=CC=CC=C1 JZEHWMUIAKALDN-UHFFFAOYSA-N 0.000 description 1
XUEHOPNFOYAYTA-UHFFFAOYSA-N 1-isocyanato-2,3-dihydro-1h-indene Chemical compound C1=CC=C2C(N=C=O)CCC2=C1 XUEHOPNFOYAYTA-UHFFFAOYSA-N 0.000 description 1
PRPINYUDVPFIRX-UHFFFAOYSA-N 1-naphthaleneacetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CC=CC2=C1 PRPINYUDVPFIRX-UHFFFAOYSA-N 0.000 description 1
125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000006017 1-propenyl group Chemical group 0.000 description 1
125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 1
238000005160 1H NMR spectroscopy Methods 0.000 description 1
UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 1
FMEVAQARAVDUNY-UHFFFAOYSA-N 2-(2-aminoethyl)phenol Chemical compound NCCC1=CC=CC=C1O FMEVAQARAVDUNY-UHFFFAOYSA-N 0.000 description 1
WSWPCNMLEVZGSM-UHFFFAOYSA-N 2-(2-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC=C1CCN WSWPCNMLEVZGSM-UHFFFAOYSA-N 0.000 description 1
WJBMRZAHTUFBGE-UHFFFAOYSA-N 2-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(CCN)=C1 WJBMRZAHTUFBGE-UHFFFAOYSA-N 0.000 description 1
ZLDPEFXFZFWBAS-HUUCEWRRSA-N 2-[(1r,2r)-1-hydroxy-2,3-dihydro-1h-inden-2-yl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1[C@H]1[C@H](O)C2=CC=CC=C2C1 ZLDPEFXFZFWBAS-HUUCEWRRSA-N 0.000 description 1
MUCOOBDMPYWSFN-UHFFFAOYSA-N 2-[(4-phenyl-1,2-oxazol-3-yl)methyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC1=NOC=C1C1=CC=CC=C1 MUCOOBDMPYWSFN-UHFFFAOYSA-N 0.000 description 1
LNLQYBWSAKHIGM-UHFFFAOYSA-N 2-amino-1-(3-aminophenyl)ethanone Chemical compound NCC(=O)C1=CC=CC(N)=C1 LNLQYBWSAKHIGM-UHFFFAOYSA-N 0.000 description 1
HEQOJEGTZCTHCF-UHFFFAOYSA-N 2-amino-1-phenylethanone Chemical compound NCC(=O)C1=CC=CC=C1 HEQOJEGTZCTHCF-UHFFFAOYSA-N 0.000 description 1
LMHHFZAXSANGGM-UHFFFAOYSA-N 2-aminoindane Chemical compound C1=CC=C2CC(N)CC2=C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 description 1
OBJMWYAZGBFFNS-UHFFFAOYSA-N 2-anilinopropanenitrile Chemical compound N#CC(C)NC1=CC=CC=C1 OBJMWYAZGBFFNS-UHFFFAOYSA-N 0.000 description 1
RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 1
HBZHNVUMFPGVHW-UHFFFAOYSA-N 2-chloro-1h-indole Chemical compound C1=CC=C2NC(Cl)=CC2=C1 HBZHNVUMFPGVHW-UHFFFAOYSA-N 0.000 description 1
ROJNYKZWTOHRNU-UHFFFAOYSA-N 2-chloro-4,5-difluoro-n-[[2-methoxy-5-(methylcarbamoylamino)phenyl]carbamoyl]benzamide Chemical compound CNC(=O)NC1=CC=C(OC)C(NC(=O)NC(=O)C=2C(=CC(F)=C(F)C=2)Cl)=C1 ROJNYKZWTOHRNU-UHFFFAOYSA-N 0.000 description 1
ZXNMIUJDTOMBPV-UHFFFAOYSA-N 2-chloroethyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCCCl)C=C1 ZXNMIUJDTOMBPV-UHFFFAOYSA-N 0.000 description 1
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
IMLAIXAZMVDRGA-UHFFFAOYSA-N 2-phenoxyethanamine Chemical compound NCCOC1=CC=CC=C1 IMLAIXAZMVDRGA-UHFFFAOYSA-N 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
YCBSRVPSWOLVMV-UHFFFAOYSA-N 2-pyridazin-3-yloxyethanamine Chemical compound NCCOC1=CC=CN=N1 YCBSRVPSWOLVMV-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
ANZIRVOGVJLJHE-UHFFFAOYSA-N 3-amino-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)C(N)CC2=C1 ANZIRVOGVJLJHE-UHFFFAOYSA-N 0.000 description 1
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
FVMDYYGIDFPZAX-UHFFFAOYSA-N 3-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=CC(O)=C1 FVMDYYGIDFPZAX-UHFFFAOYSA-N 0.000 description 1
JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 1
SFWWGMKXCYLZEG-UHFFFAOYSA-N 3-methylmorpholine Chemical compound CC1COCCN1 SFWWGMKXCYLZEG-UHFFFAOYSA-N 0.000 description 1
125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
WFFZGYRTVIPBFN-UHFFFAOYSA-N 3h-indene-1,2-dione Chemical compound C1=CC=C2C(=O)C(=O)CC2=C1 WFFZGYRTVIPBFN-UHFFFAOYSA-N 0.000 description 1
STXHPGKNMJVJKL-UHFFFAOYSA-N 4-(1,3-dioxoisoindol-2-yl)butanoyl chloride Chemical compound C1=CC=C2C(=O)N(CCCC(=O)Cl)C(=O)C2=C1 STXHPGKNMJVJKL-UHFFFAOYSA-N 0.000 description 1
BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 1
NNKKOFWZPFHHCX-UHFFFAOYSA-N 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one Chemical compound C1NC(=O)C(N)CC2=CC=CC=C21 NNKKOFWZPFHHCX-UHFFFAOYSA-N 0.000 description 1
YYEIZVYJDLYMIH-UHFFFAOYSA-N 4-chlorothiophene-2-carbaldehyde Chemical compound ClC1=CSC(C=O)=C1 YYEIZVYJDLYMIH-UHFFFAOYSA-N 0.000 description 1
XWHHYOYVRVGJJY-QMMMGPOBSA-N 4-fluoro-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(F)C=C1 XWHHYOYVRVGJJY-QMMMGPOBSA-N 0.000 description 1
GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
NSFBCHCBQIILQP-UHFFFAOYSA-N 4-phenyl-1,2-oxazole-3-carboxylic acid Chemical compound OC(=O)C1=NOC=C1C1=CC=CC=C1 NSFBCHCBQIILQP-UHFFFAOYSA-N 0.000 description 1
RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 description 1
201000001320 Atherosclerosis Diseases 0.000 description 1
241000283725 Bos Species 0.000 description 1
JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
208000002177 Cataract Diseases 0.000 description 1
229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
241000282693 Cercopithecidae Species 0.000 description 1
102000029816 Collagenase Human genes 0.000 description 1
108060005980 Collagenase Proteins 0.000 description 1
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
101710088194 Dehydrogenase Proteins 0.000 description 1
208000007342 Diabetic Nephropathies Diseases 0.000 description 1
208000032131 Diabetic Neuropathies Diseases 0.000 description 1
206010012689 Diabetic retinopathy Diseases 0.000 description 1
235000005459 Digitaria exilis Nutrition 0.000 description 1
BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
239000005977 Ethylene Substances 0.000 description 1
PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
241000282326 Felis catus Species 0.000 description 1
108010010803 Gelatin Proteins 0.000 description 1
208000010412 Glaucoma Diseases 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
208000035150 Hypercholesterolemia Diseases 0.000 description 1
208000031226 Hyperlipidaemia Diseases 0.000 description 1
206010020772 Hypertension Diseases 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
102000004877 Insulin Human genes 0.000 description 1
108090001061 Insulin Proteins 0.000 description 1
239000008002 Krebs-Henseleit bicarbonate buffer Substances 0.000 description 1
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
239000012448 Lithium borohydride Substances 0.000 description 1
101150104182 MOB2 gene Proteins 0.000 description 1
229910015834 MSH1 Inorganic materials 0.000 description 1
102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
241001529870 Meoma Species 0.000 description 1
101150091136 Mob4 gene Proteins 0.000 description 1
LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
235000019502 Orange oil Nutrition 0.000 description 1
101100338491 Oryza sativa subsp. japonica HCT1 gene Proteins 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
229930040373 Paraformaldehyde Natural products 0.000 description 1
229930182555 Penicillin Natural products 0.000 description 1
JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
102000009569 Phosphoglucomutase Human genes 0.000 description 1
244000046146 Pueraria lobata Species 0.000 description 1
235000010575 Pueraria lobata Nutrition 0.000 description 1
241000269435 Rana <genus> Species 0.000 description 1
YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 1
102000057028 SOS1 Human genes 0.000 description 1
108700022176 SOS1 Proteins 0.000 description 1
101100495309 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CDH1 gene Proteins 0.000 description 1
101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 description 1
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
101150100839 Sos1 gene Proteins 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
206010052428 Wound Diseases 0.000 description 1
208000027418 Wounds and injury Diseases 0.000 description 1
241001507534 Zora Species 0.000 description 1
238000002835 absorbance Methods 0.000 description 1
229960001413 acetanilide Drugs 0.000 description 1
239000000061 acid fraction Substances 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
150000001266 acyl halides Chemical class 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
125000003282 alkyl amino group Chemical group 0.000 description 1
150000001350 alkyl halides Chemical class 0.000 description 1
125000005153 alkyl sulfamoyl group Chemical group 0.000 description 1
125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
125000004414 alkyl thio group Chemical group 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 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
239000000908 ammonium hydroxide Substances 0.000 description 1
239000011609 ammonium molybdate Substances 0.000 description 1
APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
235000018660 ammonium molybdate Nutrition 0.000 description 1
229940010552 ammonium molybdate Drugs 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
229940035676 analgesics Drugs 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
239000000730 antalgic agent Substances 0.000 description 1
230000000844 anti-bacterial effect Effects 0.000 description 1
230000003178 anti-diabetic effect Effects 0.000 description 1
230000000843 anti-fungal effect Effects 0.000 description 1
239000000935 antidepressant agent Substances 0.000 description 1
229940005513 antidepressants Drugs 0.000 description 1
239000003472 antidiabetic agent Substances 0.000 description 1
229940121375 antifungal agent Drugs 0.000 description 1
125000003710 aryl alkyl group Chemical group 0.000 description 1
229960005070 ascorbic acid Drugs 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
239000011668 ascorbic acid Substances 0.000 description 1
SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 1
125000002785 azepinyl group Chemical group 0.000 description 1
WRZFLCLEKSWAFE-UHFFFAOYSA-N benzyl n-[2-(2-hydroxyphenyl)ethyl]carbamate Chemical compound OC1=CC=CC=C1CCNC(=O)OCC1=CC=CC=C1 WRZFLCLEKSWAFE-UHFFFAOYSA-N 0.000 description 1
CWBHKBKGKCDGDM-UHFFFAOYSA-N bis[(2,2,2-trifluoroacetyl)oxy]boranyl 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OB(OC(=O)C(F)(F)F)OC(=O)C(F)(F)F CWBHKBKGKCDGDM-UHFFFAOYSA-N 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
239000008280 blood Substances 0.000 description 1
HJZVHUQSQGITAM-UHFFFAOYSA-N butanamide Chemical compound CC[CH]C(N)=O HJZVHUQSQGITAM-UHFFFAOYSA-N 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
229910000019 calcium carbonate Inorganic materials 0.000 description 1
150000004657 carbamic acid derivatives Chemical class 0.000 description 1
150000001718 carbodiimides Chemical class 0.000 description 1
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
125000001721 carboxyacetyl group Chemical group 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
150000001768 cations Chemical class 0.000 description 1
238000004113 cell culture Methods 0.000 description 1
230000022131 cell cycle Effects 0.000 description 1
229940081734 cellulose acetate phthalate Drugs 0.000 description 1
238000000451 chemical ionisation Methods 0.000 description 1
150000001805 chlorine compounds Chemical class 0.000 description 1
FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
229940106681 chloroacetic acid Drugs 0.000 description 1
238000010549 co-Evaporation Methods 0.000 description 1
239000011248 coating agent Substances 0.000 description 1
238000000576 coating method Methods 0.000 description 1
229960002424 collagenase Drugs 0.000 description 1
230000021615 conjugation Effects 0.000 description 1
229910052802 copper Inorganic materials 0.000 description 1
239000006071 cream Substances 0.000 description 1
239000013078 crystal Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 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
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
230000007423 decrease Effects 0.000 description 1
238000011161 development Methods 0.000 description 1
UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
229960003957 dexamethasone Drugs 0.000 description 1
208000033679 diabetic kidney disease Diseases 0.000 description 1
125000005117 dialkylcarbamoyl group Chemical group 0.000 description 1
FDKCTEWMJWRPDS-UHFFFAOYSA-N dialuminum;trimagnesium;trisilicate Chemical compound [Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-] FDKCTEWMJWRPDS-UHFFFAOYSA-N 0.000 description 1
IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
231100000673 dose–response relationship Toxicity 0.000 description 1
229940079593 drug Drugs 0.000 description 1
230000004406 elevated intraocular pressure Effects 0.000 description 1
238000013504 emergency use authorization Methods 0.000 description 1
239000002702 enteric coating Substances 0.000 description 1
238000009505 enteric coating Methods 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
BEGBSFPALGFMJI-UHFFFAOYSA-N ethene;sodium Chemical group [Na].C=C BEGBSFPALGFMJI-UHFFFAOYSA-N 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
125000006627 ethoxycarbonylamino group Chemical group 0.000 description 1
FDLDWKIEWAWOSL-UHFFFAOYSA-N ethyl acetate;2-methylpentane Chemical compound CCCC(C)C.CCOC(C)=O FDLDWKIEWAWOSL-UHFFFAOYSA-N 0.000 description 1
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
238000010265 fast atom bombardment Methods 0.000 description 1
235000013305 food Nutrition 0.000 description 1
125000000524 functional group Chemical group 0.000 description 1
239000007789 gas Substances 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
235000011852 gelatine desserts Nutrition 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
230000002440 hepatic effect Effects 0.000 description 1
125000005842 heteroatom Chemical group 0.000 description 1
229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
201000001421 hyperglycemia Diseases 0.000 description 1
239000005457 ice water Substances 0.000 description 1
238000011534 incubation Methods 0.000 description 1
125000001041 indolyl group Chemical group 0.000 description 1
238000001802 infusion Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
150000002485 inorganic esters Chemical class 0.000 description 1
239000002198 insoluble material Substances 0.000 description 1
229940125396 insulin Drugs 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
239000011630 iodine Substances 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
229910052742 iron Inorganic materials 0.000 description 1
208000028867 ischemia Diseases 0.000 description 1
KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
125000001786 isothiazolyl group Chemical group 0.000 description 1
239000008101 lactose Substances 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
159000000003 magnesium salts Chemical class 0.000 description 1
150000002689 maleic acids Chemical class 0.000 description 1
229910052748 manganese Inorganic materials 0.000 description 1
125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
RXYCUKSOYJWGPE-UHFFFAOYSA-N methyl 2-azidoacetate Chemical compound COC(=O)CN=[N+]=[N-] RXYCUKSOYJWGPE-UHFFFAOYSA-N 0.000 description 1
YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
101150093855 msh1 gene Proteins 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
230000001537 neural effect Effects 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
238000010606 normalization Methods 0.000 description 1
239000010502 orange oil Substances 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
125000003431 oxalo group Chemical group 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
229920002866 paraformaldehyde Polymers 0.000 description 1
229940049954 penicillin Drugs 0.000 description 1
125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
238000005897 peptide coupling reaction Methods 0.000 description 1
230000010412 perfusion Effects 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
239000002831 pharmacologic agent Substances 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
108091000115 phosphomannomutase Proteins 0.000 description 1
150000003014 phosphoric acid esters Chemical class 0.000 description 1
125000005633 phthalidyl group Chemical group 0.000 description 1
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
239000002574 poison Substances 0.000 description 1
231100000614 poison Toxicity 0.000 description 1
230000000291 postprandial effect Effects 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 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
159000000001 potassium salts Chemical class 0.000 description 1
239000002243 precursor Substances 0.000 description 1
238000002360 preparation method Methods 0.000 description 1
VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
229910052832 pyrope Inorganic materials 0.000 description 1
150000003233 pyrroles Chemical class 0.000 description 1
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
239000002994 raw material Substances 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
230000003893 regulation of appetite Effects 0.000 description 1
230000004044 response Effects 0.000 description 1
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
201000001370 sclerosteosis 1 Diseases 0.000 description 1
230000028327 secretion Effects 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
229940001584 sodium metabisulfite Drugs 0.000 description 1
235000010262 sodium metabisulphite Nutrition 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
229960005322 streptomycin Drugs 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
229940124530 sulfonamide Drugs 0.000 description 1
125000004434 sulfur atom Chemical group 0.000 description 1
239000000829 suppository Substances 0.000 description 1
125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
238000001665 trituration Methods 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

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Animal Behavior & Ethology (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Engineering & Computer Science (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Diabetes (AREA)
Obesity (AREA)
Hematology (AREA)
Vascular Medicine (AREA)
Child & Adolescent Psychology (AREA)
Cardiology (AREA)
Urology & Nephrology (AREA)
Heart & Thoracic Surgery (AREA)
Emergency Medicine (AREA)
Endocrinology (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Pyrrole Compounds (AREA)
Indole Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Enzymes And Modification Thereof (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

UA2003021026A 2000-09-06 2001-08-31 Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase UA73781C2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
GBGB0021831.3A GB0021831D0 (en)	2000-09-06	2000-09-06	Chemical compounds
PCT/SE2001/001880 WO2002020530A1 (fr)	2000-09-06	2001-08-31	Amides de pyrrolyle bicycliques servant d'inhibiteurs de glycogene phosphorylase

Publications (1)

Publication Number	Publication Date
UA73781C2 true UA73781C2 (en)	2005-09-15

Family

ID=9898927

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
UA2003021026A UA73781C2 (en)	2000-09-06	2001-08-31	Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase

Country Status (30)

Country	Link
US (1)	US20030232875A1 (fr)
EP (1)	EP1317459B1 (fr)
JP (1)	JP2004508376A (fr)
KR (1)	KR100802369B1 (fr)
CN (2)	CN1264846C (fr)
AT (1)	ATE263772T1 (fr)
AU (2)	AU8283301A (fr)
BG (1)	BG107624A (fr)
BR (1)	BR0113606A (fr)
CA (1)	CA2417594A1 (fr)
CZ (1)	CZ2003616A3 (fr)
DE (1)	DE60102710T2 (fr)
DK (1)	DK1317459T3 (fr)
EE (1)	EE200300083A (fr)
ES (1)	ES2217183T3 (fr)
GB (1)	GB0021831D0 (fr)
HU (1)	HUP0400784A3 (fr)
IL (1)	IL154291A0 (fr)
IS (1)	IS2110B (fr)
MX (1)	MXPA03001512A (fr)
NO (1)	NO20031024L (fr)
NZ (1)	NZ524011A (fr)
PL (1)	PL361024A1 (fr)
PT (1)	PT1317459E (fr)
RU (1)	RU2003104013A (fr)
SK (1)	SK2592003A3 (fr)
TR (1)	TR200401659T4 (fr)
UA (1)	UA73781C2 (fr)
WO (1)	WO2002020530A1 (fr)
ZA (1)	ZA200301013B (fr)

Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CO5271699A1 (es) *	2000-01-24	2003-04-30	Pfizer Prod Inc	Procedimiento para el tratamiento de cardiomiopatia utilizando inhibidores de la glucogeno fosforilasa
PE20020856A1 (es) *	2001-02-13	2002-11-11	Aventis Pharma Gmbh	1,2,3,4-tetrahidronaftil aminas aciladas
TWI243164B (en)	2001-02-13	2005-11-11	Aventis Pharma Gmbh	Acylated indanyl amines and their use as pharmaceuticals
GB0205175D0 (en)	2002-03-06	2002-04-17	Astrazeneca Ab	Chemical compounds
GB0205166D0 (en) *	2002-03-06	2002-04-17	Astrazeneca Ab	Chemical compounds
GB0205176D0 (en)	2002-03-06	2002-04-17	Astrazeneca Ab	Chemical compounds
GB0205165D0 (en)	2002-03-06	2002-04-17	Astrazeneca Ab	Chemical compounds
GB0205162D0 (en)	2002-03-06	2002-04-17	Astrazeneca Ab	Chemical compounds
GB0205170D0 (en)	2002-03-06	2002-04-17	Astrazeneca Ab	Chemical compounds
DE10215908B4 (de) *	2002-04-11	2005-08-18	Aventis Pharma Deutschland Gmbh	Acyl-3-carboxyphenyl-harnstoffderivate und deren Verwendung als Arzneimittel
DE10215907A1 (de) *	2002-04-11	2003-11-06	Aventis Pharma Gmbh	Acyl-4-carboxyphenyl-harnstoffderivate, Verfahren zu deren Herstellung und deren Verwendung
US7057046B2 (en) *	2002-05-20	2006-06-06	Bristol-Myers Squibb Company	Lactam glycogen phosphorylase inhibitors and method of use
DE10225635C1 (de) *	2002-06-07	2003-12-24	Aventis Pharma Gmbh	N-Benzoylureido-Zimtsäurederivate, Verfahren zu deren Herstellung und deren Verwendung
ATE444284T1 (de) *	2002-06-17	2009-10-15	Saltigo Gmbh	Verfahren zur herstellung von mono-n- sulfonylierten diaminen
ATE443041T1 (de) *	2002-07-11	2009-10-15	Sanofi Aventis Deutschland	Harnstoff- und urethan-substituierte acylharnstoffe, verfahren zu deren herstellung und deren verwendung als arzneimittel
US7186735B2 (en)	2002-08-07	2007-03-06	Sanofi-Aventis Deutschland Gmbh	Acylated arylcycloalkylamines and their use as pharmaceuticals
EP1388535A1 (fr) *	2002-08-07	2004-02-11	Aventis Pharma Deutschland GmbH	Arylcycloalkylamines acylés et leurs utilisations comme produits pharmaceutiques
GB0222909D0 (en)	2002-10-03	2002-11-13	Astrazeneca Ab	Novel process and intermediates
GB0222912D0 (en)	2002-10-03	2002-11-13	Astrazeneca Ab	Novel process and intermediates
BR0316099A (pt)	2002-11-07	2005-09-27	Pfizer Prod Inc	Agentes antidiabéticos
MXPA05011176A (es)	2003-04-17	2005-12-14	Pfizer Prod Inc	Derivados de carboxamida como agentes antidiabeticos.
ATE473974T1 (de) *	2003-05-21	2010-07-15	Prosidion Ltd	Pyrrolopyridin-2-carbonsäuren als hemmer der glycogenphosphorylase
US7405210B2 (en)	2003-05-21	2008-07-29	Osi Pharmaceuticals, Inc.	Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
WO2004113345A1 (fr) *	2003-06-20	2004-12-29	Japan Tobacco Inc.	Compose de pyrrole condense et son utilisation comme medicament
GB0318463D0 (en) *	2003-08-07	2003-09-10	Astrazeneca Ab	Chemical compounds
GB0318464D0 (en) *	2003-08-07	2003-09-10	Astrazeneca Ab	Chemical compounds
GB0319690D0 (en) *	2003-08-22	2003-09-24	Astrazeneca Ab	Chemical compounds
GB0319759D0 (en) *	2003-08-22	2003-09-24	Astrazeneca Ab	Chemical compounds
WO2005020985A1 (fr) *	2003-08-29	2005-03-10	Astrazeneca Ab	Derives d'indolamide possedant une activite inhibitrice de la glycogene phosphorylase
WO2005020986A1 (fr) *	2003-08-29	2005-03-10	Astrazeneca Ab	Derives d'amide heterocyclique ayant une activite inhibitrice de la glycogene phosphorylase
GB0320422D0 (en) *	2003-08-30	2003-10-01	Astrazeneca Ab	Chemical compounds
PL380887A1 (pl)	2003-12-29	2007-04-02	Sepracor Inc.	Pirolowe i pirazolowe inhibitory DAAO
US7453002B2 (en)	2004-06-15	2008-11-18	Bristol-Myers Squibb Company	Five-membered heterocycles useful as serine protease inhibitors
WO2006055435A1 (fr)	2004-11-15	2006-05-26	Bristol-Myers Squibb Company	Derives de 2-aminonaphtalene et inhibiteurs de la glycogene phosphorylase associes
US7226942B2 (en)	2004-11-15	2007-06-05	Bristol-Myers Squibb Company	2-amino-4-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7365061B2 (en)	2004-11-15	2008-04-29	Bristol-Myers Squibb Company	2-Amino-3-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
WO2006053274A2 (fr) *	2004-11-15	2006-05-18	Bristol-Myers Squibb Company	Derives de tetraline 2-amino-1-fonctionnalises et inhibiteurs correspondants de glycogene phosphorylase
PT1819704E (pt)	2004-12-02	2008-10-06	Prosidion Ltd	Derivado amida de ácido pirrolopiridina-2-carboxílico útil como inibidor de glicogénio fosforilase
US20090298745A1 (en) *	2004-12-02	2009-12-03	Gerard Hugh Thomas	Treatment of Diabetes with Glycogen Phosphorylase Inhibitors
JP2008526999A (ja) *	2005-01-19	2008-07-24	メルクエンドカムパニーインコーポレーテッド	アルツハイマー病治療用ベータ−セクレターゼインヒビターとして活性な置換へテロ環含有三級カルビナミン
EP1848693A1 (fr) *	2005-02-05	2007-10-31	AstraZeneca AB	Derives d'indanamide presentant une activite inhibitrice de la glycogene phosphorylase
KR20070107108A (ko) *	2005-02-05	2007-11-06	아스트라제네카 아베	화학적 화합물
AU2007205114B2 (en)	2006-01-06	2012-11-08	Sunovion Pharmaceuticals Inc.	Cycloalkylamines as monoamine reuptake inhibitors
CA2636275C (fr)	2006-01-06	2013-02-12	Sepracor Inc.	Inhibiteurs de recaptage de monoamine a base de tetralone
AU2007233041B2 (en)	2006-03-31	2013-05-02	Sepracor Inc.	Preparation of chiral amides and amines
PE20080251A1 (es)	2006-05-04	2008-04-25	Boehringer Ingelheim Int	Usos de inhibidores de dpp iv
US7884124B2 (en)	2006-06-30	2011-02-08	Sepracor Inc.	Fluoro-substituted inhibitors of D-amino acid oxidase
WO2008047821A1 (fr) *	2006-10-18	2008-04-24	Takeda Pharmaceutical Company Limited	Composé hétérocyclique fusionné
US7902252B2 (en)	2007-01-18	2011-03-08	Sepracor, Inc.	Inhibitors of D-amino acid oxidase
AU2008259841B2 (en)	2007-05-31	2015-02-05	Sunovion Pharmaceuticals Inc.	Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors
US8969514B2 (en)	2007-06-04	2015-03-03	Synergy Pharmaceuticals, Inc.	Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US20100152200A1 (en) *	2008-11-17	2010-06-17	The Regents Of The University Of Michigan	Alphavirus inhibitors and uses thereof
US20130156720A1 (en)	2010-08-27	2013-06-20	Ironwood Pharmaceuticals, Inc.	Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
US9616097B2 (en)	2010-09-15	2017-04-11	Synergy Pharmaceuticals, Inc.	Formulations of guanylate cyclase C agonists and methods of use
AU2014274812B2 (en)	2013-06-05	2018-09-27	Bausch Health Ireland Limited	Ultra-pure agonists of guanylate cyclase C, method of making and using same
DK3186242T3 (da)	2014-08-29	2021-12-20	Tes Pharma S R L	Alfa-amino-beta-carboxymuconsyre-semialdehyd-decarboxylasehæmmere
RU2716136C2 (ru)	2015-07-02	2020-03-06	Ф. Хоффманн-Ля Рош Аг	Бициклические лактамы и способы их применения
JP6974331B2 (ja)	2016-02-05	2021-12-01	デナリセラピューティクスインコーポレイテッドDenali Therapeutics Inc.	化合物、組成物及び方法
AR109950A1 (es)	2016-10-14	2019-02-06	Tes Pharma S R L	INHIBIDORES DE LA ÁCIDO a-AMINO-b-CARBOXIMUCÓNICO SEMIALDEHÍDO DESCARBOXILASA
WO2018073193A1 (fr)	2016-10-17	2018-04-26	F. Hoffmann-La Roche Ag	Lactames de pyridone bicycliques et leurs méthodes d'utilisation
US11072607B2 (en)	2016-12-16	2021-07-27	Genentech, Inc.	Inhibitors of RIP1 kinase and methods of use thereof
WO2019204537A1 (fr)	2018-04-20	2019-10-24	Genentech, Inc.	Dérivés de n-[4-oxo-2,3-dihydro-1,5-benzoxazépin-3-yl]-5,6-dihydro-4h-pyrrolo[1,2-b]pyrazol e-2-carboxamide et composés apparentés en tant qu'inhibiteurs de la kinase rip1 pour le traitement, par exemple, du syndrome du côlon irritable (ibs)
BR112021009589A2 (pt)	2018-11-20	2021-08-17	Tes Pharma S.R.L.	inibidores de semialdeído descarboxilase de ácido alfa-amino-beta-carboximucônico
TW202115086A (zh) *	2019-06-28	2021-04-16	美商輝瑞大藥廠	Bckdk抑制劑
EP4066896A4 (fr) *	2019-11-27	2024-03-27	Riken	Inhibiteur de g9a

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3706810A (en) *	1970-09-15	1972-12-19	American Cyanamid Co	N-morpholinoalkyl-thieno(3,2-b)pyrrole-5-carboxamides
US4692522A (en) *	1985-04-01	1987-09-08	Merck & Co., Inc.	Benzofused lactams useful as cholecystokinin antagonists
US4720503A (en) *	1985-08-02	1988-01-19	Merck & Co., Inc.	N-substituted fused-heterocyclic carboxamide derivatives as dual cyclooxygenase and lipoxygenase inhibitors
US4668769A (en) *	1985-08-02	1987-05-26	Hoover Dennis J	Oxa- and azahomocyclostatine polypeptides
US4599198A (en) *	1985-08-02	1986-07-08	Pfizer Inc.	Intermediates in polypeptide synthesis
FR2601368B1 (fr) *	1986-07-08	1989-04-07	Synthelabo	Derives de nitrofuranne, leur preparation et leur application en therapeutique.
DE3629545A1 (de) *	1986-08-30	1988-03-10	Bayer Ag	Dihydropyridinverbindungen, verfahren zu ihrer herstellung und ihre verwendung
US4751231A (en) *	1987-09-16	1988-06-14	Merck & Co., Inc.	Substituted thieno[2,3-b]pyrrole-5-sulfonamides as antiglaucoma agents
ES2081747B1 (es) *	1993-09-07	1997-01-16	Esteve Labor Dr	Amidas derivadas de tienopirroles, su preparacion y su aplicacion como medicamentos.
US5863903A (en) *	1994-03-09	1999-01-26	Novo Nordisk A/S	Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes
FR2723739B1 (fr) *	1994-08-19	1997-02-14	Sanofi Sa	Derives de glycinamide, procedes pour leur preparation et medicaments les contenant.
CA2224062C (fr) *	1995-06-06	2001-09-04	Pfizer Limited	(indole-2-carbonyl-)-glycinamides substitues en n et leurs derives, servant d'inhibiteurs de la glycogene phosphorylase
US5952322A (en) *	1996-12-05	1999-09-14	Pfizer Inc.	Method of reducing tissue damage associated with non-cardiac ischemia using glycogen phosphorylase inhibitors
US5998463A (en) *	1998-02-27	1999-12-07	Pfizer Inc	Glycogen phosphorylase inhibitors
AU2825899A (en) *	1998-03-12	1999-09-27	Novo Nordisk A/S	Modulators of protein tyrosine phosphatases (ptpases)
DE60007592T2 (de) *	1999-09-30	2004-09-16	Pfizer Products Inc., Groton	Bicyclische Pyrrolylamide als Glycogenphosphorylase-Inhibitoren
CO5271699A1 (es) *	2000-01-24	2003-04-30	Pfizer Prod Inc	Procedimiento para el tratamiento de cardiomiopatia utilizando inhibidores de la glucogeno fosforilasa
US6555569B2 (en) *	2000-03-07	2003-04-29	Pfizer Inc.	Use of heteroaryl substituted N-(indole-2-carbonyl-) amides for treatment of infection
US7057046B2 (en) *	2002-05-20	2006-06-06	Bristol-Myers Squibb Company	Lactam glycogen phosphorylase inhibitors and method of use

2000
- 2000-09-06 GB GBGB0021831.3A patent/GB0021831D0/en not_active Ceased
2001
- 2001-08-31 UA UA2003021026A patent/UA73781C2/uk unknown
- 2001-08-31 DE DE60102710T patent/DE60102710T2/de not_active Expired - Fee Related
- 2001-08-31 CA CA002417594A patent/CA2417594A1/fr not_active Abandoned
- 2001-08-31 CN CNB018183220A patent/CN1264846C/zh not_active Expired - Fee Related
- 2001-08-31 JP JP2002525151A patent/JP2004508376A/ja not_active Withdrawn
- 2001-08-31 AU AU8283301A patent/AU8283301A/xx active Pending
- 2001-08-31 IL IL15429101A patent/IL154291A0/xx unknown
- 2001-08-31 PT PT01961577T patent/PT1317459E/pt unknown
- 2001-08-31 NZ NZ524011A patent/NZ524011A/en unknown
- 2001-08-31 SK SK259-2003A patent/SK2592003A3/sk unknown
- 2001-08-31 BR BR0113606-2A patent/BR0113606A/pt not_active IP Right Cessation
- 2001-08-31 RU RU2003104013/04A patent/RU2003104013A/ru not_active Application Discontinuation
- 2001-08-31 MX MXPA03001512A patent/MXPA03001512A/es active IP Right Grant
- 2001-08-31 CN CNA2006100818966A patent/CN1896078A/zh active Pending
- 2001-08-31 US US10/344,506 patent/US20030232875A1/en not_active Abandoned
- 2001-08-31 EP EP01961577A patent/EP1317459B1/fr not_active Expired - Lifetime
- 2001-08-31 KR KR1020037003265A patent/KR100802369B1/ko not_active Expired - Fee Related
- 2001-08-31 DK DK01961577T patent/DK1317459T3/da active
- 2001-08-31 WO PCT/SE2001/001880 patent/WO2002020530A1/fr not_active Ceased
- 2001-08-31 PL PL01361024A patent/PL361024A1/xx unknown
- 2001-08-31 TR TR2004/01659T patent/TR200401659T4/xx unknown
- 2001-08-31 CZ CZ2003616A patent/CZ2003616A3/cs unknown
- 2001-08-31 ES ES01961577T patent/ES2217183T3/es not_active Expired - Lifetime
- 2001-08-31 HU HU0400784A patent/HUP0400784A3/hu unknown
- 2001-08-31 EE EEP200300083A patent/EE200300083A/xx unknown
- 2001-08-31 AU AU2001282833A patent/AU2001282833B2/en not_active Ceased
- 2001-08-31 AT AT01961577T patent/ATE263772T1/de not_active IP Right Cessation
2003
- 2003-02-05 ZA ZA200301013A patent/ZA200301013B/en unknown
- 2003-02-24 IS IS6727A patent/IS2110B/is unknown
- 2003-03-05 NO NO20031024A patent/NO20031024L/no not_active Application Discontinuation
- 2003-03-10 BG BG107624A patent/BG107624A/bg unknown

Also Published As

Publication number	Publication date
NZ524011A (en)	2004-08-27
BR0113606A (pt)	2003-06-24
CN1896078A (zh)	2007-01-17
AU8283301A (en)	2002-03-22
NO20031024D0 (no)	2003-03-05
NO20031024L (no)	2003-03-05
DE60102710D1 (de)	2004-05-13
IS6727A (is)	2003-02-24
DE60102710T2 (de)	2005-04-14
HK1055299A1 (en)	2004-01-02
TR200401659T4 (tr)	2004-09-21
HUP0400784A3 (en)	2007-09-28
PL361024A1 (en)	2004-09-20
MXPA03001512A (es)	2003-06-09
CA2417594A1 (fr)	2002-03-14
GB0021831D0 (en)	2000-10-18
KR20030025305A (ko)	2003-03-28
WO2002020530A1 (fr)	2002-03-14
CN1473163A (zh)	2004-02-04
EP1317459A1 (fr)	2003-06-11
ZA200301013B (en)	2004-05-05
DK1317459T3 (da)	2004-07-12
CN1264846C (zh)	2006-07-19
SK2592003A3 (en)	2003-08-05
US20030232875A1 (en)	2003-12-18
HUP0400784A2 (hu)	2004-07-28
JP2004508376A (ja)	2004-03-18
KR100802369B1 (ko)	2008-02-14
EE200300083A (et)	2004-12-15
RU2003104013A (ru)	2004-08-20
ATE263772T1 (de)	2004-04-15
ES2217183T3 (es)	2004-11-01
EP1317459B1 (fr)	2004-04-07
IS2110B (is)	2006-05-15
PT1317459E (pt)	2004-08-31
CZ2003616A3 (cs)	2003-05-14
IL154291A0 (en)	2003-09-17
BG107624A (bg)	2004-01-30
AU2001282833B2 (en)	2006-07-06

Publication	Publication Date	Title
UA73781C2 (en)	2005-09-15	Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase
EP3538526B1 (fr)	2024-04-10	Composés mono et spirocycliques contenant du cyclobutane et de l'azétidine en tant qu'inhibiteurs de l'intégrine alpha v
EP1335915B1 (fr)	2008-01-02	Derives de tetrahydrobenzazepine utiles en tant que modulateurs des recepteurs d3 de la dopamine (agents antipsychotiques)
KR100771184B1 (ko)	2007-10-29	바소프레신 수용체 길항제로서의 트리사이클릭 벤조디아제핀
KR101050700B1 (ko)	2011-07-20	칼슘 수용체 조절 화합물 및 이의 용도
AU2001282833A1 (en)	2002-06-13	Bicyclic pyrrolyl amides as glucogen phosphorylase inhibitors
KR100347479B1 (ko)	2002-12-06	트리시클릭디아제핀바조프레신길항질및옥시토신길항질,및이의제조방법
SK286568B6 (sk)	2009-01-07	Inhibítory farnezyl proteín transferázy
CN109661396A (zh)	2019-04-19	作为rock抑制剂的螺稠合环状脲
MXPA04008614A (es)	2004-12-06	Derivados de amida heterociclica como inhibidores de la glucogeno-fosforilasa.
WO2024238633A2 (fr)	2024-11-21	Inhibiteurs de kras g12s et g12c
CN109153663A (zh)	2019-01-04	作为rock抑制剂的三唑酮类化合物和四唑酮类化合物
CN105073741A (zh)	2015-11-18	作为rock抑制剂的酞嗪酮及异喹啉酮
EP3704114B1 (fr)	2022-11-23	Composés spirocycliques en tant que modulateurs du récepteur de farnésoïde x
KR20040091101A (ko)	2004-10-27	글리코겐 포스포릴라제 억제 활성을 갖는 헤테로시클릭아미드 유도체
TW200304817A (en)	2003-10-16	Chemical compounds
EP1784408A1 (fr)	2007-05-16	Triazolobenzodiazepines et leur utilisation en tant qu'antagonistes de la vasopressine
CA1321996C (fr)	1993-09-07	Diazepinones condenses, methodes de preparation et compositions pharmaceutiques a base de diazepinones
EP0008950A2 (fr)	1980-03-19	Dérivés de pyrimido(1,6-a)indole et intermédiaires, procédés pour leur préparation et compositions pharmaceutiques les contenant
HK1055299B (en)	2004-10-21	Bicyclic pyrrolyl amides as glucogen phosphorylase inhibitors
WO1997017351A1 (fr)	1997-05-15	Derives spiro piperidine en tant qu'antagonistes du recepteur de 5mt
WO2025131062A1 (fr)	2025-06-26	Composé oléfinique, son procédé de préparation et son utilisation en médecine
WO1981000568A1 (fr)	1981-03-05	Benzodiazepinones, leur procede de preparation, leur utilisation
JP2006503869A (ja)	2006-02-02	ジベンゾキシアゼピン類